Point-of-care human milk concentration by passive osmosis: comprehensive analysis of fresh human milk samples.

OBJECTIVE: Preterm infants need enrichment of human milk (HM) for optimal growth. This study evaluated a novel, point-of-care human milk concentration (HMC) process for water removal from fresh HM samples by passive osmotic concentration. STUDY DESIGN: Nineteen fresh HM samples were concentrated by incubation with the HMC devices for 3 h at 4 °C. Pre- and post-concentration HM samples were compared by HM properties for: pH, osmolality, macronutrients, enzyme activity, bioactive, and total cell viability. RESULTS: Passive osmotic concentration reduced HM volume by an average of 16.3% ± 3.8% without a significant effect on pH or cell viability. Ten of the 41 HM components did not differ significantly (p > 0.05) between pre- and post-concentration samples. Twenty-three increased within the expected range by volume reduction. Six increased more than expected, two less than expected, and none decreased significantly. CONCLUSION: Passive osmotic concentration of fresh HM can concentrate HM components by selective removal of water. HM osmolality and pH remained within neonatal feeding parameters.

Inhaled Treprostinil in Pulmonary Hypertension Associated with COPD: PERFECT study results.

INTRODUCTION: Pulmonary hypertension accompanying chronic obstructive pulmonary disease (PH-COPD) is associated with worse outcomes than COPD alone. There are currently no approved therapies to treat PH-COPD. The PERFECT study (NCT03496623) evaluated the safety and efficacy of inhaled treprostinil (iTRE) in this patient population. METHODS: Patients with PH-COPD (mean pulmonary artery pressures ≥30 mmHg and pulmonary vascular resistances ≥4 Wood units) were enrolled in a multicentre, randomised (1:1), double-blind, placebo-controlled, 12-week, crossover study. A contingent parallel design was also prespecified and implemented, based on a blinded interim analysis of missing data. Patients received treatment with iTRE up to 12 breaths (72 µg) 4 times daily or placebo. The primary efficacy end point was change in peak 6-minute walk distance (6 MWD) at Week 12. RESULTS: In total, 76 patients were randomised, 64 in the original crossover design and 12 in the contingent parallel design; 66 patients received iTRE and 58 received placebo. The study was terminated early at the recommendation of the Data and Safety Monitoring Committee based on the totality of evidence that iTRE increased the risk of serious adverse events and suggestive evidence of an increased risk of mortality. The change in 6MWD was numerically worse with iTRE exposure than with placebo exposure. CONCLUSIONS: The risk-benefit observations associated with iTRE in patients with PH-COPD did not support continuation of the PERFECT study. The results of this study do not support iTRE as a viable treatment option in patients with PH-COPD.

Aircraft noise exposure and body mass index among female participants in two Nurses' Health Study prospective cohorts living around 90 airports in the United States.

OBJECTIVE: Aircraft noise exposure is linked to cardiovascular disease risk. One understudied candidate pathway is obesity. This study investigates the association between aircraft noise and obesity among female participants in two prospective Nurses' Health Study (NHS and NHSII) cohorts. METHODS: Aircraft day-night average sound levels (DNL) were estimated at participant residential addresses from modeled 1 dB (dB) noise contours above 44 dB for 90 United States (U.S.) airports in 5-year intervals 1995-2010. Biennial surveys (1994-2017) provided information on body mass index (BMI; dichotomized, categorical) and other individual characteristics. Change in BMI from age 18 (BMI18; tertiles) was also calculated. Aircraft noise exposures were dichotomized (45, 55 dB), categorized (<45, 45-54, ≥55 dB) or continuous for exposure ≥45 dB. Multivariable multinomial logistic regression using generalized estimating equations were adjusted for individual characteristics and neighborhood socioeconomic status, greenness, population density, and environmental noise. Effect modification was assessed by U.S. Census region, climate boundary, airline hub type, hearing loss, and smoking status. RESULTS: At baseline, the 74,848 female participants averaged 50.1 years old, with 83.0%, 14.8%, and 2.2% exposed to <45, 45-54, and ≥55 dB of aircraft noise, respectively. In fully adjusted models, exposure ≥55 dB was associated with 11% higher odds (95% confidence interval [95%CI]: -1%, 24%) of BMIs ≥30.0, and 15% higher odds (95%CI: 3%, 29%) of membership in the highest tertile of BMI18 (ΔBMI 6.7 to 71.6). Less-pronounced associations were observed for the 2nd tertile of BMI18 (ΔBMI 2.9 to 6.6) and BMI 25.0-29.9 as well as exposures ≥45 versus <45 dB. There was evidence of DNL-BMI trends (ptrends ≤ 0.02). Stronger associations were observed among participants living in the West, arid climate areas, and among former smokers. DISCUSSION: In two nationwide cohorts of female nurses, higher aircraft noise exposure was associated with higher BMI, adding evidence to an aircraft noise-obesity-disease pathway.

Influences on clinical trial participation: Enhancing recruitment through a gender lens - A scoping review.

Background: Suboptimal clinical trial recruitment contributes to research waste. Evidence suggests there may be gender-based differences in willingness to participate in clinical research. Identifying gender-based differences impacting the willingness of trial participation may assist trial recruitment. Objectives: To examine factors that influence the willingness of men and women to participate in clinical trials and to identify modifiable factors that may be targeted to optimise trial participation. Material and methods: Electronic databases were searched with key words relating to 'gender', 'willingness to participate' and 'trial'. Included studies were English language and reported gender-based differences in willingness to participate in clinical trials, or factors that influence a single gender to participate in clinical trials. Studies were excluded if they described the demographic factors of trial participants or if the majority of participants were pregnant. Extracted data were coded, categorized, analysed thematically and interpreted using Arksey and O'Malley's framework. Results: Sixty-three studies were included. Two main themes were identified: trial characteristics and participant characteristics. A number of gender-based differences moderating willingness to participate were observed although only one, 'concern for self' was found to influence actual trial participation rates between genders. Conclusion: The relationship between factors influencing willingness to participate in clinical trials is complex. The influence of gender on willingness to participate, while important, may be moderated by other factors including socioeconomic status, ethnicity and health condition. Exploring factors that influence willingness to participate specific to a study cohort likely offers the most promise to optimise trial recruitment of that cohort.

Study protocol of a randomized controlled trial to assess the efficacy of the "PrEPare for Work" intervention to enhance PrEP uptake and optimize adherence for HIV prevention among male sex workers in the U.S.

BACKGROUND: Male sex workers (MSWs), specifically cisgender men who exchange sex for money, goods, drugs, or other items of value with other cisgender men, are at high risk for HIV infection. Compared to men not engaged in sex work, MSWs are more likely to engage in frequent condomless sex with paying and non-paying sexual partners. While MSWs are often included as a subgroup of gay and bisexual men, data show that a large proportion identify as heterosexual; additionally, most MSWs do not identify as "sex workers." This places MSWs in a unique position where they may not engage with traditional HIV prevention programs, and when they do, they may not feel comfortable, leading to poor retention. Thus, HIV prevention interventions that address MSWs' unique life circumstances and provide support in exploring their sexual health options are needed. METHODS: In this protocol paper, we describe the design and procedures for a National Institute of Health-funded, randomized controlled trial testing the efficacy of "PrEPare for Work,"- a theory-based, manualized PrEP uptake and adherence intervention for MSW - using a 2-stage randomization design. Stage 1: MSWs are equally randomized to receive either the "PrEPare for Work Stage 1 intervention" (strength-based case management and facilitated PrEP linkage) or Standard of Care (SOC) to evaluate successful PrEP uptake (prescription filled) within two months post-randomization. Stage 2: Those who initiate PrEP are then equally re-randomized to receive either the "PrEPare for Work Stage 2 intervention" (1-on-1 skills training, problem-solving, and motivational interviewing adherence counseling and personalized, daily text message reminders) or SOC to assess adherence (Tenofovir concentrations in hair) over 12 months of follow up. Planned analyses will examine intervention efficacy, specific conceptual mediators, and hypothesized moderators. DISCUSSION: Based on our extensive preliminary research, multi-component, theory-informed interventions targeting this subpopulation of MSWs' unique life circumstances are urgently needed. In this study, we are evaluating whether "PrEPare for Work" can improve PrEP uptake and adherence among MSWs. If this intervention is efficacious, it would be readily disseminated to diverse community organizations that serve MSWs and possibly other community or clinic-based settings. TRIAL REGISTRATION: ClinicalTrials.gov number NCT05736614, registered February 8, 2023.

Induced Endothelial Cell Cycle Arrest Prevents Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Distinct endothelial cell cycle states (early G1 versus late G1) provide different "windows of opportunity" to enable the differential expression of genes that regulate venous versus arterial specification, respectively. Endothelial cell cycle control and arteriovenous identities are disrupted in vascular malformations including arteriovenous shunts, the hallmark of hereditary hemorrhagic telangiectasia (HHT). To date, the mechanistic link between endothelial cell cycle regulation and the development of arteriovenous malformations (AVMs) in HHT is not known. METHODS: We used BMP (bone morphogenetic protein) 9/10 blocking antibodies and endothelial-specific deletion of activin A receptor like type 1 (Alk1) to induce HHT in Fucci (fluorescent ubiquitination-based cell cycle indicator) 2 mice to assess endothelial cell cycle states in AVMs. We also assessed the therapeutic potential of inducing endothelial cell cycle G1 state in HHT to prevent AVMs by repurposing the Food and Drug Administration-approved CDK (cyclin-dependent kinase) 4/6 inhibitor (CDK4/6i) palbociclib. RESULTS: We found that endothelial cell cycle state and associated gene expressions are dysregulated during the pathogenesis of vascular malformations in HHT. We also showed that palbociclib treatment prevented AVM development induced by BMP9/10 inhibition and Alk1 genetic deletion. Mechanistically, endothelial cell late G1 state induced by palbociclib modulates the expression of genes regulating arteriovenous identity, endothelial cell migration, metabolism, and VEGF-A (vascular endothelial growth factor A) and BMP9 signaling that collectively contribute to the prevention of vascular malformations. CONCLUSIONS: This study provides new insights into molecular mechanisms leading to HHT by defining how endothelial cell cycle is dysregulated in AVMs because of BMP9/10 and Alk1 signaling deficiencies, and how restoration of endothelial cell cycle control may be used to treat AVMs in patients with HHT.

Associations between long-term aircraft noise exposure, cardiovascular disease, and mortality in US cohorts of female nurses.

There is limited research examining aircraft noise and cardiovascular disease (CVD) risk. The objective of this study was to investigate associations of aircraft noise with CVD among two US cohorts, the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII). Methods: Between 1994 and 2014, we followed 57,306 NHS and 60,058 NHSII participants surrounding 90 airports. Aircraft noise was modeled above 44 A-weighted decibels (dB(A)) and linked to geocoded addresses. Based on exposure distributions, we dichotomized exposures at 50 dB(A) and tested sensitivity of this cut-point by analyzing aircraft noise as categories (<45, 45-49, 50-54, ≥55) and continuously. We fit cohort-specific Cox proportional hazards models to estimate relationships between time-varying day-night average sound level (DNL) and CVD incidence and CVD and all-cause mortality, adjusting for fixed and time-varying individual- and area-level covariates. Results were pooled using random effects meta-analysis. Results: Over 20 years of follow-up, there were 4529 CVD cases and 14,930 deaths. Approximately 7% (n = 317) of CVD cases were exposed to DNL ≥50 dB(A). In pooled analyses comparing ≥50 with <50 dB(A), the adjusted hazard ratio for CVD incidence was 1.00 (95% confidence interval: 0.89, 1.12). The corresponding adjusted hazard ratio for all-cause mortality was 1.02 (95% confidence interval: 0.96, 1.09). Patterns were similar for CVD mortality in NHS yet underpowered. Conclusions: Among participants in the NHS and NHSII prospective cohorts who generally experience low exposure to aircraft noise, we did not find adverse associations of aircraft noise with CVD incidence, CVD mortality, or all-cause mortality.

The Many Hosts of Mycobacteria 9 (MHM9): A conference report.

The Many Hosts of Mycobacteria (MHM) meeting series brings together basic scientists, clinicians and veterinarians to promote robust discussion and dissemination of recent advances in our knowledge of numerous mycobacterial diseases, including human and bovine tuberculosis (TB), nontuberculous mycobacteria (NTM) infection, Hansen's disease (leprosy), Buruli ulcer and Johne's disease. The 9th MHM conference (MHM9) was held in July 2022 at The Ohio State University (OSU) and centered around the theme of "Confounders of Mycobacterial Disease." Confounders can and often do drive the transmission of mycobacterial diseases, as well as impact surveillance and treatment outcomes. Various confounders were presented and discussed at MHM9 including those that originate from the host (comorbidities and coinfections) as well as those arising from the environment (e.g., zoonotic exposures), economic inequality (e.g. healthcare disparities), stigma (a confounder of leprosy and TB for millennia), and historical neglect (a confounder in Native American Nations). This conference report summarizes select talks given at MHM9 highlighting recent research advances, as well as talks regarding the historic and ongoing impact of TB and other infectious diseases on Native American Nations, including those in Southwestern Alaska where the regional TB incidence rate is among the highest in the Western hemisphere.

The long-term effects of aggressive spasticity reducing treatment, including selective dorsal rhizotomy, on joint kinematic outcomes of persons with cerebral palsy.

BACKGROUND: Selective dorsal rhizotomy (SDR) creates a large and permanent reduction of spasticity for children with cerebral palsy (CP). Previous SDR outcomes studies have generally lacked appropriate control groups, had limited sample sizes, or reported short-term follow-up, limiting evidence for improvement in long-term gait function. RESEARCH QUESTION: Does aggressive spasticity management for individuals with CP improve long-term gait kinematics (discrete joint kinematics) compared to a control group of individuals with CP with minimal spasticity management? METHODS: This study was a secondary analysis - focused on joint-level kinematics - of a previous study evaluating the long-term outcomes of SDR. Two groups of participants were recruited based on a retrospectively completed baseline clinical gait study. One group received aggressive spasticity treatment including a selective dorsal rhizotomy (Yes-SDR group), while the other group had minimal spasticity management (No-SDR group). Both groups had orthopedic surgery treatment. Groups were matched on baseline spasticity. All participants prospectively returned for a follow-up gait study in young adulthood (greater than 21 years of age and at least 10 years after baseline). Change scores in discrete kinematic variables from baseline to follow-up were assessed using a linear model that included treatment arm (Yes-SDR, No-SDR), baseline age, and baseline kinematic value. For treatment arm, 5° and 5 Gait Deviation Index points were selected as thresholds to be considered a meaningful difference between treatment groups. RESULTS: At follow-up, there were no meaningful differences in pelvis, hip, knee, or ankle kinematic variable changes between treatment arms. Max knee flexion - swing showed a moderate treatment effect for Yes-SDR, although it did not reach the defined threshold. SIGNIFICANCE: Aggressive spasticity treatment does not result in meaningful differences in gait kinematics for persons with cerebral palsy in young adulthood compared to minimal spasticity management with both groups having orthopedic surgery.

Interlacing in Atomic Resolution Scanning Transmission Electron Microscopy.

Fast frame rates are desirable in scanning transmission electron microscopy for a number of reasons: controlling electron beam dose, capturing in situ events, or reducing the appearance of scan distortions. While several strategies exist for increasing frame rates, many impact image quality or require investment in advanced scan hardware. Here, we present an interlaced imaging approach to achieve minimal loss of image quality with faster frame rates that can be implemented on many existing scan controllers. We further demonstrate that our interlacing approach provides the best possible strain precision for a given electron dose compared with other contemporary approaches.

14th century Yersinia pestis genomes support emergence of pestis secunda within Europe.

Pestis secunda (1356-1366 CE) is the first of a series of plague outbreaks in Europe that followed the Black Death (1346-1353 CE). Collectively this period is called the Second Pandemic. From a genomic perspective, the majority of post-Black Death strains of Yersinia pestis thus far identified in Europe display diversity accumulated over a period of centuries that form a terminal sub-branch of the Y. pestis phylogeny. It has been debated if these strains arose from local evolution of Y. pestis or if the disease was repeatedly reintroduced from an external source. Plague lineages descended from the pestis secunda, however, are thought to have persisted in non-human reservoirs outside Europe, where they eventually gave rise to the Third Pandemic (19th and 20th centuries). Resolution of competing hypotheses on the origins of the many post-Black Death outbreaks has been hindered in part by the low representation of Y. pestis genomes in archaeological specimens, especially for the pestis secunda. Here we report on five individuals from Germany that were infected with lineages of plague associated with the pestis secunda. For the two genomes of high coverage, one groups within the known diversity of genotypes associated with the pestis secunda, while the second carries an ancestral genotype that places it earlier. Through consideration of historical sources that explore first documentation of the pandemic in today's Central Germany, we argue that these data provide robust evidence to support a post-Black Death evolution of the pathogen within Europe rather than a re-introduction from outside. Additionally, we demonstrate retrievability of Y. pestis DNA in post-cranial remains and highlight the importance of hypothesis-free pathogen screening approaches in evaluations of archaeological samples.

Connexin 37 sequestering of activated-ERK in the cytoplasm promotes p27-mediated endothelial cell cycle arrest.

Connexin37-mediated regulation of cell cycle modulators and, consequently, growth arrest lack mechanistic understanding. We previously showed that arterial shear stress up-regulates Cx37 in endothelial cells and activates a Notch/Cx37/p27 signaling axis to promote G1 cell cycle arrest, and this is required to enable arterial gene expression. However, how induced expression of a gap junction protein, Cx37, up-regulates cyclin-dependent kinase inhibitor p27 to enable endothelial growth suppression and arterial specification is unclear. Herein, we fill this knowledge gap by expressing wild-type and regulatory domain mutants of Cx37 in cultured endothelial cells expressing the Fucci cell cycle reporter. We determined that both the channel-forming and cytoplasmic tail domains of Cx37 are required for p27 up-regulation and late G1 arrest. Mechanistically, the cytoplasmic tail domain of Cx37 interacts with, and sequesters, activated ERK in the cytoplasm. This then stabilizes pERK nuclear target Foxo3a, which up-regulates p27 transcription. Consistent with previous studies, we found this Cx37/pERK/Foxo3a/p27 signaling axis functions downstream of arterial shear stress to promote endothelial late G1 state and enable up-regulation of arterial genes.

Transformation of alignment files improves performance of variant callers for long-read RNA sequencing data.

Long-read RNA sequencing (lrRNA-seq) produces detailed information about full-length transcripts, including novel and sample-specific isoforms. Furthermore, there is an opportunity to call variants directly from lrRNA-seq data. However, most state-of-the-art variant callers have been developed for genomic DNA. Here, there are two objectives: first, we perform a mini-benchmark on GATK, DeepVariant, Clair3, and NanoCaller primarily on PacBio Iso-Seq, data, but also on Nanopore and Illumina RNA-seq data; second, we propose a pipeline to process spliced-alignment files, making them suitable for variant calling with DNA-based callers. With such manipulations, high calling performance can be achieved using DeepVariant on Iso-seq data.

Community partnerships are fundamental to ethical ancient DNA research.

The ethics of the scientific study of Ancestors has long been debated by archaeologists, bioanthropologists, and, more recently, ancient DNA (aDNA) researchers. This article responds to the article "Ethics of DNA research on human remains: five globally applicable guidelines" published in 2021 in Nature by a large group of aDNA researchers and collaborators. We argue that these guidelines do not sufficiently consider the interests of community stakeholders, including descendant communities and communities with potential, but yet unestablished, ties to Ancestors. We focus on three main areas of concern with the guidelines. First is the false separation of "scientific" and "community" concerns and the consistent privileging of researcher perspectives over those of community members. Second, the commitment of the guidelines' authors to open data ignores the principles and practice of Indigenous Data Sovereignty. Further, the authors argue that involving community members in decisions about publication and data sharing is unethical. We argue that excluding community perspectives on "ethical" grounds is convenient for researchers, but it is not, in fact, ethical. Third, we stress the risks of not consulting communities that have established or potential ties to Ancestors, using two recent examples from the literature. Ancient DNA researchers cannot focus on the lowest common denominator of research practice, the bare minimum that is legally necessary. Instead, they should be leading multidisciplinary efforts to create processes to ensure communities from all regions of the globe are identified and engaged in research that affects them. This will often present challenges, but we see these challenges as part of the research, rather than a distraction from the scientific endeavor. If a research team does not have the capacity to meaningfully engage communities, questions must be asked about the value and benefit of their research.

Aging With Incarceration Histories: An Intersectional Examination of Incarceration and Health Outcomes Among Older Adults.

OBJECTIVES: Experiences with incarceration are linked to poor mental and physical health across the life course. The purpose of this research is to examine whether incarceration histories are associated with worse physical and mental health among older adults. We apply an intersectionality framework and consider how the intersection of sexism and racism leads to unequal health outcomes following incarceration among women and people of color. METHODS: We employ 2 measures of health (i.e., number of depressive symptoms and physical limitations) to broadly capture mental and physical health. Using data from Waves 11 and 12 of the Health and Retirement Study, we estimated a series of general linear models to analyze differences in health by incarceration history, gender/sex, and race/ethnicity. RESULTS: Findings suggest that experiences with incarceration are associated with a greater number of physical limitations and more depressive symptoms among older men and women, net of sociodemographic characteristics, early-life conditions, and lifetime stressful events. Formerly incarcerated women, particularly women of color, had more physical limitations and depressive symptoms relative to other groups. DISCUSSION: These findings suggest that incarceration histories have far-reaching health implications. Older women of color with incarceration histories experience markedly high levels of physical limitations and depressive symptoms in later life.

When left hands touch: shadow vows and Jung's quaternity.

Is there a connection between the exchange of vows and the fighting and suffering of couples that are unique to the institution of marriage? This essay introduces the concept of Shadow Vows, the unacknowledged assumptions, agreements, and obligations each partner brings to the relationship, which the authors believe are often responsible for longstanding marital discord and strife. The authors ground the existence of shadow vows in Jung's quaternity, alchemy, typology, archetypal theory, and depth approaches to couple therapy. The essay concludes with a list of themes indicative of shadow vow enactments in clinical work with couples.

Y a-t-il un lien entre l'échange des vœux et les conflits et souffrances des couples, un lien qui serait spécifique à l'institution du mariage ? Cet article introduit le concept de « vœux de l'ombre ¼ - les présomptions non-reconnues, les compromis, les obligations que chaque partenaire amène dans la relation. Les auteurs pensent que de tels vœux sont souvent responsables de discorde et querelles durables dans un couple marié. Les auteurs fondent l'existence de ces vœux de l'ombre dans la quaternité Jungienne, l'alchimie, la typologie, la théorie des archétypes et la thérapie de couple selon la psychologie des profondeurs. L'article se termine par une liste de thèmes révélateurs des mises en acte de ces vœux de l'ombre dans le travail clinique avec des couples.

Existe una conexión entre el intercambio de votos y el conflicto y sufrimiento de las parejas, que es única a la institución del matrimonio? El presente ensayo introduce el concepto de 'sombra de los votos' - las asunciones, acuerdos y obligaciones no reconocidas que cada integrante de la pareja trae a la relación, las cuales los autores creen que a menudo son responsables de largos conflictos y desavenencias en el matrimonio. Los autores basan la existencia de la sombra de los votos en la noción de cuaternidad de Jung, alquimia, tipología, teoría arquetipal, y los abordajes en psicología profunda a la terapia de pareja. El ensayo concluye con una lista de temas indicativos de actuaciones del lado sombrío de los votos en el trabajo clínico con parejas.

Endothelial cell cycle state determines propensity for arterial-venous fate.

During blood vessel development, endothelial cells become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues. Arterial-venous specification occurs in conjunction with suppression of endothelial cell cycle progression; however, the mechanistic role of cell cycle state is unknown. Herein, using Cdh5-CreERT2;R26FUCCI2aR reporter mice, we find that venous endothelial cells are enriched for the FUCCI-Negative state (early G1) and BMP signaling, while arterial endothelial cells are enriched for the FUCCI-Red state (late G1) and TGF-ß signaling. Furthermore, early G1 state is essential for BMP4-induced venous gene expression, whereas late G1 state is essential for TGF-ß1-induced arterial gene expression. Pharmacologically induced cell cycle arrest prevents arterial-venous specification defects in mice with endothelial hyperproliferation. Collectively, our results show that distinct endothelial cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous fate.

Ancient Yersinia pestis and Salmonella enterica genomes from Bronze Age Crete.

During the late 3rd millennium BCE, the Eastern Mediterranean and Near East witnessed societal changes in many regions, which are usually explained with a combination of social and climatic factors.1-4 However, recent archaeogenetic research forces us to rethink models regarding the role of infectious diseases in past societal trajectories.5 The plague bacterium Yersinia pestis, which was involved in some of the most destructive historical pandemics,5-8 circulated across Eurasia at least from the onset of the 3rd millennium BCE,9-13 but the challenging preservation of ancient DNA in warmer climates has restricted the identification of Y. pestis from this period to temperate climatic regions. As such, evidence from culturally prominent regions such as the Eastern Mediterranean is currently lacking. Here, we present genetic evidence for the presence of Y. pestis and Salmonella enterica, the causative agent of typhoid/enteric fever, from this period of transformation in Crete, detected at the cave site Hagios Charalambos. We reconstructed one Y. pestis genome that forms part of a now-extinct lineage of Y. pestis strains from the Late Neolithic and Bronze Age that were likely not yet adapted for transmission via fleas. Furthermore, we reconstructed two ancient S. enterica genomes from the Para C lineage, which cluster with contemporary strains that were likely not yet fully host adapted to humans. The occurrence of these two virulent pathogens at the end of the Early Minoan period in Crete emphasizes the necessity to re-introduce infectious diseases as an additional factor possibly contributing to the transformation of early complex societies in the Aegean and beyond.

Pre-Exposure Prophylaxis Barriers, Facilitators and Unmet Need Among Rural People Who Inject Drugs: A Qualitative Examination of Syringe Service Program Client Perspectives.

Background: People who inject drugs (PWID) are at high risk for HIV infection, yet in rural areas PWID are understudied with respect to prevention strategies. Kentucky is notable for heavy rural HIV burden and increasing rates of new HIV diagnoses attributable to injection drug use. Despite high need and the strong evidence for Pre-Exposure Prophylaxis (PrEP) as a gold-standard biomedical HIV prevention tool, scale up has been limited among PWID in Kentucky and elsewhere. This paper explores individual, environmental, and structural barriers and facilitators of PrEP care from the perspective of PWID in rural Kentucky. Methods: Data are drawn from an ongoing NIH-funded study designed to adapt and integrate a PrEP initiation intervention for high-risk PWID at point of care in two rural syringe service programs (SSPs) in southeastern Kentucky. As part of this initiative, a qualitative study guided by PRISM (Practical, Robust, Implementation, and Sustainability Model) was undertaken to gather SSP client perspectives on intervention needs related to PrEP, competing needs related to substance use disorder, as well as tangible supports for and barriers to PrEP uptake. Recruitment and interviews were conducted during September-November 2021 with 26 SSP clients, 13 from each of the two SSP sites. A semi-structured guide explored injection behaviors, SSP use, knowledge of PrEP, perceived barriers to PrEP, as well as aspects of the risk environment (e.g., housing instability, community stigma) that may impact PrEP uptake. Interviews were digitally recorded, transcribed verbatim and verified by project staff. A detailed coding scheme was developed and applied by independent coders using NVivo. Coded transcripts were synthesized to identify salient themes in the data using the principles of thematic analysis All study procedures were approved by the University IRB. Results: Participants were 96% white, 42% female, with a median age of 41 years (range 21-62); all reported injection use within the past month. Overall, we found low PrEP awareness among this sample, yet interest in PrEP was high, with several indicating PrEP is urgently needed. Clients reported overwhelmingly positive experiences at the SSPs, considering them trusted and safe locations to receive health services, and were enthusiastic about the integration of co-located PrEP services. Lack of basic HIV and PrEP knowledge and health literacy were in evidence, which contributed to common misperceptions about personal risk for HIV. Situational risks related to substance use disorder, particularly in the context of withdrawal symptoms and craving, often lead to heightened HIV injection and sexual risk behaviors. Stigma related to substance use and HIV arose as a concern for PrEP uptake, with several participants reflecting that privacy issues would impact their preferences for education, prescribing and monitoring of PrEP. Noted tangible barriers included inconsistent access to phone service and transportation. Primary supports included high levels of insurance coverage, consistent pharmacy access, and histories with successful medication management for other health conditions. Conclusions: Drawing on the critical perspectives of people with substance use disorder, our findings provide important and actionable information on individual and environmental barriers and facilitators of PrEP uptake among rural PWID at high risk for HIV infection. These data will drive the adaptation and implementation of a client-centered approach to integrated PrEP care within rurally located SSP settings to address unmet needs for PrEP care.

Voices from the Newspaper Club: Patient Life at a State Psychiatric Hospital (1988-1992).

The authors conducted a qualitative analysis of thirty-seven issues of The DDU Review, a newsletter produced by residents of the Dual Diagnosis Unit, a residential unit for people who had diagnoses of developmental disability and serious mental illness in the Central State Hospital (Indiana, USA). The analysis of the newsletters produced between September 1988 and June 1992 revealed three major themes: 1) the mundane; 2) good behavior; and 3) advocacy. Contrary to the authors' expectations, the discourse of medicalization-such as relations with physicians, diagnoses, and medications-receive little attention. Instead, the patient-journalists focus on prosaic aspects of institutional life. The patients used their writing as a form self-definition and advocacy. The authors argue that even though it is tempting to consider the patients' emphasis on good behavior as evidence of institutional control, internalized discipline, and medicalization, a more nuanced interpretation, which focuses on how the patients' understood their own experiences, is warranted. Researchers must also recognize the ways in which The DDU Review reveals the patient-journalists' experience of an institutional life that includes non-medical staff (attendants, secretaries, and therapists), varied social relationships among patients, and negotiated freedoms.