The PAX LC Trial: A Decentralized, Phase 2, Randomized, Double-blind Study of Nirmatrelvir/Ritonavir Compared with Placebo/Ritonavir for Long COVID.

INTRODUCTION: Individuals with long COVID lack evidence-based treatments and have difficulty participating in traditional site-based trials. Our digital, decentralized trial investigates the efficacy and safety of nirmatrelvir/ritonavir, targeting viral persistence as a potential cause of long COVID. METHODS: The PAX LC trial (NCT05668091) is a Phase 2, 1:1 randomized, double-blind, superiority, placebo-controlled trial in 100 community-dwelling, highly symptomatic adult participants with long COVID residing in the 48 contiguous US states to determine the efficacy, safety, and tolerability of 15 days of nirmatrelvir/ritonavir compared with placebo/ritonavir. Participants are recruited via patient groups, cultural ambassadors, and social media platforms. Medical records are reviewed through a platform facilitating participant-mediated data acquisition from electronic health records nationwide. During the drug treatment, participants complete daily digital diaries using a web-based application. Blood draws for eligibility and safety assessments are conducted at or near participants' homes. The study drug is shipped directly to participants' homes. The primary endpoint is the PROMIS-29 Physical Health Summary Score difference between baseline and Day 28, evaluated by a mixed model repeated measure analysis. Secondary endpoints include PROMIS-29 (Mental Health Summary Score and all items), Modified GSQ-30 with supplemental symptoms questionnaire, COVID Core Outcome Measures for Recovery, EQ-5D-5L (Utility Score and all items), PGIS 1 and 2, PGIC 1 and 2, and healthcare utilization. The trial incorporates immunophenotyping to identify long COVID biomarkers and treatment responders. CONCLUSION: The PAX LC trial uses a novel decentralized design and a participant-centric approach to test a 15-day regimen of nirmatrelvir/ritonavir for long COVID.

Long COVID Characteristics and Experience: A Descriptive Study from the Yale LISTEN Research Cohort.

OBJECTIVE: To describe the experience of people with long COVID symptomatology and characterize the psychological, social, and financial challenges they experience. BACKGROUND: The experience of people with long COVID needs further amplification, especially with a comprehensive focus on symptomatology, treatments, and impact on daily life and finances. METHODS: We collected data from individuals aged 18 and older reporting long COVID as participants in the Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study. The sample population included 441 participants surveyed between May 2022 and July 2023. We evaluated their demographic characteristics, socioeconomic and psychological status, index infection period, health status, quality of life, symptoms, treatments, pre-pandemic comorbidities, and new-onset conditions. RESULTS: Overall, the median age of the participants with long COVID was 46 years (IQR: 38 to 57 years); 74% were women, 86% were Non-Hispanic White, and 93% were from the United States. Participants reported low health status measured by the Euro-QoL visual analogue scale, with a median score of 49 (IQR: 32 to 61). Participants documented a diverse range of symptoms, with all 96 possible symptom choices being reported. Additionally, participants had tried many treatments (median number of treatments: 19, IQR: 12 to 28). They were also experiencing psychological distress, social isolation, and financial stress. CONCLUSIONS: Despite having tried numerous treatments, participants with long COVID continued to experience an array of health and financial challenges-findings that underscore the failure of the healthcare system to address the medical needs of people with long COVID. These insights highlight the need for crucial medical, mental health, financial, and community support services, as well as further scientific investigation, to address the complex impact of long COVID.

Sex differences in symptomatology and immune profiles of Long COVID.

Strong sex differences in the frequencies and manifestations of Long COVID (LC) have been reported with females significantly more likely than males to present with LC after acute SARS-CoV-2 infection 1-7 . However, whether immunological traits underlying LC differ between sexes, and whether such differences explain the differential manifestations of LC symptomology is currently unknown. Here, we performed sex-based multi-dimensional immune-endocrine profiling of 165 individuals 8 with and without LC in an exploratory, cross-sectional study to identify key immunological traits underlying biological sex differences in LC. We found that female and male participants with LC experienced different sets of symptoms, and distinct patterns of organ system involvement, with female participants suffering from a higher symptom burden. Machine learning approaches identified differential sets of immune features that characterized LC in females and males. Males with LC had decreased frequencies of monocyte and DC populations, elevated NK cells, and plasma cytokines including IL-8 and TGF-ß-family members. Females with LC had increased frequencies of exhausted T cells, cytokine-secreting T cells, higher antibody reactivity to latent herpes viruses including EBV, HSV-2, and CMV, and lower testosterone levels than their control female counterparts. Testosterone levels were significantly associated with lower symptom burden in LC participants over sex designation. These findings suggest distinct immunological processes of LC in females and males and illuminate the crucial role of immune-endocrine dysregulation in sex-specific pathology.

Complications of Implanted Vagus Nerve Stimulation: A Systematic Review and Meta-analysis.

INTRODUCTION: Vagus Nerve Stimulation (VNS) has emerged as a promising tool in ischemic stroke rehabilitation. However, there has been no systematic review summarizing its adverse effects, critical information for patients and providers when obtaining informed consent for this novel treatment. This systematic review and meta-analysis reports the adverse effects of VNS. METHODS: A systematic review was performed in accordance with PRISMA guidelines to identify common complications after VNS therapy. The search was executed in: Cochrane Central Register of Controlled Trials, Embase, and Ovid MEDLINE. All prospective, randomized controlled trials using implanted VNS therapy in adult patients were eligible for inclusion. Case studies and studies lacking complete complication reports were excluded. Extracted data included technology name, location of implantation, follow-up duration, purpose of VNS, and adverse event rates. RESULTS: After title-and-abstract screening of 4933 studies, 21 were selected for final inclusion. Across these studies, 1474 patients received VNS implantation. VNS was used as a potential therapy for epilepsy (9), depression (8), anxiety (1), ischemic stroke (1), chronic heart failure (1), and fibromyalgia (1). The 5 most common post-implant adverse events were voice alteration/hoarseness (n=671, 45.5%), paresthesia (n = 233, 15.8%), cough (n = 221, 15.0%), dyspnea (n = 211, 14.3%), and pain (n = 170, 11.5%). CONCLUSIONS: Complications from VNS are mild and transient, with reduction in severity and number of adverse events with increasing follow-up time. In prior studies, VNS has served as treatment option in several instances of treatment-resistant conditions, such as epilepsy and psychiatric conditions, and its use in stroke recovery and rehabilitation should continue to be explored.

Vagus nerve stimulation for enhanced stroke recovery after intracerebral hemorrhage: illustrative case.

BACKGROUND: Randomized controlled trial (RCT) evidence has revealed the efficacy of vagus nerve stimulation (VNS) paired with rehabilitation therapy, over therapy alone, for upper-limb functional recovery after ischemic stroke. However, this technique has not yet been described for the recovery of chronic motor deficits after hemorrhagic stroke. OBSERVATIONS: Three years after left putaminal intracerebral hemorrhagic stroke with chronic upper-limb functional deficits, a patient was treated with VNS for enhanced stroke recovery. VNS was paired with 6 weeks of in-clinic physical therapy, resulting in upper-limb functional improvement of 14 points on the Fugl-Meyer Assessment Upper Extremity (FMA-UE) index for stroke recovery (maximum score of 66 equating to normal function). This improvement was more than 1 standard deviation above the improvement documented in the first successful RCT of VNS paired with therapy for ischemic stroke (5.0 ± 4.4 improvement on FMA-UE). LESSONS: VNS is a promising therapy for enhanced recovery after hemorrhagic stroke and may offer greater improvement in function compared to that after ischemic stroke. Improvement in function can occur years after the time of intracerebral hemorrhage.

Efficacy and safety of using auditory-motor entrainment to improve walking after stroke: a multi-site randomized controlled trial of InTandemTM.

Walking slowly after stroke reduces health and quality of life. This multi-site, prospective, interventional, 2-arm randomized controlled trial (NCT04121754) evaluated the safety and efficacy of an autonomous neurorehabilitation system (InTandemTM) designed to use auditory-motor entrainment to improve post-stroke walking. 87 individuals were randomized to 5-week walking interventions with InTandem or Active Control (i.e., walking without InTandem). The primary endpoints were change in walking speed, measured by the 10-meter walk test pre-vs-post each 5-week intervention, and safety, measured as the frequency of adverse events (AEs). Clinical responder rates were also compared. The trial met its primary endpoints. InTandem was associated with a 2x larger increase in speed (Δ: 0.14 ± 0.03 m/s versus Δ: 0.06 ± 0.02 m/s, F(1,49) = 6.58, p = 0.013), 3x more responders (40% versus 13%, χ2(1) ≥ 6.47, p = 0.01), and similar safety (both groups experienced the same number of AEs). The auditory-motor intervention autonomously delivered by InTandem is safe and effective in improving walking in the chronic phase of stroke.

Relationships between body composition, anthropometrics, and standard lipid panels in a normative population.

Introduction: More than one third of adults in the United States (US) meet the clinical criteria for a diagnosis of metabolic syndrome, but often diagnosis is challenging due to healthcare access, costs and discomfort with the process and invasiveness associated with a standard medical examination. Less invasive and more accessible approaches to collecting biometric data may have utility in identifying individuals at risk of diagnoses, such as metabolic syndrome or dyslipidemia diagnoses. Body composition is one such source of biometric data that can be non-invasively acquired in a home or community setting that may provide insight into an individual's propensity for a metabolic syndrome diagnosis. Here we investigate possible associations between body composition, anthropometrics and lipid panels in a normative population. Methods: Healthy participants visited the Lab100 clinic location at a hospital setting in New York City and engaged in a wellness visit led by a nurse practitioner. Blood was analyzed at point-of-care using the Abbott Piccolo Xpress portable diagnostic analyzer (Abbott Laboratories, IL, USA) and produced direct measures of total cholesterol (TC), high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), very-low density lipoprotein (VLDL-C), and triglycerides (TG). Body composition and anthropometric data were collected using two separate pieces of equipment during the same visit (Fit3D and InBody570). Regression analysis was performed to evaluate associations between all variables, after adjusting for age, sex, race, AUDIT-C total score (alcohol use), and current smoking status. Results: Data from 199 participants were included in the analysis. After adjusting for variables, percentage body fat (%BF) and visceral fat levels were significantly associated with every laboratory lipid value, while waist-to-hip ratio also showed some significant associations. The strongest associations were detected between %BF and VLDL-C cholesterol levels (t = 4.53, p = 0.0001) and Triglyceride levels (t = 4.51, p = 0.0001). Discussion: This initial, exploratory analysis shows early feasibility in using body composition and anthropometric data, that can easily be acquired in community settings, to identify people with dyslipidemia in a normative population.

Retrospective case-control study to compare exoskeleton-assisted walking with standard care in subacute non-traumatic brain injury patients.

BACKGROUND: Advanced technologies are increasingly used to address impaired mobility after neurological insults, with growing evidence of their benefits for various populations. However, certain robotic devices have not been extensively investigated in specific conditions, limiting knowledge about optimal application for healthcare. OBJECTIVE: To compare effectiveness of conventional gait training with exoskeleton-assisted walking for non-traumatic brain injury during early stage rehabilitation. METHODS: Clinical evaluation data at admission and discharge were obtained in a retrospective case-control design. Patients received standard of care physical therapy either using Ekso GT or not. Within- or between-group statistical tests were performed to determine change over time and interventional differences. RESULTS: This study analyzed forty-nine individuals (33% female), 20 controls and 29 Ekso participants who were equivalent at baseline. Both groups improved in Functional Independence Measure scores and ambulation ability (p < .00001 and p < .001, respectively). Control subjects demonstrated significantly different distance walked and assistance level values at discharge from those who were treated with the exoskeleton (p < .01). CONCLUSION: Robotic locomotion is non-inferior for subacute functional recovery after non-traumatic brain injury. Conventional therapy produced larger gait performance gains during hospitalization. Further research is needed to understand specific factors influencing efficacy and the long-term implications after rehabilitation.

Dysautonomia, but Not Cardiac Dysfunction, Is Common in a Cohort of Individuals with Long COVID.

Despite the prevalence of dysautonomia in people with Long COVID, it is currently unknown whether Long COVID dysautonomia is routinely accompanied by structural or functional cardiac alterations. In this retrospective observational study, the presence of echocardiographic abnormalities was assessed. Left ventricular (LV) chamber sizes were correlated to diagnostic categories and symptoms via standardized patient-reported outcome (PRO) questionnaires. A total of 203 individuals with Long COVID without pre-existing cardiac disease and with available echocardiograms were included (mean age, 45 years; 67% female). Overall, symptoms and PRO scores for fatigue, breathlessness, quality of life, disability, anxiety and depression were not different between those classified with post-COVID dysautonomia (PCD, 22%) and those unclassified (78%). An LV internal diameter at an end-diastole z score < -2 was observed in 33 (16.5%) individuals, and stroke volume (SV) was lower in the PCD vs. unclassified subgroup (51.6 vs. 59.2 mL, 95% C.I. 47.1-56.1 vs. 56.2-62.3). LV end-diastolic volume (mean diff. (95% CI) -13 [-1--26] mL, p = 0.04) and SV (-10 [-1--20] mL, p = 0.03) were smaller in those individuals reporting a reduction in physical activity post-COVID-19 infection, and smaller LVMI was weakly correlated with worse fatigue (r = 0.23, p = 0.02). The majority of individuals with Long COVID report shared symptoms and did not demonstrate cardiac dysfunction on echocardiography.

Post-Vaccination Syndrome: A Descriptive Analysis of Reported Symptoms and Patient Experiences After Covid-19 Immunization.

Introduction: A chronic post-vaccination syndrome (PVS) after covid-19 vaccination has been reported but has yet to be well characterized. Methods: We included 241 individuals aged 18 and older who self-reported PVS after covid-19 vaccination and who joined the online Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study from May 2022 to July 2023. We summarized their demographics, health status, symptoms, treatments tried, and overall experience. Results: The median age of participants was 46 years (interquartile range [IQR]: 38 to 56), with 192 (80%) identifying as female, 209 (87%) as non-Hispanic White, and 211 (88%) from the United States. Among these participants with PVS, 127 (55%) had received the BNT162b2 [Pfizer-BioNTech] vaccine, and 86 (37%) received the mRNA-1273 [Moderna] vaccine. The median time from the day of index vaccination to symptom onset was three days (IQR: 1 day to 8 days). The time from vaccination to symptom survey completion was 595 days (IQR: 417 to 661 days). The median Euro-QoL visual analogue scale score was 50 (IQR: 39 to 70). The five most common symptoms were exercise intolerance (71%), excessive fatigue (69%), numbness (63%), brain fog (63%), and neuropathy (63%). In the week before survey completion, participants reported feeling unease (93%), fearfulness (82%), and overwhelmed by worries (81%), as well as feelings of helplessness (80%), anxiety (76%), depression (76%), hopelessness (72%), and worthlessness (49%) at least once. Participants reported a median of 20 (IQR: 13 to 30) interventions to treat their condition. Conclusions: In this study, individuals who reported PVS after covid-19 vaccination had low health status, high symptom burden, and high psychosocial stress despite trying many treatments. There is a need for continued investigation to understand and treat this condition.

Distinguishing features of long COVID identified through immune profiling.

Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2-4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.

SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC).

Millions of people are suffering from Long COVID or post-acute sequelae of COVID-19 (PASC). Several biological factors have emerged as potential drivers of PASC pathology. Some individuals with PASC may not fully clear the coronavirus SARS-CoV-2 after acute infection. Instead, replicating virus and/or viral RNA-potentially capable of being translated to produce viral proteins-persist in tissue as a 'reservoir'. This reservoir could modulate host immune responses or release viral proteins into the circulation. Here we review studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir in PASC samples. Mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology, including coagulation, microbiome and neuroimmune abnormalities, are delineated. We identify research priorities to guide the further study of a SARS-CoV-2 reservoir in PASC, with the goal that clinical trials of antivirals or other therapeutics with potential to clear a SARS-CoV-2 reservoir are accelerated.

Spatiotemporal parameters from remote smartphone-based gait analysis are associated with lower extremity functional scale categories.

Objective: Self-report tools are recommended in research and clinical practice to capture individual perceptions regarding health status; however, only modest correlations are found with performance-based results. The Lower Extremity Functional Scale (LEFS) is one well-validated measure of impairment affecting physical activities that has been compared with objective tests. More recently, mobile gait assessment software can provide comprehensive motion tracking output from ecologically valid environments, but how this data relates to subjective scales is unknown. Therefore, the association between the LEFS and walking variables remotely collected by a smartphone was explored. Methods: Proprietary algorithms extracted spatiotemporal parameters detected by a standard integrated inertial measurement unit from 132 subjects enrolled in physical therapy for orthopedic or neurological rehabilitation. Users initiated ambulation recordings and completed questionnaires through the OneStep digital platform. Discrete categories were created based on LEFS score cut-offs and Analysis of Variance was applied to estimate the difference in gait metrics across functional groups (Low-Medium-High). Results: The main finding of this cross-sectional retrospective study is that remotely-collected biomechanical walking data are significantly associated with individuals' self-evaluated function as defined by LEFS categorization (n = 132) and many variables differ between groups. Velocity was found to have the strongest effect size. Discussion: When patients are classified according to subjective mobility level, there are significant differences in quantitative measures of ambulation analyzed with smartphone-based technology. Capturing real-time information about movement is important to obtain accurate impressions of how individuals perform in daily life while understanding the relationship between enacted activity and relevant clinical outcomes.

The digital motor output: a conceptual framework for a meaningful clinical performance metric for a motor neuroprosthesis.

In recent years, the majority of the population has become increasingly reliant on continuous and independent control of smart devices to conduct activities of daily living. Upper extremity movement is typically required to generate the motor outputs that control these interfaces, such as rapidly and accurately navigating and clicking a mouse, or activating a touch screen. For people living with tetraplegia, these abilities are lost, significantly compromising their ability to interact with their environment. Implantable brain computer interfaces (BCIs) hold promise for restoring lost neurologic function, including motor neuroprostheses (MNPs). An implantable MNP can directly infer motor intent by detecting brain signals and transmitting the motor signal out of the brain to generate a motor output and subsequently control computer actions. This physiological function is typically performed by the motor neurons in the human body. To evaluate the use of these implanted technologies, there is a need for an objective measurement of the effectiveness of MNPs in restoring motor outputs. Here, we propose the concept of digital motor outputs (DMOs) to address this: a motor output decoded directly from a neural recording during an attempted limb or orofacial movement is transformed into a command that controls an electronic device. Digital motor outputs are diverse and can be categorized as discrete or continuous representations of motor control, and the clinical utility of the control of a single, discrete DMO has been reported in multiple studies. This sets the stage for the DMO to emerge as a quantitative measure of MNP performance.

Post-COVID Conditions and Burden of Disease.

Post-COVID condition (PCC), also known as long COVID, is a multi-systemic illness estimated to affect 10% to 20% of those infected, regardless of age, baseline health status, or initial symptom severity. PCC has affected millions of lives, with long-lasting debilitating effects, but unfortunately it remains an underrecognized and therefore poorly documented condition. Defining and disseminating the burden of PCC is essential for developing effective public health strategies to address this issue in the long term.

Long COVID: pathophysiological factors and abnormalities of coagulation.

Acute COVID-19 infection is followed by prolonged symptoms in approximately one in ten cases: known as Long COVID. The disease affects ~65 million individuals worldwide. Many pathophysiological processes appear to underlie Long COVID, including viral factors (persistence, reactivation, and bacteriophagic action of SARS CoV-2); host factors (chronic inflammation, metabolic and endocrine dysregulation, immune dysregulation, and autoimmunity); and downstream impacts (tissue damage from the initial infection, tissue hypoxia, host dysbiosis, and autonomic nervous system dysfunction). These mechanisms culminate in the long-term persistence of the disorder characterized by a thrombotic endothelialitis, endothelial inflammation, hyperactivated platelets, and fibrinaloid microclots. These abnormalities of blood vessels and coagulation affect every organ system and represent a unifying pathway for the various symptoms of Long COVID.

Engagement in an mHealth-Guided Exercise Therapy Program Is Associated With Reductions in Chronic Musculoskeletal Pain.

CONTEXT: Chronic musculoskeletal pain costs the US $980 billion annually. Conservative treatments are the criterion standard, but scalable methods of treatment remain to be evaluated. OBJECTIVE: The aim of the study is to determine the effects of pain reduction and the perceived benefits of an mHealth exercise therapy program. DESIGN: This is a retrospective observational study on data from 3109 people (18-98, 49% female) with musculoskeletal pain in an mHealth exercise program. Presession pain was measured via 11-point numeric rating scale and nonstandardized single-item questions for work and quality of life; all were analyzed using mixed-effects models. RESULTS: By 11 sessions, there was an estimated a 2.09-point decrease in average numeric rating scale pain levels. There was an average percent increase of approximately 0.7 points for work life and quality of life ( tdf =6,632 = 12.06, P < 0.001). User engagement was high; 46% of participants were performing more than one session per day, and 88% were engaging within a week, indicating the feasibility of the deployment of an mHealth exercise app. CONCLUSIONS: An mHealth exercise program was associated with significant decrease in pain and increased perceived benefits in a large population. These findings serve as preliminary findings of the feasibility for mHealth exercise interventions as scalable tools to improve chronic musculoskeletal pain outcomes.