Abstract Background Individuals with post-acute COVID syndrome (PAC), also known as long-COVID, have new or continuing symptoms lasting more than 1 month from COVID-19 infection. Patients may present with neuropsychiatric (NP) and non-NP symptoms. Whether prior mental health disorders correlate with NP symptoms is unknown. The study aims were to describe the demographics, clinical factors, comorbid conditions, and presenting symptoms of PAC. Methods We included patients evaluated at Baystate Health PAC clinic from January 2021-April 2022, with prior COVID-19 infection and new or persistent symptoms of at least 6 weeks. We defined the primary presenting symptoms as NP (cognitive dysfunction (brain fog), anxiety, or depression) or non-NP (dyspnea, fatigue, dizziness, palpitations). The clinician’s diagnostic impression was recorded and characterized as NP or non-NP. Demographics Results We randomly selected 150 of 250 clinic patients for chart review. Most were women, 117 (78%); mean age was 52. Most 106 (71%) had mild acute COVID illness; 36 (24%) were hospitalized. 49% (n=73) had a pre-existing mental health disorder: mood disorder (depression/bipolar) 26 (17%), anxiety 18 (12%), both anxiety and mood disorder 27 (18%). The most common presenting symptoms in order of frequency were fatigue, dyspnea, brain fog, anxiety, depression, and palpitations. 106 (71%) had at least 1 NP presenting symptom or combination of NP symptoms; cognitive dysfunction with anxiety in 23 (15%), and cognitive dysfunction with anxiety and mood disorder in 13 (9%). The clinician's final diagnostic impression was fatigue (47%), cognitive dysfunction (36%), anxiety (29%) depression (33%) and PTSD (3%). A NP diagnosis was made in 81 (54%). Primary Symptoms Primary Diagnosis Conclusion The majority of PAC clinic patients were female and had mild COVID illness. We noted a high prevalence of pre-existing mental health disorders. More than two-thirds presented with one or more NP symptom. Further studies should explore the association of pre-COVID mental health disorders with PAC. Disclosures All Authors: No reported disclosures

Background Clostridioides difficile infection (CDI) is a major cause of hospital-acquired diarrhea and is associated with substantial morbidity and mortality. Recurrences following treatment are common. Fecal microbiota transplantation (FMT) is a therapeutic intervention in which stool from a healthy donor is administered to a patient with recurrent CDI. Studies to date of predictors of FMT failure have primarily included inpatients. In this study, we aimed to describe FMT failure rates within one year of FMT and evaluate factors associated with FMT failure. Methodology We conducted an exploratory retrospective study of consecutive patients who underwent outpatient FMT at a single tertiary care center in Western Massachusetts from December 2014 through September 2018. We collected patient data including demographics, CDI-related factors, and FMT-related factors. FMT failure was defined as non-response or recurrence of diarrhea, associated with positive stool C. difficile toxin or polymerase chain reaction. Unadjusted relative risk (RR) and 95% confidence intervals for factors associated with FMT failure were estimated using log-binomial regression. Results A total of 92 patients were included with a mean age of 64 years. CDI severity was mild or moderate in 73% and severe or fulminant in 27%. The most common FMT indication was recurrent CDI in 76% of patients. FMT failure occurred in 25 of 92 (27%) patients, with half occurring within 11 days. Factors associated with FMT failure were active malignancy (RR = 2.56), prior hospitalizations (RR = 2.42), and receipt of non-CDI antibiotics within six months of FMT (RR = 2.80). We did not observe strong associations for risk of FMT failure with age ≥65, sex, use of proton pump inhibitors or H2 receptor agonists, history of colectomy, immunosuppression, history of malignancy, diabetes, appendectomy, CDI severity, or probiotic use. Conclusions Active malignancy, prior CDI hospitalizations, and non-CDI antibiotics within six months before FMT were associated with FMT failure in the outpatient setting. Knowledge of the above factors may help inform shared decision-making with patients at risk for FMT failure.

The findings presented here provide new insights into how HIV and cellular gene expression change after stopping ART in both noncontrollers and posttreatment controllers. Posttreatment control is associated with an early ability to limit increases in multiply-spliced HIV RNA, a delayed (and presumably immune-mediated) ability to reverse an initial rise in processive/completed HIV transcripts, and multiple differences in cellular gene expression pathways.

HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4 + and CD8 + T cell activation, lower CD4 + T cell exhaustion, and more robust Gag-specific CD4 + T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4 + T cell% and CD4 + /CD8 + ratio, more functional NK cells, and a lower CD4 + T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.

Background In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials. gov registration: NCT04320615. Findings By day 60, 24.5% (72/294) of patients in the tocilizumab arm and 25.0% (36/144) in the placebo arm died (weighted difference -0.5% [95% CI -9.1 to 8 .0]), and 67.0% (197/294) in the tocilizumab arm and 63.9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24.1% (71/295) of patients in the tocilizumab arm and 29.4% (42/143) in the placebo arm. Median time to negative reverse transcriptase-quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15.0 days (95% CI 14.0 to 21.0) in the tocilizumab arm and 21.0 days (95% CI 14.0 to 28.0) in the placebo arm. All tested patients had positive test results for neutralising anti-SARS-CoV-2 antibodies at day 60. Interpretation There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.

Context.Guidelines recommend antibiotic therapy for acute exacerbations of chronic obstructive pulmonary disease (COPD), but the evidence is based on small, heterogeneous trials, few of which include hospitalized patients.Objective.To compare the outcomes of patients treated with antibiotics in the first 2 hospital days with those treated later or not at all. Design, Setting, and Patients.Retrospective cohort of patients aged 40 years or older who were hospitalized from January 1, 2006, through December 31, 2007, for acute exacerbations of COPD at 413 acute care facilities throughout the United States. Main Outcome Measures.A composite measure of treatment failure, defined as the initiation of mechanical ventilation after the second hospital day, inpatient mortality, or readmission for acute exacerbations of COPD within 30 days of discharge; length of stay and hospital costs.Result.Of 84 621 patients, 79% received at least 2 consecutive days of antibiotic treatment.Treated patients were less likely than nontreated patients to receive mechanical ventilation after the second

Clinical trials including an analytical treatment interruption (ATI) are vital for evaluating the efficacy of novel strategies for HIV remissions. We briefly describe an interactive tool for predicting viral rebound timing in ATI trials and the impact of posttreatment controller (PTC) definitions on PTC frequency estimates. A 4-week viral load threshold of 1000 cps/ml provides both high specificity and sensitivity for PTC detection. PTC frequency varies greatly based on the definition of a PTC.

ABSTRACTBACKGROUNDCOVID-19 is associated with immune dysregulation and hyperinflammation. Tocilizumab is an anti–interleukin-6 receptor antibody.METHODSPatients hospitalized with severe COVID-19 pneumonia receiving standard care were randomized (2:1) to double-blinded intravenous tocilizumab 8 mg/kg or placebo. The primary outcome measure was clinical status on a 7-category ordinal scale at day 28 (1, discharged/ready for discharge; 7, death).RESULTSOverall, 452 patients were randomized; the modified-intention-to-treat population included 294 tocilizumab-treated and 144 placebo-treated patients. Clinical status at day 28 was not statistically significantly improved for tocilizumab versus placebo (P=0.36). Median (95% CI) ordinal scale values at day 28: 1.0 (1.0 to 1.0) for tocilizumab and 2.0 (1.0 to 4.0) for placebo (odds ratio, 1.19 [0.81 to 1.76]). There was no difference in mortality at day 28 between tocilizumab (19.7%) and placebo (19.4%) (difference, 0.3% [95% CI, –7.6 to 8.2]; nominal P=0.94). Median time to hospital discharge was 8 days shorter with tocilizumab than placebo (20.0 and 28.0, respectively; nominal P=0.037; hazard ratio 1.35 [95% CI 1.02 to 1.79]). Median duration of ICU stay was 5.8 days shorter with tocilizumab than placebo (9.8 and 15.5, respectively; nominal P=0.045). In the safety population, serious adverse events occurred in 34.9% of 295 patients in the tocilizumab arm and 38.5% of 143 in the placebo arm.CONCLUSIONSIn this randomized placebo-controlled trial in hospitalized COVID-19 pneumonia patients, tocilizumab did not improve clinical status or mortality. Potential benefits in time to hospital discharge and duration of ICU stay are being investigated in ongoing clinical trials.Trial registrationClinicalTrials.gov NCTG432G615

BACKGROUNDPeople with human immunodeficiency virus (PWH) face increased risks for heart failure and adverse heart failure outcomes. Myocardial steatosis predisposes to diastolic dysfunction, a heart failure precursor. We aimed to characterize myocardial steatosis and associated potential risk factors among a subset of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) participants.METHODSEighty-two PWH without known heart failure successfully underwent cardiovascular magnetic resonance spectroscopy, yielding data on intramyocardial triglyceride (IMTG) content (a continuous marker for myocardial steatosis extent). Logistic regression models were applied to investigate associations between select clinical characteristics and odds of increased or markedly increased IMTG content.RESULTSMedian (Q1, Q3) IMTG content was 0.59% (0.28%, 1.15%). IMTG content was increased (> 0.5%) among 52% and markedly increased (> 1.5%) among 22% of participants. Parameters associated with increased IMTG content included age (P = .013), body mass index (BMI) ≥ 25 kg/m2 (P = .055), history of intravenous drug use (IVDU) (P = .033), and nadir CD4 count < 350 cells/mm³ (P = .055). Age and BMI ≥ 25 kg/m2 were additionally associated with increased odds of markedly increased IMTG content (P = .049 and P = .046, respectively).CONCLUSIONSA substantial proportion of antiretroviral therapy-treated PWH exhibited myocardial steatosis. Age, BMI ≥ 25 kg/m2, low nadir CD4 count, and history of IVDU emerged as possible risk factors for myocardial steatosis in this group.CLINICAL TRIALS REGISTRATIONNCT02344290; NCT03238755.

Powassan virus (POWV) encephalitis is a rare tickborne illness. We describe the clinical course, laboratory findings, and imaging for a patient with POWV in Massachusetts, USA. Clinical presentation and laboratory findings were nonspecific. Improvement on brain magnetic resonance imaging after 2 weeks preceded clinical improvement by months, suggesting possible prognostic value.

HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems.

ABSTRACT Analytic treatment interruption (ATI) studies are required to evaluate strategies aimed at achieving ART-free HIV remission, but the impact of ATI on the viral reservoir remains unclear. We validated a DNA size selection-based assay for measuring levels of integrated HIV DNA and applied it to assess the effects of short-term ATI on the HIV reservoir. Samples from participants from four AIDS Clinical Trials Group ATI studies were assayed for integrated HIV DNA levels. Cryopreserved peripheral blood mononuclear cells (PBMCs) were obtained for 12 participants with available samples pre-ATI and approximately 6 months after ART resumption. Four participants also had samples available during the ATI. The median duration of ATI was 12 weeks. Validation of the HIV integrated DNA size-exclusion (HIDE) assay was performed using samples spiked with unintegrated HIV DNA, HIV-infected cell lines, and participant PBMCs. The HIDE assay eliminated 99% of unintegrated HIV DNA species and strongly correlated with the established Alu- gag assay. For the majority of individuals, integrated DNA levels increased during ATI and subsequently declined upon ART resumption. There was no significant difference in the levels of integrated HIV DNA between the pre- and post-ATI time points, with a median ratio of post- to pre-ATI HIV DNA levels of 0.95. Using a new integrated HIV DNA assay, we found minimal change in the levels of integrated HIV DNA in participants who underwent an ATI, followed by 6 months of ART. This suggests that short-term ATI can be conducted without a significant impact on the levels of integrated proviral DNA in the peripheral blood. IMPORTANCE Interventions aimed at achieving sustained antiretroviral therapy (ART)-free HIV remission require treatment interruption trials to assess their efficacy. However, these trials are accompanied by safety concerns related to the expansion of the viral reservoir. We validated an assay that uses an automated DNA size-selection platform for quantifying levels of integrated HIV DNA and is less sample- and labor-intensive than current assays. Using stored samples from AIDS Clinical Trials Group studies, we found that short-term ART discontinuation had minimal impact on integrated HIV DNA levels after ART resumption, providing reassurance about the reservoir effects of short-term treatment interruption trials.

Background:HIV posttreatment controllers are rare individuals who start antiretroviral therapy (ART), but maintain HIV suppression after treatment interruption. The frequency of posttreatment control and posttreatment interruption viral dynamics have not been well characterized. Methods:Posttreatment controllers were identified from 14 studies and defined as individuals who underwent treatment interruption with viral loads ≤400 copies/mL at two-thirds or more of time points for ≥24 weeks. Viral load and CD4+ cell dynamics were compared between posttreatment controllers and noncontrollers. Results:Of the 67 posttreatment controllers identified, 38 initiated ART during early HIV infection. Posttreatment controllers were more frequently identified in those treated during early versus chronic infection (13% vs 4%, P < .001). In posttreatment controllers with weekly viral load monitoring, 45% had a peak posttreatment interruption viral load of ≥1000 copies/mL and 33% had a peak viral load ≥10000 copies/mL. Of posttreatment controllers, 55% maintained HIV control for 2 years, with approximately 20% maintaining control for ≥5 years. Conclusions:Posttreatment control was more commonly identified amongst early treated individuals, frequently characterized by early transient viral rebound and heterogeneous durability of HIV remission. These results may provide mechanistic insights and have implications for the design of trials aimed at achieving HIV remission.

Men who have sex with men (MSM) are at greater risk for human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Several studies have demonstrated that HIV pre-exposure prophylaxis (PrEP) for MSM can lower rates of HIV acquisition. However, PrEP may lead to risk compensation and higher rates of non-HIV STIs. We hypothesized that PCPs’ knowledge of CDC recommendations for STIs and PrEP in MSM would be low. To assess knowledge of CDC STI screening and PrEP recommendations we emailed an anonymous questionnaire, to 314 primary care physicians and mid-level practitioners employed by Baystate Medical Center, a 716-bed academic medical center in Springfield, MA. Knowledge scores were calculated as the number of correct items, divided by the total number of items. One-way analysis of variance and Fisher’s exact test was used to test for knowledge differences between groups. P < 0.05 was considered statistically significant. One hundred and thirty of 314 invited clinicians opted in and 109 completed the survey (35% effective response rate). Most respondents (89%, n = 97) were physicians, the remainder (n = 12, 11%) were mid-level practitioners. Thirty-seven respondents (34%) reported having been trained in MSM-specific care. The mean ± SD knowledge score was 49% ± 29% (range: 0% to 100%). Knowledge was low whether respondents reported receiving previous training in MSM-specific care or not (knowledge score 49% if yes vs. 48% if no, P = 0.87) or receiving specific STD screening education (knowledge score = 51% if yes vs. 41% if no, P = 0.14). Seventy-two respondents (66%) reported providing care for MSM patients of which 29 (40%) reported having discussed PrEP with at least a few patients in the last year. Among the 29 who discussed PrEP at least once, 13 (45%) correctly answered the PrEP indication question compared with 8 (24%) of those who did not discuss PrEP. PCP knowledge of STI screening guidelines and PrEP indications for MSM is low, even among those PCPs who reported receiving MSM-specific training. In light of studies demonstrating PrEP can lead to lower HIV transmission rates among MSM while potentially increasing STI rates, efforts to educate clinicians on PrEP and STI screening should be a priority. All authors: No reported disclosures.

Fostering a strong and empathetic patient–physician relationship is essential for the success of the HIV therapeutic plan. A comprehensive understanding of all medical and psychiatric comorbidities, medication history, exposures, risk behaviors, and current state of health is fundamental in caring for the HIV-infected individual. All patients with HIV newly in care need a complete history and physical examination. The physical exam needs to be comprehensive both for the assessment of current complaints and for baseline comparison with future findings. Providers must be aware of the cultural, social, and sexual diversity of their patient population to help foster patient–provider communication.

The authors regret that the clinical trial number for Project INSPIRE (R01AA018944) in Section 2.1, "Ethical considerations," should read: NCT01077310. The authors would like to apologize for any inconvenience caused. An evaluation of hepatic enzyme elevations among HIV-infected released prisoners enrolled in two randomized placebo-controlled trials of extended release naltrexoneJournal of Substance Abuse TreatmentVol. 47Issue 1PreviewExtended-release naltrexone (XR-NTX), an approved treatment for opioid or alcohol dependence, is a once-monthly injectable formulation of naltrexone. Hepatotoxicity concerns have limited its use, necessitating further investigation. This study aims to examine hepatic enzyme levels in participants of 2 randomized placebo-controlled trials (RCTs) of XR-NTX. Hepatic transaminases were measured in 85 patients enrolled in RCTs of XR-NTX among HIV-infected prisoners, transitioning to the community and receiving treatment for either dependence on alcohol (52.9%), opioids (44.7%) or both (16.5%). Full-Text PDF

BACKGROUNDThe American Thoracic Society and Infectious Diseases Society of America guidelines for management of healthcare‐associated pneumonia (HCAP), first published in 2005, have been controversial regarding the selection of empiric broad‐spectrum antibiotics, whether the criteria for HCAP predicts the likelihood of infection with multidrug resistant organisms, and whether HCAP patients have improved outcomes when treated with empiric broad‐spectrum antibiotics.METHODSA retrospective cohort study at 488 US hospitals from July 2007 to November 2011. Patients who met criteria for HCAP were included. Guideline‐concordant antibiotics were assessed based on guideline recommendations. We assessed changes in hospital rates of concordant antibiotic use over time and their correlation with outcomes.RESULTSAmong 149,963 patients with HCAP, 19.6% received fully guideline‐concordant antibiotics, 21.7% received partially concordant antibiotics, and 58.9% received discordant antibiotics. Guideline concordance increased over time. Rates of fully or partially concordant antibiotics varied across hospitals (median 36.4%; interquartile range 25.8%‐49.1%). Among patients who received discordant antibiotics, 81.5% were treated according to community‐acquired pneumonia (CAP) guidelines. On average, the rate of guideline concordance increased by 2.2% per 6‐month interval, while hospital level rates of mortality, excess length of stay, and progression to respiratory failure did not change.CONCLUSIONSIn this large, nationally representative cohort, only 1 in 5 patients with risk factors for HCAP received treatment that was fully in accordance with guidelines, and many received CAP therapy instead. At the hospital level, increases in the use of concordant antibiotics were not associated with declines in mortality, excess length of stay, or progression to respiratory failure.

BACKGROUND Fluoroquinolones have equivalent oral and intravenous bioavailability, but hospitalized patients with community-acquired pneumonia (CAP) generally are treated intravenously. Our objectives were to compare outcomes of hospitalized CAP patients initially receiving intravenous vs oral respiratory fluoroquinolones. METHODS This was a retrospective cohort study utilizing data from 340 hospitals involving CAP patients admitted to a non-intensive care unit (ICU) setting from 2007 to 2010, who received intravenous or oral levofloxacin or moxifloxacin. The primary outcome was in-hospital mortality. Secondary outcomes included clinical deterioration (transfer to ICU, initiation of vasopressors, or invasive mechanical ventilation [IMV] initiated after the second hospital day), antibiotic escalation, length of stay (LOS), and cost. RESULTS Of 36 405 patients who met inclusion criteria, 34 200 (94%) initially received intravenous treatment and 2205 (6%) received oral treatment. Patients who received oral fluoroquinolones had lower unadjusted mortality (1.4% vs 2.5%; P = .002), and shorter mean LOS (5.0 vs 5.3; P < .001). Multivariable models using stabilized inverse propensity treatment weighting revealed lower rates of antibiotic escalation for oral vs intravenous therapy (odds ratio [OR], 0.84; 95% confidence interval [CI], .74-.96) but no differences in hospital mortality (OR, 0.82; 95% CI, .58-1.15), LOS (difference in days 0.03; 95% CI, -.09-.15), cost (difference in $-7.7; 95% CI, -197.4-182.0), late ICU admission (OR, 1.04; 95% CI, .80-1.36), late IMV (OR, 1.17; 95% CI, .87-1.56), or late vasopressor use (OR, 0.94; 95% CI, .68-1.30). CONCLUSIONS Among hospitalized patients who received fluoroquinolones for CAP, there was no association between initial route of administration and outcomes. More patients may be treated orally without worsening outcomes.