In most patients, current antiretroviral therapy (ART) regimens can rapidly reduce plasma viral load. However, even after years of effective treatment, a significant proportion of patients show ...residual plasma viremia below the clinical detection limit. Although residual viremia might be associated with increased chronic immune activation and morbidity, its origin and its potential role in the replenishment of the viral reservoir during suppressive ART is not completely understood. We performed an in-depth genetic analysis of the total and episomal cell-associated viral DNA (vDNA) repertoire in purified CD4(+) T cell subsets of three HIV-infected individuals, and used phylogenetic analysis to explore its relationship with plasma viruses.
The predominant proviral reservoir was established in naïve or memory (central and transitional) CD4(+) T cell subsets in patients harboring X4- or R5-tropic viruses, respectively. Regardless of the viral tropism, most plasma viruses detected under suppressive ART resembled the proviral reservoir identified in effector and transitional memory CD4(+) T-cell subsets in blood, suggesting that residual viremia originates from these cells in either blood or lymphoid tissue. Most importantly, sequences in episomal vDNA in CD4(+) T-cells were not well represented in residual viremia.
Viral tropism determines the differential distribution of viral reservoir among CD4(+) T-cell subsets. In spite of viral tropism, the effector and transitional memory CD4(+) T-cells subsets are the main source of residual viremia during suppressive ART, even though their contribution to the total proviral pool is small. However, the lack of concordance between residual viremia and viral variants driving de novo infection of CD4(+) T cells on ART may reflect the predominance of defective plasma HIV RNA genomes. These findings highlight the need for monitoring the multiple viral RNA/DNA persistence markers, based on their differential contribution to viral persistence.
Objective
Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large ...multicenter cross‐sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE‐HS) correlate with clinical features.
Methods
We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1‐weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA‐Epilepsy consortium, comprising 804 people with MTLE‐HS and 1625 healthy controls from 25 centers. Features with a moderate case–control effect size (Cohen d ≥ .5) were used to train an event‐based model (EBM), which estimates a sequence of disease‐specific biomarker changes from cross‐sectional data and assigns a biomarker‐based fine‐grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance.
Results
In MTLE‐HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10−16), age at onset (ρ = −.18, p = 9.82 × 10−7), and ASM resistance (area under the curve = .59, p = .043, Mann–Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE‐HS with mild or nondetectable abnormality on T1W MRI.
Significance
From cross‐sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE‐HS subjects in other cohorts and help establish connections between imaging‐based progression staging and clinical features.
In young adults (18 to 49 years old), investigation of the acute respiratory distress syndrome (ARDS) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been limited. We ...evaluated the risk factors and outcomes of ARDS following infection with SARS-CoV-2 in a young adult population.
A retrospective cohort study was conducted between January 1st, 2020 and February 28th, 2021 using patient-level electronic health records (EHR), across 241 United States hospitals and 43 European hospitals participating in the Consortium for Clinical Characterization of COVID-19 by EHR (4CE). To identify the risk factors associated with ARDS, we compared young patients with and without ARDS through a federated analysis. We further compared the outcomes between young and old patients with ARDS.
Among the 75,377 hospitalized patients with positive SARS-CoV-2 PCR, 1001 young adults presented with ARDS (7.8% of young hospitalized adults). Their mortality rate at 90 days was 16.2% and they presented with a similar complication rate for infection than older adults with ARDS. Peptic ulcer disease, paralysis, obesity, congestive heart failure, valvular disease, diabetes, chronic pulmonary disease and liver disease were associated with a higher risk of ARDS. We described a high prevalence of obesity (53%), hypertension (38%- although not significantly associated with ARDS), and diabetes (32%).
Trough an innovative method, a large international cohort study of young adults developing ARDS after SARS-CoV-2 infection has been gather. It demonstrated the poor outcomes of this population and associated risk factor.
Designer DNA structures have garnered much interest as a way of assembling novel nanoscale architectures with exquisite control over the positioning of discrete molecules or nanoparticles. Exploiting ...this potential for a variety of applications such as light-harvesting, molecular electronics, or biosensing is contingent on the degree to which various nanoarchitectures with desired molecular functionalizations can be realized, and this depends critically on characterization. Many techniques exist for analyzing DNA-organized nanostructures; however, these are almost never used in concert because of overlapping concerns about their differing character, measurement environments, and the disparity in DNA modification chemistries and probe structure or size. To assess these concerns and to see what might be gleaned from a multimodal characterization, we intensively study a single DNA nanostructure using a multiplicity of methods. Our test bed is a linear 100 base-pair double-stranded DNA that has been modified by a variety of chemical handles, dyes, semiconductor quantum dots, gold nanoparticles, and electroactive labels. To this we apply a combination of physical/optical characterization methods including electrophoresis, atomic force microscopy, transmission electron microscopy, dynamic light scattering, Förster resonance energy transfer, voltammetry, and structural modeling. In general, the results indicate that the differences among the techniques are not so large as to prevent their effective use in combination, that the data tend to be corroborative, and that differences observed among them can actually be quite informative.
While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking.
A ...retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1–365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021.
Advanced age (HR 2.77, 95%CI 2.53–3.04, p < 0.0001), severe COVID-19 (HR 2.91, 95%CI 2.03–4.17, p < 0.0001), severe AKI (KDIGO stage 3: HR 4.22, 95%CI 3.55–5.00, p < 0.0001), and ischemic heart disease (HR 1.26, 95%CI 1.14–1.39, p < 0.0001) were associated with worse mortality outcomes. AKI severity (KDIGO stage 3: HR 0.41, 95%CI 0.37–0.46, p < 0.0001) was associated with worse kidney function recovery, whereas remdesivir use (HR 1.34, 95%CI 1.17–1.54, p < 0.0001) was associated with better kidney function recovery. In a subset of patients without chronic kidney disease, advanced age (HR 1.38, 95%CI 1.20–1.58, p < 0.0001), male sex (HR 1.67, 95%CI 1.45–1.93, p < 0.0001), severe AKI (KDIGO stage 3: HR 11.68, 95%CI 9.80–13.91, p < 0.0001), and hypertension (HR 1.22, 95%CI 1.10–1.36, p = 0.0002) were associated with post-AKI kidney function impairment. Furthermore, patients with COVID-19-associated AKI had significant and persistent elevations of baseline serum creatinine 125% or more at 180 days (RR 1.49, 95%CI 1.32–1.67) and 365 days (RR 1.54, 95%CI 1.21–1.96) compared to COVID-19 patients with no AKI.
COVID-19-associated AKI was associated with higher mortality, and severe COVID-19-associated AKI was associated with worse long-term post-AKI kidney function recovery.
Authors are supported by various funders, with full details stated in the acknowledgement section.
It has been suggested that there is an increased risk of treatment failure in episodes of MRSA bloodstream infection (BSI) caused by strains with high vancomycin MICs. However, it is unknown if this ...phenomenon may also act as a risk factor for the development of infective endocarditis (IE).
We analysed 207 episodes of catheter-related (CR)-BSI recruited from June 2008 to December 2009 within a prospective study on MRSA BSI in 21 Spanish hospitals. Vancomycin susceptibility was centrally tested. The impact of high vancomycin MIC values (≥1.5 mg/L by Etest) on the subsequent development of IE was investigated by Cox regression.
High vancomycin MIC values were observed in 46.9% of the isolates. Initial therapy consisted of vancomycin 99 episodes (44.7%), daptomycin 25 (12.1%), linezolid 18 (8.7%) and other antistaphylococcal agents 16 (7.7%). Haematogenous complications occurred in 41 patients (19.8%), including 10 episodes complicated by IE. Early (48 h) and late (30 day) all-cause mortality were 3.4% and 25.1%, respectively. High vancomycin MIC isolates were more common among patients that developed IE compared with those free from this complication 90.9% (9/10) versus 44.7% (88/197); P = 0.007. This association remained significant after adjusting for multiple confounders (including initial antibiotic therapy and catheter removal) in different models (minimum hazard ratio: 9.18; 95% CI: 1.16-72.78; P = 0.036). There were no differences in mortality according to vancomycin MIC values.
Decreased susceptibility to vancomycin acted as a predictor of the development of IE complicating MRSA CR-BSI.
The well-known helical conformations of double stranded DNA and poly(alanine) are stabilized by inter- and intramolecular hydrogen bonds, respectively. Perfluorinated n-alkanes also exhibit stable ...helical conformations, with ordered chiralities at low temperatures. In the absence of hydrogen bonds, one may ask what forces stabilize perfluorinated n-alkane helices. We combine ab initio and empirical data to study the likely classical source of this helical behavior. Past studies point to bad sterics (van der Waals interactions) between neighboring fluorine atoms as the source of helicity in perfluorinated linear alkanes. In these early studies electrostatics were ignored. We undertook a detailed force field parameter optimization strategy, using experimental and ab initio data, to obtain transferable, uncorrelated estimates of the separate classical energy components. We find that the dominant energy term, the source of helicity, is electrostatics. The coulomb repulsion, from a classical fixed-charge model, reproduces reasonably well the position of the energy minima and the energy barrier between the helical and the all-trans conformations. Polarization effects, changes in atomic charges as a result of conformational changes, are not significant. Dihedral interactions and van der Waals terms adjust the exact position of the minima only slightly. In the absence of electrostatic contributions, van der Waals and dihedral interactions predict the incorrect stable conformations.
Background and aim
Over 80% (365/454) of the nation’s centers participated in the Italian Society of Nephrology COVID-19 Survey. Out of 60,441 surveyed patients, 1368 were infected as of April 23rd, ...2020. However, center-specific proportions showed substantial heterogeneity. We therefore undertook new analyses to identify explanatory factors, contextual effects, and decision rules for infection containment.
Methods
We investigated fixed factors and contextual effects by multilevel modeling. Classification and Regression Tree (CART) analysis was used to develop decision rules.
Results
Increased positivity among hemodialysis patients was predicted by center location incidence rate ratio (IRR) 1.34, 95% confidence interval (CI) 1.20–1.51, positive healthcare workers (IRR 1.09, 95% CI 1.02–1.17), test-all policy (IRR 5.94, 95% CI 3.36–10.45), and infected proportion in the general population (IRR 1.002, 95% CI 1.001–1.003) (all p < 0.01). Conversely, lockdown duration exerted a protective effect (IRR 0.95, 95% CI 0.94–0.98) (p < 0.01). The province-contextual effects accounted for 10% of the total variability. Predictive factors for peritoneal dialysis and transplant cases were center location and infected proportion in the general population. Using recursive partitioning, we identified decision thresholds at general population incidence ≥ 229 per 100,000 and at ≥ 3 positive healthcare workers.
Conclusions
Beyond fixed risk factors, shared with the general population, the increased and heterogeneous proportion of positive patients is related to the center’s testing policy, the number of positive patients and healthcare workers, and to contextual effects at the province level. Nephrology centers may adopt simple decision rules to strengthen containment measures timely.
Summary
Little data are available on renal toxicity exerted by direct‐acting antivirals (DAAs) in real life. The aim of this study was to assess the impact of direct‐acting antivirals against ...hepatitis C virus infection currently used in Spain and Portugal on the estimated glomerular filtration rate (eGFR) in clinical practise. From an international, prospective multicohort study, patients treated with DAAs for at least 12 weeks and with eGFR ≥30 mL/min per 1.73 m2 at baseline were selected. eGFR was determined using the CKD‐EPI formula. A total of 1131 patients were included; 658 (58%) were HIV/HCV‐coinfected patients. Among the 901 patients treated for 12 weeks, median (interquartile range) eGFR was 100 (87‐107) at baseline vs 97 (85‐105) mL/min per 1.73 m2 at week 12 of follow‐up (FU12) post‐treatment (P < .001). For HIV‐coinfected subjects who received tenofovir plus a ritonavir‐boosted HIV protease inhibitor (PI/r), baseline vs FU12 eGFR were 104 (86‐109) vs 104 (91‐110) mL/min per 1.73 m2 (P = .913). Among subjects receiving ombitasvir/paritaprevir with or without dasabuvir, eGFR did not show any significant change. Of 1100 subjects with eGFR >60 mL/min per 1.73 m2 at baseline, 22 (2%) had eGFR <60 mL/min per 1.73 m2 at FU12, but none presented with eGFR <30 mL/min per 1.73 m2. In conclusion, eGFR slightly declines during therapy with all‐oral DAAs and this effect persists up to 12 weeks after stopping treatment in subjects with normal to moderately impaired renal function, regardless of HIV status. Concomitant use of tenofovir plus PI/r does not seem to have an impact on eGFR.
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