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After stroke, many people substantially reduce use of their impaired hand in daily life, even if they retain even a moderate level of functional hand ability. Here, we tested whether providing real-time, wearable feedback on the number of achieved hand movements, along with a daily goal, can help people increase hand use intensity. Twenty participants with chronic stroke wore the Manumeter, a novel magnetic wristwatch/ring system that counts finger and wrist movements. We randomized them to wear the device for three weeks with (feedback group) or without (control group) real-time hand count feedback and a daily goal. Participants in the control group used the device as a wristwatch, but it still counted hand movements. We found that the feedback group wore the Manumeter significantly longer (11.2 ± 1.3 h/day) compared to the control group (10.1 ± 1.1 h/day). The feedback group also significantly increased their hand counts over time (p = 0.012, slope = 9.0 hand counts/hour per day, which amounted to ~2000 additional counts per day by study end), while the control group did not (p-value = 0.059; slope = 4.87 hand counts/hour per day). There were no significant differences between groups in any clinical measures of hand movement ability that we measured before and after the feedback period, although several of these measures improved over time. Finally, we confirmed that the previously reported threshold relationship between hand functional capacity and daily use was stable over three weeks, even in the presence of feedback, and established the minimal detectable change for hand count intensity, which is about 30% of average daily intensity. These results suggest that disuse of the hand after stroke is temporarily modifiable with wearable feedback, but do not support that a 3-week intervention of wearable hand count feedback provides enduring therapeutic gains.

Age-related changes in proprioception are known to affect postural stability, yet the extent to which such changes affect the finger joints is poorly understood despite the importance of finger proprioception in the control of skilled hand movement. We quantified age-related changes in finger proprioception in 37 healthy young, middle-aged, and older adults using two robot-based tasks wherein participants’ index and middle fingers were moved by an exoskeletal robot. The first task assessed finger position sense by asking participants to indicate when their index and middle fingers were directly overlapped during a passive crisscross movement; the second task assessed finger movement detection by asking participants to indicate the onset of passive finger movement. When these tasks were completed without vision, finger position sense errors were 48 % larger in older adults compared to young participants ( p  < 0.05); proprioceptive reaction time was 78 % longer in older adults compared to young adults ( p  < 0.01). When visual feedback was provided in addition to proprioception, these age-related differences were no longer apparent. No difference between dominant and non-dominant hand performance was found for either proprioception task. These findings demonstrate that finger proprioception is impaired in older adults, and visual feedback can be used to compensate for this deficit. The findings also support the feasibility and utility of the FINGER robot as a sensitive tool for detecting age-related decline in proprioception.

Background This paper describes the design and preliminary testing of FINGER (Finger Individuating Grasp Exercise Robot), a device for assisting in finger rehabilitation after neurologic injury. We developed FINGER to assist stroke patients in moving their fingers individually in a naturalistic curling motion while playing a game similar to Guitar Hero ® a . The goal was to make FINGER capable of assisting with motions where precise timing is important. Methods FINGER consists of a pair of stacked single degree-of-freedom 8-bar mechanisms, one for the index and one for the middle finger. Each 8-bar mechanism was designed to control the angle and position of the proximal phalanx and the position of the middle phalanx. Target positions for the mechanism optimization were determined from trajectory data collected from 7 healthy subjects using color-based motion capture. The resulting robotic device was built to accommodate multiple finger sizes and finger-to-finger widths. For initial evaluation, we asked individuals with a stroke (n = 16) and without impairment (n = 4) to play a game similar to Guitar Hero ® while connected to FINGER. Results Precision design, low friction bearings, and separate high speed linear actuators allowed FINGER to individually actuate the fingers with a high bandwidth of control (−3 dB at approximately 8 Hz). During the tests, we were able to modulate the subject’s success rate at the game by automatically adjusting the controller gains of FINGER. We also used FINGER to measure subjects’ effort and finger individuation while playing the game. Conclusions Test results demonstrate the ability of FINGER to motivate subjects with an engaging game environment that challenges individuated control of the fingers, automatically control assistance levels, and quantify finger individuation after stroke.

Background In stroke rehabilitation, wearable technology can be used as an intervention modality by providing timely, meaningful feedback on motor performance. Stroke survivors’ preferences may offer a unique perspective on what metrics are intuitive, actionable, and meaningful to change behavior. However, few studies have identified feedback preferences from stroke survivors. This project aims to determine the ease of understanding and movement encouragement of feedback based on wearable sensor data (both arm/hand use and mobility) for stroke survivors and to identify preferences for feedback metrics (mode, content, frequency, and timing). Methods A sample of 30 chronic stroke survivors wore a multi-sensor system in the natural environment over a 1-week monitoring period. The sensor system captured time in active movement of each arm, arm use ratio, step counts and stance time symmetry. Using the data from the monitoring period, participants were presented with a movement report with visual displays of feedback about arm/hand use, step counts and gait symmetry. A survey and qualitative interview were used to assess ease of understanding, actionability and components of feedback that users found most meaningful to drive lasting behavior change. Results Arm/hand use and mobility sensor-derived feedback metrics were easy to understand and actionable. The preferred metric to encourage arm/hand use was the hourly arm use bar plot, and similarly the preferred metric to encourage mobility was the hourly steps bar plot, which were each ranked as top choice by 40% of participants. Participants perceived that quantitative (i.e., step counts) and qualitative (i.e., stance time symmetry) mobility metrics provided complementary information. Three main themes emerged from the qualitative analysis: (1) Motivation for behavior change, (2) Real-time feedback based on individual goals, and (3) Value of experienced clinicians for prescription and accountability. Participants stressed the importance of having feedback tailored to their own personalized goals and receiving guidance from clinicians on strategies to progress and increase functional movement behavior in the unsupervised home and community setting. Conclusion The resulting technology has the potential to integrate engineering and personalized rehabilitation to maximize participation in meaningful life activities outside clinical settings in a less structured environment.

The human motor system quickly entrains rhythmic limb movement to the resonant frequency of mechanical systems with which it interacts, suggesting that entrainment to an appropriately designed training device might be a convenient way to teach desired movements. We tested this possibility by asking healthy subjects ( N  = 30) to learn to move with a desired movement timing using a simple resonating arm training device: a lever attached to a manual wheelchair. The subjects tried to learn to roll the lever-driven wheelchair back and forth in place at a target frequency initially presented using a series of auditory beeps. One-third of the subjects trained without resonance and with no further feedback about rolling frequency; their performance did not improve. Another group trained with continual visual feedback of frequency error but no resonance; they quickly learned to roll the chair at the target frequency, as evidenced at both short-term and long-term (1 day later) retention tests. A third group trained with elastic bands attached to the lever that caused the system to resonate at the target frequency, providing a timing template. While these participants quickly entrained to the target frequency during training, they did not accurately reproduce this frequency when the system was no longer resonant, moving too slowly with the same systematic error at both the short-term and long-term retention tests. They also did not exhibit a timing aftereffect on the initial movements made when they transitioned from a resonant to non-resonant system or vice versa. This suggests they did not realize they were performing the task with a temporal error. Entrainment to mechanical resonance conveys usable information about movement timing, but seems to cause that movement timing to be perceived as slower than it actually is, as if a putative internal clock speeds up, which is a factor to consider in designing machine-assisted motor training.

The quest for Earth-like planets is a major focus of current exoplanet research. Although planets that are Earth-sized and smaller have been detected, these planets reside in orbits that are too close to their host star to allow liquid water on their surfaces. We present the detection of Kepler-186f, a 1.11 ± 0.14 Earth-radius planet that is the outermost of five planets, all roughly Earth-sized, that transit a 0.47 ± 0.05 solar-radius star. The intensity and spectrum of the star's radiation place Kepler-186f in the stellar habitable zone, implying that if Kepler-186f has an Earth-like atmosphere and water at its surface, then some of this water is likely to be in liquid form.

AML cells carrying R882 mutations in DNMT3A fail to sense and repair DNA damage induced by standard-dose chemotherapy as a result of impaired chromatin remodeling Although the majority of patients with acute myeloid leukemia (AML) initially respond to chemotherapy, many of them subsequently relapse, and the mechanistic basis for AML persistence following chemotherapy has not been determined. Recurrent somatic mutations in DNA methyltransferase 3A ( DNMT3A ), most frequently at arginine 882 ( DNMT3A R882 ), have been observed in AML 1 , 2 , 3 and in individuals with clonal hematopoiesis in the absence of leukemic transformation 4 , 5 . Patients with DNMT3A R882 AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy 6 , 7 , suggesting that DNMT3A R882 cells persist and drive relapse 8 . We found that Dnmt3a mutations induced hematopoietic stem cell expansion, cooperated with mutations in the FMS-like tyrosine kinase 3 gene ( Flt3 ITD ) and the nucleophosmin gene ( Npm1 c ) to induce AML in vivo, and promoted resistance to anthracycline chemotherapy. In patients with AML, the presence of DNMT3A R882 mutations predicts minimal residual disease, underscoring their role in AML chemoresistance. DNMT3A R882 cells showed impaired nucleosome eviction and chromatin remodeling in response to anthracycline treatment, which resulted from attenuated recruitment of histone chaperone SPT-16 following anthracycline exposure. This defect led to an inability to sense and repair DNA torsional stress, which resulted in increased mutagenesis. Our findings identify a crucial role for DNMT3A R882 mutations in driving AML chemoresistance and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.

Adenoid cystic carcinoma (ACC) is a rare malignancy of the salivary glands with poor long-term outcomes and with a need for improved imaging and therapeutic options. Prostate-specific membrane antigen (PSMA) expression has been observed in ACC and preliminary studies have demonstrated PET imaging using 68 Ga-functionalized PSMA agents for positron emission tomography (PET). We aimed to assess the extent of PSMA expression in a collection of archival ACC samples and demonstrate the feasibility of using  18 F-DCFPyL for PSMA PET imaging of ACC. PSMA expression levels were assessed in 77 ACC and 11 unaffected parotid gland control samples by immunohistochemistry and quantified by mean H-score. Three patients with metastatic ACC, who had previously undergone local resection, were imaged with 18 F-DCFPyL PSMA PET in a prospective, pilot trial setting. Demographic, oncologic, and treatment history from the PET patient cohort were acquired at the time of imaging. Maximum standardized uptake values (SUV max ) were obtained from representative presumptive metastatic lesions on the  18 F-DCFPyL scans by manual placement of regions-of-interest. PSMA expression was detected in 52% of archival ACC samples, compared to 18% in the unaffected salivary glands. Moderate or high levels of PSMA expression (H-score > 5) were seen in 37% of samples. Radiotracer avid disease was identified on PET imaging of all three patients with tumor SUV max values of 4.1, 4.0, and 2.0, corresponding to tumor-to-liver ratios of 0.7, 1.0, and 0.4 respectively. We find that PSMA is expressed in a majority of histologic samples from patients with ACC. We also demonstrated the feasibility of  18 F-DCFPyL PSMA-targeted PET imaging in the assessment of ACC. Overall, the tumor uptake on  18 F-DCFPyL PET was modest compared to lesional uptake seen in prostate cancer. Given the potential role of PSMA-targeted agents in the management of ACC, broadening access to PSMA PET through F-18-labeled PSMA PET agents is important. Clinical trials investigating the use of PSMA-targeted radioligand therapies for ACC are underway.

Worsening and improving renal function during acute heart failure have been associated with adverse outcomes but few studies have considered the admission level of renal function upon which these changes are superimposed. The objective of this study was to evaluate definitions that incorporate both admission renal function and change in renal function. 696 patients with acute heart failure with calculable eGFR were classified by admission renal function (Reduced [R, eGFR<45 ml/min] or Preserved [P, eGFR≥45 ml/min]) and change over hospital admission (worsening [WRF]: eGFR ≥20% decline; stable [SRF]; and improving [IRF]: eGFR ≥20% increase). The primary outcome was all-cause mortality. The prevalence of Pres and Red renal function was 47.8% and 52.2%. The frequency of R-WRF, R-SRF, and R-IRF was 11.4%, 28.7%, and 12.1%, respectively; the incidence of P-WRF, P-SRF, and P-IRF was 5.7%, 35.3%, and 6.8%, respectively. Survival was shorter for patients with R-WRF compared to R-IRF (median survival times 13.9 months (95%CI 7.7-24.9) and 32.5 months (95%CI 18.8-56.1), respectively), resulting in an acceleration factor of 2.3 (p = 0.016). Thus, an increase compared with a decrease in renal function was associated with greater than two times longer survival among patients with Reduced renal function.

The transits of two Sun-like stars by small planets in an open star cluster are reported; such a stellar environment is unlike that of most planet-hosting field stars, and suggests that the occurrence of planets is unaffected by the stellar environment in open clusters. A global rate of planet formation Until now only four planets — with masses similar to Jupiter — have been found orbiting stars in old open clusters, compared with more than 800 — mostly Neptune-sized — orbiting 'field stars' outside clusters. Most stars and planets form in open clusters that break up within a few hundred million years as stars drift away to become field stars. Older open clusters survive because they were denser in stars when they formed, a stellar environment very different from that of other planet-hosting field stars. This paper, part of the Kepler Cluster Study, describes observations of the transits of two Sun-like stars by planets smaller than Neptune in the 1-billion-year-old open cluster NGC6811. This demonstrates that small planets can form and survive in a dense cluster environment, and implies that the frequency and properties of planets in open clusters are consistent with those of planets around field stars in our Galaxy. Most stars and their planets form in open clusters. Over 95 per cent of such clusters have stellar densities too low (less than a hundred stars per cubic parsec) to withstand internal and external dynamical stresses and fall apart within a few hundred million years 1 . Older open clusters have survived by virtue of being richer and denser in stars (1,000 to 10,000 per cubic parsec) when they formed. Such clusters represent a stellar environment very different from the birthplace of the Sun and other planet-hosting field stars. So far more than 800 planets have been found around Sun-like stars in the field 2 . The field planets are usually the size of Neptune or smaller 3 , 4 , 5 . In contrast, only four planets have been found orbiting stars in open clusters 6 , 7 , 8 , all with masses similar to or greater than that of Jupiter. Here we report observations of the transits of two Sun-like stars by planets smaller than Neptune in the billion-year-old open cluster NGC6811. This demonstrates that small planets can form and survive in a dense cluster environment, and implies that the frequency and properties of planets in open clusters are consistent with those of planets around field stars in the Galaxy.