Assessment of a screening tool to aid home-based identification of adolescents (aged 10-14) living with HIV in Zambia and South Africa: HPTN 071 (PopART) study.

INTRODUCTION: The HPTN071 (PopART) for Youth (P-ART-Y) study evaluated the acceptability and uptake of a community-level combination HIV prevention package including universal testing and treatment (UTT) among young people in Zambia and South Africa. We determined whether a four-question primary care level screening tool, validated for use in clinical settings, could enhance community (door-to-door) identification of undiagnosed HIV-positive younger adolescents (aged 10-14) who are frequently left out of HIV interventions. METHOD: Community HIV-care Providers (CHiPs) contacted and consented adolescents in their homes and offered them participation in the PopART intervention. CHiPs used a four question-screening tool, which included: history of hospital admission; recurring skin problems; poor health in last 3 months; and death of at least one parent. A "yes" response to one or more questions was classified as being "at risk" of being HIV-positive. Rapid HIV tests were offered to all children. Data were captured through an electronic data capture device from August 2016 to December 2017. The sensitivity, specificity, positive predictive value and negative predictive value were estimated for the screening tool, using the rapid HIV test result as the gold standard. RESULTS: In our 14 study sites, 33,710 adolescents aged 10-14 in Zambia and 8,610 in South Africa participated in the study. About 1.3% (427/33,710) and 1.2% (106/8,610) self-reported to be HIV positive. Excluding the self-reported HIV-positive, we classified 11.3% (3,746/33,283) of adolescents in Zambia and 17.5% (1,491/8,504) in South Africa as "at risk". In Zambia the estimated sensitivity was 35.3% (95% CI 27.3%-44.2%) and estimated specificity was 88.9% (88.5%-89.2%). In South Africa the sensitivity was 72.3% (26.8%-94.9%) and specificity was 82.5% (81.6-83.4%). CONCLUSION: The sensitivity of the screening tool in a community setting in Zambia was low, so this tool should not be considered a substitute for universal testing where that is possible. In South Africa the sensitivity was higher, but with a wide confidence interval. Where universal testing is not possible the tool may help direct resources to adolescents more likely to be living with undiagnosed HIV. TRIAL REGISTRATION: Clinical Trial Number: NCT01900977.

Filamin A Is a Prognostic Serum Biomarker for Differentiating Benign Prostatic Hyperplasia from Prostate Cancer in Caucasian and African American Men.

Prostate cancer represents a significant health risk to aging men, in which diagnostic challenges to the identification of aggressive cancers remain unmet. Prostate cancer screening is driven by the prostate-specific antigen (PSA); however, in men with benign prostatic hyperplasia (BPH) due to an enlarged prostate and elevated PSA, PSA's screening utility is diminished, resulting in many unnecessary biopsies. To address this issue, we previously identified a cleaved fragment of Filamin A (FLNA) protein (as measured with IP-MRM mass spectrometry assessment as a prognostic biomarker for stratifying BPH from prostate cancer and subsequently evaluated its expanded utility in Caucasian (CA) and African American (AA) men. All men had a negative digital rectal examination (DRE) and PSA between 4 and 10 ng/mL and underwent prostate biopsy. In AA men, FLNA serum levels exhibited diagnostic utility for stratifying BPH from patients with aggressive prostate cancer (0.71 AUC and 12.2 OR in 48 men with BPH and 60 men with PCa) and outperformed PSA (0.50 AUC, 2.2 OR). In CA men, FLNA serum levels also exhibited diagnostic utility for stratifying BPH from patients with aggressive prostate cancer (0.74 AUC and 19.4 OR in 191 men with BPH and 109 men with PCa) and outperformed PSA (0.46 AUC, 0.32 OR). Herein, we established FLNA alone as a serum biomarker for stratifying men with BPH vs. those with high Gleason (7-10) prostate cancers compared to the current diagnostic paradigm of using PSA. This approach demonstrates clinical actionability of FLNA alone without the requirement of prostate volume measurement as a test with utility in AA and CA men and represents a significant opportunity to decrease the number of unnecessary biopsies in aggressive prostate cancer diagnoses.

Male Survivors of Domestic Violence, Challenges in Cultural Response, and Impact on Identity and Help-Seeking Behaviors: A Systematic Review.

Male experiences of domestic and relational violence have been only marginally explored in the literature. In connection to this, attitudes in the community and among service providers and criminal justice system entities can vary dramatically. This variance in attitudes creates an instability which has a differential impact on the help-seeking behaviors of victims. Additionally, help-seeking behaviors are often influenced by internalized shame and confusion on the part of the survivors themselves when their social constructions of masculinity do not align with lived experience. More is needed to understand the nature of male survivorship in situations of relational violence. A systematic review was conducted to begin organizing the data on the topic. This review started with 15,547 peer-reviewed articles. Those were systematically narrowed to a total of 16 of the most recent pieces of empirical science on the topic. The final articles were thematically analyzed. Findings suggest (a) cultural stigma around constructions of masculinity, (b) fear of disclosure, and (c) negative experiences with criminal justice and support system responses, among the highest drivers for the disparate experience and hesitation to seek help.

The role of Culex territans mosquitoes in the transmission of Batrachochytrium dendrobatidis to amphibian hosts.

BACKGROUND: Mosquitoes are the deadliest organisms in the world, killing an estimated 750,000 people per year due to the pathogens they can transmit. Mosquitoes also pose a major threat to other vertebrate animals. Culex territans is a mosquito species found in temperate zones worldwide that feeds almost exclusively on amphibians and can transmit parasites; however, little is known about its ability to transmit other pathogens, including fungi. Batrachochytrium dendrobatidis (Bd) is a topical pathogenic fungus that spreads through contact. With amphibian populations around the world experiencing mass die-offs and extinctions due to this pathogen, it is critical to study all potential modes of transmission. Because Cx. territans mosquitoes are in contact with their hosts for long periods of time while blood-feeding, we hypothesize that they can transmit and pick up Bd. METHODS: In this study, we first assessed Cx. territans ability to transfer the fungus from an infected surface to a clean one under laboratory conditions. We also conducted a surveillance study of Bd infections in frogs and mosquitoes in the field (Mountain Lake Biological station, VA, USA). In parallel, we determined Cx. territans host preference via blood meal analysis of field caught mosquitoes. RESULTS: We found that this mosquito species can carry the fungus to an uninfected surface, implying that they may have the ability to transmit Bd to their amphibian hosts. We also found that Cx. territans feed primarily on green frogs (Rana clamitans) and bullfrogs (Rana catesbeiana) and that the prevalence of Bd within the frog population at our field site varied between years. CONCLUSIONS: This study provides critical insights into understanding the role of amphibian-biting mosquitoes in transmitting pathogens, which can be applied to disease ecology of susceptible amphibian populations worldwide.

High-throughput optical sensing of peri-cellular oxygen in cardiac cells: system characterization, calibration, and testing.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a scalable experimental model relevant to human physiology. Oxygen consumption of hiPSC-CMs has not been studied in high-throughput (HT) format plates used in pre-clinical studies. Here, we provide comprehensive characterization and validation of a system for HT long-term optical measurements of peri-cellular oxygen in cardiac syncytia (human iPSC-CM and human cardiac fibroblasts), grown in glass-bottom 96-well plates. Laser-cut oxygen sensors having a ruthenium dye and an oxygen-insensitive reference dye were used. Ratiometric measurements (409 nm excitation) reflected dynamic changes in oxygen, as validated with simultaneous Clark electrode measurements. Emission ratios (653 nm vs. 510 nm) were calibrated for percent oxygen using two-point calibration. Time-dependent changes in the Stern-Volmer parameter, ksv, were observed during the initial 40-90 min of incubation, likely temperature-related. Effects of pH on oxygen measurements were negligible in the pH range of 4-8, with a small ratio reduction for pH > 10. Time-dependent calibration was implemented, and light exposure time was optimized (0.6-0.8 s) for oxygen measurements inside an incubator. Peri-cellular oxygen dropped to levels <5% within 3-10 h for densely-plated hiPSC-CMs in glass-bottom 96-well plates. After the initial oxygen decrease, samples either settled to low steady-state or exhibited intermittent peri-cellular oxygen dynamics. Cardiac fibroblasts showed slower oxygen depletion and higher steady-state levels without oscillations, compared to hiPSC-CMs. Overall, the system has great utility for long-term HT monitoring of peri-cellular oxygen dynamics in vitro for tracking cellular oxygen consumption, metabolic perturbations, and characterization of the maturation of hiPSC-CMs.

A standard 96-well based high throughput microfluidic perfusion biofilm reactor for in situ optical analysis.

Biofilm infections represent a major public health threat due to their high tolerance to antimicrobials and the lack of specific anti-biofilm drugs. To develop such drugs, it is crucial to have high-throughput biofilm growth systems that can emulate in vivo conditions without the cost and complexity of animal models. However, no current biofilm reactor can provide in vivo-like conditions in a high throughput standard microtiter format. This paper demonstrates a novel high-throughput (HT) microfluidic perfusion biofilm reactor (HT-µPBR) compatible with a standard 96-well microtiter plate for in situ optical analysis. A snap-on liquid-tight cover for standard microtiter plates was designed and fabricated with fluidic channels to provide closed-loop recirculating perfusion. Our system takes steps toward providing in vivo-like conditions with controlled shear stress and nutrient delivery. We describe the system fabrication and usage in optical analysis of biomass and viability of Escherichia coli (E. coli) biofilms. The HT-µPBR was set to perfuse at 1 mL/min corresponding to an average shear rate of approximately [Formula: see text] on the bottom surface of a single well. Biofilms were detected on well plate bottoms and measured using a fluorescence microscope and plate reader to determine biomass and viability. Samples cultured in the HT-µPBR showed increased biomass while maintaining viability after 24 h. The HT-µPBR can further be combined with HT antibiotic susceptibility testing and additional optical techniques such as time-lapse imaging to improve understanding of the drug reaction mechanism as well as the optimization of drug combinations and delivery profiles.

Enantioselective Synthesis of Tropane Scaffolds by an Organocatalyzed 1,3-Dipolar Cycloaddition of 3-Oxidopyridinium Betaines and Dienamines.

Tropane alkaloids constitute a compound-class which is structurally defined by a central 8-azabicyclo[3.2.1]octane core. A diverse bioactivity profile combined with an unusual aza-bridged bicyclic framework has made tropanes molecules-of-interest within organic chemistry. Enantioselective examples of (5+2) cycloadditions between 3-oxidopyridinium betaines and olefins remain unexplored, despite 3-oxidopyridinium betaines being useful reagents in organic synthesis. The first asymmetric (5+2) cycloaddition of 3-oxidopyridinium betaines is reported, affording tropane derivatives in up to quantitative yield and with excellent control of peri-, regio-, diastereo-, and enantioselectivity. The reactivity is enabled by dienamine-activation of α,ß-unsaturated aldehydes combined with in situ formation of the pyridinium reaction-partner. A simple N-deprotection protocol allows for liberation of the tropane alkaloid motif, and synthetic elaborations of the cycloadducts demonstrate their synthetic utility to achieve highly diastereoselective modification around the bicyclic framework. DFT computations suggest a stepwise mechanism where regio- and stereoselectivity are defined during the first bond-forming step in which the pyridinium dipole exerts critical conformational control over its dienamine partner. In the second bond-forming step, a kinetic preference toward an initial (5+4) cycloadduct was identified; however, a lack of catalyst turn-over, reversibility, and thermodynamic bias favoring a (5+2) cycloadduct rendered the reaction fully periselective.

A handheld plug-and-play microfluidic liquid handling automation platform for immunoassays.

Lab-on-a-chip technologies and microfluidics have pushed miniaturized liquid handling to unprecedented precision, integration, and automation, which improved the reaction efficiency of immunoassays. However, most microfluidic immunoassay systems still require bulky infrastructures, such as external pressure sources, pneumatic systems, and complex manual tubing and interface connections. Such requirements prevent plug-and-play operation at the point-of-care (POC) settings. Here we present a fully automated handheld general microfluidic liquid handling automation platform with a plug-and-play 'clamshell-style' cartridge socket, a miniature electro-pneumatic controller, and injection-moldable plastic cartridges. The system achieved multi-reagent switching, metering, and timing control on the valveless cartridge using electro-pneumatic pressure control. As a demonstration, a SARS-CoV-2 spike antibody sandwich fluorescent immunoassay (FIA) liquid handling was performed on an acrylic cartridge without human intervention after sample introduction. A fluorescence microscope was used to analyze the result. The assay showed a limit of detection at 31.1 ng/mL, comparable to some previously reported enzyme-linked immunosorbent assays (ELISA). In addition to automated liquid handling on the cartridge, the system can operate as a 6-port pressure source for external microfluidic chips. A rechargeable battery with a 12 V 3000 mAh capacity can power the system for 42 h. The footprint of the system is 16.5 × 10.5 × 7 cm, and the weight is 801 g, including the battery. The system can find many other POC and research applications requiring complex liquid manipulation, such as molecular diagnostics, cell analysis, and on-demand biomanufacturing.

High-throughput optical sensing of peri-cellular oxygen in cardiac cells: system characterization, calibration, and testing.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a scalable experimental model relevant to human physiology. Oxygen consumption of hiPSC-CMs has not been studied in high-throughput (HT) format plates used in pre-clinical studies. Here, we provide comprehensive characterization and validation of a system for HT long-term optical measurements of peri-cellular oxygen in cardiac syncytia (human iPSC-CM and human cardiac fibroblasts), grown in glass-bottom 96-well plates. Laser-cut oxygen sensors having a ruthenium dye and an oxygen-insensitive reference dye were used. Ratiometric measurements (409nm excitation) reflected dynamic changes in oxygen, as validated with simultaneous Clark electrode measurements. Emission ratios (653nm vs. 510nm) were calibrated for percent oxygen using two-point calibration. Time-dependent changes in the Stern-Volmer parameter, Ksv, were observed during the initial 40 min of incubation, likely temperature-related. Effects of pH on oxygen measurements were negligible in the pH range of 4 to 8, with a small ratio reduction for pH>10. Time-dependent calibration was implemented, and light exposure time was optimized (0.6 to 0.8s) for oxygen measurements inside an incubator. Peri-cellular oxygen dropped to levels < 5% within 3 -10 hours for densely-plated hiPSC-CMs in glass-bottom 96-well plates. After the initial oxygen decrease, samples either settled to low steady-state or exhibited intermittent peri-cellular oxygen dynamics. Cardiac fibroblasts showed slower oxygen depletion and higher steady-state levels without oscillations, compared to hiPSC-CMs. Overall, the system has great utility for long-term HT monitoring of peri-cellular oxygen dynamics in vitro for tracking cellular oxygen consumption, metabolic perturbations, and characterization of the maturation of hiPSC-CMs.

Influence of Achiral Phosphine Ligands on a Synergistic Organo- and Palladium-Catalyzed Asymmetric Allylic Alkylation.

An unusual diastereodivergent stereoselective allylation reaction is presented. It consists of a palladium-catalyzed allylation reaction of an organocatalytically generated amino isobenzofulvene, where the diastereoselectivity is controlled by the electronic properties of a monodentate, achiral ligand on palladium. One major diastereoisomer is formed using triarylphosphines substituted with neutral or electron-donating substituents of the aryl group, while those with electron-withdrawing substituents favor the other diastereoisomer. The diastereoselectivity correlates with the Taft inductive parameter of substituents on the triarylphosphine ligand on palladium. The synergistic reaction involves both a catalytic secondary amine catalyst for the indene-aldehyde activation and the monodentate phosphine ligands on palladium, affording a highly enantioselective reaction with up to 98 % enantiomeric excess. Based on computational investigations, the role of the monodentate phosphine ligand on the diastereoselectivity is discussed.

The Pericapsular Nerve Group (PENG) block combined with Local Infiltration Analgesia (LIA) compared to placebo and LIA in hip arthroplasty surgery: a multi-center double-blinded randomized-controlled trial.

BACKGROUND: The PEricapsular Nerve Group (PENG) block is a novel regional analgesia technique that provides improved analgesia in patients undergoing hip surgery while preserving motor function. In this study the PENG block was investigated for analgesia in elective total hip arthroplasty (THA). METHODS: In this multi-centre double-blinded randomized-controlled trial, in addition to spinal anesthesia and local infiltration analgesia (LIA), THA patients received either a PENG block or a sham block. The primary outcome was pain score (numeric rating scale 0-10) 3 h postoperatively (Day 0). Secondary outcomes were postoperative quadriceps muscle strength, postoperative Day 1 pain scores, opiate use, complications, length of hospital stay, and patient-reported outcome measures. RESULTS: Sixty patients were randomized and equally allocated between groups. Baseline demographics were similar. Postoperative Day 0, the PENG group experienced less pain compared to the sham group (PENG: 14 (47%) patients no pain, 14 (47%) mild pain, 2 (6%) moderate/severe pain versus sham: 6 (20%) no pain, 14 (47%) mild pain, 10 (33%) moderate/severe pain; p = 0.03). There was no difference in quadriceps muscle strength between groups on Day 0 (PENG: 23 (77%) intact versus sham: 24 (80%) intact; p = 0.24) and there were no differences in other secondary outcomes. CONCLUSIONS: Patients receiving a PENG block for analgesia in elective THA experience less postoperative pain on Day 0 with preservation of quadriceps muscle strength. Despite these short-term benefits, no quality of recovery or longer lasting postoperative effects were detected.

Enantioselective (8+3) Cycloadditions by Activation of Donor-Acceptor Cyclopropanes Employing Chiral Brønsted Base Catalysis.

A novel enantioselective (8+3) cycloaddition between donor-acceptor cyclopropanes and heptafulvenoids catalysed by a chiral bifunctional Brønsted base is described. Importantly, the reaction, which leverages an anionic activation strategy, is divergent from prototypical Lewis-acid activation protocols. A series of cyclopropylketones react with tropones affording the desired (8+3) cycloadducts in high yield and enantiomeric excess. For barbiturate substituted heptafulvenes, the (8+3) cycloaddition with cyclopropylketones proceeds in good yield, excellent diastereoselectivity and high enantiomeric excess. The experimental work is supported by DFT calculations, which indicate that the bifunctional organocatalyst activates both the donor-acceptor cyclopropane and tropone; the reaction proceeds in a step-wise manner with the ring-closure being the stereodetermining step.

Effects of epistasis and recombination between vaccine-escape and virulence alleles on the dynamics of pathogen adaptation.

Pathogen adaptation to public health interventions such as vaccination may take tortuous routes and involve multiple mutations at different locations in the pathogen genome, acting on distinct phenotypic traits. Yet how these multi-locus adaptations jointly evolve is poorly understood. Here we consider the joint evolution of two adaptations: pathogen escape from the vaccine-induced immune response and adjustments to pathogen virulence affecting transmission or clearance. We elucidate the role played by epistasis and recombination, with an emphasis on the different protective effects of vaccination. We show that vaccines blocking infection, reducing transmission and/or increasing clearance generate positive epistasis between the vaccine-escape and virulence alleles, favouring strains that carry both mutations, whereas vaccines reducing virulence mortality generate negative epistasis, favouring strains that carry either mutation but not both. High rates of recombination can affect these predictions. If epistasis is positive, frequent recombination can prevent the transient build-up of more virulent escape strains. If epistasis is negative, frequent recombination between loci can create an evolutionary bistability, favouring whichever adaptation is more accessible. Our work provides a timely alternative to the variant-centred perspective on pathogen adaptation and captures the effect of different types of vaccine on the interference between multiple adaptive mutations.

Focal p53 protein expression and lymphovascular invasion in primary prostate tumors predict metastatic progression.

TP53 is one of the most frequently altered genes in prostate cancer. The precise assessment of its focal alterations in primary tumors by immunohistochemistry (IHC) has significantly enhanced its prognosis. p53 protein expression and lymphovascular invasion (LVI) were evaluated for predicting metastatic progression by IHC staining of representative whole-mounted prostate sections from a cohort of 189 radical prostatectomy patients with up to 20 years of clinical follow-up. Kaplan-Meier survival curves were used to examine time to distant metastasis (DM) as a function of p53 expression and LVI status. TP53 targeted sequencing was performed in ten tumors with the highest expression of p53 staining. Nearly half (49.8%) of prostate tumors examined showed focal p53 expression while 26.6% showed evidence of LVI. p53(+) tumors had higher pathologic T stage, Grade Group, Nuclear Grade, and more frequent LVI. p53 expression of > 5% and LVI, individually and jointly, are associated with poorer DM-free survival. TP53 mutations were detected in seven of ten tumors sequenced. Four tumors with the highest p53 expression harbored likely pathogenic or pathogenic mutations. High levels of p53 expression suggest the likelihood of pathogenic TP53 alterations and, together with LVI status, could enhance early prognostication of prostate cancer progression.

Recommendations for effective documentation in regional anesthesia: an expert panel Delphi consensus project.

BACKGROUND AND OBJECTIVES: Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. METHODS: Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement. RESULTS: Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. CONCLUSION: By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia.

Early life skin microbial trajectory as a function of vertical and environmental transmission in Bornean foam-nesting frogs.

BACKGROUND: The amphibian skin microbiome is an important mediator of host health and serves as a potential source of undiscovered scientifically significant compounds. However, the underlying modalities of how amphibian hosts obtain their initial skin-associated microbiome remains unclear. Here, we explore microbial transmission patterns in foam-nest breeding tree frogs from Southeast Asia (Genus: Polypedates) whose specialized breeding strategy allows for better delineation between vertically and environmentally derived microbes. To facilitate this, we analyzed samples associated with adult frog pairs taken after mating-including adults of each sex, their foam nests, environments, and tadpoles before and after environmental interaction-for the bacterial communities using DNA metabarcoding data (16S rRNA). Samples were collected from frogs in-situ in Brunei, Borneo, a previously unsampled region for amphibian-related microbial diversity. RESULTS: Adult frogs differed in skin bacterial communities among species, but tadpoles did not differ among species. Foam nests had varying bacterial community composition, most notably in the nests' moist interior. Nest interior bacterial communities were discrete for each nest and overall displayed a narrower diversity compared to the nest exteriors. Tadpoles sampled directly from the foam nest displayed a bacterial composition less like the nest interior and more similar to that of the adults and nest exterior. After one week of pond water interaction the tadpole skin microbiome shifted towards the tadpole skin and pond water microbial communities being more tightly coupled than between tadpoles and the internal nest environment, but not to the extent that the skin microbiome mirrored the pond bacterial community. CONCLUSIONS: Both vertical influence and environmental interaction play a role in shaping the tadpole cutaneous microbiome. Interestingly, the interior of the foam nest had a distinct bacterial community from the tadpoles suggesting a limited environmental effect on tadpole cutaneous bacterial selection at initial stages of life. The shift in the tadpole microbiome after environmental interaction indicates an interplay between underlying host and ecological mechanisms that drive community formation. This survey serves as a baseline for further research into the ecology of microbial transmission in aquatic animals.

Mosaic vaccination: How distributing different vaccines across a population could improve epidemic control.

Although vaccination has been remarkably effective against some pathogens, for others, rapid antigenic evolution results in vaccination conferring only weak and/or short-lived protection. Consequently, considerable effort has been invested in developing more evolutionarily robust vaccines, either by targeting highly conserved components of the pathogen (universal vaccines) or by including multiple immunological targets within a single vaccine (multi-epitope vaccines). An unexplored third possibility is to vaccinate individuals with one of a number of qualitatively different vaccines, creating a "mosaic" of individual immunity in the population. Here we explore whether a mosaic vaccination strategy can deliver superior epidemiological outcomes to "conventional" vaccination, in which all individuals receive the same vaccine. We suppose vaccine doses can be distributed between distinct vaccine "targets" (e.g., different surface proteins against which an immune response can be generated) and/or immunologically distinct variants at these targets (e.g., strains); the pathogen can undergo antigenic evolution at both targets. Using simple mathematical models, here we provide a proof-of-concept that mosaic vaccination often outperforms conventional vaccination, leading to fewer infected individuals, improved vaccine efficacy, and lower individual risks over the course of the epidemic.

Epigenetic memories and the evolution of infectious diseases.

Genes with identical DNA sequence may show differential expression because of epigenetic marks. Where epigenetic marks respond to past conditions, they represent a form of "memory". Despite their medical relevance, the impact of memories on the evolution of infectious diseases has rarely been considered. Here we explore the evolution of virulence in pathogens that carry memories of the sex of their previous host. We show that this form of memory provides information about the sex of present and future hosts when the sexes differ in their pathogen's transmission pattern. Memories of past hosts enable the evolution of greater virulence in infections originating from one sex and infections transmitted across sexes. Thus, our results account for patterns of virulence that have, to date, defied medical explanation. In particular, it has been observed that girls infected by boys (or boys infected by girls) are more likely to die from measles, chickenpox and polio than girls infected by girls (or boys infected by boys). We also evaluate epigenetic therapies that tamper with the memories of infecting pathogens. More broadly, our findings imply that pathogens can be selected to carry memories of past environments other than sex. This identifies new directions in personalised medicine.

Clinical utility of a serum biomarker panel in distinguishing prostate cancer from benign prostate hyperplasia.

Prostate-specific antigen (PSA) screening for prostate cancer (PCa) is limited by the lack of specificity but is further complicated in the benign prostatic hyperplasia (BPH) population which also exhibit elevated PSA, representing a clear unmet need to distinguish BPH from PCa. Herein, we evaluated the utility of FLNA IP-MRM, age, and prostate volume to stratify men with BPH from those with PCa. Diagnostic performance of the biomarker panel was better than PSA alone in discriminating patients with negative biopsy from those with PCa, as well as those who have had multiple prior biopsies (AUC 0.75 and 0.87 compared to AUC of PSA alone 0.55 and 0.57 for patients who have had single compared to multiple negative biopsies, respectively). Of interest, in patients with PCa, the panel demonstrated improved performance than PSA alone in those with Gleason scores of 5-7 (AUC 0.76 vs. 0.56) and Gleason scores of 8-10 (AUC 0.74 vs. 0.47). With Gleason scores (8-10), the negative predictive value of the panel is 0.97, indicating potential to limit false negatives in aggressive cancers. Together, these data demonstrate the ability of the biomarker panel to perform better than PSA alone in men with BPH, thus preventing unnecessary biopsies.

Understanding the evolution of multiple drug resistance in structured populations.

The evolution of multidrug resistance (MDR) is a pressing public health concern. Yet many aspects, such as the role played by population structure, remain poorly understood. Here, we argue that studying MDR evolution by focusing upon the dynamical equations for linkage disequilibrium (LD) can greatly simplify the calculations, generate more insight, and provide a unified framework for understanding the role of population structure. We demonstrate how a general epidemiological model of MDR evolution can be recast in terms of the LD equations. These equations reveal how the different forces generating and propagating LD operate in a dynamical setting at both the population and metapopulation levels. We then apply these insights to show how the LD perspective: (i) explains equilibrium patterns of MDR, (ii) provides a simple interpretative framework for transient evolutionary dynamics, and (iii) can be used to assess the consequences of different drug prescription strategies for MDR evolution.