Analysis of the movement of an exoskeleton for the upper limb

Background/Introduction Pulmonary embolism (PE) is caused by blockage of pulmonary arteries by thrombus. The sources of thrombus are thought to be mostly veins in lower extremities, whereas deep vein thrombosis (DVT) in upper extremities rarely occurs spontaneously. Recent studies reported that DVT in upper extremities might have significant complications, and DVT in upper extremities could be increasing. However, there is a paucity of data on patients with DVT in upper extremities, leading to uncertainty in optimal treatment strategies including anticoagulation therapy. Purpose We sought to evaluate the clinical characteristics, management strategies, and long-term outcomes of patients with DVT in upper extremities in a large observational database in Japan. Methods The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic venous thromboembolism (VTE) objectively confirmed by imaging examination or by autopsy among 29 centers in Japan between January 2010 and August 2014. The current study population consisted of 2498 patients with DVT in upper or lower extremities, after excluding 381 patients with PE only, 144 patients who had thrombus in locations other than upper or lower extremities, and 4 patients with DVT in both upper and lower extremities. The study patients were divided into 2 groups: patients with DVT in upper extremities and patients with DVT in lower extremities. We compared the clinical characteristics, management strategies and long-term outcomes between the 2 groups. Results There were 74 patients (3.0%) with upper extremities DVT and 2498 patients (97%) with lower extremities DVT. Patients with upper extremities DVT more often had active cancer at diagnosis (58%) and central venous catheter use (22%). The proportion of concomitant PE at diagnosis was lower in patients with upper extremities DVT than in those with lower extremities DVT (14% and 51%, P<0.001). Discontinuation of anticoagulation therapy was more frequent in patients with upper extremities DVT (63.8% and 29.8% at 1-year, P<0.001). The cumulative 3-year incidence of recurrent VTE was not different between the 2 groups (9.8% and 7.4%, P=0.43) (Figure). After adjusting confounders, the risks of upper extremities DVT relative to lower extremities DVT for recurrent VTE remained insignificant (HR 0.94, 95% CI 0.36–2.01, P=0.89). Kaplan-Meier event curves for recurrence Conclusions The prevalence of patients with DVT in upper extremities was 3.0% in the current large-scale real-world registry. Patients with DVT in upper extremities more often had active cancer at diagnosis and central venous catheter use as a transient risk factor for VTE, and less often had concomitant PE. Patients with DVT in upper extremities had similar long-term risk for recurrent VTE as those with DVT in lower extremities despite shorter duration of anticoagulation. Acknowledgement/Funding Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation

We examined the effect of amount of muscle mass involved in moderate-intensity continuous physical exercise on executive function. To this end, fifty-five participants completed two acute physical exercise sessions on an airbike ergometer using the upper and lower limbs simultaneously and only the upper limbs, and a resting control session in a randomized order. The physical exercise session lasted 30 min and was performed at moderate intensity (between 64 %-76 % of maximal heart rate evaluated in graded maximal exercise testing). Participants took the Stroop test (congruent and incongruent trials) before and after the sessions to assess executive performance. For the congruent trial, both physical exercise interventions improved executive function performance (pre vs. post, p-value = 0.002 and 0.003 for physical exercise with upper limbs and physical exercise with upper and lower limbs, respectively). Furthermore, executive function performance was higher after the physical exercise interventions than after the control session (p-value = 0.002 and 0.004 for physical exercise with upper limbs and physical exercise with upper and lower limbs, respectively). For the incongruent trial, both physical exercise interventions also improved executive function performance (pre vs. post, p-value < 0.001 for physical exercise with upper limbs and physical exercise with upper and lower limbs, respectively). However, there were no significant differences after both physical exercise interventions and resting control session (p-value = 0.175). Executive function (congruent trial) was positively impacted by acute aerobic physical exercise regardless of the amount of muscle mass involved (upper limbs or upper plus lower limbs). Therefore, we recommend aerobic physical exercise with less or more muscle mass involved to improve cognitive function.

During gait rehabilitation, therapists or robotic devices often supply physical assistance to a patient's lower limbs to aid stepping. The expensive equipment and intensive manual labor required for these therapies limit their availability to patients. One alternative solution is to design devices where patients could use their upper limbs to provide physical assistance to their lower limbs (i.e., self-assistance). To explore potential neural effects of coupling upper and lower limbs, we investigated neuromuscular recruitment during self-driven and externally driven lower limb motion. Healthy subjects exercised on a recumbent stepper using different combinations of upper and lower limb exertions. The recumbent stepper mechanically coupled the upper and lower limbs, allowing users to drive the stepping motion with upper and/or lower limbs. We instructed subjects to step with 1) active upper and lower limbs at an easy resistance level (active arms and legs); 2) active upper limbs and relaxed lower limbs at easy, medium, and hard resistance levels (self-driven); and 3) relaxed upper and lower limbs while another person drove the stepping motion (externally driven). We recorded surface electromyography (EMG) from six lower limb muscles. Self-driven EMG amplitudes were always higher than externally driven EMG amplitudes (P < 0.05). As resistance and upper limb exertion increased, self-driven EMG amplitudes also increased. EMG bursts during self-driven and active arms and legs stepping occurred at similar times. These results indicate that active upper limb movement increases neuromuscular activation of the lower limbs during cyclic stepping motions. Neurologically impaired humans that actively engage their upper limbs during gait rehabilitation may increase neuromuscular activation and enhance activity-dependent plasticity.

Bilateral force control and coordination in upper and lower limbs are important functions for executing activities of daily living. Although upper and lower limbs may reveal distinct bilateral motor control patterns because of different motor networks involvements, no one has examined the possibility that upper and lower limbs reveal distinct bilateral force control and coordination patterns. This study investigated bilateral force control and coordination patterns between upper and lower limbs in healthy young adults. Thirty-two healthy young adults (mean±SD of age = 23.2±2.2 years; 16 Females) performed bilateral hand-grip and ankle-dorsiflexion force control tasks at 10 % and 40 % of maximal voluntary contraction. Bilateral force control performances were evaluated by calculating mean force, force symmetry, force accuracy, and force variability. To estimate bilateral force coordination, we used cross-correlation with time lag. Further, we examined the relationship between bilateral force control and coordination patterns of upper and lower limbs by conducting Pearson's correlation analysis. Bilateral maximal and mean forces of lower limbs were significantly less than those for upper limbs. At higher targeted force level, force accuracy and variability in lower limbs were significantly lower than those for upper limbs. More negative correlation coefficient values appeared in lower limbs as compared with upper limbs. Finally, bilateral force control performances in upper limbs were related to those in lower limbs although no significant correlation was observed for interlimb coordination patterns. These findings suggest that bilateral motor control and coordination patterns were different between upper and lower limbs although the level of bilateral upper and lower motor control capabilities was presumably influenced by shared motor control processes for each individual.See also the graphical abstract(Fig. 1).

The current literature on the major complications of embolo-sclerotherapy of upper and lower extremity vascular malformations is scarce. Evaluating and understanding the rates and types of potential major complications of embolo-sclerotherapy of vascular malformations help treatment planning and informed consent. Therefore, this study reviewed major complications following embolo-sclerotherapy of all upper and lower extremity vascular malformations in a single specialized multidisciplinary vascular malformation center over a 5-year period. All patients with vascular malformations underwent multidisciplinary directed intervention. Demographic, procedural, follow-up, and complication data were collected prospectively in a dedicated database, and reviewed retrospectively. Major complications for upper and lower extremity vascular malformations from 1 January 2013 to 31 December 2017 were analyzed. All embolo-sclerotherapies of high-flow vascular malformations (HFVMs) were performed under selective catheter angiography and direct injection, but low-flow vascular malformations (LFVM) with direct injection only. Major complications were defined as any tissue or functional damage caused by direct injection, distal embolization, or tissue reaction. Seventy patients (median age of 25 years; 44 males and 26 females) had 150 embolo-sclerotherapy procedures for upper extremity vascular malformation. Of these, 28 patients had embolo-sclerotherapy for HFVM and 42 patients for LFVM; total 78 and 72 procedures, respectively. A total of 107 patients (median age of 26 years; 42 males and 65 females) had 160 embolo-sclerotherapy interventions for lower extremity vascular malformations. Of these, 18 patients had embolo-sclerotherapy for HFVM and 89 patients for LFVM; total of 30 and 130 procedures, respectively. The overall major complication rates following embolo-sclerotherapy of upper and lower extremity vascular malformations were 14.3% and 4.7%, respectively (P = 0.030). In the upper extremity HFVM group, major complications from embolo-sclerotherapy occurred in five patients; three ischemic fingers requiring amputation and two skin ulcerations. Meanwhile, in the upper extremity LFVM group, major complications occurred in five patients; one median nerve injury requiring nerve grafting and hand therapy, one hand contracture requiring tendon release, and three skin ulcerations. There was only one major complication, which was cellulitis in the lower extremity HFVM group. In the lower extremity LFVM group, major complications occurred in four patients; two skin ulcerations, one cellulitis, and one deep vein thrombosis. Embolo-sclerotherapy is relatively safe for upper and lower extremity vascular malformations in a high-volume experienced center where our major complication rates were 14.3% and 4.7%, respectively, which compare favorably or similar to those reported in most recent literature. These outcomes will direct treatment strategies to avoid local and systemic toxic complications in the upper and lower extremity, for both HFVM and LFVM, and to improve informed consent.

ObjectiveRobot-assisted neuro-rehabilitation therapy plays a central role in upper extremity recovery of stroke. However, the efficacy of robotic training on the upper extremity is not yet well defined, and little attention has been devoted to its potential effect on the lower extremity. The aim of this study was to compare the efficacy of robot-assisted training and therapist-mediated enhanced upper extremity therapy on the upper and lower extremities.MethodsA randomized clinical trial involving 172 stroke survivors was conducted in China. All participants received either robot-assisted training or enhanced upper extremity therapy for 3 weeks. Fugl-Meyer assessment upper extremity subscale (FMA-UE), Fugl-Meyer assessment lower extremity subscale (FMA-LE), and Modified Barthel Index were administered at baseline, mid-treatment (1 week after treatment start), and post-treatment.ResultsParticipants in the robot-assisted training group showed a significant improvement in the hemiplegia extremity, which was non-inferior to the enhanced upper extremity therapy group in FMA-UE (p < 0.05), while suggesting greater motor recovery of lower extremity in FMA-LE (p < 0.05) compared with the enhanced upper extremity therapy group. A marked increase in Modified Barthel Index was observed within groups; however, no significant difference was found between groups.ConclusionRobot-assisted training is non-inferior but not better in reducing impairment of the upper extremity and appears to be superior in reducing impairment of the lower extremity compared with enhanced upper extremity therapy for stroke survivors.LAY ABSTRACTAlthough post-stroke robot-assisted training of the upper extremity has been widely studied, its efficacy is not yet well defined, and its effects on the lower extremity are unknown. This study aimed to evaluate the effects of upper extremity robot-assisted training on the upper and lower extremities in stroke survivors. Robot-assisted training is non-inferior in improving the function of the upper extremity and superior in improving the function of the lower extremity compared with enhanced upper extremity therapy. Robot-assisted training can be used for functional recovery of the upper and lower extremities in stroke survivors.

Objective:The study aimed to assess the electrophysiological parameters (Hofmann reflex [H-reflex] and motor nerve conduction velocity [MNCV]) on children’s upper and lower limbs with lumbosacral meningomyelocele (MMC) and age-matched control to see the effect of the MMC on the cervical segment of the spinal cord.Materials and Methods:The present study was performed on infants with lumbosacral MMC. Twenty-five infants were examined with a mean age of 50 days of either sex. Out of them, 13 infants were in control and the remaining 12 were diagnosed with MMC. The H-reflex parameter and MNCV were recorded in these children’s right upper and lower limbs.Results:H-reflex was elicited in all the control group babies. In MMC, the H-reflex was elicited in the upper limbs. However, H-reflex was not elicited in the lower limbs of a few MMC babies. The upper limb’s H-reflex parameters and conduction velocity were significantly higher than those corresponding lower limbs in control babies. In MMC, where the H-reflex was elicited, such differences in the lower and upper limbs were not observed. However, the values of MNCV in the upper limb (right median nerve) were significantly less, and the values of Hmax in the lower limb (soleus muscle) were significantly more in MMC babies than in the control group.Conclusions:The values of electrophysiological parameters were higher in the upper limbs as compared to the corresponding lower limbs in control. These values were not altered in the upper limbs than those corresponding lower limbs of MMC, suggesting that motor function development was impaired/delayed in the spinal segment cranial to MMC lesion, and motor impairment in MMC children is mostly a result of upper motor neuron dysfunction.

Introduction Severe frostbite injury can lead to significant long-term functional impairments. This study aims to assess long-term function and symptom resolution in upper vs. lower extremity frostbite. We hypothesize that symptom resolution is slower in upper extremity injury and need for functional assistance is higher in lower extremity injury. Methods A longitudinal cohort of 182 severe frostbite injured patients, defined with a post-rewarming perfusion deficit on imaging and/or clinical diagnosis, included 137 patients with isolated upper or lower extremity injury. Analyses were stratified by amputation and only included those with documented symptoms (neurogenic pain, edema, and numbness) or need for functional assistance (aid with activities of daily living (ADLs) or ambulation) at discharge. Logistic regression was performed to assess need for functional assistance and Cox regression analyzed time to symptom resolution. Results There were equal distribution between upper extremity (51%) and lower extremity (49%) frostbite injuries. Most upper (61%) and lower (66%) extremity injured patients needed assistance at discharge. The overall rate of amputation was 27%, (33% lower and 21% upper, p = 0.133). In patients without amputations, logistic regression showed no significant difference in functional assistance need between upper and lower extremity injuries (OR 1.32, p=0.709). However, among those with amputations, lower extremity injuries were associated with significantly worse functional outcomes (OR 21.67, p=0.008). Cox regression showed non-significant differences in time to symptom resolution between upper and lower extremity injuries in non-amputees (fig 1) and amputees (fig 2). Conclusions This study offers a novel analysis of extremity-specific outcomes, providing new insights into functional recovery and symptom resolution in the largest contemporary cohort of severe frostbite patients. Lower extremity amputees required more functional assistance, while no significant differences in symptom resolution were observed between upper and lower extremity injuries. These findings can guide tailored rehabilitation strategies, enhance functional outcomes, and improve resource allocation in burn care settings. Future research should explore whether limited access to assistive devices, particularly for upper extremity amputees, contributes to differing outcomes. Applicability of Research to Practice Collaborative efforts to delineate access to assistive-devices and define standard symptom measurements in frostbite injuries may help improve functional outcomes in this high need, low resourced population. Funding for the Study N/A

BackgroundThe aim of this study was to evaluate the effects of rehabilitation in terms of changes in the body mass composition in the upper and lower limbs depending on the length of time after stroke and the age of the patient.Material/MethodsEighty-two patients after ischemic stroke were tested 3 times: on admission, after 5 weeks, and 3 months after leaving the hospital (follow-up). During each examination, a segmental analysis of the components of the body mass of the upper limbs and lower limbs was performed, depending on the side of paresis.ResultsPatients between 7 and 12 months after stroke with right-sided paresis had a reduction of fat (P=0.027) and an increase in muscle tissue in the lower (P=0.030) and upper limbs with paresis (P=0.037), as well as in the healthy upper limb (P=0.034) after rehabilitation. Only in the youngest age group (25–44 years) and in patients with left-sided paresis was there a decrease of adipose tissue in the healthy upper (P=0.012) and paresis limbs (P=0.032) and an increase in the muscle tissue mass in the right upper limb (P=0.010) after rehabilitation.ConclusionsThe rehabilitation program had a significant impact on the change in the composition of body mass in upper and lower limbs in people with right-sided paresis, particularly 7 to 12 months after stroke and in the youngest age group (25–44 years). These results may be useful in planning a rehabilitation program for stroke patients to consider the patient’s dominant hand and neglect.

There are neural connections between the upper and lower limbs of humans that enable muscle activation in one limb pair (upper or lower) to modulate muscle activation in the other limb pair (lower or upper, respectively). The aims of this study were to extend previous findings regarding submaximal exercise to maximal effort exercise and determine whether there is an ipsilateral or contralateral bias to the neural coupling during a rhythmic locomotor-like task. We measured upper and lower limb muscle activity, joint kinematics, and limb forces in neurologically intact subjects (n = 16) as they performed recumbent stepping using different combinations of upper and lower limb efforts. We found increased muscle activation in passive lower limbs during active upper limb effort compared with passive upper limb effort. Likewise, increased muscle activation in passive upper limbs occurred during active lower limb effort compared with passive lower limb effort, suggesting a bidirectional effect. Maximal muscle activation in the active lower limbs was not different between conditions with active upper limb effort and conditions with passive upper limb movement. Similarly, maximal muscle activation in the active upper limbs was not different between conditions with active lower limb effort and conditions with passive lower limb movement. Further comparisons revealed that neural coupling was primarily from active upper limb muscles to passive ipsilateral lower limb muscles. These findings indicate that interlimb neural coupling affects muscle recruitment during maximal effort upper and lower limb rhythmic exercise and provides insight into the architecture of the neural coupling.

The Role of the Upper Extremity Neuromusculoskeletal Evaluator at Peace and at War

A crawling paradigm was performed by healthy adults to examine inter-limb coupling patterns and to understand how central pattern generators (CPGs) for the upper and lower limbs are coordinated. Ten participants performed hands-and-feet crawling on two separate treadmills, one for the upper limbs and another one for the lower limbs, the speed of each of them being changed independently. A 1:1 frequency relationship was often maintained even when the treadmill speed was not matched between the upper and lower limbs. However, relative stance durations in the upper limbs were only affected by changes of the upper limb treadmill speed, suggesting that although absolute times are adjusted, the relative proportions of stances and swing do not adapt to changes in lower limb treadmill speeds. With large differences between treadmill speeds, changes in upper and lower limb coupling ratio tended to occur when the upper limbs stepped at slower speeds than the lower limbs, but more rarely the other way around. These findings are in sharp contrast with those in the cat, where forelimbs always follow the rhythm of the faster moving hindlimbs. However, the fact that an integer frequency ratio is often maintained between the upper and lower limbs supports evidence of coupled CPG control. We speculate that the preference for the upper limb to decrease step frequency at lower speeds in humans may be due to weaker ascending propriospinal connections and/or a larger influence of cortical control on the upper limbs which allows for an overriding of spinal CPG control.

Introduction: Physical capabilities are an important parameter of the functional development of adolescents, not only by chronological age but also by their maturational state, as individuals with the same chronological age can have different performance to their less mature counterparts. Objective: To compare and relate the physical capabilities and hormonal markers according to sex and maturity of adolescents. Method: The sample consisted of adolescents of both sexes, aged 10 to 14 years. We evaluated the maturity achieved by a predictive equation of skeletal age, physical capabilities (explosive power of upper and lower limbs, velocity of upper limbs and agility) and hormonal markers (testosterone and oestradiol) via chemiluminescence. Results: Females showed more advanced maturational status, higher weight, body height and oestradiol levels; males performed better in the explosive force of upper and lower limbs, upper limb speed, agility and testosterone levels. In the normal maturational state males showed greater skeletal age, body weight, body height, explosive strength of upper and lower limbs, and testosterone levels; the females in the normal maturational state had higher skeletal age, body weight, body height, explosive upper limb strength and oestradiol levels. In the male correlation analysis, bone age was related to the explosive strength of upper and lower limbs and testosterone; while bone age in females was related to explosive upper limb strength and oestradiol. Conclusion: It is concluded that maturation, testosterone and oestradiol levels play an important role in the physical aspects and performance of motor skills of adolescents, especially in upper limb force which was more related to the maturation obtained by skeletal age of males and females.

Objective: The aim of this study is to evaluate a novel composite measure of active range of motion (XA) and determine whether this measure correlates with active function. Design: Post hoc analysis of two randomized, placebo-controlled, double-blind studies with open-label extensions exploring changes in active function with abobotulinumtoxinA. Setting: Tertiary rehabilitation centers in Australia, Europe, and the United States. Subjects: Adults with upper (n = 254) or lower (n = 345) limb spastic paresis following stroke or brain trauma. Interventions: AbobotulinumtoxinA (⩽5 treatment cycles) in the upper or lower limb. Main measures: XA was used to calculate a novel composite measure (CXA), defined as the sum of XA against elbow, wrist, and extrinsic finger flexors (upper limb) or soleus and gastrocnemius muscles (lower limb). Active function was assessed by the Modified Frenchay Scale and 10-m comfortable barefoot walking speed in the upper limb and lower limb, respectively. Correlations between CXA and active function at Weeks 4 and 12 of open-label cycles were explored. Results: CXA and active function were moderately correlated in the upper limb (P < 0.0001–0.0004, r = 0.476–0.636) and weakly correlated in the lower limb (P < 0.0001–0.0284, r = 0.186–0.285) at Weeks 4 and 12 of each open-label cycle. Changes in CXA and active function were weakly correlated only in the upper limb (Cycle 2 Week 12, P = 0.0160, r = 0.213; Cycle 3 Week 4, P = 0.0031, r = 0.296). Across cycles, CXA improvements peaked at Week 4, while functional improvements peaked at Week 12. Conclusion: CXA is a valid measure for functional impairments in spastic paresis. CXA improvements following abobotulinumtoxinA injection correlated with and preceded active functional improvements.

Background Pain and stiffness are characteristic clinical features of axial Spondyloarthritis (axSpA), leading to functional impairment. Patients describe beneficial effects of physical activity, suggesting a possible involvement of muscle tissue. Body composition data in young axSpA patients with short disease duration are scarce and its implications in muscle strength are not yet clarified. Objectives The purpose of this study is to assess the muscle strength and body composition of different body segments (trunk, upper and lower limbs), in patients with axSpA and to compare them with healthy controls. Methods Patients with clinical diagnosis of axSpA meeting the ASAS classification criteria, aged 18 to 50 years, with symptoms duration ≤ 10 years, were included in this study. Healthy individuals matched by gender and age (1:1) were used as control group (HC). Muscle strength was measured by resisted hand-held dynamometer performed by a single reader, in three different body segments: trunk, upper and lower limbs (on both sides). The mean strength of right and left, upper and lower limbs, was calculated and used in the analysis. Strength of each body segment was also normalized to the total lean mass (LM) of the respective segment. Body composition was measured by octapolar multifrequency bioelectrical impedance analysis (InBody770). Physical activity was assessed by the International Physical Activity Questionnaire (IPAQ). Fisher’s exact test or chi-square test and Mann-Whitney U test were used to compare differences between groups. Results A total of 27 axSpA patients and 27 HC were included. Mean age was 36.5 ± 1.0 years, 67% were males. There was no significant difference between both groups in terms of age, gender, body mass index and physical activity. AxSpA patients had a mean symptoms duration of 7.0 ± 0.9 years. AxSpA patients had lower muscle strength in the upper limbs (50.55 ± 31.60 vs 71.70±31.41 p=0.023) and lower limbs (52.25±18.45 vs 59.83±9.75, p=0.001), compared to HC. Trunk muscle strength did not show any difference between groups (59.10±26.1 vs 56.45±11.2, p=0.856). There were no significant differences in LM and body water, between both groups, for each segment (upper limbs, lower limbs and trunk). Fat mass was significantly higher in the trunk (10.90±8.80 vs 8.10±5.83, p=0.035) and upper limbs (1.40±1.35 vs 0.88±1.0, p=0.05) of axSpA patients, but not in the lower limbs (3.10±1.90 vs 2.45±1.68, p=0.157). Normalized appendicular muscle strength was lower in axSpA patients (upper limbs: 18.63±8.25 vs 21.21±5.92, p=0.018) (Table). Conclusion Young patients with short duration have reduced appendicular muscle strength, compared to HC, with no differences in LM, suggesting a possible muscle dysfunction. Further studies are needed to confirm these findings and understand the underlying pathophysiological mechanisms. Disclosure of Interests Agna Neto: None declared, Rita Pinheiro Torres: None declared, Lucia Domingues: None declared, Diana Teixeira: None declared, Santiago Rodrigues-Manica Grant/research support from: Novartis, MSD, Speakers bureau: Novartis, Jose Marona: None declared, Carina Lopes: None declared, Joao Lagoas Gomes: None declared, Tiago Costa: None declared, Maria Joao Goncalves: None declared, Ines Silva: None declared, Paula Carreto: None declared, Walter Castelao: None declared, Margarida Mateus: None declared, Manuela Costa: None declared, Sandra Falcao: None declared, Ana Filipa Mourao: None declared, Atlas Sardoo: None declared, Sara Maia: None declared, Conceicao Calhau: None declared, Jaime Branco: None declared, Fernando Pimentel dos Santos Grant/research support from: From Abbvie and Novartis, Speakers bureau: Abbvie, Novartis, Pfizer, Biogen,