Reflections on 40 Years of AIDS.

June 2021 marks the 40th anniversary of the first description of AIDS. On the 30th anniversary, we defined priorities as improving use of existing interventions, clarifying optimal use of HIV testing and antiretroviral therapy for prevention and treatment, continuing research, and ensuring sustainability of the response. Despite scientific and programmatic progress, the end of AIDS is not in sight. Other major epidemics over the past decade have included Ebola, arbovirus infections, and coronavirus disease (COVID-19). A benchmark against which to compare other global interventions is the HIV/AIDS response in terms of funding, coordination, and solidarity. Lessons from Ebola and HIV/AIDS are pertinent to the COVID-19 response. The fifth decade of AIDS will have to position HIV/AIDS in the context of enhanced preparedness and capacity to respond to other potential pandemics and transnational health threats.

A Data Visualization and Dissemination Resource to Support HIV Prevention and Care at the Local Level: Analysis and Uses of the AIDSVu Public Data Resource.

BACKGROUND: AIDSVu is a public resource for visualizing HIV surveillance data and other population-based information relevant to HIV prevention, care, policy, and impact assessment. OBJECTIVE: The site, AIDSVu.org, aims to make data about the US HIV epidemic widely available, easily accessible, and locally relevant to inform public health decision making. METHODS: AIDSVu develops visualizations, maps, and downloadable datasets using results from HIV surveillance systems, other population-based sources of information (eg, US Census and national probability surveys), and other data developed specifically for display and dissemination through the website (eg, pre-exposure prophylaxis [PrEP] prescriptions). Other types of content are developed to translate surveillance data into summarized content for diverse audiences using infographic panels, interactive maps, local and state fact sheets, and narrative blog posts. RESULTS: Over 10 years, AIDSVu.org has used an expanded number of data sources and has progressively provided HIV surveillance and related data at finer geographic levels, with current data resources providing HIV prevalence data down to the census tract level in many of the largest US cities. Data are available at the county level in 48 US states and at the ZIP Code level in more than 50 US cities. In 2019, over 500,000 unique users consumed AIDSVu data and resources, and HIV-related data and insights were disseminated through nearly 4,000,000 social media posts. Since AIDSVu's inception, at least 249 peer-reviewed publications have used AIDSVu data for analyses or referenced AIDSVu resources. Data uses have included targeting of HIV testing programs, identifying areas with inequitable PrEP uptake, including maps and data in academic and community grant applications, and strategically selecting locations for new HIV treatment and care facilities to serve high-need areas. CONCLUSIONS: Surveillance data should be actively used to guide and evaluate public health programs; AIDSVu translates high-quality, population-based data about the US HIV epidemic and makes that information available in formats that are not consistently available in surveillance reports. Bringing public health surveillance data to an online resource is a democratization of data, and presenting information about the HIV epidemic in more visual formats allows diverse stakeholders to engage with, understand, and use these important public health data to inform public health decision making.

Progress in the HIV epidemic: Identifying goals and measuring success.

Substantial progress has been made towards the goal of ending the HIV/AIDS epidemic due to advancements in both prevention and treatment of HIV. However, major challenges still remain. We describe basic principles of epidemic control in the context of HIV and identify a number of attainable goals in terms of control and elimination of HIV in specific populations and risk groups, given currently available HIV prevention and treatment methods. Currently available HIV prevention methods make it a feasible goal to eliminate HIV transmission attributable to mother-to-child transmission and blood transfusions. Reductions in transmission attributable to sexual behavior and injection drug use are feasible, but elimination of these modes of transmission will require further advancements in behavioral and biomedical HIV prevention. With regard to HIV-related mortality, we argue that elimination of death due to HIV-related causes is a feasible goal. HIV-related deaths should be treated as sentinel events triggering epidemiological investigation into the breakdowns in the HIV care continuum that led to them. We briefly discuss additional considerations that will affect the success of HIV prevention programs.

Design of a Multiband Global Navigation Satellite System Radio Frequency Interference Monitoring Front-End with Synchronized Secondary Sensors.

This paper investigates the challenges of developing a multi-frequency radio frequency interference (RFI) monitoring and characterization system that is optimized for ease of deployment and operation as well as low per unit cost. To achieve this, we explore the design and development of a multiband global navigation satellite system (GNSS) front-end which is intrinsically capable of synchronizing side channel information from non-RF sensors, such as inertial measurement units and integrated power meters, to allow the simultaneous production of substantial amounts of sampled spectrum while also allowing low-cost, real-time monitoring and logging of detected RFI events. While the inertial measurement unit and barometer are not used in the RFI investigation discussed, the design features that provide for their precise synchronization with the RF sample stream are presented as design elements worth consideration. The designed system, referred to as Four Independent Tuners with Data-packing (FITWD), was utilized in a data collection campaign over multiple European and Scandinavian countries in support of the determination of the relative occurrence rates of L1/E1 and L5/E5a interference events and intensities where it proved itself a successful alternative to larger and more expensive commercial solutions. The dual conclusions reached were that it was possible to develop a compact low-cost, multi-channel radio frequency (RF) front-end that implicitly supported external data source synchronization, and that such monitoring systems or similar capabilities integrated within receivers are likely to be needed in the future due to the increasing occurrence rates of GNSS RFI events.

Tools for Metagenomic Analysis at Wastewater Treatment Plants:Application to a Foaming Episode.

Metagenomic analysis is a powerful approach for wholesale characterizations of microbial populations like those that operate within municipal wastewater treatment plants. It is well known that many problems are associated with the overgrowth or undergrowth of specific bacterial genera. We describe a database of the combined metagenomes of activated sludge aeration basins from around the globe and use it as a reference to study the population of a foamy activated sludge aeration basin. We show that foam production is associated with blooms of mycolic acid producing genera, especially Mycobacterium. We confirm this bloom using the acid-fast stain, and we show that genes involved with mycolic acid production are enriched in the foam-producing sample. In addition, we show that this sample has unusual nitrifying populations. We suggest that low-cost DNA sequencing and publicly available tools for shotgun metagenomic analyses, including those described here, might broadly facilitate wastewater treatment plant operation.

Benefit of adjunctive tacrolimus in connective tissue disease-interstitial lung disease.

We evaluated the safety and effectiveness of adjunctive tacrolimus therapy with conventional immunosuppression in patients with severe connective tissue disease-related interstitial lung disease (CTD-ILD). We included patients from our interstitial lung disease (ILD) registry with CTD-ILD, in whom tacrolimus was added to corticosteroids and an additional immunosuppressive agent. Demographic data, clinical features, lung function, radiographic images, and pathologic findings were reviewed. Effectiveness was assessed by comparing pulmonary function tests (PFTs) closest to tacrolimus initiation to PFTs approximately 6-12 months later. Corticosteroid dose at these time points was also evaluated. We report adverse events attributed to tacrolimus. Seventeen patients with CTD-ILD were included in adverse event analysis; twelve were included in efficacy analysis. Length of tacrolimus therapy ranged from 6 to 110 months (mean 38.8 months ± 31.4). The mean improvement in percent predicted total lung capacity was 7.5% ± 11.7 (p = 0.02). Forced vital capacity mean improvement was 7.4% ± 12.5 (p = 0.06). The average decrease in corticosteroid dose at follow-up was 20.3 mg ± 25.2 (p = 0.02) with complete discontinuation in six patients. No patients experienced a life-threatening adverse event attributed to tacrolimus. Tacrolimus can be effective and is well tolerated as an adjunctive therapy and allows tapering of corticosteroids.

Admitting to uncertainty in the LR.

In this paper I argue that, given our current state of knowledge, reporting uncertainty in the likelihood ratio is best practice. This may in time be replaced by reporting a Bayes factor, but we are currently unable to do this in all but the simplest of examples.

The Diagnosis and Treatment of Antisynthetase Syndrome.

Anti-synthetase syndrome is an autoimmune condition, characterized by antibodies directed against an aminoacycl transfer RNA synthetase along with clinical features that can include interstitial lung disease, myositis, Raynaud's phenomenon, and arthritis. There is a higher prevalence and increased severity of interstitial lung disease in patients with anti-synthetase syndrome, as compared to dermatomyositis and polymyositis, inflammatory myopathies with which it may overlap phenotypically. Diagnosis is made by a multidisciplinary approach, synthesizing rheumatology and pulmonary evaluations, along with serologic, radiographic, and occasionally muscle and/or lung biopsy results. Patients with anti-synthetase syndrome often require multi-modality immunosuppressive therapy in order to control the muscle and/or pulmonary manifestations of their disease. The long-term care of these patients mandates careful attention to the adverse effects and complications of chronic immunosuppressive therapy, as well as disease-related sequelae that can include progressive interstitial lung disease necessitating lung transplantation, pulmonary hypertension, malignancy and decreased survival. It is hoped that greater awareness of the clinical features of this syndrome will allow for earlier diagnosis and appropriate treatment to improve outcomes in patients with anti-synthetase syndrome.

Modeling forward stutter: toward increased objectivity in forensic DNA interpretation.

Forward stutter, or over stutter, one repeat unit length larger than the parent allele (N + 1 stutter), is a relatively rare product of the PCR amplification of STRs used in forensic DNA analysis. We have investigated possible explanatory variables for the occurrence and size of forward stutter for four different autosomal multiplexes. In addition, we have investigated models used to predict the expected heights of forward stutter. For all tetra and penta-nucleotide repeats we can find no correlation between allelic peak height, marker, or longest uninterrupted sequence in the allele. The data fit a gamma distribution with no explanatory variables. For the single trinucleotide repeat present in two of the four multiplexes (D22S1045) forward stutter is much more common and the best explanatory variable appears to be back stutter height. This suggests some fundamental cocausation of high backward and forward stutter for this locus.

A comparison of statistical models for the analysis of complex forensic DNA profiles.

Complex mixtures and LtDNA profiles are difficult to interpret. As yet there is no consensus within the forensic biology community as to how these profiles should be interpreted. This paper is a review of some of the current interpretation models, highlighting their weaknesses and strengths. It also discusses what a forensic biologist requires in an interpretation model and if this can be realistically executed under current justice systems.

Helping formulate propositions in forensic DNA analysis.

The Bayesian paradigm is the preferred approach to evidence interpretation. It requires the evaluation of the probability of the evidence under at least two propositions. The value of the findings (i.e., our LR) will depend on these propositions and the case information, so it is crucial to identify which propositions are useful for the case at hand. Previously, a number of principles have been advanced and largely accepted for the evaluation of evidence. In the evaluation of traces involving DNA mixtures there may be more than two propositions possible. We apply these principles to some exemplar situations. We also show that in some cases, when there are no clear propositions or no defendant, a forensic scientist may be able to generate explanations to account for observations. In that case, the scientist plays a role of investigator, rather than evaluator. We believe that it is helpful for the scientist to distinguish those two roles.

Geographical variation of shoeprint comparison class correspondences.

The underlying principles involved in the interpretation of shoeprint comparisons have become a topical subject due to criticisms in the 2009 National Academy of Science (NAS) report on forensic sciences[1]. Difficulties in the application and understanding of these principles were also highlighted in a recent court ruling [2-5] and subsequent discussion of the ruling. We report here a survey that may inform some aspects of this interpretation and discuss the implications of findings from this survey in the light of that court ruling and more importantly the NAS report. 1,511 shoeprints were taken from student volunteers in Auckland, Wellington and Dunedin, New Zealand. 500 shoeprints were sampled from student volunteers at Australian universities. 100 from each of the University of Technology in Sydney, University of Queensland in Brisbane, University of Newcastle, Charles Sturt University in Bathurst and University of Canberra, Australia. These cities are distributed along the east coast of Australia. The shoeprints, taken from each country, were compared against each other for the presence of any pattern correspondences However shoeprints have not been compared between countries. In all locations the pattern of some common and many rare outsole patterns was repeated, with Converse Chuck Taylor All Stars and Vans Canvas Era common in all locations.

An inter-laboratory comparison of probabilistic genotyping parameters and evaluation of performance on DNA mixtures from different laboratories.

Probabilistic genotyping (PG) is becoming the preferred standard for evidence interpretation, amongst forensic DNA laboratories, especially those in the United States. Various groups have expressed concern about reliability of PG systems, especially for mixtures beyond two contributors. Studies involving interlaboratory testing of known mixtures have been identified as ways to evaluate the reliability of PG systems. Reliability means different things in different contexts. However, it suffices here to think about it as a mixture of precision and accuracy. We might also consider whether a system is prone to producing misleading results - for example large likelihood ratios (LRs) when the POI is truly not a contributor, or small LRs when the POI is a truly a contributor. In this paper we show that the PG system STRmix™ is relatively unaffected by differences in parameter settings. That is, a DNA mixture that is analyzed in different laboratories using STRmix™ will result in different LRs, but less than 0.05% of these LRs would result in a different, or misleading conclusion as long as the LR is greater than 50. For the purposes of this study, we define LRs assigned using different parameters for the same mixtures as similar if the LR of the true POI is greater than the LRs generated for 99.9% of the general population. These findings are based on an interlaboratory study involving eight laboratories that provided twenty known DNA mixtures of two to four contributors and their individual laboratory STRmix™ parameters. The eight sets of laboratory parameters included differences in STR kits and PCR cycles as well as the peak, stutter, and locus specific amplification efficiency variances.

Developing an interpretation model for body fluid identification.

Criminal investigations, particularly sexual assaults, frequently require the identification of body fluid type in addition to body fluid donor to provide context. In most cases this can be achieved by conventional methods, however, in certain scenarios, alternative molecular methods are required. An example of this is the detection of menstrual fluid and vaginal material, which are not able to be identified using conventional techniques. Endpoint reverse-transcription PCR (RT-PCR) is currently used for this purpose to amplify body fluid specific messenger RNA (mRNA) transcripts in forensic casework. Real-time quantitative reverse-transcription PCR (RT-qPCR) is a similar method but utilises fluorescent markers to generate quantitative results in the form of threshold cycle (Cq) values. Despite the uncertainty surrounding body fluid identification, most interpretation guidelines utilise categorical statements. Probabilistic modelling is more realistic as it reflects biological variation as well as the known performance of the method. This research describes the application of various machine learning models to single-source mRNA profiles obtained by RT-qPCR and assesses their performance. Multinomial logistic regression (MLR), Naïve Bayes (NB), and linear discriminant analysis (LDA) were used to discriminate between the following body fluid categories: saliva, circulatory blood, menstrual fluid, vaginal material, and semen. We identified that the performance of MLR was somewhat improved when the quantitative dataset of the original Cq values was used (overall accuracy of approximately 0.95) rather than presence/absence coded data (overall accuracy of approximately 0.94). This indicates that the quantitative information obtained by RT-qPCR amplification is useful in assigning body fluid class. Of the three classification methods, MLR performed the best. When we utilised receiver operating characteristic curves to observe performance by body fluid class, it was clear that all methods found difficulty in classifying menstrual blood samples. Future work will involve the modelling of body fluid mixtures, which are common in samples analysed as part of sexual assault investigations.

Extending the discussion on inconsistency in forensic decisions and results.

The subject of inter- and intra-laboratory inconsistency was recently raised in a commentary by Itiel Dror. We re-visit an inter-laboratory trial, with which some of the authors of this current discussion were associated, to diagnose the causes of any differences in the likelihood ratios (LRs) assigned using probabilistic genotyping software. Some of the variation was due to different decisions that would be made on a case-by-case basis, some due to laboratory policy and would hence differ between laboratories, and the final and smallest part was the run-to-run difference caused by the Monte Carlo aspect of the software used. However, the net variation in LRs was considerable. We believe that most laboratories will self-diagnose the cause of their difference from the majority answer and in some, but not all instances will take corrective action. An inter-laboratory exercise consisting of raw data files for relatively straightforward mixtures, such as two mixtures of three or four persons, would allow laboratories to calibrate their procedures and findings.