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Background Droplet digital PCR (ddPCR) has been shown to be more sensitive and precise in the quantification of SARS-CoV-2 when compared to traditional quantitative RT-PCR. Multiple studies have explored associations between SARS-CoV-2 viral load and patient outcomes; however, few have used ddPCR technology. Here we investigated the associations between viral load measured using ddPCR and clinical presentation and outcomes. Methods We performed a retrospective observational study of individuals who tested positive for COVID-19 at the VA San Diego between August 2020 and December 2021. SARS-CoV-2 viral load from nasopharyngeal swabs was determined using ddPCR. Baseline demographics, past medical history, clinical course, and laboratory data were abstracted from the chart. Results A total of 696 individuals were included, 86% (n=603) of whom were male. The average age was 50-years-old [range: 19-98]. Three-quarters of individuals (76%, n=528) were unvaccinated at diagnosis. Frequency of comorbidities are shown in Table 1. The majority of individuals developed symptoms with 75% (n=516) reporting respiratory symptoms, 47% (n=317) fever, 34% (n=230) GI symptoms, and 23% (n=161) loss of taste and/or smell. A total of 24% of veterans were evaluated only in the emergency department, 21% (n=149) were admitted to the hospital; 9% (n=60) required ICU level of care, 33% of these (n=20) required intubation, and 16 individuals died during hospitalization. SARS-CoV-2 log10 viral load was not associated with age, and only a weak correlation was seen with time from onset of symptoms (r2=-0.1, p=0.04). No association was observed between viral load and peak CRP, ferritin, d-dimer, or nadir absolute lymphocyte count. Mean viral load was significantly higher in veterans reporting fever (5.0 vs 5.4, p=0.02) and respiratory symptoms (4.7 vs 5.3, p=0.01). Interestingly, vaccinated veterans also had higher viral loads(5.8 vs 5.0, p< 0.0001). Baseline characteristics of individuals with COVID-19 Histogram of COVID-19 RNA viral load Conclusion Fever and respiratory symptoms were associated with higher viral loads as expected. The association of vaccination with higher viral load may reflect selection bias for infections in the delta wave. Future work will include multivariate analyses to adjust for medical history and timing of sampling. Disclosures Sanjay R. Mehta, MD, Zibdy Health: Advisor/Consultant.

BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection. OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone. DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multinational, multicenter trial. PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: Intravenous ensovibep, 600 mg, or placebo. MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90. RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR

The ubiquity of smart speakers is increasing, with a growing number of households utilising these devices to make calls over the telephony network. As the technology is typically configured to retain the cellular phone number of the user, it presents challenges in applications where knowledge of the true call origin is required. There are a wide range of makes and models for these devices, as is the case with cell phones, and it is challenging to detect the general category as a smart speaker or cell, independent of the designated phone number. In this paper, we present an approach to differentiate between calls originating from smart speakers and ones from cellular devices using only the audio. We present a feature set that characterises the relevant acoustic information, such as the degree of reverberation and noise, to distinguish between these categories. When evaluated on a dataset spanning multiple models for each device category, as well as different modes-of-usage and microphone-speaker distances, the method yields an Equal Error Rate (EER) of 12.6%.

HIV-associated lymphomas (HALs) have high rates of latent infection by gammaherpesviruses (GHVs). We hypothesized that proteasome inhibition would induce lytic activation of GHVs and inhibit HIV infectivity via preservation of cytidine deaminase APOBEC3G, improving lymphoma control. We tested this oncolytic and antiviral strategy by using bortezomib combined with ifosfamide, carboplatin, and etoposide (ICE) alone or with rituximab (ICE/R) in relapsed/refractory HAL. A 3+3 dose-escalation design was used with a 7-day lead-in period of single-agent bortezomib. Bortezomib was administered intravenously on days 1 and 8 of each cycle at 1 of 4 dose levels: 0.7, 1.0, 1.3, or 1.5 mg/m2. ICE began day 8 of cycle 1 and day 1 of subsequent cycles. Rituximab was included on day 1 of cycles 2 to 6 for CD20+ lymphomas. Twenty-three patients were enrolled. The maximum tolerated dose of bortezomib was not reached. Grade 4 toxicities attributable to bortezomib were limited to myelosuppression. Responses occurred in 17 (77%) of 22 patients receiving any protocol therapy. The 1-year overall survival was 57%. After bortezomib alone, both patients with Kaposi sarcoma herpesvirus (KSHV)–positive lymphoma had more than a 1-log increase in KSHV viral load. In 12 patients with Epstein-Barr virus (EBV)–positive lymphoma, median values of EBV viral load increased. Undetectable HIV viremia at baseline in the majority of patients limited evaluation of HIV inhibition. APOBEC3G levels increased in 75% of evaluable patients. Bortezomib combined with ICE/R in patients with relapsed/refractory HAL is feasible with response and survival comparing favorably against previously reported second-line therapies. Changes in GHV viral loads and APOBEC3G levels trended as hypothesized. This trial was registered at www.clinicaltrials.gov as #NCT00598169.

Author(s): Chaillon, Antoine; Sun, Xiaoying; Cachay, Edward R; Looney, David; Wyles, David; Garfein, Richard S; Martin, Thomas CS; Jain, Sonia; Mehta, Sanjay R; Smith, Davey M; Little, Susan J; Martin, Natasha K | Abstract: BackgroundLittle is known about the hepatitis C virus (HCV) epidemic among HIV-infected men who have sex with men (HIV+ MSM) in the United States. In this study, we aimed to determine the incidence of primary HCV infection among HIV+ MSM in San Diego, California.MethodsWe performed a retrospective cohort analysis of HCV infection among HIV+ MSM attending 2 of the largest HIV clinics in San Diego. Incident HCV infection was assessed among HIV+ MSM with a negative anti-HCV test and subsequent HCV test between 2000 and 2017, with data censored to 2015. HCV reinfection was assessed among HIV+ MSM successfully treated for HCV between 2008 and 2015. Infection/reinfection rates were calculated using person-time methods.ResultsAmong 3068 initially HCV-seronegative HIV+ MSM, 178 new infections occurred over 15 796 person-years, giving an incidence of 1.13 per 100 person-years (/100py; 95% confidence interval [CI], 0.97-1.31). Incidence was stable from 2000 to 2014 (0.83/100py; 95% CI, 0.41-1.48), with an increase to 3.01/100py (95% CI, 1.97-4.42) in 2015 (P = .02). Among 43 successfully treated patients, 3 were reinfected.ConclusionsHCV incidence is high among HIV+ MSM in San Diego, with evidence suggesting a recent increase in 2015. Strong HCV testing guidelines and active prevention efforts among HIV+ MSM are urgently needed that include rapid diagnosis, treatment, and risk reduction.

Yeast cell lines were genetically engineered to display Hepatitis C virus (HCV) core antigen linked to gold binding peptide (GBP) as a dual-affinity biobrick chimera. These multifunctional yeast cells adhere to the gold sensor surface while simultaneously acting as a "renewable" capture reagent for anti-HCV core antibody. This streamlined functionalization and detection strategy removes the need for traditional purification and immobilization techniques. With this biobrick construct, both optical and electrochemical immunoassays were developed. The optical immunoassays demonstrated detection of anti-HCV core antibody down to 12.3pM concentrations while the electrochemical assay demonstrated higher binding constants and dynamic range. The electrochemical format and a custom, low-cost smartphone-based potentiostat ($20 USD) yielded comparable results to assays performed on a state-of-the-art electrochemical workstation. We propose this combination of synthetic biology and scalable, point-of-care sensing has potential to provide low-cost, cutting edge diagnostic capability for many pathogens in a variety of settings.

RATIONALE: To date the only quantifiable measure of neural changes that define sleep is electroencephalography (EEG). Although widely used for clinical testing, scalp-electrode EEG is costly and poorly tolerated by sleeping patients. OBJECTIVES: This is a pilot study to assess the agreement between EEG recordings obtained from a new ear-EEG sensor and those obtained simultaneously from standard scalp electrodes. METHODS: Participants were 4 healthy men, ages 25 to 36 years. During naps, EEG tracings were recorded simultaneously from the ear sensor and standard scalp electrodes. A clinical expert, blinded to the data collection, analyzed 30-second epochs of recordings from both devices using standardized criteria. The agreement between scalp- and ear-recordings was assessed. MEASUREMENTS AND MAIN RESULTS: We scored 360 epochs (scalp-EEG and ear-EEG) of which 254 (70.6%) were scored as non-rapid-eye movement (NREM) sleep using scalp-EEG. The ear-EEG sensor had a sensitivity of 0.88 (95% CI 0.82 to 0.92) and specificity of 0.78 (95% CI 0.70 to 0.84) in detecting N2/N3 sleep. The kappa coefficient, between the scalp- and ear-EEG, was 0.65 (95% CI 0.58 to 0.73). As a sleep monitor (all NREM sleep stages versus wake), the in-ear sensor had a sensitivity of 0.91 (95% CI 0.87 to 0.94) and specificity of 0.66 (95% CI 0.56 to 0.75). The kappa coefficient was 0.60 (95% CI 0.50 to 0.69). CONCLUSIONS: Substantial agreement was observed between recordings derived from a new ear-EEG sensor and conventional scalp electrodes on 4 healthy volunteers during daytime naps.

Lithium (Li) is the mainstay mood stabilizer for the treatment of bipolar disorder (BD), although its mode of action is not yet fully understood nor is it effective in every patient. We sought to elucidate the mechanism of action of Li and to identify surrogate outcome markers that can be used to better understand its therapeutic effects in BD patients classified as good (responders) and poor responders (nonresponders) to Li treatment. To accomplish these goals, RNA-sequencing gene expression profiles of lymphoblastoid cell lines (LCLs) were compared between BD Li responders and nonresponders with healthy controls before and after treatment. Several Li-responsive gene coexpression networks were discovered indicating widespread effects of Li on diverse cellular signaling systems including apoptosis and defense response pathways, protein processing and response to endoplasmic reticulum stress. Individual gene markers were also identified, differing in response to Li between BD responders and nonresponders, involved in processes of cell cycle and nucleotide excision repair that may explain part of the heterogeneity in clinical response to treatment. Results further indicated a Li gene expression signature similar to that observed with clonidine treatment, an α2-adrenoceptor agonist. These findings provide a detailed mechanism of Li in LCLs and highlight putative surrogate outcome markers that may permit for advanced treatment decisions to be made and for facilitating recovery in BD patients.