A methylation clock model of mild SARS-CoV-2 infection provides insight into immune dysregulation.

DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly symptomatic SARS-CoV-2 infection. The differential methylation caused by asymptomatic or mildly symptomatic infections was indistinguishable. While differential gene expression largely returned to baseline levels after the virus became undetectable, some differentially methylated sites persisted for months of follow-up, with a pattern resembling autoimmune or inflammatory disease. We leveraged these responses to construct methylation-based machine learning models that distinguished samples from pre-, during-, and postinfection time periods, and quantitatively predicted the time since infection. The clinical trajectory in the young adults and in a diverse cohort with more severe outcomes was predicted by the similarity of methylation before or early after SARS-CoV-2 infection to the model-defined postinfection state. Unlike the phenomenon of trained immunity, the postacute SARS-CoV-2 epigenetic landscape we identify is antiprotective.

Priorities for HIV and chronic pain research: results from a survey of individuals with lived experience.

The Global Task Force on Chronic Pain in HIV published seven research priorities in the field of HIV-associated chronic pain in 2019: (1) causes; (2) management; (3) treatment individualization and integration with addiction treatment; (4) mental and social health factors; (5) prevalence; (6) treatment cost effectiveness; and (7) prevention. The current study used a web-based survey to determine whether the research topics were aligned with the priorities of adults with lived experiences of HIV and chronic pain. We also collected information about respondents' own pain and treatment experiences. We received 311 survey responses from mostly US-based respondents. Most respondents reported longstanding, moderate to severe, multisite pain, commonly accompanied by symptoms of anxiety and/or depression. The median number of pain treatments tried was 10 (IQR = 8, 13), with medications and exercise being the most common modalities, and opioids being viewed as the most helpful. Over 80% of respondents considered all research topics either "extremely important" or "very important". Research topic #2, which focused on optimizing management of pain in people with HIV, was accorded the greatest importance by respondents. These findings suggest good alignment between the priorities of researchers and US-based people with lived experience of HIV-associated chronic pain.

SARS-CoV-2 Transmission among Marine Recruits during Quarantine.

BACKGROUND: The efficacy of public health measures to control the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been well studied in young adults. METHODS: We investigated SARS-CoV-2 infections among U.S. Marine Corps recruits who underwent a 2-week quarantine at home followed by a second supervised 2-week quarantine at a closed college campus that involved mask wearing, social distancing, and daily temperature and symptom monitoring. Study volunteers were tested for SARS-CoV-2 by means of quantitative polymerase-chain-reaction (qPCR) assay of nares swab specimens obtained between the time of arrival and the second day of supervised quarantine and on days 7 and 14. Recruits who did not volunteer for the study underwent qPCR testing only on day 14, at the end of the quarantine period. We performed phylogenetic analysis of viral genomes obtained from infected study volunteers to identify clusters and to assess the epidemiologic features of infections. RESULTS: A total of 1848 recruits volunteered to participate in the study; within 2 days after arrival on campus, 16 (0.9%) tested positive for SARS-CoV-2, 15 of whom were asymptomatic. An additional 35 participants (1.9%) tested positive on day 7 or on day 14. Five of the 51 participants (9.8%) who tested positive at any time had symptoms in the week before a positive qPCR test. Of the recruits who declined to participate in the study, 26 (1.7%) of the 1554 recruits with available qPCR results tested positive on day 14. No SARS-CoV-2 infections were identified through clinical qPCR testing performed as a result of daily symptom monitoring. Analysis of 36 SARS-CoV-2 genomes obtained from 32 participants revealed six transmission clusters among 18 participants. Epidemiologic analysis supported multiple local transmission events, including transmission between roommates and among recruits within the same platoon. CONCLUSIONS: Among Marine Corps recruits, approximately 2% who had previously had negative results for SARS-CoV-2 at the beginning of supervised quarantine, and less than 2% of recruits with unknown previous status, tested positive by day 14. Most recruits who tested positive were asymptomatic, and no infections were detected through daily symptom monitoring. Transmission clusters occurred within platoons. (Funded by the Defense Health Agency and others.).

SARS-CoV-2 Outbreak Dynamics in an Isolated US Military Recruit Training Center With Rigorous Prevention Measures.

BACKGROUND: Marine recruits training at Parris Island experienced an unexpectedly high rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite preventive measures including a supervised, 2-week, pre-entry quarantine. We characterize SARS-CoV-2 transmission in this cohort. METHODS: Between May and November 2020, we monitored 2,469 unvaccinated, mostly male, Marine recruits prospectively during basic training. If participants tested negative for SARS-CoV-2 by quantitative polymerase chain reaction (qPCR) at the end of quarantine, they were transferred to the training site in segregated companies and underwent biweekly testing for 6 weeks. We assessed the effects of coronavirus disease 2019 (COVID-19) prevention measures on other respiratory infections with passive surveillance data, performed phylogenetic analysis, and modeled transmission dynamics and testing regimens. RESULTS: Preventive measures were associated with drastically lower rates of other respiratory illnesses. However, among the trainees, 1,107 (44.8%) tested SARS-CoV-2-positive, with either mild or no symptoms. Phylogenetic analysis of viral genomes from 580 participants revealed that all cases but one were linked to five independent introductions, each characterized by accumulation of mutations across and within companies, and similar viral isolates in individuals from the same company. Variation in company transmission rates (mean reproduction number R 0 ; 5.5 [95% confidence interval [CI], 5.0, 6.1]) could be accounted for by multiple initial cases within a company and superspreader events. Simulations indicate that frequent rapid-report testing with case isolation may minimize outbreaks. CONCLUSIONS: Transmission of wild-type SARS-CoV-2 among Marine recruits was approximately twice that seen in the community. Insights from SARS-CoV-2 outbreak dynamics and mutations spread in a remote, congregate setting may inform effective mitigation strategies.

Toward safer opioid prescribing: effects of the TOWER intervention on HIV care providers.

ABSTRACTRates of opioid use disorder and associated deaths remain alarmingly high. Measures to address the epidemic have included reductions in opioid prescribing, in part guided by the Centers for Disease Control Opioid Prescribing Guideline (CDCG). While reductions in over-prescribing have occurred, these measures have also resulted in decreased access and adverse outcomes for some stable opioid-treated chronic pain patients. The TOWard SafER Opioid Prescribing (TOWER) intervention was designed to support HIV primary care providers in use of the CDCG and in decision-making and patient-provider communication regarding safe opioid prescribing. Eleven HIV primary care providers and 40 of their patients were randomized into intervention and control groups. Transcripts from 21 patient visits were analyzed, focusing on opioid and pain-related communications. Findings from this research indicate greater alignment with the CDCG among visits carried out with providers in the TOWER intervention group. However, control group visits were notably consistent with guideline recommendations in several key areas. Differences observed between the intervention and control group visits demonstrate intervention strengths, as well as areas where additional work needs to be done to ensure prescribing and communication consistent with the CDCG.

Patient recommendations for opioid prescribing in the context of HIV care: findings from a set of public deliberations.

It is widely acknowledged that the growing opioid epidemic and associated increase in overdose deaths necessitates a reexamination of processes and procedures related to an opioid prescription for the treatment of chronic pain. However, the perspectives of patients, including those at the highest risk for opioid-related harms, are largely missing from this reexamination. To partially address the gap, we conducted a pair of one-day public deliberations on opioid prescribing in the context of HIV care. Results included recommendations and perspectives from people living with HIV that detail how providers can best assess patient needs, communicate regarding opioids, and reduce the risk of misuse. Participants emphasized the importance of building trust with patients and taking an extensive patient history prior to making decisions about whether to initiate or end an opioid prescription. This trust - together with an understanding of the origin of a patient's pain, history of drug use and other therapies tried - was perceived as essential to effective monitoring and pain management, as well as promotion of positive health outcomes. Ensuring that such patient perspectives are incorporated into the operationalization of guidelines for safe opioid prescribing may help to improve outcomes and quality of care for people living with HIV.

Validation of the Safer Opioid Prescribing Evaluation Tool (SOPET) for Assessing Adherence to the Centers for Disease Control Opioid Prescribing Guidelines.

OBJECTIVE: In response to the opioid epidemic, the Centers for Disease Control and Prevention issued guidelines (CDCG) in 2016 for the prescription of opioids for chronic pain. To facilitate research into whether CDCG implementation will lead to reductions in opioid prescribing and improved patient safety, we sought to validate a tool that quantifies CDCG adherence based on clinical documentation. DESIGN: The Safe Opioid Prescribing Evaluation Tool (SOPET) was developed in four phases as part of a study to improve the implementation of the CDCG in the clinical setting. Four raters with varying levels of clinical experience and expertise were trained to use the SOPET and then used it to evaluate 21 baseline patient encounters. Intraclass correlation coefficient (ICC) estimates and their 95% confident intervals (CIs) were calculated for the total SOPET score based on a mean-rating (k = 4), absolute-agreement, two-way random-effects model. For intrarater reliability, two-way mixed-effect models were used. RESULTS: Inter-rater reliability was good, with an average-measures ICC of 0.82 (95% CI = 0.63-0.92). Intrarater reliability was excellent for the three raters, who were MDs, with average-measures ICCs as follows: 0.92 (95% CI = 0.81-0.97), 0.97 (95% CI = 0.92-0.99), 0.99 (95% CI = 0.99-0.99). However, the intrarater reliability for the non-MD rater was lower 0.69 (95% CI = 0.22-0.88). CONCLUSIONS: Overall, the SOPET is useful for evaluating implementation of the CDCG in clinical documentation. It is an important first step in the design of future studies assessing whether adherence to the CDCG improves patient safety outcomes.

The effect of pyridostigmine on small intestinal bacterial overgrowth (SIBO) and plasma inflammatory biomarkers in HIV-associated autonomic neuropathies.

Small intestinal bacterial overgrowth (SIBO) is common among patients with HIV-associated autonomic neuropathies (HIV-AN) and may be associated with increased bacterial translocation and elevated plasma inflammatory biomarkers. Pyridostigmine is an acetylcholinesterase inhibitor which has been used to augment autonomic signaling. We sought preliminary evidence as to whether pyridostigmine could improve proximal gastrointestinal motility, reduce SIBO, reduce plasma sCD14 (a marker of macrophage activation and indirect measure of translocation), and reduce the inflammatory cytokines IL-6 and TNFα in patients with HIV-AN. Fifteen participants with well-controlled HIV, HIV-AN, and SIBO were treated with 8 weeks of pyridostigmine (30 mg PO TID). Glucose breath testing for SIBO, gastric emptying studies (GES) to assess motility, plasma sCD14, IL-6, and TNFα, and gastrointestinal autonomic symptoms were compared before and after treatment. Thirteen participants (87%) experienced an improvement in SIBO following pyridostigmine treatment; with an average improvement of 50% (p = 0.016). There was no change in gastrointestinal motility; however, only two participants met GES criteria for gastroparesis at baseline. TNFα and sCD14 levels declined by 12% (p = 0.004) and 19% (p = 0.015), respectively; there was no significant change in IL-6 or gastrointestinal symptoms. Pyridostigmine may ameliorate SIBO and reduce levels of sCD14 and TNFα in patients with HIV-AN. Larger placebo-controlled studies are needed to definitively delineate how HIV-AN affects gastrointestinal motility, SIBO, and systemic inflammation in HIV, and whether treatment improves clinical outcomes.

Comorbid Pain Syndromes in HIV-Associated Peripheral Neuropathy.

Objective: Peripheral neuropathy (PN) is a common complication of HIV. There is increasing awareness that some forms of PN, particularly small-fiber neuropathies, can be associated with chronic widespread pain syndromes. Given the high prevalence of both PN and chronic pain in HIV, we sought to determine whether patients with a diagnosis of HIV-PN were more likely to experience other chronic pain syndromes. Methods: Data were obtained from the Clinical Data Warehouse maintained by our institution. All HIV-infected patients receiving standard of care antiretroviral therapy in our institution's primary care HIV clinic (N = 638) were included. Diagnoses of HIV-PN and other chronic pain disorders were established based on clinician-assigned ICD-9/10 codes. Results: Sixty-eight patients (11%) had a diagnosis of HIV-PN. Patients with HIV-PN were more than twice as likely to have other chronic pain disorders (66% vs 32%, χ2 = 30.3, P < 0.001). Patients with HIV-PN were also older and more likely to have substance use and psychiatric disorders; however, the association of HIV-PN with other chronic pain disorders persisted after adjusting for relevant confounders (χ2(5) = 81.38, P < 0.001). Conclusions: Patients with HIV-PN commonly experience other chronic pain disorders. Clinicians managing HIV-PN should seek a broad understanding of patients' pain experience as this may alter management strategies. Researchers studying HIV-PN should consider how the presence of other pain disorders might affect outcomes.

Assessment of autonomic symptoms in a medically complex, urban patient population.

PURPOSE: Urban, minority communities are disproportionately affected by the chronic diseases associated with autonomic neuropathy; however validated measures of autonomic symptoms have not been studied in these complex populations. We sought to validate the Autonomic Symptom Profile (ASP) in a low income, medically complex, urban patient population. METHODS: Ninety-seven adults were recruited from the outpatient neurology clinic of an academic medical center serving the East Harlem neighborhood of New York City. Participants completed the ASP, and underwent a comprehensive neurologic examination, and a standardized battery of autonomic function tests (quantitative sweat testing, heart rate response to deep breathing (HRDB), Valsalva maneuver, and tilt table). Burden of chronic disease was summarized using the Charlson co-morbidity index (CCI), and detailed medication history was obtained. RESULTS: The ASP displayed good internal consistency (Cronbach's α = .88), even among lower literacy participants. In univariate analyses, the ASP was correlated with HRDB (r = -.301, p = .002), a marker of cardiac autonomic neuropathy, with the CCI (r = .37, p < .001), and with use of medications with autonomic effects [t(95) = -2.13, p = .036]. However, in multivariate analysis, only the CCI remained significant. CONCLUSIONS: In this urban, predominantly minority patient population, the symptoms captured by the ASP were more closely associated with burden of medical disease than with autonomic dysfunction. Due to this lack of specificity, it is essential that results from autonomic questionnaires be interpreted in the context of the neurologic history and exam, burden of co-morbid illness and medications, and most importantly autonomic function tests.

A Mixed-Methods Pilot Study of Mindfulness-Based Stress Reduction for HIV-Associated Chronic Pain.

Treatment guidelines for chronic pain recommend nonpharmacologic modalities as part of a comprehensive management plan. Chronic pain is common among people living with HIV/AIDS, but there is little data to guide the choice of nonpharmacologic therapies in this complex population. We performed a mixed-methods feasibility study of Mindfulness-Based Stress Reduction (MBSR) versus health education control with 32 inner city, HIV-infected participants. Outcome measures included: the Brief Pain Inventory, Perceived Stress Scale, HIV Symptoms Index, autonomic function testing, and audiotaped focus groups. Post-intervention, participants reported modest improvements in pain measures and perceived stress, but no effect of group assignment was observed. At 3-month follow-up, 79% of MBSR participants were still practicing, and pain intensity was improved, whereas in the control group pain intensity had worsened. Qualitative analysis revealed a strong sense of community in both groups, but only MBSR was perceived as useful for relaxation and pain relief.

Barriers to Chronic Pain Measurement: A Qualitative Study of Patient Perspectives.

OBJECTIVE: Preliminary evidence suggests that chronic pain patients complete pain intensity measures using idiosyncratic methods. Our objective was to understand these methods and how they might impact the psychometric properties of the instruments. DESIGN: A qualitative focus-group based study. SETTING: An academic center in New York City. SUBJECTS: Outpatients (n = 36) with chronic low back pain, or neuropathic pain due to diabetes or HIV. METHODS: Participants were divided into three focus groups based on their pain condition, and asked to discuss pain intensity measures (visual analog and numeric rating scales for average pain over 24 hours; Brief Pain Inventory; and McGill Pain Questionnaire). Audio-recordings were transcribed and analyzed using an inductive thematic method. RESULTS: We discovered four main themes, and five sub-themes: 1) doubt that pain can be accurately measured (subthemes: pain measurement is influenced by things other than pain, the numbers used to rate pain do not have an absolute meaning, and preference for pain intensity ratings "in the middle" of the scale); 2) confusion regarding the definition of pain; 3) what experiences to use as referents (subthemes: appropriate comparator experiences and the interpretation of the anchors of the scale); and 4) difficulty averaging pain. CONCLUSIONS: The themes discovered suggest that patients include sensations and experiences other than pain intensity in their ratings, experience the rating of pain as a comparative task, and do not use the scale in a linear manner. These themes are relevant to understanding the validity and scale properties of commonly used pain intensity measures.

Incobotulinum Toxin-A in Professional Musicians with Focal Task-Specific Dystonia: A Double Blind, Placebo Controlled, Cross-Over Study.

Background: Musician's focal task-specific dystonia is a complex disorder of fine motor control, with incomplete understanding of its etiology. There have been relatively few trials of botulinum toxin in upper limb task-specific dystonia, and prior studies have yielded variable results, leading to skepticism regarding the utility of this approach in elite performers. Methods: We conducted a double-blind, placebo-controlled, randomized, cross-over study of incobotulinum toxin-A in 21 professional musicians with focal upper extremity task-specific dystonia affecting performance on their instrument, using a novel paradigm of initial injections followed by booster injections at two- and four-week intervals. The primary outcome measure was the change in blinded dystonia rating of the active arm by two expert raters using a Clinical Global Impression numeric scale at week 8 compared to enrollment. Findings: 19 men and 2 women with musicians' dystonia were enrolled over a six-year period. Nineteen patients completed the study. Analysis of the primary outcome measure in comparison to baseline revealed a change in dystonia severity of P = 0.04 and an improvement in overall musical performance of P = 0.027. No clinically significant weakness was observed, and neutralizing antibodies to toxin were not found. Interpretation: Despite its small sample size, our study demonstrated a statistically significant benefit of incobotulinum toxin-A injections as a treatment for musicians' task-specific dystonia. Tailoring the use of toxin with booster injections allowed refinement of dosing strategy and outcomes, with benefits that were meaningful to patients clearly visible on videotaped evaluations. In addition to its application to musicians' dystonia, this approach may have relevance to optimize application of botulinum toxin in other forms of focal dystonia such as blepharospasm, cervical dystonia, writer's cramp, and spasmodic dysphonia.

Hypnosis for treatment of HIV neuropathic pain: a preliminary report.

OBJECTIVE: Painful HIV distal sensory polyneuropathy (HIV-DSP) is the most common nervous system disorder in HIV patients. The symptoms adversely affect patients' quality of life and often diminish their capacity for independent self-care. No interventions have been shown to be consistently effective in treating the disorder. The purpose of the present study was to determine whether hypnosis could be a useful intervention in the management of painful HIV-DSP. METHOD: Participants were 36 volunteers with HIV-DSP who received three weekly training sessions in self-hypnosis. Participants were followed for pain and its sequelae for 7 weeks prior to the intervention, and for 7 weeks postintervention. Participants remained on the same standard-of-care pain regimen for the entire 17 weeks of the protocol. The primary outcome measure was the Short Form McGill Pain Questionnaire cale (SFMPQ) total pain score. Other outcome measures assessed changes in affective state and quality of life. RESULTS: Mean SFMPQ total pain scores were reduced from 17.8 to 13.2 (F[1, 35] = 16.06, P < 0.001). The reductions were stable throughout the 7-week postintervention period. At exit, 26 out of 36 (72%) had improved pain scores. Of the 26 who improved, mean pain reduction was 44%. Improvement was found irrespective of whether or not participants were taking pain medications. There was also evidence for positive changes in measures of affect and quality of life. CONCLUSION: Brief hypnosis interventions have promise as a useful and well-tolerated tool for managing painful HIV-DSP meriting further investigation.

Mapping disease regulatory circuits at cell-type resolution from single-cell multiomics data.

Resolving chromatin-remodeling-linked gene expression changes at cell-type resolution is important for understanding disease states. Here we describe MAGICAL (Multiome Accessibility Gene Integration Calling and Looping), a hierarchical Bayesian approach that leverages paired single-cell RNA sequencing and single-cell transposase-accessible chromatin sequencing from different conditions to map disease-associated transcription factors, chromatin sites, and genes as regulatory circuits. By simultaneously modeling signal variation across cells and conditions in both omics data types, MAGICAL achieved high accuracy on circuit inference. We applied MAGICAL to study Staphylococcus aureus sepsis from peripheral blood mononuclear single-cell data that we generated from subjects with bloodstream infection and uninfected controls. MAGICAL identified sepsis-associated regulatory circuits predominantly in CD14 monocytes, known to be activated by bacterial sepsis. We addressed the challenging problem of distinguishing host regulatory circuit responses to methicillin-resistant and methicillin-susceptible S. aureus infections. Although differential expression analysis failed to show predictive value, MAGICAL identified epigenetic circuit biomarkers that distinguished methicillin-resistant from methicillin-susceptible S. aureus infections.

Disparities in telehealth utilization in patients with pain during COVID-19.

Introduction: The shift from in-person visits to telehealth visits during the COVID-19 pandemic presented unique challenges for patients with pain. Disparities in health care access already existed, and the impact of telehealth on these inequities has not been studied. Objectives: To identify sociodemographic characteristics of patients with pain obtaining care through video, telephone, and in-person visits as social distancing restrictions evolved during the COVID-19 pandemic. Methods: Using our institutional clinical data warehouse, we identified 3314 patients with pain receiving care at a large academic institution in New York City during a baseline period (September 23, 2019-March 22, 2020) and counted telephone, video, and in-person visits during the following conditions: a shutdown period (March 23, 2020-May 23, 2020), when nonessential in-person visits were strictly limited, and a reopening period (May 23, 2020-September 23, 2020), when restrictions were relaxed and in-person visits were available. Patients were categorized into 4 groups based on the technology used to complete a visit: (1) video, (2) telephone, (3) in-person, and (4) no visit. Results: Patients who were older, publicly insured, and identified as Black or Hispanic were overrepresented in the telephone visit group during shutdown and the in-person group during reopening. A video visit during shutdown increased the likelihood of continued video visit use during reopening despite the return of in-person visits. Conclusions: Results show differences in how patients with pain accessed clinical care in a socially distanced world and that flexibility in method of health care delivery may reduce barriers to access. Future research will identify factors (eg, Internet access, digital literacy, provider-patient relationships) driving heterogeneity in telehealth use in patients with pain.

Comparison of Ultrasound and Electrical Stimulation Guidance for Onabotulinum Toxin-A Injections: A Randomized Crossover Study.

Background: Botulinum neurotoxin (BoNT) injection is an established therapy for limb spasticity and focal limb dystonia. Comparative benefits of injection guidance procedures have not been rigorously studied. Objectives: We compared 2 targeting techniques for onabotulinumtoxin-A (onabotA) injection for the treatment of focal hand dystonia and upper limb spasticity: electrophysiologic guidance using electrical stimulation (E-stim) and ultrasound (US). Methods: This was a 2-center, randomized, crossover, assessor-blinded trial. Participants with focal hand dystonia or upper limb spasticity, on stable onabotA therapy for at least 2 previous injection cycles, were randomly assigned to either E-stim or US with crossover at 3 months. The primary outcome was improvement in dystonia or spasticity severity on a visual analog scale (VAS; 0-100) measured 1 month after each injection. The secondary outcome was participant discomfort assessed on a VAS. Repeated-measures analysis of covariance was used with linear mixed-model covariate selection. Results: A total of 19 participants (13 men) completed the study, 10 with upper limb spasticity and 9 with dystonia. Benefit was equivalent between the 2 techniques (VAS least-square mean [LSmean] 51.5 mm with US and 53.1 with E-stim). E-stim was perceived as more uncomfortable by participants (VAS LSmean 34.5 vs. 19.9 for E-stim and US, respectively). Procedure duration was similar with the 2 procedures. There were no serious adverse events related to either approach. Conclusions: US and E-Stim localization guidance techniques provide equivalent efficacy in onabotA injections for spasticity and dystonia. US guidance injections are more comfortable for participants. Both techniques are effective guidance methods, with US potentially preferable based on participant comfort.

Toward Safer Opioid Prescribing in HIV care (TOWER): a mixed-methods, cluster-randomized trial.

BACKGROUND: The 2016 U.S. Centers for Disease Control Opioid Prescribing Guideline (CDC Guideline) is currently being revised amid concern that it may be harmful to people with chronic pain on long-term opioid therapy (CP-LTOT). However, a methodology to faithfully implement the CDC guideline, measure prescriber adherence, and systematically test its effect on patient and public health outcomes is lacking. We developed and tested a CDC Guideline implementation strategy (termed TOWER), focusing on an outpatient HIV-focused primary care setting. METHODS: TOWER was developed in a stakeholder-engaged, multi-step iterative process within an Information, Motivation and Behavioral Skills (IMB) framework of behavior change. TOWER consists of: 1) a patient-facing opioid management app (OM-App); 2) a progress note template (OM-Note) to guide the office visit; and 3) a primary care provider (PCP) training. TOWER was evaluated in a 9-month, randomized-controlled trial of HIV-PCPs (N = 11) and their patients with HIV and CP-LTOT (N = 40). The primary outcome was CDC Guideline adherence based on electronic health record (EHR) documentation and measured by the validated Safer Opioid Prescribing Evaluation Tool (SOPET). Qualitative data including one-on-one PCP interviews were collected. We also piloted patient-reported outcome measures (PROMs) reflective of domains identified as important by stakeholders (pain intensity and function; mood; substance use; medication use and adherence; relationship with provider; stigma and discrimination). RESULTS: PCPs randomized to TOWER were 48% more CDC Guideline adherent (p < 0.0001) with significant improvements in use of: non-pharmacologic treatments, functional treatment goals, opioid agreements, prescription drug monitoring programs (PDMPs), opioid benefit/harm assessment, and naloxone prescribing. Qualitative data demonstrated high levels of confidence in conducting these care processes among intervention providers, and that OM-Note supported these efforts while experience with OM-App was mixed. There were no intervention-associated safety concerns (defined as worsening of any of the PROMs). CONCLUSIONS: CDC-guideline adherence can be promoted and measured, and is not associated with worsening of outcomes for people with HIV receiving LTOT for CP. Future work would be needed to document scalability of these results and to determine whether CDC-guideline adherence results in a positive effect on public health. Trial registration https://clinicaltrials.gov/ct2/show/NCT03669939 . Registration date: 9/13/2018.

Asymptomatic SARS-CoV-2 Infection Is Associated With Higher Levels of Serum IL-17C, Matrix Metalloproteinase 10 and Fibroblast Growth Factors Than Mild Symptomatic COVID-19.

Young adults infected with SARS-CoV-2 are frequently asymptomatic or develop only mild disease. Because capturing representative mild and asymptomatic cases require active surveillance, they are less characterized than moderate or severe cases of COVID-19. However, a better understanding of SARS-CoV-2 asymptomatic infections might shed light into the immune mechanisms associated with the control of symptoms and protection. To this aim, we have determined the temporal dynamics of the humoral immune response, as well as the serum inflammatory profile, of mild and asymptomatic SARS-CoV-2 infections in a cohort of 172 initially seronegative prospectively studied United States Marine recruits, 149 of whom were subsequently found to be SARS-CoV-2 infected. The participants had blood samples taken, symptoms surveyed and PCR tests for SARS-CoV-2 performed periodically for up to 105 days. We found similar dynamics in the profiles of viral load and in the generation of specific antibody responses in asymptomatic and mild symptomatic participants. A proteomic analysis using an inflammatory panel including 92 analytes revealed a pattern of three temporal waves of inflammatory and immunoregulatory mediators, and a return to baseline for most of the inflammatory markers by 35 days post-infection. We found that 23 analytes were significantly higher in those participants that reported symptoms at the time of the first positive SARS-CoV-2 PCR compared with asymptomatic participants, including mostly chemokines and cytokines associated with inflammatory response or immune activation (i.e., TNF-α, TNF-ß, CXCL10, IL-8). Notably, we detected 7 analytes (IL-17C, MMP-10, FGF-19, FGF-21, FGF-23, CXCL5 and CCL23) that were higher in asymptomatic participants than in participants with symptoms; these are known to be involved in tissue repair and may be related to the control of symptoms. Overall, we found a serum proteomic signature that differentiates asymptomatic and mild symptomatic infections in young adults, including potential targets for developing new therapies and prognostic tests.

Serum Fc-Mediated Monocyte Phagocytosis Activity Is Stable for Several Months after SARS-CoV-2 Asymptomatic and Mildly Symptomatic Infection.

We investigated the temporal profile of multiple components of the serological response after asymptomatic or mildly symptomatic SARS-CoV-2 infection, in a cohort of 67 previously SARS-CoV-2 naive young adults, up to 8.5 months after infection. We found a significant decrease of spike IgG and neutralization antibody titers from early (11 to 56 days) to late (4 to 8.5 months) time points postinfection. Over the study period, S1-specific IgG levels declined significantly faster than that of the S2-specific IgG. Further, serum antibodies from PCR-confirmed participants cross-recognized S2, but not S1, of the betacoronaviruses HKU1 and OC43, suggesting a greater degree of cross-reactivity of S2 among betacoronaviruses. Antibody-Dependent Natural Killer cell Activation (ADNKA) was detected at the early time point but significantly decreased at the late time point. Induction of serum Antibody-Dependent Monocyte Phagocytosis (ADMP) was detected in all the infected participants, and its levels remained stable over time. Additionally, a reduced percentage of participants had detectable neutralizing activity against the Beta (50%), Gamma (61 to 67%), and Delta (90 to 94%) variants, both early and late postinfection, compared to the ancestral strain (100%). Antibody binding to S1 and RBD of Beta, Gamma, Delta (1.7 to 2.3-fold decrease), and Omicron (10 to 16-fold decrease) variants was also significantly reduced compared to the ancestral SARS-CoV-2 strain. Overall, we found variable temporal profiles of specific components and functionality of the serological response to SARS-CoV-2 in young adults, which is characterized by lasting, but decreased, neutralizing activity and antibody binding to S1, stable ADMP activity, and relatively stable S2-specific IgG levels. IMPORTANCE Adaptive immunity mediated by antibodies is important for controlling SARS-CoV-2 infection. While vaccines against COVID-19 are currently widely distributed, a high proportion of the global population is still unvaccinated. Therefore, understanding the dynamics and maintenance of the naive humoral immune response to SARS-CoV-2 is of great importance. In addition, long-term responses after asymptomatic infection are not well-characterized, given the challenges in identifying such cases. Here, we investigated the longitudinal humoral profile in a well-characterized cohort of young adults with documented asymptomatic or mildly symptomatic SARS-CoV-2 infection. By analyzing samples collected preinfection, early after infection and during late convalescence, we found that, while neutralizing activity decreased over time, high levels of serum S2 IgG and Antibody-Dependent Monocyte Phagocytosis (ADMP) activity were maintained up to 8.5 months after infection. This suggests that a subset of antibodies with specific functions could contribute to long-term protection against SARS-CoV-2 in convalescent unvaccinated individuals.