Prions are proteins that adopt alternative conformations that become self-propagating; the PrPScprion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple ...system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/−mice expressing α-synuclein (A53T). The TgM83+/−mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/−mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.
Summary Background The effect of HIV pre-exposure prophylaxis (PrEP) depends on uptake, adherence, and sexual practices. We aimed to assess these factors in a cohort of HIV-negative people at risk of ...infection. Methods In our cohort study, men and transgender women who have sex with men previously enrolled in PrEP trials (ATN 082, iPrEx, and US Safety Study) were enrolled in a 72 week open-label extension. We measured drug concentrations in plasma and dried blood spots in seroconverters and a random sample of seronegative participants. We assessed PrEP uptake, adherence, sexual practices, and HIV incidence. Statistical methods included Poisson models, comparison of proportions, and generalised estimating equations. Findings We enrolled 1603 HIV-negative people, of whom 1225 (76%) received PrEP. Uptake was higher among those reporting condomless receptive anal intercourse (416/519 81% vs 809/1084 75%, p=0·003) and having serological evidence of herpes (612/791 77% vs 613/812 75% p=0·03). Of those receiving PrEP, HIV incidence was 1·8 infections per 100 person-years, compared with 2·6 infections per 100 person-years in those who concurrently did not choose PrEP (HR 0·51, 95% CI 0·26–1·01, adjusted for sexual behaviours), and 3·9 infections per 100 person-years in the placebo group of the previous randomised phase (HR 0·49, 95% CI 0·31–0·77). Among those receiving PrEP, HIV incidence was 4·7 infections per 100 person-years if drug was not detected in dried blood spots, 2·3 infections per 100 person-years if drug concentrations suggested use of fewer than two tablets per week, 0·6 per 100 person-years for use of two to three tablets per week, and 0·0 per 100 person-years for use of four or more tablets per week (p<0·0001). PrEP drug concentrations were higher among people of older age, with more schooling, who reported non-condom receptive anal intercourse, who had more sexual partners, and who had a history of syphilis or herpes. Interpretation PrEP uptake was high when made available free of charge by experienced providers. The effect of PrEP is increased by greater uptake and adherence during periods of higher risk. Drug concentrations in dried blood spots are strongly correlated with protective benefit. Funding US National Institutes of Health.
Reply to Niu and Drain Anderson, Peter L; Marzinke, Mark A; Glidden, David V
Clinical infectious diseases,
03/2024, Letnik:
78, Številka:
3
Journal Article
Preexposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) reduced HIV acquisition in the iPrEx trial among men who have sex with men and transgender women. ...Self-reported sexual risk behavior decreased overall, but may be affected by reporting bias. We evaluated potential risk compensation using biomarkers of sexual risk behavior.
Sexual practices were assessed at baseline and quarterly thereafter; perceived treatment assignment and PrEP efficacy beliefs were assessed at 12 weeks. Among participants with ≥1 follow-up behavioral assessment, sexual behavior, syphilis, and HIV infection were compared by perceived treatment assignment, actual treatment assignment, and perceived PrEP efficacy.
Overall, acute HIV infection and syphilis decreased during follow-up. Compared with participants believing they were receiving placebo, participants believing they were receiving FTC/TDF reported more receptive anal intercourse partners prior to initiating drug (12.8 vs. 7.7, P = 0.04). Belief in receiving FTC/TDF was not associated with an increase in receptive anal intercourse with no condom (ncRAI) from baseline through follow-up (risk ratio RR 0.9, 95% confidence interval CI: 0.6-1.4; P = 0.75), nor with a decrease after stopping study drug (RR 0.8, 95% CI: 0.5-1.3; P = 0.46). In the placebo arm, there were trends toward lower HIV incidence among participants believing they were receiving FTC/TDF (incidence rate ratio IRR 0.8, 95% CI: 0.4-1.8; P = 0.26) and also believing it was highly effective (IRR 0.5, 95% CI: 0.1-1.7; P = 0.12).
There was no evidence of sexual risk compensation in iPrEx. Participants believing they were receiving FTC/TDF had more partners prior to initiating drug, suggesting that risk behavior was not a consequence of PrEP use.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adherence to non-pharmaceutical interventions to prevent the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been highly variable across settings, particularly in the ...USA. In this Personal View, we review data supporting the importance of the viral inoculum (the dose of viral particles from an infected source over time) in increasing the probability of infection in respiratory, gastrointestinal, and sexually transmitted viral infections in humans. We also review the available evidence linking the relationship of the viral inoculum to disease severity. Non-pharmaceutical interventions might reduce the susceptibility to SARS-CoV-2 infection by reducing the viral inoculum when there is exposure to an infectious source. Data from physical sciences research suggest that masks protect the wearer by filtering virus from external sources, and others by reducing expulsion of virus by the wearer. Social distancing, handwashing, and improved ventilation also reduce the exposure amount of viral particles from an infectious source. Maintaining and increasing non-pharmaceutical interventions can help to quell SARS-CoV-2 as we enter the second year of the pandemic. Finally, we argue that even as safe and effective vaccines are being rolled out, non-pharmaceutical interventions will continue to play an essential role in suppressing SARS-CoV-2 transmission until equitable and widespread vaccine administration has been completed.
Evidence from resource-rich settings indicates that many people continue to have persistent symptoms following acute SARS-CoV-2 infection, called post-acute sequelae of COVID-19 (PASC). Only a few ...studies have described PASC in sub-Saharan Africa (SSA). We aimed to describe PASC in Liberia.
We randomly sampled all people who were reported from the most populous county to the Liberian Ministry of Health (MOH) as having a laboratory-confirmed SARS-CoV-2 infection from June to August 2021. We interviewed individuals by phone 3 to 6 months later. Those with persistence of at least one symptom were considered to have PASC.
From among 2848 people reported to the MOH from Montserrado County during the period of interest, we randomly selected 650; of these, 548 (84.3%) were reached and 505 (92.2%) of those who were contacted were interviewed. The median age was 38 years (interquartile range (IQR), 30-49), and 43.6% were female. During acute infection, 40.2% were asymptomatic, 53.9% had mild/moderate disease and 6.9% had severe/critical disease. Among the 59.8% (n = 302) who were initially symptomatic, 50.2% (n = 152) reported at least one persistent symptom; the most common persistent symptoms were fatigue (21.2%), headache (16.2%) and cough (12.6%); 40.1% reported that PASC significantly affected their daily activities. Being hospitalized with moderate disease adjusted prevalence ratio (aPR), 2.00 (95% CI, 1.59 to 2.80 or severe/critical disease aPR, 2.11 (95% CI, 1.59 to 2.80) was associated with PASC, compared with those not hospitalized. Females were more likely than males to report persistent fatigue aPR, 1.67 (95% CI, 1.08 to 2.57).
Our findings suggest that persistent symptoms may have affected a large proportion of people with initially symptomatic COVID-19 in west Africa and highlight the need to create awareness among infected people and health care professionals.
Abstract
Background
The biological processes associated with postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are unknown.
Methods
We measured ...soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (<90 days) and late (>90 days) timepoints. We defined PASC as the presence of 1 or more coronavirus disease 2019 (COVID-19)–attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed-effects models with terms for PASC and early and late recovery time periods.
Results
During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including tumor necrosis factor–α (1.14-fold higher mean ratio 95% confidence interval {CI}, 1.01–1.28; P = .028) and interferon-γ–induced protein 10 (1.28-fold higher mean ratio 95% CI, 1.01–1.62; P = .038). Among those with PASC, there was a trend toward higher interleukin 6 levels during early recovery (1.29-fold higher mean ratio 95% CI, .98–1.70; P = .07), which became more pronounced in late recovery (1.44-fold higher mean ratio 95% CI, 1.11–1.86; P < .001). These differences were more pronounced among those with a greater number of PASC symptoms.
Conclusions
Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.
Compared to individuals reporting full recovery, individuals with symptoms for >90 days following COVID-19 had subtle elevations in levels of certain markers of immune activation. Further characterization of these processes might identify therapeutic targets for those experiencing postacute sequelae of SARS-CoV-2tion.
Acute kidney injury (AKI) has numerous sequelae. Repeated episodes of AKI may be an important determinant of adverse outcomes, including chronic kidney disease and death. In a population-based cohort ...study, we sought to determine the incidence of and predictors for recurrent AKI.
Retrospective cohort study.
38,659 hospitalized members of Kaiser Permanente Northern California who experienced an episode of AKI from 2006 to 2013.
Demographic, clinical, and laboratory data, including baseline kidney function, proteinuria, hemoglobin level, comorbid conditions, and severity of AKI.
Incidence and predictors of recurrent AKI.
Multivariable Cox proportional hazard regression.
11,048 (28.6%) experienced a second hospitalization complicated by AKI during follow-up (11.2 episodes/100 person-years), with the second episode of AKI occurring a median of 0.6 (interquartile range, 0.2-1.9) years after the first hospitalization. In multivariable analyses, older age, black race, and Hispanic ethnicity were associated with recurrent AKI, along with lower estimated glomerular filtration rate, proteinuria, and anemia. Concomitant conditions, including heart failure, acute coronary syndrome, diabetes, and chronic liver disease, were also multivariable predictors of recurrent AKI. Those who had higher acuity of illness during the initial hospitalization were more likely to have recurrent AKI, but greater AKI severity of the index episode was not independently associated with increased risk for recurrent AKI. In multivariable analysis of matched patients, recurrent AKI was associated with an increased rate of death (HR, 1.66; 95% CI, 1.57-1.77).
Analyses were based on clinically available data, rather than protocol-driven timed measurements of kidney function.
Recurrent AKI is a common occurrence after a hospitalization complicated by AKI. Based on routinely available patient characteristics, our findings could facilitate identification of the subgroup of patients with AKI who may benefit from more intensive follow-up to potentially avoid recurrent AKI episodes.
Collider-conditioning bias is a common concern in clinical epidemiology and can be difficult to recognize. Collider-conditioning bias is defined as the alteration in the association between an ...exposure and an outcome under study when conditioning on (via restriction, stratification or regression adjustment) a third factor influenced by both exposure and outcome. Collider-conditioning bias may also be induced by conditioning on a third factor influenced by causes of both the exposure and outcome of primary interest. The shared consequence of the exposure and outcome (or their causes) is referred to as a collider. Collider bias can be induced by in-selection (e.g., recruitment) or out-selection (e.g., loss-to-follow-up, mortality) processes, as well as missing data or analytic choices about which variables are included as covariates. Collider-conditioning bias is especially relevant in clinical epidemiology because it is plausible whenever examining determinants of disease progression or prognosis if the exposure under study is also a cause of the initial occurrence of the disease. Collider-conditioning bias can lead to incorrect inferences about the study sample, the source population, and external populations. Drawing directed acyclic graphs (DAGs) can aid in identification of colliders and quantitative bias analysis may be useful to estimate the magnitude of collider-conditioning bias. Many notorious examples of selection bias are attributable to collider-conditioning. Identifying the potential for collider-conditioning can help researchers avoid or correct for the bias.
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