Marginated Neutrophils in the Lungs Effectively Compete for Nanoparticles Targeted to the Endothelium, Serving as a Part of the Reticuloendothelial System.

Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but has yet to achieve this goal with the vast majority of targets. One rare example of success in this pursuit has been the 25+ years of studies targeting the lung endothelium using nanoparticles conjugated to antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target the lungs' numerous marginated neutrophils, which reside in the pulmonary capillaries and patrol for pathogens. We show that marginated neutrophils' uptake of many of these "endothelial-targeted" nanocarriers is on par with endothelial uptake. This generalizes across diverse nanomaterials and targeting moieties and was even found with physicochemical lung tropism (i.e., without targeting moieties). Further, we observed this in ex vivo human lungs and in vivo healthy mice, with an increase in marginated neutrophil uptake of nanoparticles caused by local or distant inflammation. These findings have implications for nanomedicine development for lung diseases. These data also suggest that marginated neutrophils, especially in the lungs, should be considered a major part of the reticuloendothelial system (RES), with a special role in clearing nanoparticles that adhere to the lumenal surfaces of blood vessels.

Are Rights-Based Services Important? An Adolescent PrEP Demonstration Project in Brazil.

In this study, we systematically examined the importance of human rights standards and principles for rights-based pre-exposure prophylaxis (PrEP) provision for marginalized adolescents. Nested within a demonstration study of PrEP provision to adolescent men who have sex with men, travestis, and transgender women, we carried out interviews in São Paulo, Brazil with 25 adolescents, eight health providers, and six workers involved in community-based demand creation. Analysis focused on participants' narratives about aspects of human rights within service delivery, including the availability, accessibility, acceptability, and quality of services; informed decision-making; nondiscrimination; and privacy and confidentiality. Clients and service providers highlighted the importance of availing a range of services beyond PrEP and described how community outreach and social media helped promote accessibility. Acceptability centered around clients feeling heard and respected. Health workers appreciated having time to build trusting relationships with clients to ensure quality of care and support informed decision-making. Nondiscrimination was valued by all, including using clients' chosen pronouns. Privacy and confidentiality were primary concerns for clients who were not "out" about their sexuality or PrEP use; to mitigate this, health workers sought to accommodate clients' preferred channels of communication. Rights-based PrEP services can help promote engagement and retention in PrEP services, particularly for marginalized populations.

Laws governing access to sexual health services and information: contents, protections, and restrictions.

Access to sexual health services and information is critical to achieving the highest attainable standard of sexual health, and enabling legal environments are key to advancing progress in this area. In determining overall alignment with human rights standards to respect, protect, and fulfil sexual health-related rights without discrimination, there are many aspects of laws, including their specificity and content, which impact which sexual health services and information are availed, which are restricted, and for whom. To understand the nature of existing legal provisions surrounding access to sexual health services and information, we analysed the content of 40 laws in English, French, and Spanish from 18 countries for the specific sexual health services and information to which access is ensured or prohibited, and the non-discrimination provisions within these laws. Overall, there was wide variation across countries in the types of laws covering these services and the types and number of services and information ensured. Some countries covered different services through multiple laws, and most of the laws dedicated specifically to sexual health addressed only a narrow aspect of sexual health and covered a small range of services. The protected characteristics in non-discrimination provisions and the specificity of these provisions with regard to sexual health services also varied. Findings may inform national legal and policy dialogues around sexual health to identify opportunities for positive change, as well as to guide further investigation to understand the relationship between such legal provisions, the implementation of these laws within countries, and relevant sexual health outcomes.

Access to sexual health services and information is important to being able to have good sexual health. Laws are relevant because what they include and how specific they are affects what types of sexual health services people can access, what types of services are illegal, and whether or not all people can access services equally. We reviewed 40 laws in English, French, and Spanish from 18 countries to understand how many and which sexual health services and information countries ensure in their laws, which sexual health services are illegal, and which people are protected from discrimination in accessing these services. We found that countries use many different types of laws to ensure access to sexual health services or information, and most countries do not cover the same types or number of sexual health services. There are also differences in which people are specifically protected from discrimination in the laws we reviewed. These findings are important because they may help countries identify ways that access to sexual health services and information could be improved so as to improve people's sexual health. They may also guide future research.

Warming, but not infection with Borrelia burgdorferi, increases off-host winter activity in the ectoparasite, Ixodes scapularis.

Warming winters will change patterns of behaviour in temperate and polar arthropods, but we know little about the drivers of winter activity in animals such as ticks. Any changes in behaviour are likely to arise from a combination of both abiotic (e.g. temperature) and biotic (e.g. infection) drivers, and will have important consequences for survival and species interactions. Blacklegged ticks, Ixodes scapularis, have invaded Atlantic Canada and high proportions (30-50%) are infected with the bacteria causing Lyme disease, Borrelia burgdorferi. Infection is correlated with increased overwintering survival of adult females, and ticks are increasingly active in the winter, but it is unclear if infection is associated with activity. Further, we know little about how temperature drives the frequency of winter activity. Here, we exposed wild-caught, adult, female Ixodes scapularis ticks to three different winter temperature regimes (constant low temperatures, increased warming, and increased warming + variability) to determine the thermal and infection conditions that promote or suppress activity. We used automated behaviour monitors to track daily activity in individual ticks and repeated the study with fresh ticks over three years. Following exposure to winter conditions we determined whether ticks were infected with the bacteria B. burgdorferi and if infection was responsible for any patterns in winter activity. Warming conditions promoted increased activity throughout the overwintering period but infection with B. burgdorferi had no impact on the frequency or overall number of ticks active throughout the winter. Individual ticks varied in their levels of activity throughout the winter, such that some were largely dormant for several weeks, while others were active almost daily; however, we do not yet know the drivers behind this individual variation in behaviour. Overall, warming winters will heighten the risk of tick-host encounters.

Why a good law is not always good enough: a global review of restrictions to supportive laws for sexual and reproductive health and rights.

Laws and regulations provide the framework for implementing sexual and reproductive health and rights (SRHR)-related policies, programmes and services. They can promote the fulfilment of health and human rights; however, they may also limit the achievement of these goals. This study uses data collected under Sustainable Development Goal Indicator 5.6.2 to analyse SRHR-related laws and restrictions from 153 countries. Looking beyond the existence of supportive laws to assess the constellation of legal restrictions and contradictions such as criminalisation and plural legal systems provides a more nuanced understanding of factors involved in achieving full and equal access to SRHR.The interaction between restrictions and contradictions within the law disproportionately impacts some populations' health access and outcomes. Restrictions based on third-party authorisations and age are the most common restriction types, disproportionately impacting young women. Contraception, emergency contraception and abortion face the greatest number of restrictions, indicating a significant layering of barriers to family planning services. Further, plural legal systems commonly contradict guarantees of contraceptive services and emergency contraception. Our analyses suggest that one of the populations most affected by restrictions to SRH services as they appear in legal and regulatory frameworks is adolescent girls and young women in sub-Saharan Africa seeking abortion or contraceptive services.Study findings provide a critical starting point for advocacy to address legal barriers to SRH services and evidence for future policy and programming. For individual countries, this study can serve as a model for analysis of their own legal and regulatory frameworks to identify priority areas for reform efforts.

Impact of the COVID-19 pandemic and policy response on access to and utilization of reproductive, maternal, child and adolescent health services in Kenya, Uganda and Zambia.

Global health crises can negatively impact access to and utilisation of essential health services. Access to and utilisation of reproductive health services were already challenged in Sub-Saharan Africa with the COVID-19 pandemic further complicating the critical situation. This cross-sectional qualitative study aimed to assess the impact of the COVID-19 pandemic and policy responses to it on the access to, and utilization of reproductive, maternal, child and adolescent health services in Kenya, Uganda, and Zambia. It sought to explore the perspectives of women of reproductive age (18-49), frontline health workers and government representatives, all from geographies that are under-researched in this context. Using purposive sampling, key informant and in-depth interviews were carried out with 63 participants across the three countries between November 2020 and February 2021. The study population included women of reproductive age (18-49 years), front-line health service providers, and government representatives We established that COVID-19 and the policy response to it affected access to and utilization of services in the three countries, the most affected being antenatal care, delivery, family planning, and immunization services. Women reported not accessing the health facilities for various reasons. Barriers to access and utilization of services cut across all the socioecological levels. Movement restrictions, particularly in Uganda where they were most severe, and fear of contracting COVID-19 at health facilities were the most reported barriers. Weak structures at community level and inadequate supply of commodities in health facilities exacerbated the situation. Mitigation factors were put in place at different levels. There is need to strengthen the health system, particularly the supply chain and to have services closer to the community to enhance access to and utilisation of services at all times and particularly during crises such as the Covid-19 pandemic.

The ubiquity of 'self-care' in health: Why specificity matters.

Despite increased interest in self-care for health, little consensus exists around its definition and scope. The World Health Organization has published several definitions of self-care, including in a 2019 Global Guideline rooted in sexual and reproductive health and rights (SRHR), later expanded to encompass health more generally. To establish a robust understanding of self-care, this exploratory study inventorises, consolidates, presents and analyses definitions of self-care beyond the SRHR field. A pragmatic review identified definitions and conceptualisations of self-care from peer-reviewed and grey literature published between 2009 and 2021. The search identified 91 definitions of self-care from 116 relevant publications. Data extraction informed analysis to identify recurring themes and approaches, revealing three key areas of variation: self-care being: (1) defined directly or descriptively; (2) situated within individual, interpersonal or structural contexts; (3) defined broadly or topic-specifically. A multilevel conceptualisation can guide a more broadly applicable understanding of self-care: first, as an aspect of healthcare; second, as a concept operating at individual, interpersonal and institutional levels; third, as a concept that impacts specific health fields and contexts differently. A comprehensive but adaptable framework works in service of improving health and wellbeing for all, acknowledging the linkages between self-care and health-related human rights.

Determinants of Bladder Care at Night in a Subacute Ward for Aged Patients: An Observational Study.

PURPOSE: The purpose of this study was to evaluate how bladder care at night correlates to patients' mobility status. DESIGN: This was an observational study. SUBJECTS AND SETTING: The sample comprises 63 aged care subacute patients who were observed over 3 consecutive nights in an inpatient subacute aged care ward located in Melbourne, Australia. Half of the participants were female; their mean age was 82.0 (standard deviation 8.2) years. Data were collected from December 2020 to March 2021. METHODS: Outcome variables included demographic and pertinent clinical characteristics, type and timing of toileting and/or bladder care provided, and mobility classification. Descriptive statistics were used to summarize the frequency of nocturnal bladder care provided each night and as a mean over the 3 nights. The relationship between the type of care units provided and other variables was explored using a 1-way analysis of variance; values ≤.05 were deemed statistically significant. RESULTS: Findings indicate that 27% (n = 17), 41% (n = 26), and 48% (n = 30) of participants required assistance to move in bed, sit up in bed, and stand from sitting, respectively. Care episodes for both incontinence and assistance with voiding were significantly associated with functional mobility in bed ( F = 5.52, P < .001; F = 2.14, P = .02) and with ambulation independence ( F = 3.52, P = .001; F = 2.04, P = .03) but not with age or ambulation distance. CONCLUSIONS: Care provided for urinary incontinence during the night was related to the need for physical support of ambulation and poor mobility in bed. Targeted input from a multidisciplinary team is warranted to facilitate change of practice at night.

Airway epithelial cell identity and plasticity are constrained by Sox2 during lung homeostasis, tissue regeneration, and in human disease.

Maintenance of the cellular boundary between airway and alveolar compartments during homeostasis and after injury is essential to prohibit pathological plasticity which can reduce respiratory function. Lung injury and disease can induce either functional alveolar epithelial regeneration or dysplastic formation of keratinized epithelium which does not efficiently contribute to gas exchange. Here we show that Sox2 preserves airway cell identity and prevents fate changes into either functional alveolar tissue or pathological keratinization following lung injury. Loss of Sox2 in airway epithelium leads to a loss of airway epithelial identity with a commensurate gain in alveolar and basal cell identity, in part due to activation of Wnt signaling in secretory cells and increased Trp63 expression in intrapulmonary basal-like progenitors. In idiopathic pulmonary fibrosis, loss of SOX2 expression correlates with increased WNT signaling activity in dysplastic keratinized epithelium. SOX2-deficient dysplastic epithelial cells are also observed in COVID-19 damaged lungs. Thus, Sox2 provides a molecular barrier that suppresses airway epithelial plasticity to prevent acquisition of alveolar or basal cell identity after injury and help guide proper epithelial fate and regeneration.

Hyperactive mTORC1 in lung mesenchyme induces endothelial cell dysfunction and pulmonary vascular remodeling.

Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells, resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of patients with LAM develop pulmonary vascular remodeling and pulmonary hypertension. Little, however, is known regarding how LAM cells communicate with endothelial cells (ECs) to trigger vascular remodeling. In end-stage LAM lung explants, we identified EC dysfunction characterized by increased EC proliferation and migration, defective angiogenesis, and dysmorphic endothelial tube network formation. To model LAM disease, we used an mTORC1 gain-of-function mouse model with a Tsc2 KO (Tsc2KO) specific to lung mesenchyme (Tbx4LME-Cre Tsc2fl/fl), similar to the mesenchyme-specific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from mice exhibited marked transcriptomic changes despite an absence of morphological changes to the distal lung microvasculature. In contrast, 1-year-old Tbx4LME-Cre Tsc2fl/fl mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. Single-cell RNA-Seq of 1-year-old mouse lung cells identified paracrine ligands originating from Tsc2KO mesenchyme, which can signal through receptors in arterial ECs. These ECs had transcriptionally altered genes including those in pathways associated with blood vessel remodeling. The proposed pathophysiologic mesenchymal ligand-EC receptor crosstalk highlights the importance of an altered mesenchymal cell/EC axis in LAM and other hyperactive mTORC1-driven diseases. Since ECs in patients with LAM and in Tbx4LME-Cre Tsc2fl/fl mice did not harbor TSC2 mutations, our study demonstrates that constitutively active mTORC1 lung mesenchymal cells orchestrated dysfunctional EC responses that contributed to pulmonary vascular remodeling.

When Ethics and the Law Collide: A Multicenter Demonstration Cohort Study of Pre-Exposure Prophylaxis Provision to Adolescent Men Who Have Sex With Men and Transgender Women in Brazil.

PURPOSE: To explore legal and ethical challenges related to adolescents' participation in human immunodeficiency virus (HIV) research that may affect their best interests. METHODS: We analyzed the ethical principles and legal aspects of the participation of 15-17-year-old men who have sex with men and transgender women in the pre-exposure prophylaxis (PrEP) 1519 study, a PrEP demonstration cohort study in three Brazilian cities. The analyses of ethics review committees' (ERCs) evaluations and court decisions followed ethical and human rights principles. An HIV vulnerability score was created, and descriptive statistics and multivariate logistic regression were performed using data from 347 participants. RESULTS: The ERCs evaluated the benefits and risks of research participation, all finding that the benefits outweighed the risks. ERCs deferred responsibility for decisions about waiving parental consent to the judiciary. State courts reached different decisions about waiving parental consent, reflecting variation in recognition of adolescents' evolving capacities and the adolescent as a subject of sexual rights and the primary agent capable of deciding on their health and best interests. The most vulnerable adolescent participants were found in sites where the blanket waiver was in place. DISCUSSION: Judicializing the ethical review process is detrimental to fulfilling the ethical principle of justice and vulnerable adolescents' access to health research. ERCs must be sufficiently independent and autonomous and have the capacity to respect, protect, and help fulfill the rights of participants while ensuring the generation of adequate evidence to inform public health practice.

A review of place-related contextual factors in syndemics research.

This review investigates the extent to which a place-based approach has been used to conceptualize context, as well as the place-related contextual factors explored in studies that explicitly invoked a syndemic framework. The literature search focused on 29 peer-reviewed empirical syndemic studies. Only 11 studies used a place-based approach to define and measure contextual factors and the spatial context was denoted using administrative boundaries such as census tracts, counties, and countries. A narrow range of place-related contextual factors were explored and most of them were related to social and economic factors that were used to define a place. Methodological gaps like a paucity of multilevel studies and studies using a place-based approach to measure context were identified. Future syndemics research should leverage multidimensional geospatial approaches to decipher the role of place-related contextual factors in syndemic dynamics.

Systematic review and quantitative and qualitative comparative analysis of interventions to address HIV-related stigma and discrimination.

A strong global commitment exists to eliminate HIV-related stigma and discrimination, and multiple strategies to reduce or eliminate stigma and discrimination have been tried. Using a PICOTS framework and applying the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria, we undertook a systematic review to determine the success of interventions aiming to address internalized stigma, stigma and discrimination in healthcare, and at the legal or policy level, and to identify their critical success factors. Random effects meta-analyses summarized results wherever possible. We carried out a component analysis to identify and characterize successful interventions. Internalized stigma interventions were diverse: across all studies, we found a reduction of stigma but it was not statistically significant [standardized mean difference (SMD) 0.56; confidence interval (CI) 0.31-1.02; 17 studies). For interventions to address stigma and discrimination in healthcare settings, effect estimates varied considerably but most studies showed positive effects (SMD 0.71; CI 0.60-0.84, 8 studies). Boosted regression analyses found that a combined approach comprising education, counseling, community participation, support person, and access to a HIV specialist often yielded success. Studies of efforts to address stigma and discrimination through law and policy documented, mostly qualitatively, the effect of court cases and directives. Across a range of settings and populations, promising interventions have been identified that, through diverse pathways, have positively impacted the types of stigma and discrimination studied. This evidence base must be built upon and brought to scale to help reach global HIV-related targets and, most importantly, improve the health and quality of life of people with HIV.

Measuring Geographic Access to Transgender Hormone Therapy in Texas: A Three-step Floating Catchment Area Analysis.

While the extant literature has established that transgender people face significant barriers to accessing healthcare, no studies to date have offered an explicitly spatial analysis of their access to trans-specific care. This study aims to fill that gap by providing a spatial analysis of access to gender-affirming hormone therapy (GAHT) using Texas as a case study. We used the three-step floating catchment area method, which relies on census tract-level population data and location data for healthcare facilities to quantify spatial access to healthcare within a specific drive-time window, in our case 120 min. For our tract-level population estimates we adapt estimates of the rates of transgender identification from a recent data source, the Household Pulse Survey, and use these in tandem with a spatial database of GAHT providers of the lead author's creation. We then compare results of the 3SFCA with data on urbanicity and rurality, as well as which areas are deemed medically underserved. Finally, we conduct a hot-spot analysis that identifies specific areas where health services could be planned in ways that could improve both access to GAHT for trans people and access to primary care for the general population. Ultimately, we conclude that our results illustrate that patterns of access to trans-specific medical care, like GAHT, do not neatly follow patterns of access to primary care for the general population and that therefore trans communities' access to healthcare warrants specific, further investigation.

Mechanisms by Which Liposomes Improve Inhaled Drug Delivery for Alveolar Diseases.

Diseases of the pulmonary alveolus, such as pulmonary fibrosis, are leading causes of morbidity and mortality, but exceedingly few drugs are developed for them. A major reason for this gap is that after inhalation, drugs are quickly whisked away from alveoli due to their high perfusion. To solve this problem, the mechanisms by which nano-scale drug carriers dramatically improve lung pharmacokinetics using an inhalable liposome formulation containing nintedanib, an antifibrotic for pulmonary fibrosis, are studied. Direct instillation of liposomes in murine lung increases nintedanib's total lung delivery over time by 8000-fold and lung half life by tenfold, compared to oral nintedanib. Counterintuitively, it is shown that pulmonary surfactant neither lyses nor aggregates the liposomes. Instead, each lung compartment (alveolar fluid, alveolar leukocytes, and parenchyma) elutes liposomes over 24 h, likely serving as "drug depots." After deposition in the surfactant layer, liposomes are transferred over 3-6 h to alveolar leukocytes (which take up a surprisingly minor 1-5% of total lung dose instilled) in a nonsaturable fashion. Further, all cell layers of the lung parenchyma take up liposomes. These and other mechanisms elucidated here should guide engineering of future inhaled nanomedicine for alveolar diseases.

Female ticks (Ixodes scapularis) infected with Borrelia burgdorferi have increased overwintering survival, with implications for tick population growth.

The tick, Ixodes scapularis, vectors pathogens such as Borrelia burgdorferi, the bacterium that causes Lyme disease. Over the last few decades I. scapularis has expanded its range, introducing a novel health threat into these areas. Warming temperatures appear to be one cause of its range expansion to the north. However, other factors are also involved. We show that unfed adult female ticks infected with B. burgdorferi have greater overwintering survival than uninfected female ticks. Locally collected adult female ticks were placed in individual microcosms and allowed to overwinter in both forest and dune grass environments. In the spring we collected the ticks and tested both dead and living ticks for B. burgdorferi DNA. Infected ticks had greater overwintering survival compared with uninfected ticks every winter for three consecutive winters in both forest and dune grass environments. We discuss the most plausible explanations for this result. The increased winter survival of adult female ticks could enhance tick population growth. Our results suggest that, in addition to climate change, B. burgdorferi infection itself may be promoting the northern range expansion of I. scapularis. Our study highlights how pathogens could work synergistically with climate change to promote host range expansion.

Cold-induced immune activation in chill-susceptible insects.

Chilling injuries in chill-susceptible insects, such as the model dipteran Drosophila melanogaster, have been well-documented as a consequence of stressful low-temperature exposures. Cold stress also causes upregulation of genes in the insect immune pathways, some of which are also upregulated following other forms of sterile stress. The adaptive significance and underlying mechanisms surrounding cold-induced immune activation, however, are still unclear. Here, we review recent work on the roles of reactive oxygen species, damage-associated molecular patterns, and antimicrobial peptides in insect immune signaling or function. Using this emerging knowledge, we propose a conceptual model linking biochemical and molecular causes of immune activation to its consequences during and following cold stress.

Functionalization of polymeric nanoparticles with targeting VNAR ligands using vinyl sulfone conjugation.

Actively targeted drug loaded nanoparticles represent an exciting new form of therapeutics for cancer and other diseases. These formulations are complex and in order to realize their ultimate potential, optimization of their preparation is required. In this current study, we have examined the conjugation of a model targeting ligand, conjugated in a site-specific manner using a vinyl sulfone coupling approach. A disulfide-functionalized poly(L-lactide)-b-poly(oligo(ethylene glycol) methacrylate)-stat-(bis(2-methacryloyl)oxyethyl disulfide) (PLA-b-P(OEGMA-stat-DSDMA)) diblock copolymer was synthesized by simultaneous ring opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. Subsequently, the disulfide bonds of the polymer were reduced to thiols and divinyl sulfone was attached to the polymer using thiol-ene chemistry to produce the vinyl sulfone (VS)-functionalized PLA-b-P(OEGMA-stat-VSTEMA) amphiphilic block copolymer. Single emulsion - solvent evaporation was employed using a blend of this polymer with poly(D,L-lactide-co-glycolide) (PLGA) to produce VS-functionalized polymeric nanoparticles. The ability of these novel nanoparticles to attach ligands was then exemplified using a single domain variable new antigen receptor (VNAR) with a free carboxyl terminal cysteine residue. The resulting VNAR-functionalized nanoparticles were found to maintain specific affinity to their cognate antigen (DLL4) for at least 72 h at 4 °C. The simplicity of the degradable amphiphilic block copolymer synthesis and the efficiency of VNAR conjugation to the VS-functionalized nanoparticles show the potential of this platform for therapeutic development.