A kind of wearable exoskeleton soft rehabilitation glove is proposed for the dementia in Parkinson’s disease (PD) patients with loss of hand function, limited range of motion, and insufficient finger muscle strength to carry out rehabilitation exercise training in a passive or auxiliary way. A novel soft joint structure based on composite fabric material is introduced for the design of the soft glove with bionic method, and experiments are conducted to verify the effeteness of the proposed soft rehabilitation glove. The test results showed that when the fluid pressure was 0.42 MPa, the joint angle of MCP, PIP and DIP could be up to 81°, 98°, 72°, and produce output torque of 1.18Nm, 1.44Nm and 1.82Nm respectively, which meets the requirements of the hand rehabilitation. A dynamic rehabilitation-training test of the rehabilitation glove was also carried out, and the results showed that the movement frequency of soft fingers could reach 30 times/min, which is sufficient for repetitive flexion/extension exercise. In order to verify the grasping characteristics of the soft glove for irregular objects, experiments were carried out. The experimental results showed that the bionic soft glove was dexterous in grasping, which conforms to the universal grasping characteristics of human hands, has the function of assisting daily life (ADL), and meets the requirements of rehabilitation. A novel wearable exoskeleton soft rehabilitation glove with soft joint is proposed for the dementia in Parkinson's disease (PD), and continuous passive training test is conducted through sEMG and fluid-driven proportional control system. I.Dementia represents arguably the most significant social, economic, and medical crisis of our time, which is a syndrome of severe cognitive loss caused by illness or injury. Dementia caused by traumatic brain injury is usually static, while dementia caused by neurodegenerative diseases such as Alzheimer’s disease is usually progressive and can eventually be fatal. Age, neuropsychological damage, and the severity of Parkinson’s disease (PD) are risk factors for dementia, and late-onset PD is associated with a higher risk of dementia Robotics is being proposed as a solution to assist hand function recovery, and is being used to assist patients with nerve damage in hand rehabilitation training and a variety of grasping functions through a wearable driving platform, the robotic exoskeleton system. Traditional hand exoskeleton is composed of dc motor As a new product in the field of robotics, the emergence of soft robots brings a new dawn to the hand rehabilitation of such patients. Compared with the traditional rigid hand rehabilitation robots, this kind of robot not only has many advantages of the traditional robots, but has the advantages of lighter in weight, higher in safety coefficient, more convenient and more versatile, and requires only simple structural design to achieve a higher degree of freedom. Its soft actuators are mainly driven by cable et al. have developed an assisted rehabilitation soft robot et al. et al.Combining based on the fabric gloves with inflatable soft actuators, several research groups have developed wearable exoskeleton soft robotics of hand. For example, Polygerinos As introduced above, the soft robotics for hand rehabilitation are lighter, smaller in shape and cheaper to make comparing with rigid gloves. Through the combination of fabric layers with different materials , the bending movement can be generated through the differential torque of the layers. However, the finger phalanges of the soft rehabilitation device usually presented a circular arc shape, and the motion trajectory of the joint during rehabilitation was not consistent with that of the patient’s finger. In addition, the output force of the soft finger is limited due to the selection and configuration of reinforcing fibers or fabrics. For example, the density of reinforcing fibers decreases with the increase of radial length, which greatly limits the driving pressure and reduces the driving moment of the fluid actuator.In this work, combining the new application of soft robot technology and the 3D printing technology, a novel wearable exoskeleton soft rehabilitation glove with soft joint structure based on composite fabric material is proposed. The soft joint is innovatively designed to make the movement mechanism of soft gloves more consistent with the human hands based on study the fabric-reinforced joint soft rehabilitation glove. The fabric adopted in this paper is a typical anisotropic knitting material with good axial elasticity and high radial modulus, which enable soft fingers supply greater output force. The device can be adopted by PD patients to carry out rehabilitation exercise training in passive or auxiliary way, so that PD patients can actively participate in it, and it is possible to delay and improve the progress of the disease, which has a positive effect on patients with dementia in PD.II.First, the structure and movement principle of the human hand is deeply studied. Based on the principle of bionics, the articular soft rehabilitation glove with soft joint imitating the structure and principle of human hands is designed to maximize the imitation of human hands’ function by using soft materials such as silica gel and composite elastic fabric. The 3D printed silica gel matrix is used as the inner layer and the composite elastic knitted fabric is wrapped externally as the reinforcing layer of the matrix. Then, the fabric layers are cut and stitched together to form a composite elastic fabric with unique structure, which adds joint structure to fingers of rehabilitation glove, and makes the soft finger structure same as the human hand structure, which has the phalange interphalangeal joints part.A.Human fingers are composed of metacarpal, phalangeal and interphalangeal joints. According to the human anatomy, the human hand consists of five metacarpal bones and the corresponding phalanx of each metacarpal bone, and these bones are joined by many joints with little friction, has 21 DOFs, in which the thumb has 5 DOFs and the other four fingers have 4 DOFs respectively. It causes the track curvature of fingers to be variable when bending, which is called piecewise circular arc with variable curvature. At the same time, during finger grasping, only the interphalangeal joints can be bent because the phalanx part cannot be bent. In addition to the thumb, each finger is composed of distal phalanx (DP), middle phalanx (MP), proximal phalanx (PP) and distal interphalangeal joint (DIP), proximal interphalangeal joint (PIP), metacarpophalangeal joint (MCP) In human hand kinematics, each joint and finger are closely related and coupled with each other, mainly including two types: One is that the physical structure of the fingers constrains the range of motion of the joints. For example, while the distal interphalangeal joints are bent, the proximal interphalangeal joints are also slightly bent. The other kind of constraint is the movement between the joints and fingers. For example, except the thumb, the other four fingers also influence each other when moving The hand has multiple redundant DOFs, and it can simplify the structure and facilitate the modular design under the premise of meeting the requirements of clinical rehabilitation sports training. In this work, the design parameters of rehabilitation finger and phalangeal bone were determined according to the size of the patient’s hand bone. The metacarpal bone was mainly used for the connection and fixation between soft fingers, and the design parameters only needed to meet the conditions of fixation and assembly. Design parameters of finger and metacarpal bones of soft rehabilitation gloves can be seen in B.The human hand is mainly composed of bones, joints and soft tissues . The hand rotates the joint during movement, and if the exoskeleton glove cannot follow this movement, it will create a shear force that causes pain in the joint In order to imitate the biological structure of human hand, we design the soft finger as the combination of phalanges and soft joints as shown in To sum up: through the different shape variables of the fabric layer material of the bottom and back of the finger, the soft finger can realize the joint bending action. The joint parts can produce flexible bending movement, and the metacarpal and phalanx parts always maintain the original shape during the joint bending process.C.The soft joint requires that the elastic fabric has good axial elasticity and can limit the radial deformation. In this paper, one type of elastic knitted fabric is adopted which has anisotropy under stress due to the characteristics of warp and weft thread materials, the warp yarns are made of latex, and the weft yarns are polyester low-elastic yarns In order to investigate the mechanical characteristics of the adopted elastic knitted fabric, the warp and weft tensile tests were carried out on the tensile testing machine. Experimental results report that under the condition that the maximum tension is 22N, the warp deformation is 1.76mm, the elongation is 2.7%, however when the weft deformation is 65mm, the elongation is 100%, and the weft deformation is 36.93 times of the warp deformation as shown in D.According to the contour characteristics of human hand, five fingers of soft rehabilitation glove have the similar silica gel matrix structure but differential parameters. The 3D model of the silica gel matrix is rendered in It is assumed that the radial expansion of silica gel matrix and the change of wall thickness are not considered in the process of soft fingers rehabilitation, and soft joints are regarded as arcs with constant curvature. According to its bending action mechanism, in the process of soft joint bending, the length of the restricted strain layer at the joint remains unchanged, while the length of the strain layer increases gradually. The distribution of the stress state of the soft rehabilitation finger joint when it is under stress bending is rendered in Due to the limitation of the precision of the 3D printer when preparing the mold, the success rate of the finished product preparation can only be improved by ensuring a certain wall thickness in the design of the silicon matrix structure. When the wall thickness of silicon matrix E.In order to obtain good bending performance of imitating human hands for the soft finger, this work analyzes two types of soft joint structures: rectangular structure and elliptic structure as seen in For the rectangular structure, the unstretched length of the strain layer fabric in the direction of the central axis is equal everywhere and equal to As shown in F.Silica gel matrix was prepared by casting liquid silica gel in the mold. Based on the structure and design parameters of silica gel matrix obtained by previous design, the design of casting mold was carried out. The mold is made by 3D printing, and the consumable material is PLA. This silica gel matrix preparation includes the following steps: (a) reagent modulation, (b) reagent degassing, (c) mold design, printing and assembly, (d) silica gel casting, (e) baking and curing, and (f) stripping molding.After the preparation of silica gel matrix, the fabric layer material is cut based on the design parameters of silica gel matrix, soft joint, phalanx and metacarpal. After the cutting is completed, the sewing machine is used to sew two layers of single-layer fabric along the joint edges see . When thIII.To validate the proposed soft joint structure, experimental platform was constructed to study of the static characteristics of soft finger. The experimental platform is mainly composed of fluid-driven system, 3-DOFs test platform, 6-DOFs force sensor, pressure sensor, pressure transmitter and the signal acquisition system AI-01 module.A.The proposed fluid-driven system, using servo motor hydraulic cylinder integrated structure, and the motor rotation is converted into the reciprocating linear feed motion of the ball screw slider through the supporting linear screw module between them. The reciprocating linear motion of the screw push rod drives the reciprocating action of the piston rod of the hydraulic cylinder to generate water pressure, and then directly drives the soft finger. The overall layout of the fluid-driven system given in The 3-DOFs test platform is composed of three stepper motors, four sliding table modules, liquid crystal display control handle and a control cabinet see . ThroughAs shown in B.By carrying out tests on the joint bending angle, trajectory and output torque of soft finger, we can have a more intuitive and in-depth understanding of the trajectory of soft finger as well as the internal law between the torque and fluid pressure, thus providing a theoretical basis for the development of rehabilitation glove.The definition between the phalanx bone and joint angle of the soft rehabilitation finger is the same as that defined in the mechanical rehabilitation device. Each joint is taken as the joint point of the finger bone and the finger bone as the connecting rod, without considering the slight changes in the length and shape of the finger bone in the hand movement. Defined the rotation angle of each joint according to finger movement habit. According to the characteristics of human hand skeleton, when the hand is in motion, except for the thumb, the motion characteristics of the index finger, middle finger, ring finger and little finger are the same, and the movement actually occurs in only one plane. Taking index finger as an example, the joint bending experiment was studied.1)The bending degree of the joints of soft fingers and the changing law of driving pressure can reflect the bending characteristics of the body to some extent, which directly affects the efficiency of rehabilitation gloves. In the research of joint motion angle, special points are used to mark the joints of the dorsal finger, so as to track and record the two-dimensional coordinates of each finger bone when the mollusk finger is compressed and bent with a 3-DOFs test platform, and then obtain the corresponding motion track of the three finger bones.In the experiment, the length of DP of the soft finger is 25 mm, the length of MP is 30mm, and the length of PP is 45 mm. Tests were carried out with the driving water pressure of 0.07MPa, 0.14MPa, 0.21MPa, 0.28MPa, 0.35MPa and 0.42MPa, respectively. During each test, the pointer installed on the 3-DOFs test platform was adjusted to coincide with the mark points on the back of the finger, and the 2d coordinates of the joints of the corresponding soft finger under each driving pressure were recorded, and the bending posture of the fingers was also captured see . It can The bending test results of the soft joints are given in Therefore, under the initial state of low pressure, soft finger is not particularly sensitive to the bending characteristics of pressure. In the pressure range of 0.14MPa - 0.42MPa, the response rate of the three joints of soft finger to pressure shows a trend of gradually increasing first and then gradually decreasing. Because soft finger movement is weakened by radial expansion, each joint responds quickly with pressure changes. As the pressure increases, the bending angle of each joint increases, and the elongation of the fabric layer is close to the limit value, so the rate of angle increase slows down. When driving pressure is 0.42MPa, the bending angles of the three joints reached 81°, 98° and 72° respectively, shows that the soft finger structure design is reasonable and has good effect of bending. In addition, due to the large bending deformation of the silicon matrix itself, the middle part will produce greater resilience compared with other parts. Therefore, the minimum bending angle of DIP joint is 72° ultimately.2)The output torque of joints and its variation rule determine the maximum pressure that soft finger can bear and directly affect the hand rehabilitation effect. Depending on the patient’s condition, the output torque can be increased under greater pressure. Output torque measuring curve of the soft finger shows that the output torque of each joint of the soft finger increases gradually with the same amount of driving pressure see .FIGURE When the driving pressure is 0.42MPa, MCP joint, PIP joint and DIP joint can produce output torque of 1.18Nm, 1.44Nm and 1.82Nm respectively. Furthermore, the MCP joint produces the smallest driving torque and the DIP joint the largest, as the pressure increases, the torque change rate of DIP joint is faster than that of MCP joint and PIP joint, and the torque change rate increases first and then decreases. This is due to the special structural design of the soft finger joint, which makes the interphalangeal joint becomes a small constant curvature arc when the soft finger is bent, which can be regarded as a continuous soft element. At first, due to expansion, the output torque is small. When the pressure keeps increasing, the output torque keeps increasing, due to the soft finger ontology deformation is larger, the deformation recovery force generated is larger, which has a significant impact on the output torque, so the increase trend of output torque becomes slow.IV.A.To verify the performance of the soft rehabilitation glove system, control system based on surface electromyography (sEMG) was constructed and continuous passive training (CPM) test was carried out for the whole system.1)This paper uses compressed air as power source to drive and control soft rehabilitation glove. The pneumatic control system is mainly composed of sEMG acquisition system, Arduino controller, proportional regulating valve of FESTO, PWM voltage conversion module and power supply module. The physical picture of the rehabilitation glove control system can be seen in 2)For the later treatment of patients with hand dysfunction caused by spinal cord injury or cerebral apoplexy, rehabilitation therapy is mainly adopted. Above them, the most important exercise rehabilitation therapy is CPM. During the experiment, the electrodes of the sEMG sensor were put on the forearm of the subject, the soft rehabilitation glove was put on the other hand of the subject. The subjects slowly and egularly perform repetitive motions of hand stretching see  and contA measured curve of sEMG for three periods of continuous passive training are given in Considering the grasping characteristics of human hands and the resistance of patients’ hands, it is set that the pressure will increase slowly when the fingers contract, and rapidly relieve pressure when the fingers are stretched, and the highest pressure can be adjusted for patients under different conditions. According to the requirements of hand rehabilitation, the driving pressure range is set 0~0.25MPa in this experiment, the period of passive training of this subject is about 2s, the cycle of passive training is about 30 times /min. The pressure arise time is 0.32s, the stability interval is 0.613s and the pressure drop time is about 0.067s. Pressure changes in the rehabilitation gloves during continuous passive extension and convergence exercise training for one period is shown in 3)In order to verify the grasping flexibility of this fabric reinforced soft rehabilitation glove, the glove itself (not worn on the hand) was tested for the grasping of objects with different shapes as shown in V.1)Warp and weft tensile tests are carried out on the tensile testing machine for the composite warp-knitted fabric. Experimental results report that the maximum tension is 22N, the warp deformation is 1.76mm, the elongation is 2.7%, and the weft deformation is 65mm, the elongation is 100%.2)When the fluid pressure is 0.42 MPa, the bending angle of soft joints of MCP, PIP and DIP is up to 81°, 98°, 72° and can produce output torque of 1.18Nm, 1.44Nm, 1.82Nm respectively, and the joint trajectory of soft fingers conforms to the characteristics of human hands, which demonstrates that the structure design of soft finger is reasonable.3)The results show that the fabric-reinforced joint of soft rehabilitation glove can adapt to the external contour shape of the captured object. The soft rehabilitation glove controlled by EMG system can complete continuous training and have the function of assisting daily life articles to grasp.4)Although our work has made good progress in structural design and preliminary test of the soft rehabilitation glove, there are still a lot of works to be done, including optimization of the glove control system, further active treatment methods and more clinical tests for PD patients. Next step, we will carry out more in-depth research in these areas.In this work, a fabric-reinforced soft rehabilitation glove is proposed, and the soft joint structure is discussed by referring to the movement mechanism of human fingers, based on composite elastic fabric. The fabric layer is selected from commonly used textile industry fabrics, the tensile properties are experimentally analyzed, and the optimum design of the soft joint is carried out through theoretical analysis. The fabric is transformed from a single layer structure into a multi-layer composite structure with specific physical characteristics. To verify the proposed soft rehabilitation glove including specific functions, bending angle, motion trajectory, and output torque, experiments are carried for the soft finger and glove, and the relevant conclusions are obtained as follows:


Older people are often admitted for rehabilitation to improve walking, yet not everyone improves. The aim of this study was to determine key factors associated with a positive response to hospital-based rehabilitation in older people.This was a secondary data analysis from a multisite randomized controlled trial. Older people  who were admitted to geriatric rehabilitation wards with a goal to improve walking were recruited. Participants were randomized to receive additional daily physical therapy focused on mobility (n = 99), or additional social activities (n = 99). Self-selected gait speed was measured on admission and discharge. Four participants withdrew. People who changed gait speed ≥0.1 m/s were classified as ‘responders’ (n = 130); those that changed <0.1m/s were classified as ‘non-responders’ (n = 64). Multivariable logistic regression explored the association of six pre-selected participant factors  and two therapy factors  and response.Responding to rehabilitation was associated with the number of days in rehabilitation  and higher Mini Mental State Examination scores . No other factors were found to have association with responding to rehabilitation.In older people with complex health problems or multi-morbidities, better cognition and a longer stay in rehabilitation were associated with a positive improvement in walking speed. Further research to explore who best responds to hospital-based rehabilitation and what interventions improve rehabilitation outcomes is warranted.NCT01910740.Australian New Zealand Clinical Trials Registry ACTRN12613000884707; ClinicalTrials.gov Identifier  One of the most frequent reasons older people are admitted for hospital-based rehabilitation is to improve their walking. While physical rehabilitation programs lead to improved outcomes for many people, , 2 not eAn older person’s response to rehabilitation whilst in hospital may be influenced by their clinical status. Older people are more likely to have multiple co-morbidities, cognitive impairment and frailty , 5. ThesCharacteristics of the therapy intervention may also impact an older person’s response to rehabilitation. The link between exercise dosage and outcomes is well established for people with stroke, –22. ParkThe aim of this investigation was to understand key factors associated with a positive response to hospital-based rehabilitation in older people, as indicated by a clinically meaningful increase in gait speed. Our recent multi-site randomized controlled trial (RCT) conducted in older people receiving multidisciplinary, hospital-based rehabilitation, found additional supervised activity focussed on upright tasks such as standing and walking did not lead to improved gait speed . The amoThe full protocol has been published as have results of the RCT , 25. TheParticipants were recruited from four participating geriatric rehabilitation wards at two Australian hospitals. These wards typically admit people who are medically stable but require multidisciplinary management or rehabilitation to maximise function. Eligible patients were aged over 60 years old with a goal to ‘improve mobility or walking,’ determined by admission referral or treating therapist. Participants were excluded if (1) there were medical restrictions limiting mobilisation, (2) goals were non-weight bearing (e.g. to improve slide-board transfers), (3) they were enrolled in another RCT, or (4) primary reason for admission was carer training or residential care placement. Informed consent was obtained from the participant or ‘responsible person’ within 48 hours of admission, with interpreters utilised as necessary.intervention arm received a program to increase time participants spent performing upright activities, such as standing and walking. This was delivered daily (including weekends) throughout the inpatient stay and supervised by a physical therapist or assistant. Further details have been previously published   , frailty (MMSE)] , 33 co-m (MMSE)]  (CCI)] a (MMSE)] . TherapySample size was estimated for the primary hypothesis of the RCT and has been previously published . No sepaIn this secondary analysis, trial participants were analysed as a whole group. As daily upright activity time differed between intervention and control arms, group was not included in the analysis. Patient and care-related characteristics  were summarized as counts (proportions), means (SDs) or medians (IQRs) as appropriate. The univariate associations of these characteristics and the responder status was investigated using logistic regression modelling with corresponding effects reported as Odds Ratios (ORs) with 95 % confidence intervals (95 %CIs). The diagnostic utility of these characteristics for classifying the “responder” status was investigated using Receiver Operating Characteristics (ROC) analysis. Adjusted association between patient and care characteristics and the responder status was investigated using multivariable logistic regression with corresponding effects reported as adjusted Odds Ratios (aORs) with 95 %CIs.All analyses were conducted using Stata 15IC statistical software ; p-values < 0.05 were regarded as indicative of statistical significance. No correction for multiplicity of testing was undertaken due to the exploratory nature of the study.Of the 194 participants included in analysis, 130 (67 %) participants were classified as responders and 64 (33 %) participants were classified as non-responders (four participants who withdrew could not be classified). Table n = 2), 4 (n = 12) and 5 (n = 1). Frailty was therefore dichotomised and participants were reclassified as not frail (scores 0–2) or frail (scores 3–5). The number of days in rehabilitation was the only variable associated with increased odds of a person having a positive response to rehabilitation.Results of the univariate analysis are presented in Table p = 0.048) and more days receiving rehabilitation  were associated with increased odds of responding to rehabilitation. No association was found for baseline ambulation status, frailty and daily supervised upright activity time and the odds of responding to rehabilitation (see Table A multivariable model was constructed, which initially included all variables. This model demonstrated excessive collinearity; age was removed from the model, as other variables allowed more precise description of health status, and co-morbidities were removed as this included dementia which was captured with the MMSE. The resulting model included baseline ambulation status, frailty, cognition, depression, daily supervised upright activity time, and days in rehabilitation. As there was still evidence of collinearity, a model was developed with the removal of depression. The results of these two models were similar, thus the model which excludes depression has been reported. Higher MMSE scores (aOR 1.07; 95 % CI 1.00, 1.14, In hospitalized older people with muti-morbidity, only two thirds of participants achieved a ‘substantial meaningful’ improvement of 0.1 m/s in gait speed during multidisciplinary rehabilitation. Higher scores on the MMSE were associated with increased odds of responding to rehabilitation. Other participant characteristics including baseline ambulation status, frailty, co-morbidities, and depression were not related to improvements such as increased gait speed.For admission to subacute rehabilitation the people in this trial needed to have the capacity to make meaningful gains and the study specifically recruited older people with a goal to improve walking or mobility. Despite our sample being biased towards responders, around one-third did not achieve a meaningful improvement in gait speed. Other studies of hospital rehabilitation have found as few as 44 % of people achieve a clinically meaningful response to rehabilitation . AbilityThe appropriateness of criteria for determining a clinically meaningful response to hospital-based rehabilitation may also require consideration. Use of the more modest indicator of a small meaningful change of 0.05 m/s,  would haWe found better baseline cognition, assessed using MMSE, was associated with a slight increase in the odds of responding to rehabilitation, when other factors were taken into account. There is conflicting evidence in the literature about the impact of cognition on change in function during rehabilitation , 17, 36.Response to rehabilitation was not associated with baseline ambulation status, frailty, comorbidities or depression. A retrospective study of 556 older people undergoing rehabilitation found while age, depression and co-morbidities were associated with functional gain, in multivariate logistic regression only participation, ability to walk pre-admission and admission following orthopaedic surgery remained predictive . DepressWe found the odds of achieving a meaningful change in gait speed increased with an increase in the number of days of rehabilitation but was not associated with the amount of supervised upright physical activity. Rehabilitation was delivered until the person was discharged from hospital-based rehabilitation. Readiness for discharge from rehabilitation was usually decided by the treating team in conjunction with the patient; generally when rehabilitation goals were achieved, or no further gains were likely to be made. However, discharge from rehabilitation may sometimes occur prematurely or be delayed, which may impact on this finding. The number of days in rehabilitation was low, with a median of 16 days in people who responded compared with 14 days in those who did not respond. People with shorter length of stay may not have had sufficient time to achieve a meaningful change in gait speed.The lack of association between daily supervised upright activity and odds of having a positive response is in keeping with the primary analysis of the RCT, which found additional physical activity did not lead to improved walking outcomes . Links bThis was a rigorously conducted trial; data was prospectively collected from four wards over two hospital sites by an assessor blinded to interventions. However, this was a secondary analysis thus results must be interpreted with caution. People in this trial were admitted with a large range of medical conditions, therefore this was not included as a variable in the analysis. Other studies have shown that people who are admitted with an orthopaedic diagnosis are more likely to have a positive response to rehabilitation . As thisApproximately two out of every three older people admitted for hospital-based rehabilitation achieved a clinically meaningful improvement in gait speed. Increased days receiving rehabilitation and better cognition, as assessed using the MMSE, were associated with increased odds of having a positive response to rehabilitation. Baseline ambulation, frailty, co-morbidities depression and daily upright activity time were not associated with a positive response to rehabilitation.


Androgen receptor (AR) signaling is fundamental to prostate cancer (PC) progression, and hence, androgen deprivation therapy (ADT) remains a mainstay of treatment. However, augmented AR signaling via both full length AR (AR-FL) and constitutively active AR splice variants, especially AR-V7, is associated with the recurrence of castration resistant prostate cancer (CRPC). Oxidative stress also plays a crucial role in anti-androgen resistance and CRPC outgrowth. We examined whether a triterpenoid antioxidant drug, Bardoxolone-methyl, known as CDDO-Me or RTA 402, can decrease AR-FL and AR-V7 expression in PC cells. Nanomolar (nM) concentrations of CDDO-Me rapidly downregulated AR-FL in LNCaP and C4-2B cells, and both AR-FL and AR-V7 in CWR22Rv1 (22Rv1) cells. The AR-suppressive effect of CDDO-Me was evident at both the mRNA and protein levels. Mechanistically, acute exposure (2 h) to CDDO-Me increased and long-term exposure (24 h) decreased reactive oxygen species (ROS) levels in cells. This was concomitant with an increase in the anti-oxidant transcription factor, Nrf2. The anti-oxidant N-acetyl cysteine (NAC) could overcome this AR-suppressive effect of CDDO-Me. Co-exposure of PC cells to CDDO-Me enhanced the efficacy of a clinically approved anti-androgen, enzalutamide (ENZ), as evident by decreased cell-viability along with migration and colony forming ability of PC cells. Thus, CDDO-Me which is in several late-stage clinical trials, may be used as an adjunct to ADT in PC patients.  Prostate cancer (PC) is the second leading cause of cancer-related mortality in men in the United States . NotwithAR-V7  is the most significant functional protein encoding AR splice variant ,17,18,192/M phase  was obtained from Sigma-Aldrich . Enzalutamide (ENZ) was purchased from ApexBio . Cycloheximide (CHX) was bought from Cayman chemicals . CDDO-Me was purchased from Selleckchem . The drugs were dissolved in 100% DMSO and the final DMSO concentration which was used in the experiments was less than 0.1%. N-acetyl cysteine (NAC) was obtained from Santa Cruz Biotechnology , dissolved in water and diluted in media immediately before use. The primary antibodies including rabbit polyclonal anti-AR (N-20) (sc-816), mouse monoclonal anti-Nrf2 (437C2a) (sc-81342), and anti-GAPDH (sc-47724) were obtained from Santa Cruz Biotechnology. The horseradish peroxidase (HRP)-conjugated goat anti-rabbit (A0545) and goat anti-mouse (A9044) secondary antibodies were bought from Sigma-Aldrich . The goat antirabbit secondary antibody tagged with Texas red (T-2767) was bought from Thermo Scientific. MTT assays were carried out to determine the cell viability post treatment with the drug(s). Briefly, ~5000 cells were cultured in 96-well plates followed by synchronization in a serum free medium overnight. The viability of the cells was determined at 72 h post exposure to drug(s) with the MTT solution (5 mg/mL for 3–4 h at 37 °C). DMSO was used to solubilize the formazan crystals and the optical density (O.D.) was measured at 540 nm with µQuant spectrophotometric plate reader . The radioimmunoprecipitation assay (RIPA) lysis buffer (Santa Cruz Biotechnology) was used to harvest the whole cell lysates post exposure to drug(s). Quantification of the total protein was done using the bicinchoninic acid (BCA) protein assay reagent (Thermo Scientific). In brief, 10 µg of protein was electrophoresed in SDS-PAGE gels (10%) and transferred onto nitrocellulose membranes using semi-dry electro-transfer. The membranes were incubated overnight with the primary antibodies against AR (1:500 dilution), Nrf2 (1:500 dilution), and GAPDH (1:3000 dilution) at 4 °C after blocking with 5% casein in TBS-T buffer . The membranes were then incubated with the corresponding HRP-conjugated secondary antibodies (1:2000 dilution) for 1 h and developed using the Supersignal west femto substrate (Thermo Scientific). The scanning of the immunoblots was done using the ImageQuant LAS 500 scanner . Image J software  was used to quantify the band intensities. The densitometric values for AR proteins (AR-FL and AR-V7) were normalized to the GAPDH values for calculating the fold change.DCFDA/H2DCFDA—a cellular ROS assay kit  was used to measure reactive oxygen species (ROS). Cells were harvested and seeded in a dark, clear bottom 96-well microplate with 25,000 cells per well. The cells were stained with 2′,7′-dichlorofluorescin diacetate (DCFDA) and treated with different agents for the specified period of time. The DCFDA fluorescence (Ex/Em = 485/535 nm) was measured immediately using a microplate reader (Bio-Tek).6 cells per well) until a confluent monolayer was formed. A 200 µl pipette tip was used to scratch the monolayer. The wells were then washed with PBS and images (10× magnification) were captured of the wound at 0 time point with a Leica Microsystems microscope . Images of the wound were then captured at 72 h post exposure to the drug(s). The cell migration (wound closure) was measured by calculating the distance between 4–5 random points within the wound edges.Wound-heal assay was performed to monitor the migratory phenotype of PC cells post exposure to drug(s) . In brieCells (500/dish) were cultured in 60 mm petri dishes in three replicates in 2% FBS containing media and exposed to the drug(s) after 48 h. The drug(s) were replenished in the second week. After two weeks, the cell colonies were stained with 0.2% crystal violet in 20% methanol post fixation with 100% ethanol. The colony forming units (CFU) were counted with the Image J software. The total number of CFUs were then compared in untreated (control) and drug-treated cultures.4) were cultured in chamber slides  and then fixed in ice cold methanol after treatment. After permeabilization of the cells with 0.1% Triton-X 100, blocking was done in 10% goat serum. The cells were then incubated with the primary antibody (1:300 dilution) overnight at 4 °C. This was followed by incubation with the corresponding secondary antibody tagged with texas red (1:1000 dilution) for 1 h. The cover slips were mounted after nuclear stain diamino-2-phenylindole (DAPI) containing vectashield mounting media  was added to the slides. The images (60× magnification) were captured with the fluorescent microscope .Immunofluorescence microscopy (IFM) was used to visualize subcellular localization of AR post exposure to CDDO-Me. In brief, cells (3 × 10TM SYBR green supermix (Bio-Rad) was used to measure the AR transcript levels and C1000TM Thermocycler  was used to carry out the amplification reactions. The following amplification conditions were used: Priming at 95 °C for 5 min, and then 35 cycles of 95 °C for 30 s, 55 °C for 30 s, and 72 °C for 30 s. The data  for AR (AR-FL and AR-V7) transcript levels were normalized to the corresponding β-actin values for calculating the fold change.The mRNA levels for both AR-FL and AR-V7 were measured using the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In brief, after treatment, total mRNA was extracted using the RNeasy mini plus kit  in accordance with the manufacturer’s instructions. The iScript cDNA synthesis kit  was used to prepare complementary DNA (cDNA) according to the manufacturer’s instructions. The following primer sequences were used: (1) AR-FL:—forward: 5′-CAGCCTATTGCGAGAGAGCTG-3′ and reverse: 5′-GAAAGGATCTTGGGCACTTGC-3′; (2) AR-V7:—forward: 5′-CCATCTTGTCGTCTTCGGAAATGTTATGAAGC-3′ and reverse: 5′-TTTGAATGAGGCAAGTCAGCCTTTCT-3′; and (3) β-actin:—forward: 5′TGAGACCTTCAACACCCCAGCCATG-3′ and reverse: 5′-GTAGATGGGCACAGTGTGGGTG-3′. The iQt-test was used to determine significant changes from controls and p-values of < 0.05 were considered significant. The CompuSyn software  was used for synergy determination and combination index (CI) was calculated on the basis of Chou–Talalay method, which determines additive (CI = 1), synergistic (CI < 1), or antagonistic (CI > 1) effects quantitatively [The graphPad Prism (version-6) Software  was used for the statistical analyses. Results were expressed as the standard error of the mean (± SEM). A two-tailed student’s tatively . The PC cells  were exposed to increasing concentrations of CDDO-Me (0–500 nM) and AR protein levels were measured at different time points A–C. ImmuTo determine whether the CDDO-Me-mediated suppression of AR is regulated at the level of transcription or protein synthesis, we quantified AR-FL and AR-V7 specific mRNA by qRT-PCR and AR protein levels in the presence of the protein synthesis inhibitor, cycloheximide (CHX). Immunoblot analysis revealed that combined exposure to CHX and CDDO-Me reduced the half-life of AR-FL and AR-V7 protein more significantly as compared to the CHX treatment aloneA,B. ThisSeveral studies have shown that oxidative stress signaling can regulate AR expression and CRPC progression ,49. AntiTo determine whether transient induction of ROS was important for the AR-suppressive effect of CDDO-Me, the 22Rv1 cells were exposed to NAC both pre and post treatment with CDDO-Me for 24 h D. PretreTo determine whether the AR-suppression by CDDO-Me enhances the efficacy of clinically approved anti-androgens, cytotoxicity was measured in LNCaP, C4-2B, and 22Rv1 cells co-exposed to CDDO-Me and ENZ, using the MTT cell viability assay. Cell viIncreased metastatic ability of CRPC cells has been linked to increased AR signaling  and can The clonogenic ability of CRPC cells is a major determinant of metastatic growth . We carrSecond messenger signaling via the androgen receptor is indispensable for the prostate epithelial cells, not only for the normal functioning and homeostasis of the prostate gland but also for the development of prostatic neoplasms and the progression of PC to CRPC . TherefoLNCaP is an androgen-dependent cell line that was first isolated from a human metastatic prostate adenocarcinoma in the lymph node and expresses mRNA/protein of both AR and PSA ,59. C4-2The CDDO-Me-mediated suppression of AR-FL and AR-V7 was found to be regulated both at the transcriptional, as well as the translational level . Indeed,Several other Nrf2 inducing antioxidant phytochemicals such as SFN and curcumin have promising anticancer effects and are implicated to function by first inducing oxidative stress followed by increasing nuclear Nrf2 levels ,67,68,69Importantly, functional assays addressing the tumorigenic ability of PC cells, i.e., viability, migration and clonogenicity, clearly demonstrated that the AR-suppressive effects of CDDO-Me can enhance the efficacy of the clinically approved anti-androgen ENZ. Exposure to nanomolar doses of CDDO-Me was able to potentiate the efficacy of ENZ in LNCaP, C4-2B, and the ENZ resistant 22Rv1 cells by significantly decreasing the cell viability of PC cells . AndrogeAlthough we have not carried out in vivo studies in tumor-bearing animals, the potent antitumor effects seen with our drug combination were validated by measuring the clonogenic ability of PC cells in vitro . ExposurNanomolar (nM) concentrations of Bardoxolone-methyl (CDDO-Me) decreased both AR-FL and AR-V7 expression in PC cells. Therefore, CDDO-Me, which is in several late-stage clinical trials, may be used in combination with clinically approved anti-androgens such as ENZ in PC patients; both at the initial stage where tumors are overexpressing AR-FL only and at the later stage of CRPC where AR-V7 overexpressing tumors are frequently observed.


Malus domestica) M.9 rootstock, the most widely used dwarf rootstock for intensive production, and investigated the role of polar auxin transport in postembryonic organogenesis. AR formation begins with a series of founder cell divisions and elongation of the interfascicular cambium adjacent to vascular tissues. This process is associated with a relatively high indole acetic acid (IAA) content and hydrolysis of starch grains. Exogenous auxin treatment promoted this cell division, as well as the proliferation and reorganization of the endoplasmic reticulum and Golgi membrane. In contrast, treatment with the auxin transport inhibitor N-1-naphthylphthalamic acid (NPA) inhibited cell division in the basal region of the cuttings and resulted in abnormal cell divisions during the early stage of AR formation. In addition, PIN-FORMED (PIN) transcripts were differentially expressed throughout the whole AR development process. We also detected upregulation of MdPIN8 and MdPIN10 during induction; upregulation of MdPIN4, MdPIN5, and MdPIN8 during extension; and upregulation of all MdPINs during AR initiation. This research provides an improved understanding of the cellular and molecular underpinnings of the AR process in woody plants.Adventitious root (AR) formation is critical for the efficient propagation of elite horticultural and forestry crops. Despite decades of research, the cellular processes and molecular mechanisms underlying AR induction in woody plants remain obscure. We examined the details of AR formation in apple ( Adventitious root (AR) formation is essential to this process, and AR induction has been studied for decades4. AR formation is affected by many factors: juvenility; ontology; species/genotype; various environmental conditions, such as extreme temperatures and salt stress; the content of H2O2, NO, and Ca2+; and endogenous and exogenous applications of plant hormones6. Although AR formation has been studied at the anatomical level, its molecular basis, including the mechanism that triggers the process, remains unclear7. AR formation can be divided into three phases: induction, initiation, and extension, which lead to new visible root systems. ARs can initiate from internodes, callus formed at the base of cuttings, or the hypocotyl of herbaceous plants9. In apple, ARs emerge from lenticels, in which large intracellular spaces allow for gas exchange in the stems.Propagation via cuttings is the most economical method for the mass production of horticultural and forestry plants while simultaneously maintaining desirable genetic traitsArabidopsis thaliana, founder cell division gives rise to AR primordia (ARP), which then develop into new roots10. Similar to that of primary roots or lateral roots (LRs), the indeterminate growth of ARs depends on cell division and elongation, which are affected by various environmental conditions11. AR formation is regulated by nearly all the major plant hormones, with auxin strongly promoting this process12. Exogenous auxin treatment or elevated endogenous auxin levels through genetic engineering increase the rate of AR formation and the number of ARs formed, whereas impaired auxin signaling or transport via mutagenesis or auxin transport inhibitors inhibit AR initiation14.According to recent anatomical studies in 16. The relationship between the postembryonic roots of AR (and LR) formation and polar auxin transport (PAT) was established by using the auxin transport inhibitor 1-N-naphthylphthalamic acid (NPA)18. The promoting effect of PAT on AR development can be counteracted by NPA, which disrupts PAT and, consequently, AR formation19.The auxin gradient acts as a master controller of AR formation, development, and geotropic responses20 in directing cell-to-cell auxin flow22. Despite their importance, the roles of auxin and PINs in regulating this process in woody horticultural plants have rarely been studied. Here, we integrated anatomical and ultrastructural observations, hormone analysis, and the spatiotemporal expression profile of the PIN genes to investigate the details of early initiation and organization of ARP within the lenticels of apple  rootstock M.9 cuttings.The asymmetric cellular localization of PIN-FORMED (PIN) auxin efflux carriers has been shown to play a rate-limiting roleTo determine the exact position of AR formation, 6-month-old M.9 apple cuttings were cultured in Hoagland’s nutrient solution. The submerged stems were evaluated for their AR formation over a 7-day period (168 h), during which the lenticels continuously expanded Fig. . NoticeaThe cells underlying the longitudinal splitting of the lenticels were examined to better understand the dehiscence process. The cambial zone in the control cuttings had 6–8 layers of cells between the xylem and phloem, and a large number of parenchymatous cells were observed in the interfascicular cambium next to the vascular cylinder Fig. ; Fig. S1To assess the situation of AR founder cell division at the very beginning of AR initiation, we defined the AR founder cell density as the ratio of divided AR founder cells to the total number of parenchymal cells. By 168 h, the density ratio of divided founder cells to total parenchymal cells was twofold greater in IAA-treated apple cuttings than in the controls Fig. . This tiElongated founder cells were first observed at 72 h in the IAA-treated cuttings 24 h prior to their appearance in the controls Fig. . InteresTo further investigate the morphological and physiological changes during AR initiation, subcellular structures were examined with transmission electron microscopy (TEM). Numerous starch grains were observed in the plastids at the 0 and 24 h time points for all treatments Fig. . HoweverThe number and density of the mitochondria, endoplasmic reticulum, and Golgi apparatus in cells of IAA-treated cuttings were higher than those in the control cuttings at 72 h Fig. . The num5. Therefore, we evaluated the changes in the concentrations of IAA and zeatin  during AR initiation in the control and IAA-treated and NPA-treated cuttings  initiate de novo from cells, such as phloem or xylem parenchyma cells, within or adjacent to vascular tissues, such as cells of the interfascicular cambium or the phloem/cambium junction23. A typical apple stem contains collateral vascular bundles with a ring around the pith  initiate in the stem but remain dormant until the induction of AR formation by environmental conditions initiate5 or  initiateth Figs. . Initial5 or  initiateth Figs. . Therefo25. The tissues inside lenticels provide a natural channel not only for gas exchange during flooding or other abiotic stresses but also AR formation and growth. In this study, the lenticels of apple cuttings exhibited an increasingly larger crack during the early stage of AR formation , initiation (72–120 h), and extension (120–168 h). In the control and IAA-treated cuttings, the induction phase at 72 h was characterized by an increased number of founder cells with dense cytoplasm and swallow nuclei Fig. , as wellThus, AR initiation begins with the division and elongation of a large number of clustered founder cells that filled the cavity opened by lenticel splitting in the control and IAA-treated cuttings Figs. , whereas28 might regulate AR formation by modulating PAT, which regulates the auxin gradient.With elongation of the founder cells, AR formation progresses to the extension phase when the percentage of elongated cells out of the number of divided founder cells increases Fig. . Elongat30, but the exact mechanism underlying this phenomenon is still unclear. Here, we observed rapid starch grain depletion upon the initiation of AR formation in apple cuttings. It has been proposed that starch accumulation and depletion may be a biochemical indicator of early root formation in hypocotyl cuttings, which provides energy for AR formation31. This energy supplementation process is positively regulated by auxin34. In agreement with the published data, the results of our temporal and spatial analyses studies also support a key role of starch grain accumulation and degradation in AR formation in woody plants, with IAA exerting a stimulatory effect on AR formation and NPA delaying this process  and initiation (72–120 h) phases, peaking at 120 h, followed by a steady reduction after entering the elongation phase (120–168 h). ZT levels also increased during the induction and initiation phases and peaked at 96 h before they started to decrease. By contrast, NPA reduced IAA accumulation but had little effect on ZT levels. These results point to the maintenance of auxin and cytokinin homeostasis via feedback regulation. Recent studies monitoring the functions between auxin and cytokinin during the apple cutting rooting process showed that the ratio of auxin to cytokinin also increased during the AR induction phase, which may be due to the occurrence of cellular programming and the need for cell division36. Further molecular data supported that alterations in CTK levels may function as feedback in regulating the expression of auxin-related genes such as SHY2 and PIN136.Auxin appears to regulate AR formation mainly by modulating AR founder cell division and elongation during the induction and initiation stages Figs.  and 3. SPINs function in directional auxin transport while displaying differential expression patterns, reflecting their potential multifaceted roles in plant development43. In Arabidopsis, members of the PIN gene family participate in vascular PAT, root patterning, root gravitropism, sink-driven auxin gradient establishment, and apical–basal polarity49. The PIN family in apple comprises eight members, all of which are expressed differentially during AR formation  under a 16:8 L/D cycle under a light intensity of 300 μmol m−2 s−1. All plant samples were collected at 10:00 a.m. each day and were harvested every 24 h for 168 h (7 days). Plant materials used for morphological studies were fixed in 2.5% glutaraldehyde, and those used for phytohormone quantitation and gene expression analysis were frozen in liquid nitrogen and then stored at −80 °C until further use.Six-month-old apple M.9 cuttings were used for all experiments. The bases of the cuttings (0–4 cm) were submerged in ventilated hydroponic containers filled with Hoagland’s nutrient solution (pH 5.8)Plants were grown in Hoagland’s nutrient solution (control) or nutrient solution supplemented with 10 μM indole-3-acetic acid (IAA) or N-1-naphthylphthalamic acid (NPA) as positive and negative regulators of PAT, respectively. The IAA and NPA were purchased from Sigma-Aldrich  and dissolved in dimethyl sulfoxide.51. The division and elongation of AR founder cells were observed with a stereoscopic microscope , and ImageJ (v. IJ 1.46r) was used for data capture and analysis52. Statistical differences in AR density and percent elongation were determined by ANOVA in conjunction with Tukey’s post hoc test in SPSS 2053, at p < 0.05. Cryosectional samples were also used for SEM and TEM.Cryosectioning was used to observe anatomical changes during AR initiation. Samples were dehydrated and fixed in 2.5% glutaraldehyde solution according to the methods of Chen et al.54. The reverse-phase HPLC gradient parameters and selected reaction monitoring conditions for protonated or deprotonated plant hormones ([M+H]+ or [M−H]−) are listed in Supplementary Tables Submerged apple cuttings with approximately equal weight, length, and diameter were collected for each treatment, and the location 5 mm above the incision of the cuttings was used to determine IAA and ZT contents. The samples were incubated in ice-cold uptake buffer  for 15 min, followed by two 15-min washes with fresh uptake buffer. The cleared tissue was surface dried on filter paper and then weighed. The IAA and ZT levels were measured using HPLC–ESI–MS/MSMdPIN are shown in Supplementary Table MdPIN-specific primers at 1 μM each , and the data were analyzed using the 2–ΔΔCT method, with 18S rDNA serving as a reference gene for normalization55.RNA was extracted using the CTAB method, and 1 μL was used as a template for cDNA synthesis using a TaKaRa PrimeScript RT Reagent Kit . Quantitative PCR (qPCR) was performed with an ABI Prism 7900HT system  using a 10-fold dilution of the cDNA template. The naming of MdPIN family genes based on homology identification in Arabidopsis and the gene ID of each ch Table  in a finSupplemental data


It has been noted that as high as 20.3% of patients hospitalized for coronavirus disease 2019 (COVID-19) require intensive care unit (ICU) admission. This has most commonly been attributed to the development of acute respiratory distress syndrome. These patients require prolonged periods of ICU stay, averaging approximately 20 days. As people recover and are discharged, there will be a new pandemic of critical illness survivors. These patients would present with impairments and disabilities arising because of prolonged ICU stay as well as consequences of severe respiratory illness. The longer the duration of ICU stay, the higher is the risk for long-term physical, cognitive, and emotional impairments needing comprehensive and early rehabilitation. This article focuses on the indispensable role of early and interdisciplinary rehabilitation in effective disaster management, restoring functions, and improving quality of life in COVID survivors. It outlines how to practically expand rehabilitation services in a resource-limited country, such as India, and lists the limitations being faced that prevent the uniform application of rehabilitation services in India. This would help to deal with the rapid increase in demand of postacute care facilities, be it in hospital services, in the form of inpatient or outpatient rehabilitation or home care facilities, including telemedicine. Coronavirus disease 2019 (COVID-19) is a potentially serious acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).In the weeks and months following the surge in cases, there will be a rapid increase in the number of COVID-19 survivors, some of whom would have spent a long time immobilized in the ICU, battling critical illness and requiring rehabilitation. Hospitals should be well equipped with rehabilitation professionals to cater to the acute needs of survivors being discharged from the ICUs. An early rehabilitation intervention will help in speeding up recovery from residual impairments, maintaining continuity of care, improving quality of life, and overall functional outcome. The presence of physiatrists and the Physical Medicine and Rehabilitation (PM&R) Department will decongest the acute services, creating space for newly affected patients to receive acute care. In short, they will make the hospital services more efficient by decreasing the length of ICU stay and providing a proper outlet for acute services. This fact is further reinforced by the World Health Organization (WHO) Emergency Medical Team minimum standards, which recommends that rehabilitation should be a core component of patient centered care while responding to disasters.Unfortunately, in India as well, facilities for postacute and rehabilitation care are grossly lacking and are being given less priority. The purpose of this review is to explain the role of interdisciplinary rehabilitation during this pandemic and how it helps in restoring functions and improving quality of life in COVID survivors.Broadly, SARS-CoV-2 syndrome can be divided into the following 2 phases: the acute phase having predominantly respiratory symptoms, and the chronic phase comprising of sequelae of prolonged ICU stay, invasive mechanical ventilation, and prolonged immobilization.Recent literature suggests that COVID-19 virus also affects the central nervous system per se. Patients having more severe respiratory symptoms have a higher rate of neurological symptoms.Critical illness influences a wide range of long-term patient outcomes, with some impairments persisting beyond the ICU stay, resulting in chronic disability leading to post-intensive care syndrome (PICS).COVID-19 patients, who are either admitted to the ICU for severe respiratory failure or have neurological symptoms, are more predisposed to develop infection associated chronic neuroinflammation and brain cell degeneration leading to long-term neurological sequelae.The WHO has defined medical rehabilitation as “a set of interventions designed to optimize functioning and reduce disability in individuals with health conditions, in interaction with their environment”. It has been recommended that physiatrists should be included in the interdisciplinary teams for acute management as well as management of sequelae of COVID-19.A multidisciplinary care model should be followed to prevent PICS, known as the ABCDE bundle. Components of the ABCDE bundle are awakening , breathing , coordination of care and communication among various disciplines, delirium monitoring, assessment & management and early ambulation in the ICU.As patients with serious COVID-19 infection usually have other comorbidities, such as advanced age, multiple chronic ailments, obesity, and multiple organ failure, a tailor-made rehabilitation plan should be made for each patient, focusing on each impairment.The goals of rehabilitation for recovery of COVID-19 patients can be outlined as: (a) Improve pulmonary function, (b) Reverse side effects of prolonged Immobilization, (c) Improve cognitive functions and management of dysphagia, and (d) Reduce impairments and disabilities.Rehabilitation of COVID-19 patients can be categorized broadly into mildly symptomatic and severely symptomatic patients. The majority of patients in India are suffering from mild symptoms and are being managed in home isolation or at quarantine facilities made available by the government. Teleconsultation services have been made available by various government institutes, through which doctors can keep in touch with the COVID-19 positive patients being isolated at home, and refer them to a hospital in case the patient is a high-risk patient with red flags. The general public has been informed about the new telemedicine services through print and digital media. Many private hospitals have also offered packages, including regular monitoring of vitals and daily teleconsultations with doctors. Mental Health Services in the form of teleconsultation has been made available for health-care workers by the Government of India.2) > 90%, an individualized rehabilitation plan appropriate to the specific impairments of the patient should be formulated. This plan incorporates supporting pulmonary hygiene, training of bronchial clearance techniques in hypersecretive patients, and deep coughing into closed plastic bags for sputum collection to prevent any spread of virus, and teaching breathing techniques. Airway clearance techniques are not required if patient has dry cough.Patients who are severely ill require acute hospitalization. The rehabilitation management of severely symptomatic COVID-19 patients can be categorized into 2 phases. The first phase also known as acute phase, incorporates multidisciplinary management of noninvasive ventilation along with continuous monitoring of clinical parameters and signs of infections. Pulmonary rehabilitation is not recommended for patients in acute stage of ARDS and unstable patients except for positioning advice and range of motion exercises.For disability prevention, this phase of rehabilitation includes optimizing bed positioning, active-assisted or active joint mobilization, whole body muscle strengthening and frequent changes of posture. Gradually increasing the anti-gravity position based on the patient’s clinical condition until the patient can maintain an upright position, plays an indispensable role. A semi-sitting or sitting position is recommended to prevent the risk of aspiration. Prolonged prone ventilation, even more than 12 h/d is a very advantageous position for those suffering from ARDS.Those patients having significant pulmonary and neuromotor symptoms, even after discharge from the ICU, are transferred to COVID-19 wards. Patients having Functional Independence Measure (FIM) scores of less than 100 with dependence in at least 2 areas,Neuropsychological support in the form of counselling sessions, and cognitive training, such as cognitive stimulation, reorientation, etc., should be included in the rehabilitation programs of such patients. Here, it is appropriate to point out that all the components of this comprehensive inpatient rehabilitation need to be undertaken at bedside with mandatory personal protective equipment. Due to indigenous manufacturing of personal protective equipment (PPE), this should not be a limiting factor in India, as it is in some other countries.The safest mode of rehabilitation for delivering outpatient services is virtual rehabilitation or tele-rehabilitation. It minimizes contact and viral spread, and provides timely rehabilitation care amid distance. In India, media applications, such as WhatsApp, and other teleconsultation software, such as Hospital Information System, are being effectively used. Many mobile applications, such as Practo and Lybrate, have also become quite popular in providing teleconsultations in private practice. As of now these services are gaining a lot of popularity and are proving to be very useful for the patients. Virtual rehabilitation can be helpful in critical care services in ICU, wherein, whoever has been admitted with COVID in the ICU for more than 7 days, can have a virtual consultation with a physiatrist for rehabilitation service evaluation. This avenue needs to be further explored in the Indian setting. These patients, once discharged, should be followed up by tele-rehabilitation service or in-person out-patient department consultations in rehabilitation clinics, for assessing pulmonary, cognitive, behavioral, physical, balance, dysphagia issues, and so that conditions, such as PICS, are not missed.However, there are many limitations of tele-rehabilitation, such as availability of equipment and technology, especially in the rural areas. India has a vast majority of population who are poor and cannot afford a smart phone or a laptop. Other factors, such as lack of knowledge and skills to use technology, limited Internet services in the periphery, lack of satisfaction, and lack of tele-rehabilitation guidelines, serve as barriers to the efficient application of tele-rehabilitation in India uniformly.However, there is a need for post discharge care and rehabilitation of those cured of the disease to be incorporated into the system. In India, apart from its huge population and poor doctor to population ratio, lack of PM&R departments and staffing in many hospitals, in both government and private setups are major challenges. Most importantly, lack of government policies directed toward rehabilitation and lack of awareness of government and general public about the need and importance of rehabilitation of COVID-19 patients are major barriers in achieving rehabilitation of COVID-19 survivors.Physiatrists can help in the early recovery of patients with COVID-19 by delivering early rehabilitation starting from the ICU and throughout the acute hospital stay. For this, interdisciplinary rehabilitation should be initiated, which can be continued after discharge from the ICU to either inpatient rehabilitation in a specialized Rehabilitation Medicine wards or an outpatient setting, using either in-person or virtual rehabilitation.