Depression, ART Adherence, and Receipt of Case Management Services by Adults with HIV in North Carolina, Medical Monitoring Project, 2009–2013

Depression among persons with HIV is associated with antiretroviral therapy (ART) interruption and discontinuation, virological failure, and poor clinical and survival outcomes. Case management services can address needs for emotional counseling and other supportive services to facilitate HIV care engagement. Using 2009–2013 North Carolina Medical Monitoring Project data from 910 persons engaged in HIV care, we estimated associations of case management utilization with “probable current depression” and with 100% ART dose adherence. After weighting, 53.2% of patients reported receiving case management, 21.7% reported depression, and 87.0% reported ART adherence. Depression prevalence was higher among those reporting case management (24.9%) than among other patients (17.6%) (p < 0.01). Case management was associated with depression among patients living above the poverty level [adjusted prevalence ratio (aPR), 2.05; 95% confidence interval (CI) 1.25–3.36], and not among other patients (aPR, 1.01; 95% CI 0.72–1.43). Receipt of case management was not associated with ART adherence (aPR, 1.00; 95% CI 0.95–1.05). Our analysis indicates a need for more effective depression treatment, even among persons receiving case management services. Self-reported ART adherence was high overall, though lower among persons experiencing depression (unadjusted prevalence ratio, 0.92; 95% CI 0.86–0.99). Optimal HIV clinical and prevention outcomes require addressing psychological wellbeing, monitoring of ART adherence, and effective case management services

Mouse genome-wide association studies and systems genetics uncover the genetic architecture associated with hepatic pharmacokinetic and pharmacodynamic properties of a constrained ethyl antisense oligonucleotide targeting Malat1

Antisense oligonucleotides (ASOs) have demonstrated variation of efficacy in patient populations. This has prompted our investigation into the contribution of genetic architecture to ASO pharmacokinetics (PK) and pharmacodynamics (PD). Genome wide association (GWA) and transcriptomic analysis in a hybrid mouse diversity panel (HMDP) were used to identify and validate novel genes involved in the uptake and efficacy of a single dose of a Malat1 constrained ethyl (cEt) modified ASO. The GWA of the HMDP identified two significant associations on chromosomes 4 and 10 with hepatic Malat1 ASO concentrations. Stabilin 2 (Stab2) and vesicle associated membrane protein 3 (Vamp3) were identified by ciseQTL analysis. HMDP strains with lower Stab2 expression and Stab2 KO mice displayed significantly lower PK than strains with higher Stab2 expression and the wild type (WT) animals respectively, confirming the role of Stab2 in regulating hepatic Malat1 ASO uptake. GWA examining ASO efficacy uncovered three loci associated with Malat1 potency: Small Subunit Processome Component (Utp11l) on chromosome 4, Rho associated coiled-coil containing protein kinase 2 (Rock2) and Aci-reductone dioxygenase (Adi1) on chromosome 12. Our results demonstrate the utility of mouse GWAS using the HMDP in detecting genes capable of impacting the uptake of ASOs, and identifies genes critical for the activity of ASOs in vivo

TOI-3785 b: A Low-Density Neptune Orbiting an M2-Dwarf Star

Using both ground-based transit photometry and high-precision radial velocity (RV) spectroscopy, we confirm the planetary nature of TOI-3785 b. This transiting Neptune orbits an M2-Dwarf star with a period of ~4.67 days, a planetary radius of 5.14 +/- 0.16 Earth Radii, a mass of 14.95 +4.10, -3.92 Earth Masses, and a density of 0.61 +0.18, -0.17 g/cm^3. TOI-3785 b belongs to a rare population of Neptunes (4 Earth Radii < Rp < 7 Earth Radii) orbiting cooler, smaller M-dwarf host stars, of which only ~10 have been confirmed. By increasing the number of confirmed planets, TOI-3785 b offers an opportunity to compare similar planets across varying planetary and stellar parameter spaces. Moreover, with a high transmission spectroscopy metric (TSM) of ~150 combined with a relatively cool equilibrium temperature of 582 +/- 16 K and an inactive host star, TOI-3785 b is one of the more promising low-density M-dwarf Neptune targets for atmospheric follow-up. Future investigation into atmospheric mass loss rates of TOI-3785 b may yield new insights into the atmospheric evolution of these low-mass gas planets around M-dwarfs.Comment: 22 pages, 6 figures, 6 tables, Submitted to A

Increased HIV Incidence in Men Who Have Sex with Men Despite High Levels of ART-Induced Viral Suppression: Analysis of an Extensively Documented Epidemic

Background: There is interest in expanding ART to prevent HIV transmission, but in the group with the highest levels of ART use, men-who-have-sex-with-men (MSM), numbers of new infections diagnosed each year have not decreased as ART coverage has increased for reasons which remain unclear. Methods: We analysed data on the HIV-epidemic in MSM in the UK from a range of sources using an individual-based simulation model. Model runs using parameter sets found to result in good model fit were used to infer changes in HIV-incidence and risk behaviour. Results: HIV-incidence has increased (estimated mean incidence 0.30/100 person-years 1990–1997, 0.45/100 py 1998–2010), associated with a modest (26%) rise in condomless sex. We also explored counter-factual scenarios: had ART not been introduced, but the rise in condomless sex had still occurred, then incidence 2006–2010 was 68% higher; a policy of ART initiation in all diagnosed with HIV from 2001 resulted in 32% lower incidence; had levels of HIV testing been higher (68% tested/year instead of 25%) incidence was 25% lower; a combination of higher testing and ART at diagnosis resulted in 62% lower incidence; cessation of all condom use in 2000 resulted in a 424% increase in incidence. In 2010, we estimate that undiagnosed men, the majority in primary infection, accounted for 82% of new infections. Conclusion: A rise in HIV-incidence has occurred in MSM in the UK despite an only modest increase in levels of condomless sex and high coverage of ART. ART has almost certainly exerted a limiting effect on incidence. Much higher rates of HIV testing combined with initiation of ART at diagnosis would be likely to lead to substantial reductions in HIV incidence. Increased condom use should be promoted to avoid the erosion of the benefits of ART and to prevent other serious sexually transmitted infections

Molecular Phylodynamics of the Heterosexual HIV Epidemic in the United Kingdom

The heterosexual risk group has become the largest HIV infected group in the United Kingdom during the last 10 years, but little is known of the network structure and dynamics of viral transmission in this group. The overwhelming majority of UK heterosexual infections are of non-B HIV subtypes, indicating viruses originating among immigrants from sub-Saharan Africa. The high rate of HIV evolution, combined with the availability of a very high density sample of viral sequences from routine clinical care has allowed the phylodynamics of the epidemic to be investigated for the first time. Sequences of the viral protease and partial reverse transcriptase coding regions from 11,071 patients infected with HIV of non-B subtypes were studied. Of these, 2774 were closely linked to at least one other sequence by nucleotide distance. Including the closest sequences from the global HIV database identified 296 individuals that were in UK-based groups of 3 or more individuals. There were a total of 8 UK-based clusters of 10 or more, comprising 143/2774 (5%) individuals, much lower than the figure of 25% obtained earlier for men who have sex with men (MSM). Sample dates were incorporated into relaxed clock phylogenetic analyses to estimate the dates of internal nodes. From the resulting time-resolved phylogenies, the internode lengths, used as estimates of maximum transmission intervals, had a median of 27 months overall, over twice as long as obtained for MSM (14 months), with only 2% of transmissions occurring in the first 6 months after infection. This phylodynamic analysis of non-B subtype HIV sequences representing over 40% of the estimated UK HIV-infected heterosexual population has revealed heterosexual HIV transmission in the UK is clustered, but on average in smaller groups and is transmitted with slower dynamics than among MSM. More effective intervention to restrict the epidemic may therefore be feasible, given effective diagnosis programmes

TOI-5205b: A Jupiter transiting an M dwarf near the Convective Boundary

We present the discovery of TOI-5205b, a transiting Jovian planet orbiting a solar metallicity M4V star, which was discovered using TESS photometry and then confirmed using a combination of precise radial velocities, ground-based photometry, spectra and speckle imaging. The host star TOI-5205 sits near the eponymous `Jao gap', which is the transition region between partially and fully-convective M dwarfs. TOI-5205b has one of the highest mass ratio for M dwarf planets with a mass ratio of almost 0.3$\%$, as it orbits a host star that is just $0.392 \pm 0.015$ $M_{\odot}$. Its planetary radius is $1.03 \pm 0.03~R_J$, while the mass is $1.08 \pm 0.06~M_J$. Additionally, the large size of the planet orbiting a small star results in a transit depth of $\sim 7\%$, making it one of the deepest transits of a confirmed exoplanet orbiting a main-sequence star. The large transit depth makes TOI-5205b a compelling target to probe its atmospheric properties, as a means of tracing the potential formation pathways. While there have been radial velocity-only discoveries of giant planets around mid M dwarfs, this is the first transiting Jupiter with a mass measurement discovered around such a low-mass host star. The high mass of TOI-5205b stretches conventional theories of planet formation and disk scaling relations that cannot easily recreate the conditions required to form such planets.Comment: Submitted to ApJ. Comments are welcome. arXiv admin note: text overlap with arXiv:2203.0717

The Hexameric Structures of Human Heat Shock Protein 90

The human 90-kDa heat shock protein (HSP90) functions as a dimeric molecular chaperone. HSP90 identified on the cell surface has been found to play a crucial role in cancer invasion and metastasis, and has become a validated anti-cancer target for drug development. It has been shown to self-assemble into oligomers upon heat shock or divalent cations treatment, but the functional role of the oligomeric states in the chaperone cycle is not fully understood.Here we report the crystal structure of a truncated HSP90 that contains the middle segment and the carboxy-terminal domain, termed MC-HSP90. The structure reveals an architecture with triangular bipyramid geometry, in which the building block of the hexameric assembly is a dimer. In solution, MC-HSP90 exists in three major oligomer states, namely dimer, tetramer and hexamer, which were elucidated by size exclusion chromatography and analytical ultracentrifugation. The newly discovered HSP90 isoform HSP90N that lacks the N-terminal ATPase domain also exhibited similar oligomerization states as did MC-HSP90.While lacking the ATPase domain, both MC-HSP90 and HSP90N can self-assemble into a hexameric structure, spontaneously. The crystal structure of MC-HSP90 reveals that, in addition to the C-terminal dimerization domain, the residue W320 in the M domain plays a critical role in its oligomerization. This study not only demonstrates how the human MC-HSP90 forms a hexamer, but also justifies the similar formation of HSP90N by using 3D modeling analysis

TOI-3984 A b and TOI-5293 A b: two temperate gas giants transiting mid-M dwarfs in wide binary systems

We confirm the planetary nature of two gas giants discovered by TESS to transit M dwarfs with stellar companions at wide separations. TOI-3984 A ($J=11.93$) is an M4 dwarf hosting a short-period ($4.353326 \pm 0.000005$ days) gas giant ($M_p=0.14\pm0.03~\mathrm{M_{J}}$ and $R_p=0.71\pm0.02~\mathrm{R_{J}}$) with a wide separation white dwarf companion. TOI-5293 A ($J=12.47$) is an M3 dwarf hosting a short-period ($2.930289 \pm 0.000004$ days) gas giant ($M_p=0.54\pm0.07~\mathrm{M_{J}}$ and $R_p=1.06\pm0.04~\mathrm{R_{J}}$) with a wide separation M dwarf companion. We characterize both systems using a combination of ground-based and space-based photometry, speckle imaging, and high-precision radial velocities from the Habitable-zone Planet Finder and NEID spectrographs. TOI-3984 A b ($T_{eq}=563\pm15$ K and $\mathrm{TSM}=138_{-27}^{+29}$) and TOI-5293 A b ($T_{eq}=675_{-30}^{+42}$ K and $\mathrm{TSM}=92\pm14$) are two of the coolest gas giants among the population of hot Jupiter-sized gas planets orbiting M dwarfs and are favorable targets for atmospheric characterization of temperate gas giants and three-dimensional obliquity measurements to probe system architecture and migration scenarios.Comment: Submitted to AJ, 42 pages, 14 figures. arXiv admin note: substantial text overlap with arXiv:2201.0996