Background. To determine whether treatment with ritonavir-boosted protease inhibitor (PI) monotherapy is associated with detrimental effects on neurocognitive function or brain imaging markers ...compared to standard antiretroviral therapy (ART). Methods. Neuropsychological assessment and brain magnetic resonance imaging were performed at the last study visit in a subset of participants randomized to PI monotherapy (PI-mono group) or ongoing triple ART (OT group) in the PIVOT trial. We calculated a global z-score (NPZ-7) from the average of the individual test z-scores and the proportion of participants with symptomatic neurocognitive impairment (score >1 standard deviation below normative means in ≥2 cognitive domains and neurocognitive symptoms). In a subgroup, white matter hyperintensities, bicaudate index, global cortical (GCA) and medial temporal lobe atrophy scores and single voxel (basal ganglia) N-acetylaspartate (NAA)/Choline, NAA/Creatine and myo-inositol/Creatine ratios were measured. Results. 146 participants (75 PI-mono) had neurocognitive testing (median time after randomization 3.8 years), of whom 78 were imaged. We found no difference between arms in NPZ-7 score (median −0.4 (interquartile range IQR = −0.7; 0.1) vs −0.3 (IQR = −0.7; 0.3) for the PI-mono and OT groups respectively, P = .28), the proportion with symptomatic neurocognitive impairment (13% and 18% in the PI-mono and OT groups respectively; P = .41), or any of the neuroimaging variables (P > .05). Symptomatic neurocognitive impairment was associated with higher GCA score (OR = 6.2 per additional score; 95% confidence interval, 1.7–22.3 P = .005) but no other imaging variables. Conclusions. Based on a comprehensive neuropsychological assessment and brain imaging, PI monotherapy does not increase the risk of neurocognitive impairment in stable human immunodeficiency virus-positive patients.
Accurate measures of the severity of pandemic (H1N1) 2009 influenza (pH1N1) are needed to assess the likely impact of an anticipated resurgence in the autumn in the Northern Hemisphere. Severity has ...been difficult to measure because jurisdictions with large numbers of deaths and other severe outcomes have had too many cases to assess the total number with confidence. Also, detection of severe cases may be more likely, resulting in overestimation of the severity of an average case. We sought to estimate the probabilities that symptomatic infection would lead to hospitalization, ICU admission, and death by combining data from multiple sources.
We used complementary data from two US cities: Milwaukee attempted to identify cases of medically attended infection whether or not they required hospitalization, while New York City focused on the identification of hospitalizations, intensive care admission or mechanical ventilation (hereafter, ICU), and deaths. New York data were used to estimate numerators for ICU and death, and two sources of data--medically attended cases in Milwaukee or self-reported influenza-like illness (ILI) in New York--were used to estimate ratios of symptomatic cases to hospitalizations. Combining these data with estimates of the fraction detected for each level of severity, we estimated the proportion of symptomatic patients who died (symptomatic case-fatality ratio, sCFR), required ICU (sCIR), and required hospitalization (sCHR), overall and by age category. Evidence, prior information, and associated uncertainty were analyzed in a Bayesian evidence synthesis framework. Using medically attended cases and estimates of the proportion of symptomatic cases medically attended, we estimated an sCFR of 0.048% (95% credible interval CI 0.026%-0.096%), sCIR of 0.239% (0.134%-0.458%), and sCHR of 1.44% (0.83%-2.64%). Using self-reported ILI, we obtained estimates approximately 7-9 x lower. sCFR and sCIR appear to be highest in persons aged 18 y and older, and lowest in children aged 5-17 y. sCHR appears to be lowest in persons aged 5-17; our data were too sparse to allow us to determine the group in which it was the highest.
These estimates suggest that an autumn-winter pandemic wave of pH1N1 with comparable severity per case could lead to a number of deaths in the range from considerably below that associated with seasonal influenza to slightly higher, but with the greatest impact in children aged 0-4 and adults 18-64. These estimates of impact depend on assumptions about total incidence of infection and would be larger if incidence of symptomatic infection were higher or shifted toward adults, if viral virulence increased, or if suboptimal treatment resulted from stress on the health care system; numbers would decrease if the total proportion of the population symptomatically infected were lower than assumed.
Background. To our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but ...without chronic hepatitis C virus (HCV) infection. Methods. Untreated HIV-1-infected volunteers without HCV infection received 180 mg of pegylated interferon alfa-2a weekly for 12 weeks. Changes in plasma HIV-1 RNA load, CD4+ T cell counts, pharmacokinetics, pharmacodynamic measurements of 2‘,5’-oligoadenylate synthetase (OAS) activity, and induction levels of interferoninducible genes (IFIGs) were measured. Nonparametric statistical analysis was performed. Results. Eleven participants completed 12 weeks of therapy. The median plasma viral load decrease and change in CD4+ T cell counts at week 12 were 0.61 log10 copies/mL (90% confidence interval CI, 0.20–1.18 log10 copies/ mL) and -44 cells/μL (90% CI, -95 to 85 cells/μL), respectively. There was no correlation between plasma viral load decreases and concurrent pegylated interferon plasma concentrations. However, participants with larger increases in OAS level exhibited greater decreases in plasma viral load at weeks 1 and 2 (r = -0.75 90% CI, -0.93 to -0.28 and r = -0.61 90% CI, -0.87 to -0.09, respectively; estimated Spearman rank correlation). Participants with higher baseline IFIG levels had smaller week 12 decreases in plasma viral load (0.66 log10 copies/ mL 90% CI, 0.06–0.91 log10 copies/mL), whereas those with larger IFIG induction levels exhibited larger decreases in plasma viral load (-0.74 log10 copies/mL 90% CI, -0.93 to -0.21 log10 copies/mL). Conclusion. Pegylated interferon alfa-2a was well tolerated and exhibited statistically significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein levels (weeks 1 and 2) and IFIG induction levels (week 12) but not with pegylated interferon concentrations. Trial registration. ClinicalTrials.gov identifier: NCT00078442.
Liver fibrosis is common, particularly in individuals who are infected with human immunodeficiency virus (HIV). HIV‐infected individuals have excess congestive heart failure (CHF) risk compared with ...uninfected people. It remains unknown whether liver fibrosis stage influences the CHF risk or if HIV or hepatitis C virus (HCV) infection modifies this association. Our objectives were to assess whether 1) stage of liver fibrosis is independently associated with incident CHF and 2) the association between stage of liver fibrosis and incident CHF is modified by HIV/HCV status. Participants alive on or after April 1, 2003, in the Veterans Aging Cohort Study were included. Those without prevalent cardiovascular disease were followed until their first CHF event, death, last follow‐up date, or December 31, 2011. Liver fibrosis was measured using the fibrosis 4 index (FIB‐4), which is calculated using age, aminotransferases, and platelets. Cox proportional hazards regression models were adjusted for cardiovascular disease risk factors. Among 96,373 participants over 6.9 years, 3844 incident CHF events occurred. FIB‐4 between 1.45 and 3.25 (moderate fibrosis) and FIB‐4 > 3.25 (advanced fibrosis/cirrhosis) were associated with CHF (hazard ratio 95% confidence interval, 1.17 1.07‐1.27 and 1.65 1.43‐1.92, respectively). The association of advanced fibrosis/cirrhosis and incident CHF persisted regardless of HIV/HCV status. Conclusion: Moderate and advanced liver fibrosis/cirrhosis are associated with an increased risk of CHF. The association for advanced fibrosis/cirrhosis persists even among participants without hepatitis C and/or HIV infection. Assessing liver health may be important for reducing the risk of future CHF events, particularly among HIV and hepatitis C infected people among whom cardiovascular disease risk is elevated and liver disease is common. (Hepatology 2017;66:1286‐1295)
Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission.
In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial ...conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility.
Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%) (four control, one HCQ, two HCQ/AZ); no LRTI and two (2%) hospitalizations occurred in the 102 low-risk participants (one HCQ, one HCQ/AZ). There were no deaths. Among 152 participants with viral shedding at enrollment, median time to clearance was 5 days (95% CI=4–6) in HCQ, 6 days (95% CI=4–8) in HCQ/AZ, and 8 days (95% CI=6–10) in control. Viral clearance was faster in HCQ (HR=1.62, 95% CI=1.01–2.60, p = 0.047) but not HCQ/AZ (HR=1.25, p = 0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group (HCQ: HR=1.02, 95% CI-0.63–1.64, p = 0.95, HCQ/AZ: HR=0.91, 95% CI=0.57–1.45, p = 0.70).
Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection.
The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.
Trial registration ClinicalTrials.gov number NCT04354428
Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is ...interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.
Juvenile loggerhead turtles (Caretta caretta) from West Atlantic nesting beaches occupy oceanic (pelagic) habitats in the eastern Atlantic and Mediterranean, whereas larger juvenile turtles occupy ...shallow (neritic) habitats along the continental coastline of North America. Hence the switch from oceanic to neritic stage can involve a trans‐oceanic migration. Several researchers have suggested that at the end of the oceanic phase, juveniles are homing to feeding habitats in the vicinity of their natal rookery. To test the hypothesis of juvenile homing behaviour, we surveyed 10 juvenile feeding zones across the eastern USA with mitochondrial DNA control region sequences (N = 1437) and compared these samples to potential source (nesting) populations in the Atlantic Ocean and Mediterranean Sea (N = 465). The results indicated a shallow, but significant, population structure of neritic juveniles (ΦST = 0.0088, P = 0.016), and haplotype frequency differences were significantly correlated between coastal feeding populations and adjacent nesting populations (Mantel test R2 = 0.52, P = 0.001). Mixed stock analyses (using a Bayesian algorithm) indicated that juveniles occurred at elevated frequency in the vicinity of their natal rookery. Hence, all lines of evidence supported the hypothesis of juvenile homing in loggerhead turtles. While not as precise as the homing of breeding adults, this behaviour nonetheless places juvenile turtles in the vicinity of their natal nesting colonies. Some of the coastal hazards that affect declining nesting populations may also affect the next generation of turtles feeding in nearby habitats.
Although many studies have identified neural correlates of memory, relatively little is known about the circuit properties connecting single-neuron physiology to behavior. Here we developed a ...modeling framework to bridge this gap and identify circuit interactions capable of maintaining short-term memory. Unlike typical studies that construct a phenomenological model and test whether it reproduces select aspects of neuronal data, we directly fit the synaptic connectivity of an oculomotor memory circuit to a broad range of anatomical, electrophysiological, and behavioral data. Simultaneous fits to all data, combined with sensitivity analyses, revealed complementary roles of synaptic and neuronal recruitment thresholds in providing the nonlinear interactions required to generate the observed circuit behavior. This work provides a methodology for identifying the cellular and synaptic mechanisms underlying short-term memory and demonstrates how the anatomical structure of a circuit may belie its functional organization.
•Connects memory studies at the cellular, systems, and behavioral levels•Provides a methodology for fitting memory models directly to experimental data•Identifies candidate mechanisms for memory storage in the oculomotor integrator•Shows how functional connectivity can differ markedly from anatomical connectivity
Fisher et al. define the circuit interactions underlying short-term memory storage in an oculomotor microcircuit by directly fitting a computational model to cellular, anatomical, and behavioral data. The resulting model demonstrates how a circuit’s functional and anatomical connectivity can differ dramatically.
Fear associated with medical vulnerability should be considered when assessing mental health among individuals with chronic medical conditions during the COVID-19 pandemic. The objective was to ...develop and validate the COVID-19 Fears Questionnaire for Chronic Medical Conditions.
Fifteen initial items were generated based on suggestions from 121 people with the chronic autoimmune disease systemic sclerosis (SSc; scleroderma). Patients in a COVID-19 SSc cohort completed items between April 9 and 27, 2020. Exploratory factor analysis (EFA) and item analysis were used to select items for inclusion. Cronbach's alpha and Pearson correlations were used to evaluate internal consistency reliability and convergent validity. Factor structure was confirmed with confirmatory factor analysis (CFA) in follow-up data collection two weeks later.
787 participants completed baseline measures; 563 of them completed the follow-up assessment. Ten of 15 initial items were included in the final questionnaire. EFA suggested that a single dimension explained the data reasonably well. There were no indications of floor or ceiling effects. Cronbach's alpha was 0.91. Correlations between the COVID-19 Fears Questionnaire and measures of anxiety (r = 0.53), depressive symptoms (r = 0.44), and perceived stress (r = 0.50) supported construct validity. CFA supported the single-factor structure (χ2(35) = 311.2, p < 0.001, Tucker-Lewis Index = 0.97, Comparative Fit Index = 0.96, Root Mean Square Error of Approximation = 0.12).
The COVID-19 Fears Questionnaire for Chronic Medical Conditions can be used to assess fear among people at risk due to pre-existing medical conditions during the COVID-19 pandemic.
•People with chronic diseases are at risk if infected with the COVID-19 virus.•The COVID-19 Fears Questionnaire assesses fear among people with medical conditions.•121 people with scleroderma from 10 countries provided item suggestions.•Validity was supported in a sample of 787 scleroderma patients.•The questionnaire is available for use in studies during the COVID-19 crisis.
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