Sequential LASER ART and CRISPR treatments eliminate HIV-1 in a subset of infected humanized mice

Elimination of HIV-1 requires clearance and removal of integrated proviral DNA from infected cells and tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice. HIV-1 subgenomic DNA fragments, spanning the long terminal repeats and the Gag gene, are excised in vivo, resulting in elimination of integrated proviral DNA; virus is not detected in blood, lymphoid tissue, bone marrow and brain by nested and digital-droplet PCR as well as RNAscope tests. No CRISPR-Cas9 mediated off-target effects are detected. Adoptive transfer of human immunocytes from dual treated, virus-free animals to uninfected humanized mice fails to produce infectious progeny virus. In contrast, HIV-1 is readily detected following sole LASER ART or CRISPR-Cas9 treatment. These data provide proof-of-concept that permanent viral elimination is possible

Types of Stroke among People Living with HIV in the United States

Background: Most studies of stroke in people living with HIV (PLWH) do not use verified stroke diagnoses, are small, and/or do not differentiate stroke types and subtypes.Setting: CNICS, a U.S. multisite clinical cohort of PLWH in care.Methods: We implemented a centralized adjudication stroke protocol to identify stroke type, subtype, and precipitating conditions identified as direct causes including infection and illicit drug use in a large diverse HIV cohort.Results: Among 26,514 PLWH, there were 401 strokes, 75% of which were ischemic. Precipitating factors such as sepsis or same-day cocaine use were identified in 40% of ischemic strokes. Those with precipitating factors were younger, had more severe HIV disease, and fewer traditional stroke risk factors such as diabetes and hypertension. Ischemic stroke subtypes included cardioembolic (20%), large vessel atherosclerosis (13%), and small vessel (24%) ischemic strokes. Individuals with small vessel strokes were older, were more likely to have a higher current CD4 cell count than those with cardioembolic strokes and had the highest mean blood pressure of the ischemic stroke subtypes.Conclusion: Ischemic stroke, particularly small vessel and cardioembolic subtypes, were the most common strokes among PLWH. Traditional and HIV-related risk factors differed by stroke type/subtype. Precipitating factors including infections and drug use were common. These results suggest that there may be different biological phenomena occurring among PLWH and that understanding HIV-related and traditional risk factors and in particular precipitating factors for each type/subtype may be key to understanding, and therefore preventing, strokes among PLWH

State of nature 2019

State of Nature 2019 presents an overview of how the country’s wildlife is faring, looking back over nearly 50 years of monitoring to see how nature has changed in the UK, its Crown Dependencies and Overseas Territories. As well as this long-term view, we focus on what has happened in the last decade, and so whether things are getting better or worse for nature. In addition, we have assessed the pressures that are acting on nature, and the responses being made, collectively, to counter these pressures

Associations between alcohol and cigarette use and type 1 and 2 myocardial infarction among people with HIV

Objectives: People with HIV have a higher risk of myocardial infarction (MI) than the general population, with a greater proportion of type 2 MI (T2MI) due to oxygen demand–supply mismatch compared with type 1 (T1MI) resulting from atherothrombotic plaque disruption. People living with HIV report a greater prevalence of cigarette and alcohol use than do the general population. Alcohol use and smoking as risk factors for MI by type are not well studied among people living with HIV. We examined longitudinal associations between smoking and alcohol use patterns and MI by type among people living with HIV. Design and Methods: Using longitudinal data from the Centers for AIDS Research Network of Integrated Clinical Systems cohort, we conducted time-updated Cox proportional hazards models to determine the impact of smoking and alcohol consumption on adjudicated T1MI and T2MI. Results: Among 13 506 people living with HIV, with a median 4 years of follow-up, we observed 177 T1MI and 141 T2MI. Current smoking was associated with a 60% increase in risk of both T1MI and T2MI. In addition, every cigarette smoked per day was associated with a 4% increase in risk of T1MI, with a suggestive, but not significant, 2% increase for T2MI. Cigarette use had a greater impact on T1MI for men than for women and on T2MI for women than for men. Increasing alcohol use was associated with a lower risk of T1MI but not T2MI. Frequency of heavy episodic alcohol use was not associated with MI. Conclusions: Our findings reinforce the prioritization of smoking reduction, even without cessation, and cessation among people living with HIV for MI prevention and highlight the different impacts on MI type by gender

A Robust Parser-Interpreter for Jazz Chord Sequences

Hierarchical structure similar to that associated with prosody and syntax in language can be identified in the rhythmic and harmonic progressions that underlie Western tonal music. Analysing such musical struc-ture resembles natural language parsing: it requires the derivation of an underlying interpretation from an un-structured sequence of highly ambiguous elements— in the case of music, the notes. The task here is not merely to decide whether the sequence is grammati-cal, but rather to decide which among a large number of analyses it has. An analysis of this sort is a part of the cognitive processing performed by listeners familiar with a musical idiom, whether musically trained or not. Our focus is on the analysis of the structure of ex-pectations and resolutions created by harmonic progres-sions. Building on previous work, we define a theory of tonal harmonic progression, which plays a role analo-gous to semantics in language. Our parser uses a formal grammar of jazz chord sequences, of a kind widely used for natural language processing (NLP), to map music, in the form of chord sequences used by performers, onto a representation of the structured relationships between chords. It uses statistical modelling techniques used for wide-coverage parsing in NLP to make practical pars-ing feasible in the face of considerable ambiguity in the grammar. Using machine learning over a small corpus of jazz chord sequences annotated with harmonic anal-yses, we show that grammar-based musical interpreta-tion using simple statistical parsing models is more ac-curate than a baseline HMM. The experiment demon-strates that statistical techniques adapted from NLP can be profitably applied to the analysis of harmonic struc-ture