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HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms ‘graduate’ in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome., HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.

Background: Guideline-based best practice treatment for muscle invasive bladder cancer (MIBC) involves neoadjuvant chemotherapy followed by radical cystectomy (NACRC). Prior studies have shown that a minority of patients receive NACRC and older age and renal function are drivers of non-receipt of NACRC. This study investigates treatment rates and factors associated with not receiving NACRC in MIBC patients with lower comorbidity status most likely to be candidates for NACRC. Materials and Methods: Retrospective United States National Cancer Database analysis from 2006 to 2015 of MIBC patients with Charlson comorbidity index (CCI) of zero. Analysis of NACRC treatment trends in higher CCI patients was also performed. Results: 15.561 MIBC patients met inclusion criteria. 1.507 (9.7%) received NACRC within 9 months of diagnosis. NACRC increased over time (15.0% in 2015 compared to 3.6% in 2006). Higher NACRC was noted in females, cT3 or cT4 cancer, later year of diagnosis, and academic facility treatment. Lower utilization was noted for blacks and NACRC decreased with increasing age and CCI. Only 16.9% of patients aged 23-62 in the lowest age quartile with muscle invasive bladder cancer and CCI of 0 received NACRC. Conclusions: Although utilization is increasing, receipt of NACRC remains low even in populations most likely to be candidates. Further study should continue to elucidate barriers to utilization of NACRC.

Digital therapeutics, treatments delivered remotely and enabled by modern technology, facilitate the provision of personalized, evidence-based, interdisciplinary interventions to manage the complexities associated with Parkinson’s disease. In the context of the COVID-19 pandemic, the need for digital therapeutics has arguably never been greater. However, despite new advances in technology and a heightened interest due to the pandemic, digital therapeutics remain underdeveloped and underutilized. In this paper, we briefly review practical applications and emerging advances in digital therapeutic platforms that target motor and non-motor signs and healthy lifestyle behaviors such as regular exercise, a healthful diet and optimal sleep hygiene habits. Future applications which could transform personalized self-management and patient care are presented. Opportunities, drawbacks and barriers to access are discussed.

BACKGROUND AND PURPOSE Walking activity in persons with Parkinson disease (PD) is important for preventing functional decline. The contribution of walking activity to home and community mobility in PD is poorly understood. METHODS Cross-sectional baseline data (N = 69) were analyzed from a randomized controlled PD trial. The Life-Space Assessment (LSA) quantified the extent, frequency, and independence across 5 expanding levels of home and community mobility, producing individual subscores and a total score. Two additional summed scores were used to represent mobility within (Levels 1-3) and beyond (Levels 4-5) neighborhood limits. An accelerometer measured walking activity for 7 days. Regression and correlation analyses evaluated relationships between daily steps and mobility scores. Mann-Whitney U tests secondarily compared differences in mobility scores between the active and sedentary groups. RESULTS Walking activity contributed significantly to the summed Level 1-3 score (β = 0.001, P = 0.004) but not to the summed Level 4-5 (β = 0.001, P = 0.33) or total (β = 0.002, P = 0.07) scores. Walking activity was significantly related to Level 1 (ρ = 0.336, P = 0.005), Level 2 (ρ = 0.307, P = 0.010), and Level 3 (ρ = 0.314, P = 0.009) subscores. Only the summed Level 1-3 score (P = 0.030) was significantly different between the active and sedentary groups. DISCUSSION AND CONCLUSIONS Persons with PD who demonstrated greater mobility beyond the neighborhood were not necessarily more active; walking activity contributed more so to home and neighborhood mobility. Compared with LSA total score, the Level 1-3 summed score may be a more useful participation-level measure for assessing the impact of changes in walking activity.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A349).

Introduction The ketogenic diet (KD) is a high-fat, low-carbohydrate, and moderate-protein diet that has shown benefit as a treatment in neurologic disorders and may serve as a therapeutic option in individuals with psychiatric disorders. Methods A search was conducted using EBSCOhost and PubMed databases for studies relating to ketogenic or low-carbohydrate diets and psychiatric disorders. Results A total of 32 experimental or observational studies were identified by initial search strategies, 14 of which met the criteria to be included in this analysis. Although specific diet formulations varied somewhat between studies, they all generally examined low-carbohydrate dietary intake with the goal of producing a ketotic state. The studies included in this review indicated the KD was beneficial in reducing symptoms associated with various psychiatric disorders. Discussion This review summarizes the available evidence regarding the efficacy of the ketogenic diet in psychiatric disease states. Data from the studies analyzed demonstrated a positive response in individuals who were able to remain on the diet, regardless of the disease state. However, there is a need for more data to clearly define the specific benefits the KD may provide.

Improper storage and disposal of prescribed opioids can lead to diversion or accidental poisonings. Studies of emergency department and cancer patients suggest prescription opioids are rarely stored securely or disposed of when unneeded. Safe storage and disposal practices reduce risks for others living in or visiting a household. The purpose of this study is thus to examine prescription opioid storage and participation in drug take-back events among Michigan adults. Participants (N = 702) were recruited through social media advertisements to complete an online survey in July and August 2018. Logistic regression was used to examine correlates of safe storage and disposal. 8.4% (n = 59) of participants reported always keeping opioids locked; 29.8% (n = 209) reported attending a drug take-back event. Black participants and those who believed that illegal drug use was a serious problem had greater odds of locking opioids; participants with higher levels of education or who knew someone who used heroin or misused prescription opioids had lesser odds of locking opioids. Age and race were associated with take-back event participation. Findings identify factors associated with safe prescription opioid storage/disposal and indicate safe storage/disposal seldom occurs. Education and provision of safe storage equipment should be designed for diverse ages, races/ethnicities, and levels of education. Drug take-back events not hosted by law enforcement may have broader appeal, as may those led by Black or other people of color. Wider use of drug donation boxes may facilitate increased disposal among those who do not wish to or cannot attend take-back events.

Background and objectives Patients receiving opioid agonist therapies have high rates of psychiatric comorbidity. Some data suggest that comorbidity is associated with poorer treatment outcomes. The current study assessed predictors of multiple putative addictive behaviors among patients receiving opioid agonist therapies. Methods Adults (N = 176) recruited from an outpatient clinic providing opioid agonist therapy completed self-report measures of depression, anxiety, impulsivity, adverse childhood events, and the Recognizing Addictive Disorders (RAD) scale, which includes seven subscales assessing symptoms related to alcohol use, drug use, tobacco use, gambling, binge-eating, hypersexual behavior, and excessive video-gaming. Linear regression and hurdle models identified significant predictors of RAD subscales. Hurdle models included logistic regression estimation for the presence/absence of symptoms and negative binomial regression for estimation of the severity of symptoms. Results Most patients did not report significant symptoms beyond drug or tobacco use. However, 7% to 47% of participants reported some symptoms of other addictive behaviors (subscale score > 0). Higher impulsivity predicted the presence and/or increased severity of symptoms of drug use, gambling, binge-eating, and hypersexuality. Higher depression significantly predicted increased severity of drug use and binge-eating symptoms. Increased anxiety predicted lower severity of alcohol use and binge-eating and higher severity of smoking symptoms. Conclusion and scientific significance A broader range of potentially addictive symptoms may be present among patients engaged in treatment for opioid use disorder. Few studies have assessed symptoms of binge-eating, hypersexuality, and excessive video-gaming among patients receiving opioid agonist therapy. This study contributes to preliminary findings and highlights important future directions. (Am J Addict 2021;00:00-00).

To compare phakic and pseudophakic primary rhegmatogenous retinal detachments (RD) and, within phakic RD, eyes with and without cataract.Retrospective comparative clinical study.Setting: Online database of prospectively collected data. StudyPopulation: Patients aged ≥50 years who had undergone RD repair.Data included baseline demographic and clinical features, surgical details, and anatomical and functional outcomes. Univariate analysis was performed to compare pseudophakic with phakic RD, and phakic RD with and without cataract. Age and sex dependency of variables was analyzed and the association of preoperative variables with final visual acuity was assessed using multivariate analysis. MainOutcomeMeasures: Preoperative features, intraoperative management, postoperative outcomes, association of preoperative features with postoperative outcomes.Of 4,231 eyes, 1,212 were pseudophakic and 3,019 phakic, among which 310 had cataract. Pseudophakic RD showed significant differences compared with phakic RD, including older age, higher prevalence of male sex, foveal detachment, grade C proliferative vitreoretinopathy (PVR), inferior retinal breaks, inferior retinal involvement, and greater RD extent. Despite the more advanced features of pseudophakic RD, pseudophakia was a positive factor for visual outcome. Contralateral RD was more frequent in pseudophakic than phakic RD eyes (P.0001). Within phakic RD, phakic RD with cataract exhibited several similarities with pseudophakic RD, including greater age, more frequent foveal detachment, PVR, and greater RD extent.The presenting features differed significantly between pseudophakic and phakic RD, with greater occurrence of inferior retinal breaks and inferior retinal involvement in particular. Phakic RD with cataract shared several features in common with pseudophakic RD.

BACKGROUND Diabetic retinopathy causes vascular dilatation caused by hypoxia, whereas oxygen tension improvement leads to retinal vessels narrowing. Given that laser photocoagulation aims to increase the oxygen tension in the retina, we hypothesized that the narrowing of vessel caliber after the treatment could be possibly demonstrated. This study aimed to assess the changes in the caliber of retinal vessels before and after laser photocoagulation in diabetic retinopathy. METHODS This research was a prospective cohort study on the treatment of diabetic retinopathy by laser photocoagulation, and it was conducted at Universitas Hasanuddin Hospital, Makassar, Indonesia between November 2017–April 2018. Retinal vascular caliber changes were analyzed before and 6–8 weeks after photocoagulation in 30 diabetic eyes. Central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were measured using the vessel assessment and measurement platform software for images of the retina (VAMPIRE) manual annotation tool. RESULTS A significant decrease of CRVE was observed after laser photocoagulation (p

Background The rhythm of music can entrain neurons in motor cortex by way of direct connections between auditory and motor brain regions. Objective We sought to automate an individualized and progressive music-based, walking rehabilitation program using real-time sensor data in combination with decision algorithms. Methods A music-based digital therapeutic was developed to maintain high sound quality while modulating, in real-time, the tempo (ie, beats per minute, or bpm) of music based on a user’s ability to entrain to the tempo and progress to faster walking cadences in-sync with the progression of the tempo. Eleven individuals with chronic hemiparesis completed one automated 30-minute training visit. Seven returned for 2 additional visits. Safety, feasibility, and rehabilitative potential (ie, changes in walking speed relative to clinically meaningful change scores) were evaluated. Results A single, fully automated training visit resulted in increased usual (∆ 0.085 ± 0.027 m/s, P = .011) and fast (∆ 0.093 ± 0.032 m/s, P = .016) walking speeds. The 7 participants who completed additional training visits increased their usual walking speed by 0.12 ± 0.03 m/s after only 3 days of training. Changes in walking speed were highly related to changes in walking cadence ( R2 > 0.70). No trips or falls were noted during training, all users reported that the device helped them walk faster, and 70% indicated that they would use it most or all of the time at home. Conclusions In this proof-of-concept study, we show that a sensor-automated, progressive, and individualized rhythmic locomotor training program can be implemented safely and effectively to train walking speed after stroke. Music-based digital therapeutics have the potential to facilitate salient, community-based rehabilitation.

As cannabis policy is rapidly evolving and support for marijuana legalization is increasing, understanding of the public’s perception of cannabis and its associated risks is important for preventio...

Expressed emotion has been robustly associated with negative mental health outcomes. Understanding correlates of expressed emotion by family members of individuals with opioid use disorder is important, as this group faces high levels of stress and can play an important role in their loved ones' treatment. Thus, immediate family members of individuals who sought treatment for opioid problems (N = 195) completed a web-based survey that included measures of expressed emotion, self-stigma, social support, and demographic characteristics. Multiple linear regression analyses were conducted to examine correlates of two types of expressed emotion-criticism and emotional overinvolvement. Results indicated that higher self-stigma and lower social support were significantly associated with higher emotional overinvolvement. Higher self-stigma and having experienced debt related to a family member's opioid use were associated with higher criticism. Thus, self-stigma and financial burden may exacerbate likelihood of expressed emotion, whereas social support may buffer against expressed emotion.

Background Precision medicine has enormous potential to improve cancer outcomes. Over one third of the 1.5 million Americans diagnosed with cancer each year have genetic mutations that could be targeted with an FDA-approved drug to treat their disease more effectively. However, the current uptake of targeted cancer therapy in clinical practice is suboptimal. Tumor testing is not widely used, and treatments based on molecular and genomic profiling are often not prescribed when indicated. Challenges with the uptake of precision medicine may disproportionately impact cancer patients in rural communities and other underserved populations. The objective of this study is to identify the determinants of adoption and implementation of precision cancer therapy to design an implementation strategy for community oncology practices, including those in rural areas. Methods This study is an explanatory sequential mixed methods study to identify factors associated with the use of targeted cancer therapy. Levels of targeted therapy use will be ascertained by secondary analysis of medical records to identify concordance with 18 national guideline recommendations for use of precision medicine in the treatment of breast, colorectal, lung, and melanoma skin cancer. Concurrently, facilitators and barriers associated with the use of precision cancer therapy will be elicited from interviews with up to a total of 40 oncologists, administrators, pathology, and pharmacy staff across the participating sites. Qualitative analysis will be a template analysis based on the Theoretical Domains Framework. Quantitative data aggregated at the practice level will be used to rank oncology practices’ adherence to targeted cancer therapy guidelines. Determinants will be compared among high and low users to isolate factors likely to facilitate targeted therapy use. The study will be conducted in eight community oncology practices, with an estimated 4121 targeted therapy treatment decision-making opportunities over a 3-year period. Discussion Despite unprecedented investment in precision medicine, translation into practice is suboptimal. Our study will identify factors associated with the uptake of precision medicine in community settings. These findings will inform future interventions to increase equitable uptake of evidence-based targeted cancer treatment.

Online platforms represent a cost-effective option for data collection; however, it is unclear whether online administration of certain kinds of tasks (e.g., behavioral measures of aggression) poses validity threats. The present study provided a preliminary examination of effort (as indexed by total number of presses), differential drop-out, and believability of an online version of the single-session point subtraction aggression paradigm (PSAP). Two subsamples of participants were recruited; a sample recruited through Amazon’s Mechanical Turk ( n = 758) and an in-person undergraduate sample ( n = 88). All participants completed the PSAP, along with measures of trait hostility and state anger. The online sample did not differ from the in-person sample on effort (i.e., total number of presses), and did not find the task less believable. Higher scores on state anger were associated with lower likelihood of beginning the online PSAP, but were not associated with prematurely closing the task. State anger was related to aggressive responding on the PSAP. Limitations of the online PSAP and considerations for future research are discussed.

Greater wax moths (GWM, Galleria mellonella L.) are important pests of Western honey bee (Apis mellifera L.) colonies. The larval moths feed on wax combs, cast honey bee larval skins, pollen, and s...

In individuals with motor impairments such as those post-stroke or with cerebral palsy, the function of the knee extensors may be affected during walking, resulting in decreased mobility. We have designed a lightweight, hinge-free wearable robot combining soft textile exosuit components with integrated rigid components, which assists knee extension when needed but is otherwise highly transparent to the wearer. The exosuit can apply a wide range of assistance profiles using a flexible multi-point reference trajectory generator. Additionally, we implemented a controller safety limit to address the risk of hyperextension stemming from the hinge-free design. The exosuit was evaluated on six healthy participants walking uphill and downhill on a treadmill at a 10° slope with a set of joint power-inspired assistance profiles. A comparison of sagittal plane joint angles between no exosuit and exosuit unpowered conditions validated the device transparency. With positive power assistance, we observed reduction in average positive knee biological power during uphill walking (left: 17.5±3.21%, $p=0.005$ ; right: 23.2±3.54%, ${p} =0.008$ ). These initial findings show promise for the assistive capability of the device and its potential to improve the quality of gait and increase mobility in clinical populations.

Background Parkinson disease (PD) is a debilitating and chronic neurodegenerative disease resulting in ambulation difficulties. Natural walking activity often declines early in disease progression despite the relative stability of motor impairments. In this study, we propose a paradigm shift with a “connected behavioral approach” that targets real-world walking using cognitive-behavioral training and mobile health (mHealth) technology. Methods/design The Walking and mHealth to Increase Participation in Parkinson Disease (WHIP-PD) study is a twelve-month, dual site, two-arm, randomized controlled trial recruiting 148 participants with early to mid-stage PD. Participants will be randomly assigned to connected behavioral or active control conditions. Both conditions will include a customized program of goal-oriented walking, walking-enhancing strengthening exercises, and eight in-person visits with a physical therapist. Participants in the connected behavioral condition also will (1) receive cognitive-behavioral training to promote self-efficacy for routine walking behavior and (2) use a mHealth software application to manage their program and communicate remotely with their physical therapist. Active control participants will receive no cognitive-behavioral training and manage their program on paper. Evaluations will occur at baseline, three-, six-, and twelve-months and include walking assessments, self-efficacy questionnaires, and seven days of activity monitoring. Primary outcomes will include the change between baseline and twelve months in overall amount of walking activity (mean number of steps per day) and amount of moderate intensity walking activity (mean number of minutes per day in which > 100 steps were accumulated). Secondary outcomes will include change in walking capacity as measured by the six-minute walk test and ten-meter walk test. We also will examine if self-efficacy mediates change in amount of walking activity and if change in amount of walking activity mediates change in walking capacity. Discussion We expect this study to show the connected behavioral approach will be more effective than the active control condition in increasing the amount and intensity of real-world walking activity and improving walking capacity. Determining effective physical activity interventions for persons with PD is important for preserving mobility and essential for maintaining quality of life. Clinical trials registration NCT03517371, May 7, 2018. Trial registration ClinicalTrials.gov: NCT03517371. Date of registration: May 7, 2018. Protocol version: Original.

Objective: Soft robotic exosuits can improve the mechanics and energetics of walking after stroke. Building on this prior work, we evaluated the effects of the first prototype of a portable soft robotic exosuit. Methods: Exosuit-induced changes in the overground walking speed, distance, and energy expenditure of individuals post-stroke were evaluated statistically with alpha set to 0.05 and compared to minimal clinically important difference scores. Results: Compared to baseline walking without the exosuit worn, the

Introduction: Driving after cannabis use is associated with a number of risks. Examination of driving after cannabis use among young adults is particularly important, as young adults have the highest rates of cannabis use and among the highest rates of traffic crashes. The current study examines rates and correlates of driving after cannabis use among young adults (aged 18–25) who reported past month cannabis use. Methods: Participants were from Michigan and recruited through paid Facebook and Instagram advertisements between February and March 2018 (n=461). Results: Nearly a third (31.9%) of the sample reported driving after cannabis use in the past month. Young adults who were employed (aOR=1.872, p=0.045), had medical cannabis cards (aOR=2.877, p

STUDY OBJECTIVES: Individuals with opioid use disorder (OUD) may experience worsening sleep quality over time, and a subset of individuals may have sleep disturbances that precede opioid use and do not resolve following abstinence. The purpose of the present study was to (1) collect retrospective reports of sleep across the lifespan and (2) identify characteristics associated with persistent sleep disturbance and changes in sleep quality in persons with OUD. METHODS: Adults with OUD (n = 154) completed a cross-sectional study assessing current and past sleep disturbance, opioid use history, and chronic pain. Repeated-measures analysis of variance was used to examine changes in retrospectively reported sleep quality, and whether changes varied by screening positive for insomnia and/or chronic pain. Multivariate linear regression analyses were used to identify additional correlates of persistent sleep disturbance. RESULTS: Participants reported that their sleep quality declined over their lifespan. Changes in reported sleep over time varied based on whether the individual screened positive for co-occurring insomnia and/or chronic pain. In regression analyses, female sex (β = 0.16, P = .042), a greater number of treatment episodes (β = 0.20, P = .024), and positive screens for chronic pain (β = 0.19, P = .018) and insomnia (β=0.22, P = .013) were associated with self-reported persistent sleep disturbance. Only a portion of participants who screened positive for sleep disorders had received a formal diagnosis. CONCLUSIONS: OUD treatment providers should routinely screen for co-occurring sleep disturbance and chronic pain. Interventions that treat co-occurring OUD, sleep disturbance, and chronic pain are needed. CITATION: Ellis JD, Mayo JL, Gamaldo CE, Finan PH, Huhn AS. Worsening sleep quality across the lifespan and persistent sleep disturbances in persons with opioid use disorder. J Clin Sleep Med. 2022;18(2):587–595.

IntroOn August 14, a magnitude 7.2 earthquake occurred in the South of Haiti, killing over 2,200 people and leaving at least 12,000 injured. On August 17th, a joint task force coordinated the triage, treatment, and transport for patients arriving at the Port-au-Prince airport from the South.MethodsFrom August 17th-27th, approximately 243 patients were encountered at the Port-au-Prince airport. For the first three days of operations, written notes, reports, and various chat logs from WhatsApp were used to compile this data.Results243 patents were encountered at the airport Triage and Treatment from August 17 to August 27. Orthopedic injuries were the most common presenting injury with 20% of patients having a pelvis fracture (the most prevalent injury). Of the 174 with known transfer destinations, 118 (68%) were transported to one of three tertiary care hospitals, with 99 going via ground ambulance to the two in Port au Prince, and 19 going via HAA helicopter to Mirebalais. Once treatment operations were initiated, 106 patients received some form of treatment at the airport while awaiting transport.DiscussionInteragency coordination was the key to rapid scale up. To address the most prevalent patient issues, a treatment bundle was conceptualized a few days into operations that consisted of IV fluids, analgesia, IV antibiotics, wound debridement and cleaning, and tetanus prophylaxis.

Western honey bees (Apis mellifera L.) collect pollen from flowers as their source of protein, fat, vitamins, and minerals. Beekeepers feed pollen substitutes to their honey bee colonies to mitigate a lack of natural pollen resources in the environment. Despite their widespread use, it is unclear if pollen substitutes are beneficial to colony health and productivity. Herein, we review the literature regarding pollen substitute efficacy in four major categories: 1) consumption/palatability of pollen substitutes, 2) colony productivity, 3) pest and disease response, and 4) physiological response. Collectively, the literature shows a mix of positive, neutral, and negative impacts of pollen substitutes on honey bee colony health. Additionally, we recommend areas for improvement in pollen substitute research and provide comprehensive supplemental tables of pollen substitute study results. We hope this review will lead to more research on pollen substitutes given nutrition is a key factor impacting the health of managed honey bees globally.

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY’s prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

Background Whole-plant cannabis extracts are consumed by the public for medical and non-medical (“recreational”) purposes but are poorly researched compared to pure cannabinoids. There is emerging evidence that cannabis extracts comprising complex mixtures of cannabinoids may have different biological effects from that of pure cannabinoids. In the current study, we sought to assess the effect of whole-plant cannabis extracts produced from different chemotypes of cannabis on the normal behavior of zebrafish larvae. Methods Three cannabis plant chemotypes were used in this study that contained either high amounts of THC, high amounts of CBD, high but equal amounts of THC and CBD, or low but equal amounts of THC and CBD. Following solvent extraction, liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) was performed for the detection and quantitation of target cannabinoids. Larval zebrafish behavioral models were subsequently used to assess the effect of the four different whole-plant cannabis extracts on the normal larval behavior using the DanioVision behavioral tracking systems and software. To compare, changes in the behavior activity levels for 30 min periods were compared to controls using 2-way ANOVA with multiple comparisons followed by a Bonferroni post hoc test. Results It was found that the whole-plant extracts that contained high levels of THC had similar effects on larval behavior, while the high CBD and low THC:CBD extracts produced distinct effects on normal larval behavior. Exposure of larvae to concentration-matched levels of THC and CBD found in the extracts revealed that a subset of the cannabis extracts tested had similar behavioral profiles to the pure cannabinoids while others did not. Conclusions To our knowledge, this is the first study to test and compare the bioactivity of different whole-plant cannabis extracts in larval zebrafish. This work will provide a framework for future studies of distinct cannabis extracts and will be useful for comparing the bioactivity of extracts from different cannabis chemotypes as well as extracts made through various heating processes. It will also act as the first stage of assessment before testing the extracts against zebrafish models of toxicity and disease.

Objective Academic physical therapy has no universal metrics by which educational programs can measure outcomes, limiting their ability to benchmark to their own historical performance, to peer institutions, or to other health care professions. The PT-Graduation Questionnaire (GQ) survey, adapted from the Association of American Medical Colleges’ GQ, addresses this gap by offering both inter-professional insight and fine-scale assessment of physical therapist education. This study reports the first wave of findings from an ongoing multi-site trial of the PT-GQ among diverse academic physical therapy programs, including (1) benchmarks for academic physical therapy, and (2) a comparison of the physical therapist student experience to medical education benchmarks. Methods Thirty-four doctor of physical therapy (DPT) programs (13.2% nationwide sample) administered the online survey to DPT graduates during the 2019 to 2020 academic year. PT-GQ and Association of American Medical Colleges data were contrasted via Welch’s unequal-variance t test and Hedges g (effect size). Results A total of 1025 respondents participated in the study (response rate: 63.9%). The average survey duration was 31.8 minutes. Overall educational satisfaction was comparable with medicine, and respondents identified areas of curricular strength (eg, anatomy) and weakness (eg, pharmacology). DPT respondents provided higher ratings of faculty professionalism than medicine, lower rates of student mistreatment, and a lesser impact of within-program diversity on their training. One-third of respondents were less than “satisfied” with student mental health services. DPT respondents reported significantly higher exhaustion but lower disengagement than medical students, along with lower tolerance for ambiguity. Of DPT respondents who reported educational debt, one-third reported debt exceeding $150,000, the threshold above which the DPT degree loses economic power. Conclusions These academic benchmarks, using the PT-GQ, provided insight into physical therapist education and identified differences between physical therapist and medical student perceptions. Impact This ongoing trial will establish a comprehensive set of benchmarks to better understand academic physical therapy outcomes.

Importance Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. Objective To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. Design, Setting, and Participants The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) andERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. Interventions Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. Main Outcomes and Measures Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). Results A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) andERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. Conclusions and Relevance In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. Trial Registration ClinicalTrials.gov Identifier:NCT01042379

The traits of two subspecies of western honey bees, Apis mellifera scutellata and A.m. capensis, endemic to the Republic of South Africa (RSA), are of biological and commercial relevance. Nevertheless, the genetic basis of important phenotypes found in these subspecies remains poorly understood. We performed a genome wide association study on three traits of biological relevance in 234 A.m. capensis, 73 A.m. scutellata and 158 hybrid individuals. Thirteen markers were significantly associated to at least one trait (P ≤ 4.28 × 10−6): one for ovariole number, four for scutellar plate and eight for tergite color. We discovered two possible causative variants associated to the respective phenotypes: a deletion in GB46429 or Ebony (NC_007070.3:g.14101325G>del) (R69Efs*85) and a nonsense on GB54634 (NC_007076.3:g.4492792A>G;p.Tyr128*) causing a premature stop, substantially shortening the predicted protein. The mutant genotypes are significantly associated to phenotypes in A.m. capensis. Loss-of-function of Ebony can cause accumulation of circulating dopamine, and increased dopamine levels correlate to ovary development in queenless workers and pheromone production. Allelic association (P = 1.824 x 10−5) of NC_007076.3:g.4492792A>G;p.Tyr128* to ovariole number warrants further investigation into function and expression of the GB54634 gene. Our results highlight genetic components of relevant production/conservation behavioral phenotypes in honey bees.

Background After stroke, motor control is often negatively affected, leaving survivors with less muscle strength and coordination, increased tone, and abnormal synergies (coupled joint movements) in their affected upper extremity. Humeral internal and external rotation have been included in definitions of abnormal synergy but have yet to be studied in-depth. Objective Determine the ability to generate internal and external rotation torque under different shoulder abduction and adduction loads in persons with chronic stroke (paretic and non-paretic arm) and uninjured controls. Methods 24 participants, 12 with impairments after stroke and 12 controls, completed this study. A robotic device controlled abduction and adduction loading to 0, 25, and 50% of maximum strength in each direction. Once established against the vertical load, each participant generated maximum internal and external rotation torque in a dual-task paradigm. Four linear mixed-effects models tested the effect of group (control, non-paretic, and paretic), load (0, 25, 50% adduction or abduction), and their interaction on task performance; one model was created for each combination of dual-task directions (external or internal rotation during abduction or adduction). The protocol was then modeled using OpenSim to understand and explain the role of biomechanical (muscle action) constraints on task performance. Results Group was significant in all task combinations. Paretic arms were less able to generate internal and external rotation during abduction and adduction, respectively. There was a significant effect of load in three of four load/task combinations for all groups. Load-level and group interactions were not significant, indicating that abduction and adduction loading affected each group in a similar manner. OpenSim musculoskeletal modeling mirrored the experimental results of control and non-paretic arms and also, when adjusted for weakness, paretic arm performance. Simulations incorporating increased co-activation mirrored the drop in performance observed across all dual-tasks in paretic arms. Conclusion Common biomechanical constraints (muscle actions) explain limitations in external and internal rotation strength during adduction and abduction dual-tasks, respectively. Additional non-load-dependent effects such as increased antagonist co-activation (hypertonia) may cause the observed decreased performance in individuals with stroke. The inclusion of external rotation in flexion synergy and of internal rotation in extension synergy may be over-simplifications.

Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-20-02.

Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify (graduate) regimens with ≥ 85% Bayesian predictive probability of success (i.e., demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with pCR endpoint within signatures defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status. Regimens may leave the trial for futility (< 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and < 85%), or safety concerns as recommended by the independent DSMB. For HER2+ patients, the I-SPY2 control arm was 12 weekly cycles of paclitaxel+trastuzumab (TH, control) followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x4 and surgery. Patritumab is a fully human monoclonal antibody that inhibits HER3. In this experimental arm for HER2+ patients, patritumab was given q3w x 4 cycles (18mg/kg loading dose followed by 9mg/kg/dose) concurrent with paclitaxel and trastuzumab q1w x 12 weeks (PTH, treatment), followed by AC q2-3w. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 weeks after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Analysis was intention to treat. Patients who switched to non-protocol therapy count as non-pCR. Patients on treatment arm therapy at the time of arm closure are non-evaluable. Graduation potential was in 3 of 10 pre-defined signatures: all HER2+, HR-/HER2+, and HR+/HER2+. Results: The PTH regimen was stopped at the recommendation of the Safety Working Group and DSMB based on a safety event (bilateral sensorineural hearing loss, Gr 3) observed in one patient. At the time of arm closure, N=31 patients had received PTH treatment; 4 patients receiving PTH were changed to non-protocol therapy and removed from the analysis. The final estimated pCR report will consider 27 PTH and 31 TH as evaluable patients. Accrual was insufficient to assess graduation, however, there appears to be good signal in the HER2+HR- but not HER2+HR+ signatures. I-SPY 2 TRIAL Est. pCR at time of arm closureSignaturesPTH (Treatment)N= 31TH (Control)N = 31All (HER2+)0.40 (0.22 - 0.59), n=310.23 (0.09 - 0.37), n=31HR-/HER2+0.64 (0.36 - 0.91), n=110.30 (0.12 - 0.47), n=12HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19 HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19The patient who developed Gr3 sensorineural hearing loss 6 days after the 2nd patritumab (and 4th paclitaxel/trastuzumab) treatment, did not recover her hearing after patritumab was stopped, and also reported Gr3 vulvovaginal pain, vulvitis, and vaginal inflammation. Other gynecological symptoms in the PTH arm include: 1 pt with Gr1 vaginal hemorrhage, and 1 pt with Gr2 dyspareunia. There was a higher frequency of Gr3 hypokalaemia (12.5% vs. 3.2%). One pt in the PTH arm reported Gr3 small intestinal obstruction which resolved with conservative management. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial; PTH was stopped due to safety concerns, although there was activity in the HER2+ HR- signature. This is the first report of Gr3 hearing loss associated with patritumab/paclitaxel/trastuzumab, and thus attribution is uncertain. Citation Format: Teresa L Helsten, Shelly S Lo, Christina Yau, Kevin Kalinsky, Anthony D Elias, Anne M Wallace, A. Jo Chien, Janice Lu, Julie E Lang, Kathy S Albain, Erica Stringer-Reasor, Amy S Clark, Judy C Boughey, Erin D Ellis, Douglas Yee, Angela DeMichele, Claudine Isaacs, Jane Perlmutter, Hope S Rugo, Richard Schwab, Nola M. Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, Amy Wilson, Ruby Singhrao, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of patritumab/paclitaxel/trastuzumab over standard paclitaxel/trastuzumab in early stage, high-risk HER2 positive breast cancer: Results from the neoadjuvant I-SPY 2 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-02.

Overdose-death rates continue to rise, necessitating accessible medication-assisted treatment (MAT). However, national data demonstrate rural shortages. The purpose of the study was to investigate rural/urban comparisons in the Midwest and simultaneously examine the influence of rural and low-income status. We extracted 2018 public data for Michigan's 83 counties on two MAT forms: 1) methadone clinics and 2) waivered buprenorphine practitioners. Urbanicity was operationalized using Rural Urban Continuum Codes. Income was categorized with U.S. Census data. Bivariate analyses demonstrated MAT shortages among rural (pslt; .001) and low-income counties (pslt; .01). In multivariable analyses, urban counties were 35.6 and 12.2 times more likely than rural counties to have any clinic(s) (plt; .001) or practitioner(s) (plt; .05), respectively. High-income counties were 5.9 times more likely than low-income counties to have any practitioner(s) (plt; .01). These state-level findings identify targeted Michigan counties currently underserved for available MAT. Expanding treatment access to underserved communities using economic approaches is urgently needed.

Cannabis continues to be the most widely used illicit substance among youth, as many teens view the risks of cannabis consumption to be low. With cannabis laws becoming lax and dispensaries becoming more prevalent throughout the United States, highly concentrated Δ-9-tetrahydrocannibinol (THC) is becoming readily available. This article examines the available literature on consumption of concentrated THC, focusing on potential consequences of concentrate use among youth. Various methods for consuming concentrated THC, including ingestion of edibles, vaping, and dabbing, are discussed, along with associated risks of each consumption method. Recommendations for health professionals are provided.

Objective To evaluate the proof of concept of an innovative model of physical therapy Rehabilitation Enhancing Aging through Connected Health (REACH) and evaluated its feasibility and effect on physical function and health care utilization. Design Quasi-experimental 12-month clinical trial. Setting Two outpatient rehabilitation centers. Participants Community-dwelling older primary care patients with a treatment arm undergoing the intervention (n=75; mean age=77±5.9y; 54% women) and propensity matched controls derived from a longitudinal cohort study (n=430; mean age=71±7.0y; 68% women) using identical recruitment criteria (N=505). Intervention Combined outpatient and home PT augmented with a commercially available app and computer tablet. Measurements Primary outcomes included a feasibility questionnaire, exercise adherence, self-reported function, and the Short Physical Performance Battery (SPPB). Secondary outcomes included the rates of emergency department (ED) visits and hospitalizations. Results Among REACH participants, we observed a 9% dropout rate. After accounting for dropouts, with propensity matching, n=68 treatments and n=100 controls were analyzed. Over the 12-month study duration, 85% of participants adhered to the exercise program an average of 2 times a week and evaluated the treatment experience favorably. In comparison to controls, after 1 year of treatment and within multivariable regression models, REACH participants did not manifest a significant difference in patient reported function (group x time effect 1.67 units, P=.10) but did manifest significant differences in SPPB (group x time effect 0.69 units, P=.03) and gait speed (group x time effect .08m/s, P=.02). In comparison to controls, after 1 year, the rate of ED visits (group x time treatment rate=0.27, P Conclusion The REACH intervention is feasible and has proof of concept in preventing functional decline and favorably affecting health care utilization. Evaluation on a larger scale is warranted.

Histone deacetylase 3 (Hdac3) is a target of the FDA approved HDAC inhibitors, which are used for the treatment of lymphoid malignancies. Here, we used Cd19-Cre to conditionally delete Hdac3 to define its role in germinal center B cells, which represent the cell of origin for many B cell malignancies. Cd19-Cre-Hdac3−/− mice showed impaired germinal center formation along with a defect in plasmablast production. Analysis of Hdac3−/− germinal centers revealed a reduction in dark zone centroblasts and accumulation of light zone centrocytes. RNA-seq revealed a significant correlation between genes up-regulated upon Hdac3 loss and those up-regulated in Foxo1-deleted germinal center B cells, even though Foxo1 typically activates transcription. Therefore, to determine whether gene expression changes observed in Hdac3−/− germinal centers were a result of direct effects of Hdac3 deacetylase activity, we used an HDAC3 selective inhibitor and examined nascent transcription in germinal center-derived cell lines. Transcriptional changes upon HDAC3 inhibition were enriched for light zone gene signatures as observed in germinal centers. Further comparison of PRO-seq data with ChIP-seq/exo data for BCL6, SMRT, FOXO1 and H3K27ac identified direct targets of HDAC3 function including CD86, CD83 and CXCR5 that are likely responsible for driving the light zone phenotype observed in vivo.

The kinetics for surface-catalyzed alcohol dehydration reactions often depend on the structure of the alcohol. Studies of structure–activity relations across primary, secondary, and tertiary alcoho...

BACKGROUND AND PURPOSE: The purpose of this study was to assess the consistency of a novel MR safe lower extremity motor control neuroimaging paradigm to elicit reliable sensorimotor region brain activity. METHOD: Participants completed multiple sets of unilateral leg presses combining ankle, knee, and hip extension and flexion movements against resistance at a pace of 1.2 Hz while lying supine in a 3T MRI scanner. Regions of Interest (ROI) consisted of regions primarily involved in lower extremity motor control (right and left primary motor cortex, primary somatosensory cortex, pre-motor cortex, secondary somatosensory cortex, basal ganglia, and the cerebellum). RESULTS: The group analysis based on mixed effects paired samples t-test revealed no differences for brain activity between sessions (p>0.05). Intraclass correlation coefficients in the sensorimotor regions were good to excellent for average percent signal change (0.621 to 0.918) and Z-score (0.697 to 0.883), with the exception of the left secondary somatosensory cortex percent signal change (0.165). CONCLUSIONS: These results indicate that a loaded lower extremity force production and attenuation task that simulates the range of motion of squatting, stepping, and landing from a jump is reliable for longitudinal neuroimaging applications and support the use of this paradigm in further studies examining therapeutic interventions and changes in dynamic lower extremity motor function.

Summary Gait impairments are among the most common and disabling symptoms of Parkinson's disease. Nonetheless, gait is not routinely assessed quantitatively but is described in general terms that are not sensitive to changes ensuing with disease progression. Quantifying multiple gait features (eg, speed, variability, and asymmetry) under natural and more challenging conditions (eg, dual-tasking, turning, and daily living) enhanced sensitivity of gait quantification. Studies of neural connectivity and structural network topology have provided information on the mechanisms of gait impairment. Advances in the understanding of the multifactorial origins of gait changes in patients with Parkinson's disease promoted the development of new intervention strategies, such as neurostimulation and virtual reality, aimed at alleviating gait impairments and enhancing functional mobility. For clinical applicability, it is important to establish clear links between specific gait impairments, their underlying mechanisms, and disease progression to foster the acceptance and usability of quantitative gait measures as outcomes in future disease-modifying clinical trials.