Correlates of Recent HIV Testing Among People Who Inject Drugs in Rural Areas: A Multi-site Cross-Sectional Study, 2018-2020.

The Rural Opioid Initiative surveyed 2693 people who inject drugs (PWID) in eight rural U.S. areas in 2018-2020 about self-reported HIV testing in the past 6 months. Correlates of interest included receipt of any drug-related services, incarceration history, and structural barriers to care (e.g., lack of insurance, proximity to syringe service programs [SSP]). Overall, 20% of participants reported receiving an HIV test within the past 6 months. Multivariable generalized estimating equations showed that attending substance use disorder (SUD) treatment (OR 2.11, 95%CI [1.58, 2.82]), having health insurance (OR 1.42, 95%CI [1.01, 2.00]) and recent incarceration (OR 1.49, 95%CI [1.08, 2.04]) were positively associated with HIV testing, while experiencing a resource barrier to healthcare (inability to pay, lack of transportation, inconvenient hours, or lack of child care) had inverse (OR 0.73, 95%CI [0.56, 0.94]) association with HIV testing. We found that the prevalence of HIV testing among rural PWID is low, indicating an unmet need for testing. While SUD treatment or incarceration may increase chances for HIV testing for rural PWID, other avenues for expanding HIV testing, such as SSP, need to be explored.

Effects of backward-directed resistance on propulsive force generation during split-belt treadmill walking in non-impaired individuals.

Introduction: Backward-directed resistance is the resistance applied in the opposite direction of the individual's walking motion. Progressive application of backward-directed resistance during walking at a target speed engages adaptive motor control to maintain that speed. During split-belt walking, a motor control strategy must be applied that allows the person to keep up with the two belts to maintain their position on the treadmill. This situation becomes more challenging when progressive resistance is applied since each limb needs to adapt to the greater resistance to maintain the position. We propose that strategies aimed at changing relative propulsion forces with each limb may explain the motor control strategy used. This study aimed to identify the changes in propulsive force dynamics that allow individuals to maintain their position while walking on an instrumented split-belt treadmill with progressively increasing backward-directed resistance. Methods: We utilized an instrumented split-belt treadmill while users had to overcome a set of increasing backward-directed resistance through the center of mass. Eighteen non-impaired participants (mean age = 25.2 ± 2.51) walked against five levels of backward resistance (0, 5, 10, 15, and 20% of participant's body weight) in two different modalities: single-belt vs. split-belt treadmill. On the single-belt mode, the treadmill's pace was the participant's comfortable walking speed (CWS). In split-belt mode, the dominant limb's belt pace was half of the CWS, and the non-dominant limb's belt speed was at the CWS. Results: We assessed differences between single-belt vs. split-belt conditions in the slope of the linear relationship between change in propulsive impulse relative to change of backward resistance amount. In split-belt conditions, the slower limb showed a significantly steeper increase in propulsion generation compared to the fast limb across resistance levels. Discussion: As a possible explanation, the slow limb also exhibited a significantly increased slope of the change in trailing limb angle (TLA), which was strongly correlated to the propulsive impulse slope values. We conclude that the motor control strategy used to maintain position on a split-belt treadmill when challenged with backward-directed resistance is to increase the propulsive forces of the slow limb relative to the fast limb by progressively increasing the TLA. Clinical trial registration: ClinicalTrials.gov, identifier NCT04877249.

Variation in HIV Transmission Behaviors Among People Who Use Drugs in Rural US Communities.

Importance: People who use drugs (PWUD) continue to be at risk of HIV infection, but the frequency and distribution of transmission-associated behaviors within various rural communities is poorly understood. Objective: To examine the association of characteristics of rural PWUD with HIV transmission behaviors. Design, Setting, and Participants: In this cross-sectional study, surveys of PWUD in rural communities in 10 states (Illinois, Kentucky, New Hampshire, Massachusetts, North Carolina, Ohio, Oregon, Vermont, West Virginia, and Wisconsin) were collected January 2018 through March 2020 and analyzed August through December 2022. A chain-referral sampling strategy identified convenience sample seeds who referred others who used drugs. Rural PWUD who reported any past 30-day injection drug use or noninjection opioid use "to get high" were included. Exposures: Individual characteristics, including age, race, gender identity, sexual orientation, partnership status, drug of choice, and location, were collected. Main Outcomes and Measures: Past 30-day frequency of behaviors associated with HIV transmission, including drug injection, syringe sharing, opposite- and same-gender partners, transactional sex, and condomless sex, was assessed. Results: Of 3048 rural PWUD (mean [SD] age, 36.1 [10.3] years; 225 American Indian [7.4%], 96 Black [3.2%], and 2576 White [84.5%] among 3045 with responses; and 1737 men [57.0%] among 3046 with responses), most participants were heterosexual (1771 individuals [86.8%] among 2040 with responses) and single (1974 individuals [68.6%] among 2879 with responses). Opioids and stimulants were reported as drug of choice by 1636 individuals (53.9%) and 1258 individuals (41.5%), respectively, among 3033 individuals with responses. Most participants reported recent injection (2587 of 3046 individuals [84.9%] with responses) and condomless sex (1406 of 1757 individuals [80.0%] with responses), among whom 904 of 1391 individuals (65.0%) with responses indicated that it occurred with people who inject drugs. Syringe sharing (1016 of 2433 individuals [41.8%] with responses) and transactional sex (230 of 1799 individuals [12.8%] with responses) were reported less frequently. All characteristics and behaviors, except the number of men partners reported by women, varied significantly across locations (eg, mean [SD] age ranged from 34.5 [10.0] years in Wisconsin to 39.7 [11.0] years in Illinois; P < .001). In multivariable modeling, younger age (adjusted odds ratio [aOR] for ages 15-33 vs ≥34 years, 1.36; 95% CI, 1.08-1.72) and being single (aOR, 1.37; 95% CI, 1.08-1.74) were associated with recent injection; younger age (aOR, 1.49; 95% CI, 1.20-1.85) and bisexual orientation (aOR vs heterosexual orientation, 2.27; 95% CI, 1.60-3.23) with syringe sharing; gender identity as a woman (aOR vs gender identity as a man, 1.46; 95% CI, 1.01-2.12), bisexual orientation (aOR vs heterosexual orientation, 2.59; 95% CI, 1.67-4.03), and being single (aOR, 1.71; 95% CI, 1.15-2.55) with transactional sex; and bisexual orientation (aOR vs heterosexual orientation, 1.60; 95% CI, 1.04-2.46) and stimulants as the drug of choice (aOR vs opioids, 1.45; 95 CI, 1.09-1.93) with condomless sex with someone who injects drugs. Conclusions and Relevance: This study found that behaviors associated with HIV transmission were common and varied across communities. These findings suggest that interventions to reduce HIV risk among rural PWUD may need to be tailored to locally relevant factors.

Efficacy of early PET-CT directed switch to carboplatin and paclitaxel based definitive chemoradiotherapy in patients with oesophageal cancer who have a poor early response to induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial.

Background: The utility of early metabolic response assessment to guide selection of the systemic component of definitive chemoradiotherapy (dCRT) for oesophageal cancer is uncertain. Methods: In this multi-centre, randomised, open-label, phase II substudy of the radiotherapy dose-escalation SCOPE2 trial we evaluated the role of 18F-Fluorodeoxyglucose positron emission tomography (PET) at day 14 of cycle 1 of three-weekly induction cis/cap (cisplatin (60 mg/m2)/capecitabine (625 mg/m2 days 1-21)) in patients with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC). Non-responders, who had a less than 35% reduction in maximum standardised uptake value (SUVmax) from pre-treatment baseline, were randomly assigned to continue cis/cap or switch to car/pac (carboplatin AUC 5/paclitaxel 175 mg/m2) for a further induction cycle, then concurrently with radiotherapy over 25 fractions. Responders continued cis/cap for the duration of treatment. All patients (including responders) were randomised to standard (50Gy) or high (60Gy) dose radiation as part of the main study. Primary endpoint for the substudy was treatment failure-free survival (TFFS) at week 24. The trial was registered with International Standard Randomized Controlled Trial Number 97125464 and ClinicalTrials.govNCT02741856. Findings: This substudy was closed on 1st August 2021 by the Independent Data Monitoring Committee on the grounds of futility and possible harm. To this point from 22nd November 2016, 103 patients from 16 UK centres had participated in the PET-CT substudy; 63 (61.2%; 52/83 OSCC, 11/20 OAC) of whom were non-responders. Of these, 31 were randomised to car/pac and 32 to remain on cis/cap. All patients were followed up until at least 24 weeks, at which point in OSCC both TFFS (25/27 (92.6%) vs 17/25 (68%); p = 0.028) and overall survival (42.5 vs. 20.4 months, adjusted HR 0.36; p = 0.018) favoured cis/cap over car/pac. There was a trend towards worse survival in OSCC + OAC cis/cap responders (33.6 months; 95%CI 23.1-nr) vs. non-responders (42.5 (95%CI 27.0-nr) months; HR = 1.43; 95%CI 0.67-3.08; p = 0.35). Interpretation: In OSCC, early metabolic response assessment is not prognostic for TFFS or overall survival and should not be used to personalise systemic therapy in patients receiving dCRT. Funding: Cancer Research UK.

The Immediate Effects of Different Types of Augmented Feedback on Fast Walking Speed Performance and Intrinsic Motivation After Stroke.

Objective: To examine the immediate effects of different types of augmented feedback on walking speed and intrinsic motivation post-stroke. Design: A within-subjects repeated-measures design. Setting: A university rehabilitation center. Participants: Eighteen individuals with chronic stroke hemiparesis with a mean age of 55.67±13.63 years and median stroke onset of 36 (24, 81) months (N=18). Interventions: Not applicable. Primary outcome: Fast walking speed measured on a robotic treadmill for 13 meters without feedback and 13 meters with augmented feedback on each of the 3 experimental conditions: (1) without virtual reality (VR), (2) with a simple VR interface, and (3) with VR-exergame. Intrinsic motivation was measured using the Intrinsic Motivation Inventory (IMI). Results: Although the differences were not statistically significant, fast-walking speed was higher in the augmented feedback without VR (0.86±0.44 m/s); simple VR interface (0.87±0.41 m/s); VR-exergame (0.87±0.44 m/s) conditions than in the fast-walking speed without feedback (0.81±0.40 m/s) condition. The type of feedback had a significant effect on intrinsic motivation (P=.04). The post hoc analysis revealed borderline significance on IMI-interest and enjoyment between the VR-exergame condition and the without-VR condition (P=.091). Conclusion: Augmenting feedback affected the intrinsic motivation and enjoyment of adults with stroke asked to walk fast on a robotic treadmill. Additional studies with larger samples are warranted to examine the relations among these aspects of motivation and ambulation training outcomes.

Enhancement of Muscle Shortening Torque Preloaded with Muscle Lengthening is Joint-Specific.

Our cross-sectional study aimed to investigate joint specificity of concentric muscle torque enhancement after a maximum eccentric contraction for the knee versus ankle joints across two different movement velocities (120°/s and 180°/s). After a familiarization session, 22 healthy young adults randomly performed concentric (CONC) and maximum eccentric preloaded concentric (EccCONC) muscle strength tests of the knee extensors and ankle plantar flexors of the non-dominant leg on an isokinetic strength testing device. We calculated the ratio between EccCONC and CONC (EccCONC/CONC) for all the conditions as the marker of concentric muscle torque enhancement. Separate two-way (joints x velocity) within repeated measures ANOVAs were used to determine joint-specific torque differences at 120°/s and 180°/s. CONC and EccCONC were greater for the knee extensors versus ankle plantar flexors at 120°/s and 180°/s (32.86%-102%; p < 0.001 for both); however, EccCONC/CONC was greater for the ankle plantar flexors than knee extensors at 120°/s (52.4%; p < 0.001) and 180°/s (41.9%; p < 0.001). There was a trend of greater EccCONC/CONC for the knee extensors at 180°/s than 120°/s (6.6%; p = 0.07). Our results show that greater concentric muscle torque enhancement after a maximal eccentric contraction occurs for the ankle plantar flexors versus knee extensors. Whether the joint- specificity of concentric muscle torque enhancement after a maximal eccentric contraction differentially affects sports performance is unknown. Our data provide a reference framework to investigate joint-specific concentric muscle torque enhancement for general and clinical athletic populations.

Effect of psychostimulant medications on functional balance performance in persons with Attention-Deficit/Hyperactivity Disorder: A systematic review.

RATIONALE: Balance impairments are highly prevalent and underscreened in individuals with Attention-deficit/hyperactivity disorder (ADHD). Psychostimulant medications, used to treat ADHD symptoms, may improve balance performance in this population as demonstrated by a growing literature; however, there has not been a systematic investigation to understand the effects of psychostimulant medications on balance performance in individuals with ADHD. This systematic review examined the existing evidence to determine if psychostimulant medications improve balance performance in this population. METHODS: We searched PubMed, CINAHL, SPORTDiscus, Scopus, Embase and Cochrane in March 2021 and in January 2022 to locate articles relevant to the topic. Two reviewers evaluated the methodological quality of included articles using the Study Quality Assessment Tools and the PEDro scale. The reviewers rated articles for the level of evidence based on the American Academy of Neurology (AAN) criteria. The reviewers further offered recommendations for research and clinical practice based on the strength of the reviewed articles using the AAN criteria. Additionally, the reviewers gleaned important characteristics from each article, such as study design, balance domain and study results. RESULTS: Nine articles addressed the role of psychostimulant medications on balance outcomes. These articles included two Class II studies, two Class III studies and five Class IV studies. Based on study quality, this systematic review indicated low confidence in the use of psychostimulant medications for improving balance performance based on AAN criteria. CONCLUSION: Psychostimulant medications trends to enhance balance performance in individuals with ADHD. However, the lack of well-designed studies and heterogeneity of balance measures warrant additional research.

Novel lower-extremity dexterity assessment for Parkinson's disease: validation against measures of arm dexterity and general mobility.

PURPOSE: To establish criterion and construct validity of a novel, clinically feasible assessment of lower-extremity dexterity for PD patients. METHODS: Thirty-three PD patients performed a unilateral lower-extremity dexterity task "off" and "on" dopaminergic medications with each leg. The task involves iteratively tapping targets with the foot in a specified pattern, and the measured outcome is the time to complete the movement sequence, with longer times indicating worse performance. We correlated leg movement time with standard, validated measures of gait (comfortable and maximal walk speeds), general mobility (timed up and go), upper-extremity dexterity (9-Hole Pegboard), and elements of the Unified Parkinson Disease Rating Scale (MDS-UPDRS). RESULTS: We found significant relationships between lower extremity dexterity and each of these tasks "off" and "on" medications. Task performance also captures known features of PD, including dopamine-mediated improvement in performance and asymmetrical symptom presentation. CONCLUSIONS: This task provides a simple assessment of lower extremity function that correlates with validated measures of dexterity, gait, and mobility. It provides objective, continuous data, is inexpensive, requires little technical expertise/equipment, has a small physical footprint, and can be administered quickly. These features increase the feasibility of implementing this assessment tool in clinical settings.Implications for rehabilitationWe introduce a novel task that captures lower extremity dexterity in individuals with Parkinson's disease (PD).The task is validated against gold standard measures of upper extremity dexterity, gait, and general mobility.Performance on the task is sensitive to known features of PD, including dopamine-mediated improvements and asymmetrical symptom presentation.The task is easy to implement and provides higher quality data compared to other common clinical assessments (e.g., MDS-UPDRS).

Joint specificity of stretch shortening cycle potentiation at propulsion onset during jump test performance.

BACKGROUND: Joint specific stretch-shortening cycle (SSC) potentiation of lower extremity joints at propulsion onset during jump test performance (JTP) can temporally affect SSC potentiation. However, joint-specific SSC potentiation at propulsion onset during JTP is unknown. METHODS: Twenty-two healthy young adults, 12 men and 10 women, performed: vertical jumps (1) with a preliminary countermovement (CMJ), 2) from a squat position held isometrically for 2-3 seconds at the same knee angle of CMJ (SJ), and (3) after landing from a 15 cm high platform (DJ). Kinetics and kinematics of lower extremity joints were collected. The propulsion onset was calculated uniquely for the hip, knee, and ankle joints and defined as the first positive data point (after the eccentric phase) of the joint angular velocity for each respective joint. SSC potentiation was calculated as the ratio of jump height (JH) and joint extensor moments for CMJ/SJ, DJ/SJ, and DJ/CMJ. RESULTS: JH ratio for CMJ/SJ, DJ/SJ, and DJ/CMJ were >1 (all P< 0.01). Hip, knee, and ankle extensor moment ratio was >1 (all P<0.01) for CMJ/SJ and DJ/SJ, while for DJ/CMJ, extensor moment ratio was >1 only for the ankle (P<0.03). SSC potentiation was greatest at the ankle followed by the hip and knee for CMJ/SJ and DJ/SJ (all P<0.05). CONCLUSIONS: SSC potentiation at propulsion onset was largest at the ankle followed by hip and knee. Our findings emphasize the importance of the ankle versus hip and knee joints regarding SSC potentiation at the very beginning of JTP.

Factors associated with perceived ease of access to syringes in Appalachian North Carolina.

PURPOSE: To examine associations between perceived ease of syringe access, syringe sources, injection behaviors, and law enforcement (LE) interactions among people who inject drugs (PWID) in rural Appalachian North Carolina (NC). METHODS: Using respondent-driven sampling, a diverse sample of 309 self-reported PWID were recruited from rural Appalachian NC. Data were collected via audio computer-assisted self-interview technology from February 2019 through March 2020. Respondents reported demographics, sources of syringes, LE interactions, and injection behaviors. Univariate, bivariate, and linear regression analyses were performed. FINDINGS: Respondents most often obtained syringes from pharmacies and syringe service programs (SSPs). Twenty-one percent disagreed that it was easy to obtain sterile syringes, with 28% reporting low or no access to an SSP. PWID who reported longer physical distances to an SSP had greater difficulty accessing syringes (P<.001). PWID who reported greater ease of access to syringes reported engaging in receptive syringe sharing less often (P<.01). PWID who were stopped and searched by LE more often reported injecting drugs somebody else prepared with nonsterile supplies more often (P<.01). Participants shared used injection supplies more than twice as often than they shared used syringes. CONCLUSIONS: These results underscore the importance of SSPs to mitigate the spread of human immunodeficiency virus and viral hepatitis in rural areas. Supporting mobile SSP services in rural areas could increase access to sterile syringes and injection supplies. SSPs should educate PWID about the importance of not sharing injection supplies. Pharmacies could increase syringe access in areas where SSPs do not operate.

In vivo measurement of intradiscal pressure changes related to thrust and non-thrust spinal manipulation in an animal model: a pilot study.

BACKGROUND: The intervertebral disc is a known back pain generator and is frequently the focus of spinal manipulative therapy evaluation and treatment. The majority of our current knowledge regarding intradiscal pressure (IDP) changes related to spinal manual therapy involves cadaveric studies with their inherent limitations. Additional in vivo animal models are needed to investigate intervertebral disc physiological and molecular mechanisms related to spinal manipulation and spinal mobilization treatment for low back disorders. METHODS: Miniature pressure catheters (Millar SPR-1000) were inserted into either the L4-L5 or L5-L6 intervertebral disc of 3 deeply anesthetized adult cats (Oct 2012-May 2013). Changes in IDP were recorded during delivery of instrument-assisted spinal manipulation (Activator V® and Pulstar®) and motorized spinal flexion with/without manual spinous process contact. RESULTS: Motorized flexion of 30° without spinous contact decreased IDP of the L4-L5 disc by ~ 2.9 kPa, while physical contact of the L4 spinous process decreased IDP an additional ~ 1.4 kPa. Motorized flexion of 25° with L5 physical contact in a separate animal decreased IDP of the L5-L6 disc by ~ 1.0 kPa. Pulstar® impulses (setting 1-3) increased IDP of L4-L5 and L5-L6 intervertebral discs by ~ 2.5 to 3.0 kPa. Activator V® (setting 1-4) impulses increased L4-L5 IDP to a similar degree. Net changes in IDP amplitudes remained fairly consistent across settings on both devices regardless of device setting suggesting that viscoelastic properties of in vivo spinal tissues greatly dampen superficially applied manipulative forces prior to reaching deep back structures such as the intervertebral disc. CONCLUSIONS: This study marks the first time that feline in vivo changes in IDP have been reported using clinically available instrument-assisted spinal manipulation devices and/or spinal mobilization procedures. The results of this pilot study indicate that a feline model can be used to investigate IDP changes related to spinal manual therapy mechanisms as well as the diminution of these spinal manipulative forces due to viscoelastic properties of the surrounding spinal tissues. Additional investigation of IDP changes is warranted in this and/or other in vivo animal models to provide better insights into the physiological effects and mechanisms of spinal manual therapy at the intervertebral disc level.

Combined HPV 16 E2 and L1 methylation predict response to treatment with cidofovir and imiquimod in patients with vulval intraepithelial neoplasia.

BACKGROUND: Topical cidofovir and imiquimod can effectively treat approximately 55% of patients with vulval intraepithelial neoplasia (VIN), thus avoiding the need for surgery. Human papillomavirus (HPV) E⁢2 gene methylation predicts response to treatment but a methylation measurement is only obtainable in approximately 50% of patients. OBJECTIVE: This work aimed to determine if the applicability and predictive power of the E⁢2 methylation assay could be improved by combining it with the components of a host and viral DNA methylation panel (S5) that has been found to predict disease progression in patients with cervical intraepithelial neoplasia. METHODS: HPV E2 methylation and S5 classifier score were measured in fresh tissue samples collected pre-treatment from 132 patients with biopsy-proven VIN grade 3 who participated in a multicentre clinical trial and were randomised to treatment with cidofovir or imiquimod. RESULTS: Combining HPV16 E⁢2 and HPV16 L⁢1 methylation provides a biomarker that is both predictive of response to topical treatment and that can produce a clinically applicable result for all patients. Patients with HPV 16 L⁢1^high and HPV 16 E⁢2^high (36/132 (27.3%)) were more likely to respond to treatment with cidofovir (12/15 (80.0%)) than imiquimod (9/21 (42.9%)) (p= 0.026). Patients with HPV 16 L⁢1^low or HPV 16 E⁢2^low (including those with no HPV/unassessable methylation) were more likely to respond to imiquimod: 23/50 (46.0%) vs 31/46 (67.4%) (p= 0.035). CONCLUSIONS: Combined HPV E⁢2 and L⁢1 methylation is a potential predictive marker in treatment for all patients with VIN. These findings justify validation in a prospective trial.

Substance Use Disorder Treatment Providers' Knowledge and Opinions Toward Testing and Treatment of Chronic Hepatitis C in Rural North Carolina.

Poor access to care has made western North Carolina vulnerable to an outbreak of hepatitis C viral infection (HCV), particularly among persons who inject drugs (PWID). As substance use disorder (SUD) treatment providers could potentially improve linkage to HCV testing and treatment, we sought to understand SUD providers, clinic and client characteristics; referral patterns; HCV knowledge; willingness to participate in additional trainings; and local linkage-to-care pathways for treatment of substance use and HCV. Online survey data were collected from 78 SUD providers serving PWID in eight western rural North Carolina counties. Providers' attitudes toward working with HCV+ clients were very positive. One-third of providers reported a low fund of knowledge regarding HCV, HCV treatment, and financial assistance opportunities. Non-prescribing providers rarely initiated discussions about HCV testing/treatment, but were receptive to training. Respondents indicated that HCV testing and treatment were best delivered at local health departments or primary care clinics but were open to other venues where PWID access care. The vast majority of prescribing and non-prescribing providers expressed interest in obtaining training in HCV treatments, how to obtain HCV medications and topics on advanced liver disease. Data from prescribing and non-prescribing SUD providers suggest opportunities to develop or expand integrated care models for HCV testing/treatment in PWID in rural Appalachian North Carolina.

Local anatomy, stimulation site, and time alter directional deep brain stimulation impedances.

Directional deep brain stimulation (DBS) contacts provide greater spatial flexibility for therapy than traditional ring-shaped electrodes, but little is known about longitudinal changes of impedance and orientation. We measured monopolar and bipolar impedance of DBS contacts in 31 patients who underwent unilateral subthalamic nucleus deep brain stimulation as part of a randomized study (SUNDIAL, NCT03353688). At different follow-up visits, patients were assigned new stimulation configurations and impedance was measured. Additionally, we measured the orientation of the directional lead during surgery, immediately after surgery, and 1 year later. Here we contrast impedances in directional versus ring contacts with respect to local anatomy, active stimulation contact(s), and over time. Directional contacts display larger impedances than ring contacts. Impedances generally increase slightly over the first year of therapy, save for a transient decrease immediately post-surgery under general anesthesia during pulse generator placement. Local impedances decrease at active stimulation sites, and contacts in closest proximity to internal capsule display higher impedances than other anatomic sites. DBS leads rotate slightly in the immediate postoperative period (typically less than the angle of a single contact) but otherwise remain stable over the following year. These data provide useful information for setting clinical stimulation parameters over time.

Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings. METHODS: This was a randomised, double-blind, placebo-controlled trial done in the USA, Romania, and Moldova in 2020-2021, before the emergence of omicron (B.1.1.529) and omicron-lineage variants. Uninfected and unvaccinated household contacts of infected individuals, judged by the investigator to be in good health, were randomly assigned (1:1) to receive 1200 mg CAS + IMD or placebo by subcutaneous injection according to a central randomisation scheme provided by an interactive web response system; randomisation was stratified per site by the test results of a local diagnostic assay for SARS-CoV-2 and age group at baseline. COVID-19 vaccines were prohibited before randomisation, but participants were allowed to receive COVID-19 vaccination during the follow-up period. Participants who developed COVID-19 symptoms during the follow-up period underwent RT-PCR testing. Prespecified endpoints included the proportion of previously uninfected and baseline-seronegative participants (seronegative-modified full analysis set) who had RT-PCR-confirmed COVID-19 in the follow-up period (post-hoc for the timepoints of months 2-5 and 6-8 only) and underwent seroconversion (ie, became seropositive, considered a proxy for any SARS-CoV-2 infections [symptomatic and asymptomatic]; prespecified up to day 57, post-hoc for all timepoints thereafter). We also assessed the incidence of treatment-emergent adverse events. This study is registered with ClinicalTrials.gov, NCT04452318. FINDINGS: From July 13, 2020, to Oct 4, 2021, 2317 participants who were RT-PCR-negative for SARS-CoV-2 were randomly assigned, of whom 1683 (841 assigned to CAS + IMD and 842 assigned to placebo) were seronegative at baseline. During the entirety of the 8-month study, CAS + IMD reduced the risk of COVID-19 by 81·2% (nominal p<0·0001) versus placebo (prespecified analysis). During the 7-month follow-up period, protection was greatest during months 2-5, with a 100% relative risk reduction in COVID-19 (nominal p<0·0001; post-hoc analysis). Efficacy waned during months 6-8 (post-hoc analysis). Seroconversion occurred in 38 (4·5%) of 841 participants in the CAS + IMD group and in 181 (21·5%) of 842 in the placebo group during the 8-month study (79·0% relative risk reduction vs placebo; nominal p<0·0001). Six participants in the placebo group were hospitalised due to COVID-19 versus none who received CAS + IMD. Serious treatment-emergent adverse events (including COVID-19) were reported in 24 (1·7%) of 1439 participants receiving CAS + IMD and in 23 (1·6%) of 1428 receiving placebo. Five deaths were reported, none of which were due to COVID-19 or related to the study drugs. INTERPRETATION: CAS + IMD is not authorised in any US region as of Jan 24, 2022, because data show that CAS + IMD is not active against omicron-lineage variants. In this study, done before the emergence of omicron-lineage variants, a single subcutaneous 1200 mg dose of CAS + IMD protected against COVID-19 for up to 5 months of community exposure to susceptible strains of SARS-CoV-2 in the pre-exposure prophylaxis setting, in addition to the post-exposure prophylaxis setting that was previously shown. FUNDING: Regeneron Pharmaceuticals, F Hoffmann-La Roche, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

Cortical and Subthalamic Nucleus Spectral Changes During Limb Movements in Parkinson's Disease Patients with and Without Dystonia.

BACKGROUND: Dystonia is an understudied motor feature of Parkinson's disease (PD). Although considerable efforts have focused on brain oscillations related to the cardinal symptoms of PD, whether dystonia is associated with specific electrophysiological features is unclear. OBJECTIVE: The objective of this study was to investigate subcortical and cortical field potentials at rest and during contralateral hand and foot movements in patients with PD with and without dystonia. METHODS: We examined the prevalence and distribution of dystonia in patients with PD undergoing deep brain stimulation surgery.  During surgery, we recorded intracranial electrophysiology from the motor cortex and directional electrodes in the subthalamic nucleus (STN) both at rest and during self-paced repetitive contralateral hand and foot movements. Wavelet transforms and mixed models characterized changes in spectral content in patients with and without dystonia. RESULTS: Dystonia was highly prevalent at enrollment (61%) and occurred most commonly in the foot. Regardless of dystonia status, cortical recordings display beta (13-30 Hz) desynchronization during movements versus rest, while STN signals show increased power in low frequencies (6.0 ± 3.3 and 4.2 ± 2.9 Hz peak frequencies for hand and foot movements, respectively). Patients with PD with dystonia during deep brain stimulation surgery displayed greater M1 beta power at rest and STN low-frequency power during movements versus those without dystonia. CONCLUSIONS: Spectral power in motor cortex and STN field potentials differs markedly during repetitive limb movements, with cortical beta desynchronization and subcortical low-frequency synchronization, especially in patients with PD with dystonia. Greater knowledge on field potential dynamics in human motor circuits can inform dystonia pathophysiology in PD and guide novel approaches to therapy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effect of Increasing Obstacle Distances Task on Postural Stability Variables During Gait Initiation in Older Nonfallers and Fallers.

OBJECTIVE: To compare the scaling of the postural stability variables between older nonfallers and fallers during gait initiation (GI) while stepping over increasing obstacle distances. DESIGN: Cross-sectional study. SETTING: University research laboratory. PARTICIPANTS: A sample of participants (N=24) divided into 2 groups: older nonfallers (n=12) and older fallers (n=12). Participants had no known neurologic, musculoskeletal, or cardiovascular conditions that could have affected their walking, and all were independent walkers. All the participants had an adequate cognitive function to participate as indicated by a score of more than 24 on the Mini-Mental State Examination. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary dependent variables were peak anterior-posterior (AP) center of mass (CoM)-center of pressure (CoP) separation during anticipatory postural adjustments (APAs), AP CoM-CoP separation at the toe-off, and peak AP CoM-CoP separation during the swing. Secondary dependent variables were AP trunk angle during GI. Within- and between-repeated measures analysis of variance was used to compare means between groups across different task conditions for all the dependent variables. RESULTS: There was a main effect of group for peak AP CoM-CoP separation during APA (P=.018), an interaction effect between group and condition for AP CoM-CoP separation at toe-off (P=.009), and a main effect of condition for peak AP CoM-CoP separation during the swing (P<.001). We also found a main effect of group for peak AP trunk angle during the swing (P=.028). CONCLUSIONS: For GI while stepping over increasing obstacle distances, older fallers adopt a more conservative strategy of AP CoM-CoP separation than nonfallers prior to toe-off and demonstrate increased peak AP trunk lean during the swing. AP CoM-CoP separation prior to toe-off during the GI task may be a critical marker to identify fallers and warrants additional investigation.

Asymmetric walking on an incline affects aspects of positive mechanical work asymmetrically.

The purpose of this study was to determine the extent to which we could use a split-belt experimental paradigm to increase limb or joint work. Split-belt treadmill walking was combined with uphill walking at 0°, 5° and 10° in young, healthy individuals to assess whether we could specifically target increased force output between and within limbs. Thirteen healthy, young adults participated in this study. Participants performed walking trials with the left belt at 1.0 m/s and the right belt at 0.5 m/s. Repeated measures ANOVAs assessed the effects of speed of the treadmill belt and incline on total and joint specific positive extensor work as well as relative work. Mechanical work varied because of the speed and incline of the treadmill belt at the level of the total limb and across joints. Positive lower extremity relative joint work varied as a result of treadmill belt speed and treadmill incline. Positive mechanical work was greater on the limb that was on the faster treadmill belt, regardless of incline. Increases in relative knee but not hip joint work increased as incline increased. The current investigation shows that the nervous system can shift mechanical work production both between and within limbs to safely walk in a novel split-belt environment. This work extends previous research by demonstrating that researchers/clinicians can also use increasing treadmill incline (or some other means to add increased resistive forces) during split-belt treadmill walking to encourage increased mechanical output at particular limbs and/or joints which may have rehabilitation implications.

The emerging postural instability phenotype in idiopathic Parkinson disease.

Identification of individuals at high risk for rapid progression of motor and cognitive signs in Parkinson disease (PD) is clinically significant. Postural instability and gait dysfunction (PIGD) are associated with greater motor and cognitive deterioration. We examined the relationship between baseline clinical factors and the development of postural instability using 5-year longitudinal de-novo idiopathic data (n = 301) from the Parkinson's Progressive Markers Initiative (PPMI). Logistic regression analysis revealed baseline features associated with future postural instability, and we designated this cohort the emerging postural instability (ePI) phenotype. We evaluated the resulting ePI phenotype rating scale validity in two held-out populations which showed a significantly higher risk of postural instability. Emerging PI phenotype was identified before onset of postural instability in 289 of 301 paired comparisons, with a median progression time of 972 days. Baseline cognitive performance was similar but declined more rapidly in ePI phenotype. We provide an ePI phenotype rating scale (ePIRS) for evaluation of individual risk at baseline for progression to postural instability.

Development of Dynamic Measures to Assess Balance Confidence and State Anxiety While Walking at Increasing Speeds in Young and Older Adults.

The purpose of this study was to determine the test-retest reliability and construct validity of tools to assess how balance confidence (BC) and state anxiety (SA) change with progressively increasing walking speeds. Sixteen young adults and 15 older adults attended two sessions. Individuals began walking on a treadmill at 0.4 m/s Participants chose to continue increasing the treadmill speed (up to 2.0 m/s) or to discontinue the protocol while rating their BC and SA after completing each speed. BC at participants' fastest speed attempted demonstrated high and moderate test-retest reliability among young (intraclass correlation coefficient [ICC] = .908) and older adults (ICC = .704). SA for young adults and older adults was good (ICC = .833) and fair (ICC = .490), respectively. Our measures also correlated with measures of dynamic stability while walking for young (r = -.67, p = .008) and older adults (r = .54, p = .046). Our dynamic measures of BC and SA are valid and reliable in young and older adults.