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The pathological relevance of naturally occurring antibodies to β-amyloid (NAbs-Aβ) in Alzheimer’s disease (AD) remains unclear. We aimed to investigate their levels and associations with Aβ burden and cognitive decline in AD in a cross-sectional cohort from China and a longitudinal cohort from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. NAbs-Aβ levels in plasma and cerebrospinal fluid (CSF) were tested according to their epitopes. Levels of NAbs targeting the amino terminus of Aβ increased, and those targeting the mid-domain of Aβ decreased in both CSF and plasma in AD patients. Higher plasma levels of NAbs targeting the amino terminus of Aβ and lower plasma levels of NAbs targeting the mid-domain of Aβ were associated with higher brain amyloidosis at baseline and faster cognitive decline during follow-up. Our findings suggest a dynamic response of the adaptive immune system in the progression of AD and are relevant to current passive immunotherapeutic strategies.…

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis–associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)–induced PF are characterized by the altered methyl-CpG–binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor–β1 (TGF-β1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote the macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support the possibility that MBD2 could be a viable target against PF in clinical settings.…

Inflammation is a hallmark of aging and is negatively affecting female fertility. In this study, we evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in WT mice during reproductive aging. High expression of NLRP3, caspase-1, and IL-1β was also observed in granulosa cells from patients with ovarian insufficiency. Ablation of NLRP3 improved the survival and pregnancy rates and increased anti-Müllerian hormone levels and autophagy rates in ovaries. Deficiency of NLRP3 also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of Nlrp3–/– mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.…

The recovery process of COVID-19 patients is unclear. Some recovered patients complain of continued shortness of breath. Vasculopathy has been reported in COVID-19, stressing the importance of probing pulmonary microstructure and function at the alveolar-capillary interface. While computed tomography (CT) detects structural abnormalities, little is known about the impact of disease on lung function. 129Xe magnetic resonance imaging (MRI) is a technique uniquely capable of assessing ventilation, microstructure, and gas exchange. Using 129Xe MRI, we found that COVID-19 patients show a higher rate of ventilation defects (5.9% versus 3.7%), unchanged microstructure, and longer gas-blood exchange time (43.5 ms versus 32.5 ms) compared with healthy individuals. These findings suggest that regional ventilation and alveolar airspace dimensions are relatively normal around the time of discharge, while gas-blood exchange function is diminished. This study establishes the feasibility of localized lung function measurements in COVID-19 patients and their potential usefulness as a supplement to structural imaging.…

Here, we report the topology-matched design of heteromultivalent nanostructures as potent and broad-spectrum virus entry inhibitors based on the host cell membrane. Initially, we investigate the virus binding dynamics to validate the better binding performance of the heteromultivalent moieties as compared to homomultivalent ones. The heteromultivalent binding moieties are transferred to nanostructures with a bowl-like shape matching the viral spherical surface. Unlike the conventional homomultivalent inhibitors, the heteromultivalent ones exhibit a half maximal inhibitory concentration of 32.4 ± 13.7 μg/ml due to the synergistic multivalent effects and the topology-matched shape. At a dose without causing cellular toxicity, >99.99% reduction of virus propagation has been achieved. Since multiple binding sites have also been identified on the S protein of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), we envision that the use of heteromultivalent nanostructures may also be applied to develop a potent inhibitor to prevent coronavirus infection.…

The COVID-19 pandemic has created a public health crisis. Because SARS-CoV-2 can spread from individuals with presymptomatic, symptomatic, and asymptomatic infections, the reopening of societies and the control of virus spread will be facilitated by robust population screening, for which virus testing will often be central. After infection, individuals undergo a period of incubation during which viral titers are too low to detect, followed by exponential viral growth, leading to peak viral load and infectiousness and ending with declining titers and clearance. Given the pattern of viral load kinetics, we model the effectiveness of repeated population screening considering test sensitivities, frequency, and sample-to-answer reporting time. These results demonstrate that effective screening depends largely on frequency of testing and speed of reporting and is only marginally improved by high test sensitivity. We therefore conclude that screening should prioritize accessibility, frequency, and sample-to-answer time; analytical limits of detection should be secondary.…

The family Iflaviridae includes economically important viruses of the western honeybee such as deformed wing virus, slow bee paralysis virus, and sacbrood virus. Iflaviruses have nonenveloped virions and capsids organized with icosahedral symmetry. The genome release of iflaviruses can be induced in vitro by exposure to acidic pH, implying that they enter cells by endocytosis. Genome release intermediates of iflaviruses have not been structurally characterized. Here, we show that conformational changes and expansion of iflavirus RNA genomes, which are induced by acidic pH, trigger the opening of iflavirus particles. Capsids of slow bee paralysis virus and sacbrood virus crack into pieces. In contrast, capsids of deformed wing virus are more flexible and open like flowers to release their genomes. The large openings in iflavirus particles enable the fast exit of genomes from capsids, which decreases the probability of genome degradation by the RNases present in endosomes.…

Copper-containing nitrite reductases (CuNiRs), encoded by nirK gene, are found in all kingdoms of life with only 5% of CuNiR denitrifiers having two or more copies of nirK. Recently, we have identified two copies of nirK genes in several α-proteobacteria of the order Rhizobiales including Bradyrhizobium sp. ORS 375, encoding a four-domain heme-CuNiR and the usual two-domain CuNiR (Br2DNiR). Compared with two of the best-studied two-domain CuNiRs represented by the blue (AxNiR) and green (AcNiR) subclasses, Br2DNiR, a blue CuNiR, shows a substantially lower catalytic efficiency despite a sequence identity of ~70%. Advanced synchrotron radiation and x-ray free-electron laser are used to obtain the most accurate (atomic resolution with unrestrained SHELX refinement) and damage-free (free from radiation-induced chemistry) structures, in as-isolated, substrate-bound, and product-bound states. This combination has shed light on the protonation states of essential catalytic residues, additional reaction intermediates, and how catalytic efficiency is modulated.…

Transmission of highly infectious respiratory diseases, including SARS-CoV-2, is facilitated by the transport of exhaled droplets and aerosols that can remain suspended in air for extended periods of time. A passenger car cabin represents one such situation with an elevated risk of pathogen transmission. Here, we present results from numerical simulations to assess how the in-cabin microclimate of a car can potentially spread pathogenic species between occupants for a variety of open and closed window configurations. We estimate relative concentrations and residence times of a noninteracting, passive scalar—a proxy for infectious particles—being advected and diffused by turbulent airflows inside the cabin. An airflow pattern that travels across the cabin, farthest from the occupants, can potentially reduce the transmission risk. Our findings reveal the complex fluid dynamics during everyday commutes and nonintuitive ways in which open windows can either increase or suppress airborne transmission.…

Down syndrome (DS), caused by trisomy of chromosome 21, is the most significant risk factor for early-onset Alzheimer’s disease (AD); however, underlying mechanisms linking DS and AD remain unclear. Here, we show that triplication of homologous chromosome 21 genes aggravates neuroinflammation in combined murine DS-AD models. Overexpression of USP25, a deubiquitinating enzyme encoded by chromosome 21, results in microglial activation and induces synaptic and cognitive deficits, whereas genetic ablation of Usp25 reduces neuroinflammation and rescues synaptic and cognitive function in 5xFAD mice. Mechanistically, USP25 deficiency attenuates microglia-mediated proinflammatory cytokine overproduction and synapse elimination. Inhibition of USP25 reestablishes homeostatic microglial signatures and restores synaptic and cognitive function in 5xFAD mice. In summary, we demonstrate an unprecedented role for trisomy 21 and pathogenic effects associated with microgliosis as a result of the increased USP25 dosage, implicating USP25 as a therapeutic target for neuroinflammation in DS and AD.…

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.…

The recent outbreaks of SARS-CoV-2 pose a global health emergency. The SARS-CoV-2 trimeric spike (S) glycoprotein interacts with the human ACE2 receptor to mediate viral entry into host cells. We report the cryo-EM structures of a tightly closed SARS-CoV-2 S trimer with packed fusion peptide and an ACE2-bound S trimer at 2.7- and 3.8-Å resolution, respectively. Accompanying ACE2 binding to the up receptor-binding domain (RBD), the associated ACE2-RBD exhibits continuous swing motions. Notably, the SARS-CoV-2 S trimer appears much more sensitive to the ACE2 receptor than the SARS-CoV S trimer regarding receptor-triggered transformation from the closed prefusion state to the fusion-prone open state, potentially contributing to the superior infectivity of SARS-CoV-2. We defined the RBD T470-T478 loop and Y505 as viral determinants for specific recognition of SARS-CoV-2 RBD by ACE2. Our findings depict the mechanism of ACE2-induced S trimer conformational transitions from the ground prefusion state toward the postfusion state, facilitating development of anti–SARS-CoV-2 vaccines and therapeutics.…

Abstract Background Kniphofia foliosa is a flamboyant robust perennial herb which has dense clumps and tick upright rhizomes with leaves at the base. In Ethiopia, it has several vernacular names including Abelbila, Ashenda, Amelmela, Yeznjero Ageda, Shemetmetie and Yezinjero Ageda. The plant is endemic to Ethiopian highlands, where its rhizomes are traditionally used for the treatment of malaria, abdominal cramps and wound healing. In the present study, the 80% methanol extract of K. foliosa rhizomes and its constituents are tested against Plasmodium berghei in mice. Methods Isolation was carried out using column and preparative thin layer chromatography (PTLC). The chemical structures of the compounds were elucidated by spectroscopic methods (ESI–MS, 1D and 2D-NMR). Peters’ 4-day suppressive test against P. berghei in mice was utilized for in vivo anti-malarial evaluation of the test substances. Results Two compounds, namely knipholone and dianellin were isolated from the 80% methanolic extract of K. foliosa rhizomes, and characterized. The hydroalcoholic extract (400 mg/kg) and knipholone (200 mg/kg) showed the highest activity with chemosuppression values of 61.52 and 60.16%, respectively. From the dose–response plot, the median effective (ED50) doses of knipholone and dianellin were determined to be 81.25 and 92.31 mg/kg, respectively. Molecular docking study revealed that knipholone had a strong binding affinity to Plasmodium falciparum l-lactate dehydrogenase (pfLDH) target. Conclusion Results of the current study support the traditional use of the plant for the treatment of malaria.…

Abstract Background Rapid diagnostic tests (RDTs) play a key role in malaria case management. The most widely used RDT identifies Plasmodium falciparum based on immunochromatographic recognition of P. falciparum histidine-rich protein 2 (PfHRP2). Deletion of the paralogous pfhrp2 and pfhrp3 genes leads to false-negative PfHRP2-based RDTs, and has been reported in P. falciparum infections from South America and Africa. However, identification of pfhrp2/pfhrp3 deletions has usually been based only on failure to amplify these genes using PCR, without confirmation based on PfHRP2 protein expression, and understanding of the true prevalence of deletions is incomplete. Methods Deletions of pfhrp2/pfhrp3 in blood samples were investigated from cross-sectional surveys in 2012-13 in three regions of varied malaria transmission intensity in Uganda. Samples with positive Giemsa-stained thick blood smears, but negative PfHRP2-based RDTs were evaluated by PCR amplification of conserved subunit ribosomal DNA for Plasmodium species, PCR amplification of pfhrp2 and pfhrp3 genes to identify deletions, and bead-based immunoassays for expression of PfHRP2. Results Of 3516 samples collected in cross-sectional surveys, 1493 (42.5%) had positive blood smears, of which 96 (6.4%) were RDT-negative. Of these 96 RDT-negative samples, P. falciparum DNA was identified by PCR in 56 (58%) and only non-falciparum plasmodial DNA in 40 (42%). In all 56 P. falciparum-positive samples there was a failure to amplify pfhrp2 or pfhrp3: in 25 (45%) pfhrp2 was not amplified, in 39 (70%) pfhrp3 was not amplified, and in 19 (34%) neither gene was amplified. For the 39 P. falciparum-positive, RDT-negative samples available for analysis of protein expression, PfHRP2 was not identified by immunoassay in only four samples (10.3%); these four samples all had failure to amplify both pfhrp2 and pfhrp3 by PCR. Thus, only four of 96 (4.2%) smear-positive, RDT-negative samples had P. falciparum infections with deletion of pfhrp2 and pfhrp3 confirmed by failure to amplify the genes by PCR and lack of expression of PfHRP2 demonstrated by immunoassay. Conclusion False negative RDTs were uncommon. Deletions in pfhrp2 and pfhrp3 explained some of these false negatives, but most false negatives were not due to deletion of the pfhrp2 and pfhrp3 genes.…

Abstract Background: We used the ANRS-IPERGAY trial in order to qualitatively and quantitatively measure drug use among MSM under PrEP using two different methods, in order to better understand and collectively respond to risky practices. Method: We included 69 voluntaries of ANRS-IPERGAY trial. We measured drug use by two methods: (1) Drug detection by hair analysis; (2) Reported drug use by self-reported drug consumption. Results: New Psychoactive Substances (NPS) and conventional drugs were detected in 53/69 (77%) by hair analysis and in 39/69 (57%) by questionnaires. On the 219 hair segments analyzed, the most commonly used drugs were cocaine in 47/69 (68%), MDMA/ecstasy in 31/69 (45%), NPS in 27/69 (39%). On the 1,061 collected questionnaires, the most commonly used drugs were cocaine in 31/69 (45%), MDMA/ecstasy in 29/69 (42%) and NPS in 16/69 (23%). Hair analysis detects more conventional drugs and/or NPS use (p

Background: The diagnosis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) relies on characteristic clinical features synthesized as the International Network for the Study of HIV-associated IRIS (INSHI) case definition. There is no confirmatory laboratory test. Setting: Site B HIV-TB clinic in Khayelitsha, Cape Town, South Africa. Methods: Using data of participants with HIV-associated tuberculosis starting antiretroviral treatment from a prospective trial evaluating prednisone for TB-IRIS prevention, we applied latent class analysis to model a gold standard for TB-IRIS. The model-predicted probability of TB-IRIS for each participant was used to assess the performance of the INSHI case definition and compare its diagnostic accuracy with several adapted case definitions. Results: Data for this analysis were complete for 217 participants; 41% developed TB-IRIS. Our latent class model included the following parameters: respiratory symptoms, night sweats, INSHI major criteria 1, 2, and 4, maximum CRP >90 mg/l, maximum heart rate >120/min, maximum temperature >37.7 0C, and pre-ART CD4 count…

Background: Integrase strand transfer inhibitors(INSTIs) are first-line regimens for HIV treatment. We aimed to examine their impact on cognitive performance and depressive symptoms in women with HIV(WWH). Setting: Women’s Interagency HIV Study(WIHS) a multisite, prospective, cohort study Methods: WWH who started or switched to INSTI-based ART and completed neuropsychological(NP) testing and the Center for Epidemiological Studies-Depression(CES-D) scale before and after INSTI start/switch were included in the analyses. Primary outcomes were demographically corrected cognitive domain T-scores. Linear mixed effects models adjusted for relevant covariates were used to examine effects of start/switch of any INSTI and individual INSTI drugs on cognition and CES-D. Results: 639 WWH, median age 49(interquartile range 12) years, 66% Black non-Hispanic, had NP and CES-D data before and after INSTI start/switch. While 14% started INSTI-based ART, the remainder switched to INSTI-based ART from another regimen. Overall, any INSTI use was associated with poorer learning post-INSTI. Specifically, use of elvitegravir, but not raltegravir, was associated with poorer learning. In analyses restricted to INSTI switch, any INSTI use, and specifically dolutegravir use, was associated with poorer learning. Among those switching from a PI-based regimen, INSTIs overall and dolutegravir remained associated with poorer learning; switching from an NNRTI to dolutegravir was also associated with poorer learning. INSTI start/switch was not related to depressive symptom changes. Conclusions: INSTI use was associated with poorer learning among WWH. These changes were mainly observed in elvitegravir and dolutegravir users, indicating that the impact of INSTI on cognition in WWH may not be a class effect. Requests for reprints and correspondences should be addressed to: Leah H. Rubin, Ph.D., MPH, Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street/ Meyer 6-113, Baltimore, MD. 21287-7613, Phone: 443-287-0571, Fax: 410-955-0672, e-mail: lrubin@jhmi.edu The authors report no conflicts of interest related to this work. * Equally contributing authors Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

BACKGROUND: Gender-based stigma contributes to increased HIV prevalence, but little is known about psychosocial mechanisms linking stigma and HIV risk among young transgender women (YTW). SETTING: This study uses data from Project LifeSkills, a randomized controlled efficacy trial of an empowerment-based HIV prevention intervention for YTW (N=233). YTW were recruited in Boston, MA, and Chicago, IL, between 2012-2015 and completed study assessment visits at baseline and months 4 and 12. METHODS: Using autoregressive structural equation modeling, we examined whether poor social support and psychological distress at 4 months mediate the prospective relationship between gender-based stigma at baseline and condomless anal and vaginal sex (CAVS) acts at 4 and 12 months; all models were adjusted for treatment arm, HIV serostatus, study site, and sociodemographics. RESULTS: Gender-based stigma at baseline was directly associated with increased CAVS at 4 months (aIRR=1.18, 95% CI: [1.05,1.33]) and 12 months (aIRR=1.17, 95% CI: [1.02,1.34]). Gender-based stigma was also associated with higher psychological distress at 4 months (b=0.70, 95% CI: [0.13,1.27]), which in turn was marginally associated with increased CAVS at 12 months (aIRR=1.03, 95% CI: [1.00,1.06]). Contrary to expectations, poor social support at 4 months was associated with decreased CAVS at 12 months (aIRR=0.40, 95% CI: [0.28,0.59]). CONCLUSION: Future HIV prevention interventions with YTW should consider addressing experiences of gender-based stigma as well as the psychological distress that may ensue from gender-based stigma. More research is needed to understand the influence of poor social support on sexual behaviors in this population. Corresponding author: Center for Health Promotion and Health Equity, Brown University School of Public Health, Box G-S121-8, Providence, RI, 02912, United States, Phone: +1 (401) 863-6651. Email: katie_biello@brown.edu. Conflicts of interest and sources of funding: Research reported in this article was supported by award R01MH094323 (Drs. Garofalo and Mimiaga) from the National Institute of Mental Health of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors report no conflicts of interest. PKV: pablo_valente@brown.edu, KBB: katie_biello@brown.edu, AE: alberto_edeza@alumni.brown.edu, LKF: lynne_klasko-foster@brown.edu LK: lkuhns@luriechildrens.org, RG: rgarofalo@luriechildrens.org, SLR: sari.reisner@childrens.harvard.edu, MJM: mmimiaga@ph.ucla.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

No abstract available…

Background: The PrEP cascade outlines sequential steps to maximize PrEP’s impact and highlights potential intervention targets to improve PrEP implementation. We evaluate the PrEP cascade in the Together 5,000 study (T5K). Methods: T5K is an internet-based, U.S. national cohort study of PrEP-eligible men and trans persons who have sex with men who were not taking PrEP at enrollment. Using longitudinal data from baseline (2017-2018) and year one follow-up (2018-2019, n=4,229), we evaluated five steps of the PrEP cascade—PrEP contemplation: believes they are a good candidate for PrEP; PrEParation: plans to initiate PrEP; PrEP action: speaks to a provider about PrEP; PrEP initiation: receives a prescription for PrEP; and PrEP maintenance: continues to take PrEP. We compared the cascade across geographic region and identified factors associated with gaps in the cascade. Results: After one year, 1092 (26%) participants had initiated PrEP, 709 (17%) were still using PrEP, and 177 (4%) were no longer clinically indicated for PrEP. Participants in the South and Midwest were less likely to speak to a provider about PrEP or initiate PrEP. Baseline characteristics associated with lower odds of PrEP initiation at year one include: not having a college degree; earning…

Background: Transgender persons are at high risk for HIV infection. Testing is a key component of the national effort to end the HIV epidemic in the United States. Setting: Sixty-one local and state health departments (HDs) and 150 community-based organizations (CBOs) funded by the Centers for Disease Control and Prevention (CDC) to conduct HIV testing programs. Methods: We analyzed HIV testing data submitted to CDC by funded HDs and CBOs during 2012-2017. Descriptive analysis examined patterns of HIV testing and key outcomes (diagnosis of HIV infection, linkage to HIV medical care, and interview for partner services) among transgender persons. Multivariate robust Poisson regression was used to assess associations between HIV testing outcomes and demographic characteristics, census region, and test setting. Results: A total of 82,818 HIV tests were provided to transgender persons. Of these, 2,280 (2.8%) transgender persons were diagnosed with HIV infection; 1,556 (1.9%) received a new and 724 (0.9%) a previous diagnosis with HIV infection. The highest percentage of new HIV diagnosis was found among persons tested in correctional settings (4.6%), non-Hispanic Blacks (3.5%) and transgender women (2.4%).Among newly diagnosed persons, 85.0% were linked to HIV medical care ≤90 days after diagnosis and 63.5% were interviewed for partner services. Conclusions: HIV positivity was high, and the delivery of partner services was low, among transgender persons. HIV testing outcomes among transgender persons varied significantly by demographic characteristics and test setting. HIV prevention programs that are responsive to the needs of transgender persons may address gender-related disparities in HIV testing outcomes. Corresponding Author: Mesfin S. Mulatu, PhD, MPH, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Rd., NE, MS US8-2, Atlanta, Georgia 30333, E-mail: mmulatu@cdc.gov; Phone: 404-630-2066; Fax: 404-639-0929 The authors report no conflicts of interest related to this work. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Background: The structure of the HIV transmission networks can be dictated by just a few individuals. Public health intervention, such as ensuring people living with HIV adhere to antiretroviral therapy and remain virally-suppressed, can help control the spread of the virus. However, such intervention requires utilizing limited public health resource allocations. Determining which individuals are most at risk of transmitting HIV could allow public health officials to focus their limited resources on these individuals. Setting: Molecular epidemiology can help prioritize people living with HIV by patterns of transmission inferred from their sampled viral sequences. Such prioritization has been previously suggested and performed by monitoring cluster growth. In this paper, we introduce ProACT (Prioritization using AnCesTral edge lengths), a phylogenetic approach for prioritizing individuals living with HIV. Methods: ProACT starts from a phylogeny inferred from sequence data and orders individuals according to their terminal branch length, breaking ties using ancestral branch lengths. We evaluated ProACT on a real dataset of 926 HIV-1 subtype B pol data obtained in San Diego between 2005 and 2014, and a simulation datasets modelling the same epidemic. Prioritization methods are compared by their ability to predict individuals who transmit most after the prioritization. Results: Across all simulation conditions and most real data sampling conditions, ProACT outperformed monitoring cluster growth for multiple metrics of prioritization efficacy. Conclusion: The simple strategy used by ProACT improves the effectiveness of prioritization compared to state-of-the-art methods that rely on monitoring the growth of transmission clusters defined based on genetic distance. Correspondence: Siavash Mirarab, PhD, Department of Electrical and Computer Engineering, University of California, San Diego, 9500 Gilman Drive, Mail Code 0407, La Jolla, USA, 92093-0407, 858-822-6245, smirarab@ucsd.edu The authors report no conflicts of interest related to this work. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Introduction. To end the HIV epidemic, HIV prevention and PrEP promotion efforts must reach young men who have sex with men (YMSM) at greatest risk for HIV. This study qualitatively explored whether common metrics used by clinicians, scientists, and public health officials to objectively assess HIV risk align with how YMSM conceptualize their risk for HIV, and the factors that shape YMSM’s risk perceptions. Methods. Interviews with a racially/ethnically diverse sample of HIV-negative YMSM (ages 19-24, 60% Latinx; n=20) examined conceptualizations of HIV risk within the context of repeat HIV testing. Iterative, applied thematic analysis examined how participants conceptualized and constructed their HIV risk, and compared participants’ descriptions of their risk with a validated quantitative assessment of HIV risk that reliably predicts HIV seroconversion in this group. Results. Objective quantitative assessments of HIV risk poorly aligned with participants’ perceived HIV risk. Participants described their current risk in relative terms (relative to past risk, relative to friends’/peers’ risk), and described age/developmental stage and changes in knowledge about HIV prevention as key factors in risk changes over time. Other factors included substance use and trust/mistrust in sexual partners and scientific advances in HIV prevention (e.g., U=U and PrEP). Factors that influenced participants’ perceived HIV risk were similar regardless of objective risk assessment. Conclusions. Quantitative assessments of risk may poorly align with risk perception among YMSM. While objective metrics can effectively target YMSM at greatest risk for HIV transmission, interventions to improve prevention behaviors and PrEP uptake may be more effective when tailored to bridge the disconnect between objective HIV risk assessments and YMSM’s constructions of risk. Corresponding Author Information: Laramie R. Smith, PhD, University of California San Diego, Department of Medicine, Division of Infectious Diseases and Global Public Health, 9500 Gilman Drive MC 0507, La Jolla, CA 92093, Email: laramie@ucsd.edu , Phone: (858)822-1462 Conflicts of Interest and Sources of Funding: K.R.A reports an educational grant from Gilead Sciences through the University of Michigan completed in 2018; D.J.G consulted for Greenwich Bioscience, Inc.; M.H. received research funding from Gilead and Pfizer. L.R.S. is a co-investigator on a research study supported by Gilead Sciences. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a catastrophic impact worldwide (Walker et al., 2020). Although it is difficult to compare national data, mortality from COVID-19 is significantly higher in some countries than in others(Li 2020). For example, Spain, Italy, and the United Kingdom have higher mortality rates than the United States and Germany. Multiple factors contribute to this difference, including differences in aging, general health, government decisions, accessibility and quality of healthcare, and socioeconomic status (Patel et al., 2020; Raifman and Raifman, 2020).

Over the past months, the pandemic spread of SARS-CoV-2 (severe acute respiratory syndrome virus 2) has claimed more than 1.5 million lives (WHO, 2020). Current mortality rates with severe COVID-19 (coronavirus disease 2019) are approximately 5%, which is relatively high as compared to death from influenza (Faust and del Rio, 2020, Iuliano et al., 2018, WHO, 2020). Although pulmonary factors such as diffuse alveolar damage and pneumonia are major immediate causes of death in patients with COVID-19, recent studies have proposed that endotheliitis and thromboses contribute to the severity of pulmonary damage (Ackermann et al., 2020, Bryce et al., 2020, Lax et al., 2020, Levi et al., 2020, Varga et al., 2020).

Despite enhanced public health efforts to eradicate syphilis mother-to-child transmission (MTCT), maternal syphilis (diagnosed during pregnancy) remains a pressing global health concern. Nearly one third of untreated maternal syphilis cases will result in adverse pregnancy outcomes, including fetal or neonatal death (Newman et al., 2013). A 2008 analysis of multinational pre-natal clinics estimated 520,000 annual adverse pregnancy outcomes due to untreated syphilis, including 215,000 stillbirths, 90,000 neonatal deaths, and 65,000 preterm deliveries (Newman et al., 2013).

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), was first identified in December 2019 (Liu et al., 2020a). In March 2020, COVID-19 was declared a pandemic by the World Health Organisation.