The Brain Image Library: A Community-Contributed Microscopy Resource for Neuroscientists.

Advancements in microscopy techniques and computing technologies have enabled researchers to digitally reconstruct brains at micron scale. As a result, community efforts like the BRAIN Initiative Cell Census Network (BICCN) have generated thousands of whole-brain imaging datasets to trace neuronal circuitry and comprehensively map cell types. This data holds valuable information that extends beyond initial analyses, opening avenues for variation studies and robust classification of cell types in specific brain regions. However, the size and heterogeneity of these imaging data have historically made storage, sharing, and analysis difficult for individual investigators and impractical on a broad community scale. Here, we introduce the Brain Image Library (BIL), a public resource serving the neuroscience community that provides a persistent centralized repository for brain microscopy data. BIL currently holds thousands of brain datasets and provides an integrated analysis ecosystem, allowing for exploration, visualization, and data access without the need to download, thus encouraging scientific discovery and data reuse.

Dapivirine vaginal ring for HIV prevention: modelling health outcomes, drug resistance and cost-effectiveness.

INTRODUCTION: A vaginal ring containing dapivirine is effective for HIV prevention as pre-exposure prophylaxis (PrEP). We evaluated the potential epidemiological impact and cost-effectiveness of dapivirine vaginal ring PrEP among 22- to 45-year-old women in KwaZulu-Natal, South Africa. METHODS: Using mathematical modelling, we studied dapivirine vaginal ring PrEP implementation, either unprioritized, or prioritized based on HIV incidence (≥3% per year), age (22 to 29 years) or female sex worker status, alongside the implementation of voluntary medical male circumcision and antiretroviral therapy scaled-up to UNAIDS Fast-Track targets. Outcomes over the intervention (2019 to 2030) and lifetime horizons included cumulative HIV infections, life-years lived, costs and cost-effectiveness. We assessed the incremental cost-effectiveness ratios against the revealed willingness to pay ($500) and the standard (2017 per capita gross domestic product; $6161) cost-effectiveness thresholds for South Africa. RESULTS: Compared to a reference scenario without PrEP, implementation of dapivirine vaginal ring PrEP, assuming 56% effectiveness and covering 50% of 22 to 29-year-old or high-incidence women, prevented 10% or 11% of infections by 2030 respectively. Equivalent, unprioritized coverage (30%) prevented fewer infections (7%), whereas 50% coverage of female sex workers had the least impact (4%). Drug resistance attributable to PrEP was modest (2% to 4% of people living with drug-resistant HIV). Over the lifetime horizon, dapivirine PrEP implementation among female sex workers was cost-saving, whereas incidence-based PrEP cost $1898 per life-year gained, relative to PrEP among female sex workers and $989 versus the reference scenario. In a scenario of 37% PrEP effectiveness, PrEP had less impact, but prioritization to female sex workers remained cost-saving. In uncertainty analysis, female sex worker PrEP was consistently cost-saving; and over the lifetime horizon, PrEP cost less than $6161 per life-year gained in over 99% of simulations, whereas incidence- and age-based PrEP cost below $500 per life-year gained in 61% and 49% of simulations respectively. PrEP adherence and efficacy, and the effectiveness of antiretroviral therapy for HIV prevention, were the principal drivers of uncertainty in the cost-effectiveness of PrEP. CONCLUSIONS: Dapivirine vaginal ring PrEP would be cost-saving in KwaZulu-Natal if prioritized to female sex workers. PrEP's impact on HIV prevention would be increased, with potential affordability, if prioritized to women by age or incidence.

Deciphering the Effects of Injectable Pre-exposure Prophylaxis for Combination Human Immunodeficiency Virus Prevention.

Background. A long-acting injectable formulation of rilpivirine (RPV), under investigation as antiretroviral pre-exposure prophylaxis (PrEP), may facilitate PrEP adherence. In contrast, cross-resistance between RPV and nonnucleoside reverse-transcriptase inhibitors comprising first-line antiretroviral therapy (ART) could promote human immunodeficiency virus (HIV) drug resistance and reduce PrEP's effectiveness. Methods. We use novel mathematical modeling of different RPV PrEP scale-up strategies in KwaZulu-Natal, South Africa, to investigate their effects on HIV prevention and drug resistance, compared with a reference scenario without PrEP. Results. Pre-exposure prophylaxis scale-up modestly increases the proportion of prevalent drug-resistant infections, from 33% to ≤37%. The change in the number of prevalent drug-resistant infections depends on the interplay between PrEP factors (coverage, efficacy, delivery reliability, and scale-up strategy) and the level of cross-resistance between PrEP and ART. An optimistic scenario of 70% effective RPV PrEP (90% efficacious and 80% reliable delivery), among women aged 20-29 years, prevents 17% of cumulative infections over 10 years while decreasing prevalent resistance; however, prevention decreases and resistance increases with more conservative assumptions. Uncertainty analysis assuming 40%-70% cross-resistance prevalence predicts an increase in prevalent resistance unless PrEP's effectiveness exceeds 90%. Conclusions. Prioritized scale-up of injectable PrEP among women in KwaZulu-Natal could reduce HIV infections, but suboptimal effectiveness could promote the spread of drug resistance.

Cost-effectiveness of Injectable Preexposure Prophylaxis for HIV Prevention in South Africa.

BACKGROUND: Long-acting injectable antiretrovirals such as rilpivirine (RPV) could promote adherence to preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) prevention. However, the cost-effectiveness of injectable PrEP is unclear. METHODS: We constructed a dynamic model of the heterosexual HIV epidemic in KwaZulu-Natal, South Africa, and analyzed scenarios of RPV PrEP scale-up for combination HIV prevention in comparison with a reference scenario without PrEP. We estimated new HIV infections, life-years and costs, and incremental cost-effectiveness ratios (ICERs), over 10-year and lifetime horizons, assuming a societal perspective. RESULTS: Compared with no PrEP, unprioritized scale-up of RVP PrEP covering 2.5%-15% of adults prevented up to 9% of new infections over 10 years. HIV prevention doubled (17%) when the same coverage was prioritized to 20- to 29-year-old women, costing $10 880-$19 213 per infection prevented. Prioritization of PrEP to 80% of individuals at highest behavioral risk achieved comparable prevention (4%-8%) at <1% overall coverage, costing $298-$1242 per infection prevented. Over lifetime, PrEP scale-up among 20- to 29-year-old women was very cost-effective (<$1600 per life-year gained), dominating unprioritized PrEP, while risk prioritization was cost-saving. PrEP's 10-year impact decreased by almost 50% with increases in ICERs (up to 4.2-fold) in conservative base-case analysis. Sensitivity analysis identified PrEP's costs, efficacy, and reliability of delivery as the principal drivers of uncertainty in PrEP's cost-effectiveness, and PrEP remained cost-effective under the assumption of universal access to second-line antiretroviral therapy. CONCLUSIONS: Compared with no PrEP, prioritized scale-up of RPV PrEP in KwaZulu-Natal could be very cost-effective or cost-saving, but suboptimal PrEP would erode benefits and increase costs.

Anatomy and function of an excitatory network in the visual cortex.

Circuits in the cerebral cortex consist of thousands of neurons connected by millions of synapses. A precise understanding of these local networks requires relating circuit activity with the underlying network structure. For pyramidal cells in superficial mouse visual cortex (V1), a consensus is emerging that neurons with similar visual response properties excite each other, but the anatomical basis of this recurrent synaptic network is unknown. Here we combined physiological imaging and large-scale electron microscopy to study an excitatory network in V1. We found that layer 2/3 neurons organized into subnetworks defined by anatomical connectivity, with more connections within than between groups. More specifically, we found that pyramidal neurons with similar orientation selectivity preferentially formed synapses with each other, despite the fact that axons and dendrites of all orientation selectivities pass near (<5 µm) each other with roughly equal probability. Therefore, we predict that mechanisms of functionally specific connectivity take place at the length scale of spines. Neurons with similar orientation tuning formed larger synapses, potentially enhancing the net effect of synaptic specificity. With the ability to study thousands of connections in a single circuit, functional connectomics is proving a powerful method to uncover the organizational logic of cortical networks.

High-resolution reconstruction of fluorescent inclusions in mouse thorax using anatomically guided sampling and parallel Monte Carlo computing.

We present a method for high-resolution reconstruction of fluorescent images of the mouse thorax. It features an anatomically guided sampling method to retrospectively eliminate problematic data and a parallel Monte Carlo software package to compute the Jacobian matrix for the inverse problem. The proposed method was capable of resolving microliter-sized femtomole amount of quantum dot inclusions closely located in the middle of the mouse thorax. The reconstruction was verified against co-registered micro-CT data. Using the proposed method, the new system achieved significantly higher resolution and sensitivity compared to our previous system consisting of the same hardware. This method can be applied to any system utilizing similar imaging principles to improve imaging performance.

Network anatomy and in vivo physiology of visual cortical neurons.

In the cerebral cortex, local circuits consist of tens of thousands of neurons, each of which makes thousands of synaptic connections. Perhaps the biggest impediment to understanding these networks is that we have no wiring diagrams of their interconnections. Even if we had a partial or complete wiring diagram, however, understanding the network would also require information about each neuron's function. Here we show that the relationship between structure and function can be studied in the cortex with a combination of in vivo physiology and network anatomy. We used two-photon calcium imaging to characterize a functional property--the preferred stimulus orientation--of a group of neurons in the mouse primary visual cortex. Large-scale electron microscopy of serial thin sections was then used to trace a portion of these neurons' local network. Consistent with a prediction from recent physiological experiments, inhibitory interneurons received convergent anatomical input from nearby excitatory neurons with a broad range of preferred orientations, although weak biases could not be rejected.

Free-space fluorescence tomography with adaptive sampling based on anatomical information from microCT.

Image reconstruction is one of the main challenges for fluorescence tomography. For in vivo experiments on small animals, in particular, the inhomogeneous optical properties and irregular surface of the animal make free-space image reconstruction challenging because of the difficulties in accurately modeling the forward problem and the finite dynamic range of the photodetector. These two factors are fundamentally limited by the currently available forward models and photonic technologies. Nonetheless, both limitations can be significantly eased using a signal processing approach. We have recently constructed a free-space panoramic fluorescence diffuse optical tomography system to take advantage of co-registered microCT data acquired from the same animal. In this article, we present a data processing strategy that adaptively selects the optical sampling points in the raw 2-D fluorescent CCD images. Specifically, the general sampling area and sampling density are initially specified to create a set of potential sampling points sufficient to cover the region of interest. Based on 3-D anatomical information from the microCT and the fluorescent CCD images, data points are excluded from the set when they are located in an area where either the forward model is known to be problematic (e.g., large wrinkles on the skin) or where the signal is unreliable (e.g., saturated or low signal-to-noise ratio). Parallel Monte Carlo software was implemented to compute the sensitivity function for image reconstruction. Animal experiments were conducted on a mouse cadaver with an artificial fluorescent inclusion. Compared to our previous results using a finite element method, the newly developed parallel Monte Carlo software and the adaptive sampling strategy produced favorable reconstruction results.