Microneedle array delivery of Yersinia pestis recapitulates bubonic plague.

Fleas transmit Yersinia pestis directly within the dermis of mammals to cause bubonic plague. Syringe-mediated inoculation is widely used to recapitulate bubonic plague and study Y. pestis pathogenesis. However, intradermal needle inoculation is tedious, error prone, and poses a significant safety risk for laboratorians. Microneedle arrays (MNAs) are micron-scale polymeric structures that deliver materials to the dermis, while minimizing the risk of needle sticks. We demonstrated that MNA inoculation is a viable strategy to recapitulate bubonic plague and study bacterial virulence by defining the parameters needed to establish a lethal infection in the mouse model and characterizing the course of infection using live-animal optical imaging. Using MNAs, we also demonstrated that Y. pestis must overcome calprotectin-mediated zinc restriction within the dermis and dermal delivery of an attenuated mutant has vaccine potential. Together, these data demonstrate that MNAs are a safe alternative to study Y. pestis pathogenesis in the laboratory.

Association between bisphosphonate use and COVID-19 related outcomes.

Background: Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19. Methods: A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak. Results: A total of 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. A total of 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR = 0.22; 95%CI:0.21-0.23; p<0.001), COVID-19 diagnosis (OR = 0.23; 95%CI:0.22-0.24; p<0.001), and COVID-19-related hospitalization (OR = 0.26; 95%CI:0.24-0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR = 0.23; 95%CI:0.22-0.23; p<0.001) or pneumonia (OR = 0.32; 95%CI:0.31-0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2. Conclusions: Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes. Funding: This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to UHvA) and a CRI Irvington postdoctoral fellowship, CRI2453 (to PH).

The COVID-19 pandemic challenged the world to rapidly develop strategies to combat the virus responsible for the disease. While several effective vaccines and new drugs have since become available, these therapies are not always easy to access and take time to generate and distribute. To address these challenges, researchers have tried to find ways to repurpose existing medications that are already commonly used and known to be safe. One potential candidate are bisphosphonates, a family of drugs used to reduce bone loss in patients with osteoporosis. Bisphosphonates have been shown to boost the immune response to viral infections, and it has been observed that patients prescribed these drugs are less likely to develop or die from pneumonia. But whether bisphosphonates are effective against COVID-19 had not been fully explored. To investigate, Thompson, Wang et al. analyzed insurance claims data from about 8 million patients between January 2019 and June 2020, including around 450,000 individuals that had filled a prescription for bisphosphonates. Patients prescribed bisphosphonates were then compared to non-users that were similar in terms of their gender, age, the type of health insurance they had, their access to healthcare, and other health comorbidities. The study revealed that bisphosphonate users were around three to five times less likely to be tested for, diagnosed with, or hospitalized for COVID-19 during the first four months of the pandemic. They were also less commonly diagnosed with other respiratory infections in 2019, like bronchitis or pneumonia. Although the results suggest that bisphosphonates provide some protection against COVID-19, they cannot directly prove it. Verifying that bisphosphonates can treat or prevent COVID-19 and/or other respiratory infections requires more studies that follow patients in real-time rather than studying previously collected data. If such studies confirm the link, bisphosphonates could be a helpful tool to protect against COVID-19 or other virus outbreaks. The drugs are widely available, safe, and affordable, and therefore may provide an alternative for patients who cannot access other medications or vaccines.

Multimodal control of dendritic cell functions by nociceptors.

It is known that interactions between nociceptors and dendritic cells (DCs) can modulate immune responses in barrier tissues. However, our understanding of the underlying communication frameworks remains rudimentary. Here, we show that nociceptors control DCs in three molecularly distinct ways. First, nociceptors release the calcitonin gene-related peptide that imparts a distinct transcriptional profile on steady-state DCs characterized by expression of pro-interleukin-1ß and other genes implicated in DC sentinel functions. Second, nociceptor activation induces contact-dependent calcium fluxes and membrane depolarization in DCs and enhances their production of proinflammatory cytokines when stimulated. Finally, nociceptor-derived chemokine CCL2 contributes to the orchestration of DC-dependent local inflammation and the induction of adaptive responses against skin-acquired antigens. Thus, the combined actions of nociceptor-derived chemokines, neuropeptides, and electrical activity fine-tune DC responses in barrier tissues.

Quo vadis, neutrophil?

Neutrophil recruitment from blood into tissues is a hallmark of inflammation and anti-microbial host defense. In this issue, De Giovanni et al. describe an unanticipated role for a serotonin metabolite, 5-HIAA, which is produced by activated platelets and mast cells and engages the orphan receptor, GPR35, to recruit neutrophils to inflamed tissues.

Gamma Interferon Is Required for Chlamydia Clearance but Is Dispensable for T Cell Homing to the Genital Tract.

While there is no effective vaccine against Chlamydia trachomatis infection, previous work has demonstrated the importance of C. trachomatis-specific CD4+ T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host's ability to sense the cytokine gamma interferon (IFN-γ). However, it is unclear what role NR1 production or sensing of IFN-γ plays in T cell homing to the genital tract or T cell-mediated protection against C. trachomatis Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-γ-/-, and IFN-γR-/- NR1 T cells specifically home to sections in the genital tract that contain C. trachomatis We also determined that protection against infection requires production of IFN-γ from either NR1 T cells or endogenous cells, further highlighting the importance of IFN-γ in clearing C. trachomatis infection.IMPORTANCEChlamydia trachomatis is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4+ T cells are critical for Chlamydia clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to C. trachomatis Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against C. trachomatis.

Immunology-Guided Biomaterial Design for Mucosal Cancer Vaccines.

Cancer of mucosal tissues is a major cause of worldwide mortality for which only palliative treatments are available for patients with late-stage disease. Engineered cancer vaccines offer a promising approach for inducing antitumor immunity. The route of vaccination plays a major role in dictating the migratory pattern of lymphocytes, and thus vaccine efficacy in mucosal tissues. Parenteral immunization, specifically subcutaneous and intramuscular, is the most common vaccination route. However, this induces marginal mucosal protection in the absence of tissue-specific imprinting signals. To circumvent this, the mucosal route can be utilized, however degradative mucosal barriers must be overcome. Hence, vaccine administration route and selection of materials able to surmount transport barriers are important considerations in mucosal cancer vaccine design. Here, an overview of mucosal immunity in the context of cancer and mucosal cancer clinical trials is provided. Key considerations are described regarding the design of biomaterial-based vaccines that will afford antitumor immune protection at mucosal surfaces, despite limited knowledge surrounding mucosal vaccination, particularly aided by biomaterials and mechanistic immune-material interactions. Finally, an outlook is given of how future biomaterial-based mucosal cancer vaccines will be shaped by new discoveries in mucosal vaccinology, tumor immunology, immuno-therapeutic screens, and material-immune system interplay.

An Intradermal Model for Yersinia pestis Inoculation.

The dermis and the subcutaneous space vary in many fundamental characteristics, which include composition of lymphatic vessels, density of blood vasculature, and cells of the immune response. Traditional approaches employ the subcutaneous space as the preferred layer of the skin to inoculate Yersinia pestis for bubonic plague studies. Because fleas transmit Y. pestis in nature, and because these insects target the dermal layer of the skin, an intradermal model of infection is more biologically relevant than a subcutaneous model. Among many features, the use of an intradermal model results in robust and reproducible colonization of lymph nodes, blood, and deeper tissues. Remarkably, intradermal inoculation in the murine ear pinna also allows for the study of cutaneous infection without severely disrupting the architecture and physiology of the skin.

Laser Scanning Microscopy of Yersinia pestis Infected Tissues.

Laser scanning microscopy (LSM) is a technology that allows for direct observations of host-pathogen interactions during infection. Two of the most available forms of LSM are confocal and two-photon LSM. In addition to high resolution and contrast, these two technologies also provide high excitation penetrance in unsectioned samples. High penetrance allows for imaging of layers of tissue that are difficult to image with other more conventional microscopy approaches. Thus, confocal and two-photon LSM open the possibility of observing infection in a three-dimensional context, where the natural architecture of a tissue is preserved. Few studies have used LSM technology to gain insights into Yersinia pestis pathogenesis in the mammalian host. The use of LSM in the plague field has an enormous potential for the discovery of the mechanisms that lie behind key aspects of pathogenesis such as colonization, dissemination, and tissue damage. This chapter provides guidance for the implementation of confocal or two-photon LSM to study Y. pestis interactions with the host in unsectioned tissues. This document provides specific instructions applied to imaging of Y. pestis, and also discusses relevant aspects of imaging, such as the operation of laser scanning microscopes and the use of fluorescent probes.

Effectiveness of a Prevention Program for Gender-Based Intimate Partner Violence at a Colombian Primary School.

Intimate partner violence, particularly against women, is widely studied owing to its high rates, based on transnational data. Colombia, where this form of violence is considerably common, is no exception, and such violence is occurring more and more often in increasingly younger couples (10-14 years old). Further, risk factors such as wide acceptance, the justification of intimate partner violence, extremely rigid traditional gender roles, and poor socio-emotional skills play a crucial role. In accordance with this reality, a gender-based intimate partner violence prevention program was designed, implemented, and evaluated for primary school children in Colombia based on a review of successful preventive programs and an identification of the main predictors of intimate partner violence. The program was evaluated using a quantitative study with a quasi-experimental design that included an experimental and a control group. In total, 344 participants were involved in the study: 195 boys (56.7%) and 149 girls (43.4%) from the second and third grades of a primary school (average age: 7.8 years) at a Colombian educational institution. The experimental group consisted of 200 participants and the control group of 144 participants. The program's effectiveness was evaluated by measuring three groups of variables (gender stereotypes, the acceptance of violence, and socio-emotional skills) using reliable scales. To analyze the program's effectiveness, mixed ANOVAs with a within-subjects factor (when the group was measured), two between-subjects factors (group and gender), and a covariate (age) were used. The results showed that the participants in the experimental group had lower scores in gender stereotypes, acceptance of peer aggression, and acceptance of physical violence against women compared to the control group. Conversely, they had higher scores in affective empathy after the intervention; both groups showed no significant differences before the intervention. This program is highly relevant because it has proven to have a positive impact on the participants and is innovative due to the lack of preventive programs that have been implemented in primary education and evaluated within the Colombian context.

Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids.

Transport of biologically active molecules across tight epithelial barriers is a major challenge preventing therapeutic peptides from oral drug delivery. Here, we identify a set of synthetic glycosphingolipids that harness the endogenous process of intracellular lipid-sorting to enable mucosal absorption of the incretin hormone GLP-1. Peptide cargoes covalently fused to glycosphingolipids with ceramide domains containing C6:0 or smaller fatty acids were transported with 20-100-fold greater efficiency across epithelial barriers in vitro and in vivo. This was explained by structure-function of the ceramide domain in intracellular sorting and by the affinity of the glycosphingolipid species for insertion into and retention in cell membranes. In mice, GLP-1 fused to short-chain glycosphingolipids was rapidly and systemically absorbed after gastric gavage to affect glucose tolerance with serum bioavailability comparable to intraperitoneal injection of GLP-1 alone. This is unprecedented for mucosal absorption of therapeutic peptides, and defines a technology with many other clinical applications.

A Deadly Path: Bacterial Spread During Bubonic Plague.

Yersinia pestis causes bubonic plague, a fulminant disease where host immune responses are abrogated. Recently developed in vivo models of plague have resulted in new ideas regarding bacterial spread in the body. Deciphering bacterial spread is key to understanding Y. pestis and the immune responses it encounters during infection.

Comparison of Models for Bubonic Plague Reveals Unique Pathogen Adaptations to the Dermis.

UNLABELLED: Vector-borne pathogens are inoculated in the skin of mammals, most likely in the dermis. Despite this, subcutaneous (s.c.) models of infection are broadly used in many fields, including Yersinia pestis pathogenesis. We expand on a previous report where we implemented intradermal (i.d.) inoculations to study bacterial dissemination during bubonic plague and compare this model with an s.c. MODEL: We found that i.d. inoculations result in faster kinetics of infection and that bacterial dose influenced mouse survival after i.d. but not s.c. inoculation. Moreover, a deletion mutant of rovA, previously shown to be moderately attenuated in the s.c. model, was severely attenuated in the i.d. MODEL: Lastly, based on previous observations where a population bottleneck from the skin to lymph nodes was observed after i.d., but not after s.c., inoculations, we used the latter model as a strategy to identify an additional bottleneck in bacterial dissemination from lymph nodes to the bloodstream. Our data indicate that the more biologically relevant i.d. model of bubonic plague differs significantly from the s.c. model in multiple aspects of infection. These findings reveal adaptations of Y. pestis to the dermis and how these adaptations can define the progression of disease. They also emphasize the importance of using a relevant route of infection when addressing host-pathogen interactions.

Dissemination of a highly virulent pathogen: tracking the early events that define infection.

The series of events that occurs immediately after pathogen entrance into the body is largely speculative. Key aspects of these events are pathogen dissemination and pathogen interactions with the immune response as the invader moves into deeper tissues. We sought to define major events that occur early during infection of a highly virulent pathogen. To this end, we tracked early dissemination of Yersinia pestis, a highly pathogenic bacterium that causes bubonic plague in mammals. Specifically, we addressed two fundamental questions: (1) do the bacteria encounter barriers in disseminating to draining lymph nodes (LN), and (2) what mechanism does this nonmotile bacterium use to reach the LN compartment, as the prevailing model predicts trafficking in association with host cells. Infection was followed through microscopy imaging in addition to assessing bacterial population dynamics during dissemination from the skin. We found and characterized an unexpected bottleneck that severely restricts bacterial dissemination to LNs. The bacteria that do not pass through this bottleneck are confined to the skin, where large numbers of neutrophils arrive and efficiently control bacterial proliferation. Notably, bottleneck formation is route dependent, as it is abrogated after subcutaneous inoculation. Using a combination of approaches, including microscopy imaging, we tested the prevailing model of bacterial dissemination from the skin into LNs and found no evidence of involvement of migrating phagocytes in dissemination. Thus, early stages of infection are defined by a bottleneck that restricts bacterial dissemination and by neutrophil-dependent control of bacterial proliferation in the skin. Furthermore, and as opposed to current models, our data indicate an intracellular stage is not required by Y. pestis to disseminate from the skin to draining LNs. Because our findings address events that occur during early encounters of pathogen with the immune response, this work can inform efforts to prevent or control infection.

Sexuality in old age: key issues,gender differences and future proposals / Sexualidade na velhice: questões-chave, as diferenças de gênero e propostas futuras

This work presents a brief overview of some of the most important issues related to sexuality during old age. First, it presents the state of the current situation, in order to later explore some of the elements that have been considered key factors in experiencing sexuality, specifically in this stage of life, while exploring certain needs and difficulties. Similarly, some of the differences between men and women, within this context, are presented. Finally, future proposals aimed at better understanding this topic in old age are presented, with suggestions on how to improve wellbeing and care in regard to sexuality among the aging population.(AU)

Este trabalho apresenta uma breve descrição de algumas das questões mais importantes relacionadas com a sexualidade durante a velhice. Primeiro, apresenta-se o estado da situação atual, para depois explorar alguns dos elementos que foram considerados fatores-chave na vivência da sexualidade, especificamente nesta fase da vida, ao explorar certas necessidades e dificuldades. Do mesmo modo, algumas das diferenças entre homens e mulheres, neste contexto, são apresentadas. Finalmente, as propostas futuras que visam a uma melhor compreensão deste tema na terceira idade são expostas, com sugestões sobre como melhorar o bem-estar e cuidados em relação à sexualidade da população idosa.(AU)

Sexuality in old age: key issues,gender differences and future proposals / Sexualidade na velhice: questões-chave, as diferenças de gênero e propostas futuras

This work presents a brief overview of some of the most important issues related to sexuality during old age. First, it presents the state of the current situation, in order to later explore some of the elements that have been considered key factors in experiencing sexuality, specifically in this stage of life, while exploring certain needs and difficulties. Similarly, some of the differences between men and women, within this context, are presented. Finally, future proposals aimed at better understanding this topic in old age are presented, with suggestions on how to improve wellbeing and care in regard to sexuality among the aging population.

Este trabalho apresenta uma breve descrição de algumas das questões mais importantes relacionadas com a sexualidade durante a velhice. Primeiro, apresenta-se o estado da situação atual, para depois explorar alguns dos elementos que foram considerados fatores-chave na vivência da sexualidade, especificamente nesta fase da vida, ao explorar certas necessidades e dificuldades. Do mesmo modo, algumas das diferenças entre homens e mulheres, neste contexto, são apresentadas. Finalmente, as propostas futuras que visam a uma melhor compreensão deste tema na terceira idade são expostas, com sugestões sobre como melhorar o bem-estar e cuidados em relação à sexualidade da população idosa.

[Reincarceration of drug-dependent prisoners released into a therapeutic community, according to pretreatment variables]. / Reingreso en prisión de reclusos drogodependientes excarcelados a una comunidad terapéutica, en función de variables previas al tratamiento.

The main aim of this paper is to identify the criminal and penitentiary pretreatment variables associated with re-entry into prison in a population of drug-dependent inmates who had been released from different prisons in Castilla and Leon (Spain) to finish their prison sentence in a Therapeutic Community. The study population was 120 male inmates. The documentary sources consulted for collecting information were the prison record, the classification and treatment protocol and the social record. These official records were consulted in the Burgos Penitentiary, responsible for custody of the documents. Applying a descriptive statistical analysis with contingency tables, the pre-treatment variables that showed the strongest association with re-entry into prison were family prison history, total sentence exceeding five years, imprisonments prior to the sentence in question, change to a higher security level, revocation of parole, breach of the terms of a sentence, completion of sentence in prison and, especially, age at first entry into prison between 16 and 21 years. It was confirmed through logistic regression analysis that the variable age at which participants entered prison for the first time is critical, given the impact that prison can have at an early age. These results provide a profile of the drug-dependent inmate at greatest risk of making poor use of measures alternative to prison.

Elimination of Onchocerca volvulus Transmission in the Huehuetenango Focus of Guatemala.

In Latin America, onchocerciasis is targeted for elimination by 2012 through twice-yearly mass treatment of the eligible population with ivermectin. In Guatemala, two of the four historical endemic foci have demonstrated elimination of transmission, following World Health Organization guidelines. Using established guidelines ophthalmological, serological, and entomological evaluations were conducted in 2007-8 to determine the transmission status of onchocerciasis in the Huehuetenango focus. The prevalence of Onchocerca volvulus microfilariae in the anterior segment of the eye in 365 residents was 0% (95% confidence interval [CI] 0-0.8%), the prevalence of infection of O. volvulus in Simulium ochraceum among 8252 flies collected between November 2007 and April 2008 was 0% (95% CI 0-0.02%), and the prevalence of antibodies to a recombinant O. volvulus antigen in 3118 school age children was 0% (95% CI 0-0.1%). These results showed transmission interruption; thus, in 2009 mass treatment was halted and posttreatment surveillance began. To verify for potential recrudescence an entomological evaluation (from December 2010 to April 2011) was conducted during the 2nd and 3rd year of posttreatment surveillance. A total of 4587 S. ochraceum were collected, and the prevalence of infection of O. volvulus was 0% (95% CI 0-0.04%). Transmission of onchocerciasis in the Huehuetenango focus has been eliminated.

Transexualidad y vejez: una realidad por conocer / Transsexuality and aging: an important reality to investigate

El presente trabajo hace un breve recorrido por algunas de las cuestiones de mayor relevancia para las personas transexuales durante la vejez. En primer lugar, expone el estado de la cuestión actual sobre la transexualidad durante la vejez y las líneas de trabajo que han abordado de manera específica la vejez de las personas transexuales, exponiendo cuáles son sus necesidades específicas y las dificultades encontradas. Finalmente refleja diversas propuestas de futuro destinadas a mejorar el bienestar de las personas transexuales mayores.(AU)

This paper makes a brief tour of some most important issues for transsexual people in old age. Firstly, it exposes the current needs and difficulties on transsexualism aging and focuses upon studies of age on transsexuals. Finally, this review propose several proposals to improve wellbeing of older transsexual people.(AU)

Transexualidad y vejez: una realidad por conocer / Transsexuality and aging: an important reality to investigate

El presente trabajo hace un breve recorrido por algunas de las cuestiones de mayor relevancia para las personas transexuales durante la vejez. En primer lugar, expone el estado de la cuestión actual sobre la transexualidad durante la vejez y las líneas de trabajo que han abordado de manera específica la vejez de las personas transexuales, exponiendo cuáles son sus necesidades específicas y las dificultades encontradas. Finalmente refleja diversas propuestas de futuro destinadas a mejorar el bienestar de las personas transexuales mayores...

This paper makes a brief tour of some most important issues for transsexual people in old age. Firstly, it exposes the current needs and difficulties on transsexualism aging and focuses upon studies of age on transsexuals. Finally, this review propose several proposals to improve wellbeing of older transsexual people...

Assessment of a sexual coercion prevention program for adolescents.

This study's focus is to evaluate a sexual coercion prevention program in adolescents. Using a before-and-after design with both a treatment group (n = 93) and a control group (n = 76), an intervention of seven sessions was completed. Said sessions included such content as conceptualizing sexual freedom, sexual coercion and voluntary consent, analyzing different sexual coercion tactics and the contexts in which they occur, empathy toward the victim, and developing abilities to avoid risky situations. Other risk factors for coercive behavior and sexual victimization are explored as well, such as alcohol use, sexist attitudes and inadequate communication, among others. The intervention's results include a decrease in stereotypical beliefs about the opposite sex and increased empathy toward victims of sexual coercion. These changes were maintained with the passage of time. Also, in the treatment group, a more acute decline was observed in the proportion of young people engaging in sexually coercive behaviors, This article emphasizes the importance, necessity and efficacy of such interventions, and discusses and analyzes possible improvements to the program for its future implementation.