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Introduction: People experiencing homelessness (PEH) are highly vulnerable to discrimination and violence, which impact physical and mental health. The study examines past-month discrimination and violence against PEH in Los Angeles County (LAC)., Methods: A total of 332 PEH in LAC were surveyed about their past-month experiences with discrimination, physical violence, and sexual violence from April-July 2023. Analyses were conducted in 2023., Results: 31.8% of respondents reported experiencing discrimination daily and 53.9% reported it weekly, whereas rates of lifetime discrimination in studies of general populations of minoritized groups range between 13-60%. Nearly half of respondents who reported experiencing discrimination (49.6%) believed that their housing situation was the reason they were targeted. Victimization was also common, with 16.0% of participants experiencing physical violence and 7.5% experiencing sexual violence in the past 30 days. These rates of past-month victimization are high when compared to past-year physical violence (3.0%) and sexual violence (0.24%) among general populations in major U.S. cities. In multivariate regression analyses, discrimination was associated with being unsheltered in a vehicle (p<0.05) or outdoors (p<0.001), weekly illicit drug use (p<0.01), and psychological distress (p<0.001); violent victimization was associated with being sheltered (p<0.05) or unsheltered outdoors (p<0.001), physical health conditions (p<0.05), and psychological distress (p<0.01); and sexual victimization was associated with non-male gender (p<0.05) and being unsheltered outdoors (p<0.05). Discrimination and victimization outcomes were not associated with any race/ethnicity, sexual orientation, or time homeless characteristics., Conclusions: Study findings highlight the dangers of homelessness in the U.S., particularly for those who are unsheltered outdoors., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite major successes with inhibitory receptor blockade in cancer, the identification of novel inhibitory receptors as putative drug targets is needed due to lack of durable responses, therapy resistance, and side effects. Most inhibitory receptors signal via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and previous studies estimated that our genome contains over 1600 ITIM-bearing transmembrane proteins. However, testing and development of these candidates requires increased understanding of their expression patterns and likelihood to function as inhibitory receptor. Therefore, we designed a novel bioinformatics pipeline integrating machine learning-guided structural predictions and sequence-based likelihood models to identify putative inhibitory receptors. Using transcriptomics data of immune cells, we determined the expression of these novel inhibitory receptors, and classified them into previously proposed functional categories. Known and putative inhibitory receptors were expressed across different immune cell subsets with cell type-specific expression patterns. Furthermore, putative immune inhibitory receptors were differentially expressed in subsets of tumour infiltrating T cells. In conclusion, we present an inhibitory receptor pipeline that identifies 51 known and 390 novel human inhibitory receptors. This pipeline will support future drug target selection across diseases where therapeutic targeting of immune inhibitory receptors is warranted., Competing Interests: AS AS is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, AM AMB is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, Hv HJR is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, SV, RK, AY No competing interests declared, Mv MV is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, JK JK is cofounder, shareholder and scientific advisor of GADETA. JK is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, CK CK is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, MP IR is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, LM LM has received funding for investigator-initiated studies on inhibitory receptors from Boehringer Ingelheim, NextCure, NGM Biopharmaceuticals and Argenx. LM is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, (© 2024, Singh et al.)

Leptospirosis and toxoplasmosis are re-emerging zoonosis caused by infection with pathogenic spirochaetes of Leptospira and the protozoa Toxoplasma gondii, respectively. Wild boars (Sus scrofa), an exotic invasive species in Brazil, could play a role in the diseases' epidemiological cycles, but this issue is still unexplored. This study aimed to evaluate the Leptospira spp. and T. gondii seropositivity in wild boars in Rio Grande do Sul state, south Brazil. Of evaluated animals, 16% (13/80) and 85% (52/61) had antibodies to T. gondii and Leptospira spp., respectively. Sex, weight, age, hunt location and season of hunt were evaluated by their association with seropositivity for both pathogens, but none of them had statistical significance. This study revealed that wild boars should be considered as a potential source of Leptospira spp. and T. gondii dissemination for humans and animal species in shared environments in Rio Grande do Sul state., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

There are two dominant approaches to implementing permanent supportive housing (PSH), namely place-based (PB) and scattered-site (SS). Formal guidance does not distinguish between these two models and only specifies that PSH should be reserved for those who are most vulnerable with complex health needs. To consider both system- and self-selection factors that may affect housing assignment, this study applied the Gelberg-Anderson behavioral model for vulnerable populations to compare predisposing, enabling, and need factors among people experiencing homelessness (PE) by whether they were assigned to PB-PSH (n = 272) or SS-PSH (n = 185) in Los Angeles County during the COVID-19 pandemic. This exploratory, observational study also included those who were approved but did not receive PSH (n = 94). Results show that there are notable differences between (a) those who received PSH versus those who did not, and (b) those in PB-PSH versus SS-PSH. Specifically, PEH who received PSH were more likely to be white, US-born, have any physical health condition, and have lower health activation scores. PEH who received PB- versus SS-PSH were more likely to be older, Black, have any alcohol use disorder, and have higher health activation scores. These findings suggest that homeless service systems may consider PB-PSH more appropriate for PEH with higher needs but also raises important questions about how race may be a factor in the type of PSH that PEH receive and whether PSH is received at all., (© 2024. The Author(s).)

Background: While different proposals exist for a guideline on reporting Delphi studies, none of them has yet established itself in the health and social sciences and across the range of Delphi variants. This seems critical because empirical studies demonstrate a diversity of modifications in the conduction of Delphi studies and sometimes even errors in the reporting. The aim of the present study is to close this gap and formulate a general reporting guideline., Method: In an international Delphi procedure, Delphi experts were surveyed online in three rounds to find consensus on a reporting guideline for Delphi studies in the health and social sciences. The respondents were selected via publications of Delphi studies. The preliminary reporting guideline, containing 65 items on five topics and presented for evaluation, had been developed based on a systematic review of the practice of Delphi studies and a systematic review of existing reporting guidelines for Delphi studies. Starting in the second Delphi round, the experts received feedback in the form of mean values, measures of dispersion, a summary of the open-ended responses and their own response in the previous round. The final draft of the reporting guideline contains the items on which at least 75% of the respondents agreed by assigning scale points 6 and 7 on a 7-point Likert scale., Results: 1,072 experts were invited to participate. A total of 91 experts completed the first Delphi round, 69 experts the second round, and 56 experts the third round. Of the 65 items in the first draft of the reporting guideline, consensus was ultimately reached for 38 items addressing the five topics: Title and Abstract (n = 3), Context (n = 7), Method (n = 20), Results (n = 4) and Discussion (n = 4). Items focusing on theoretical research and on dissemination were either rejected or remained subjects of dissent., Discussion: We assume a high level of acceptance and interdisciplinary suitability regarding the reporting guideline presented here and referred to as the "Delphi studies in social and health sciences-recommendations for an interdisciplinary standardized reporting" (DELPHISTAR). Use of this reporting guideline can substantially improve the ability to compare and evaluate Delphi studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Niederberger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mutations in the lysosomal membrane protein CLN3 cause Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). Activation of the lysosomal ion channel TRPML1 has previously been shown to be beneficial in several neurodegenerative disease models. Here, we tested whether TRPML1 activation rescues disease-associated phenotypes in CLN3-deficient retinal pigment epithelial (ARPE-19 CLN3-KO) cells. ARPE-19 CLN3-KO cells accumulate LAMP1 positive organelles and show lysosomal storage of mitochondrial ATPase subunit C (SubC), globotriaosylceramide (Gb3), and glycerophosphodiesters (GPDs), whereas lysosomal bis(monoacylglycero)phosphate (BMP/LBPA) lipid levels were significantly decreased. Activation of TRPML1 reduced lysosomal storage of Gb3 and SubC but failed to restore BMP levels in CLN3-KO cells. TRPML1-mediated decrease of storage was TFEB-independent, and we identified TRPML1-mediated enhanced lysosomal exocytosis as a likely mechanism for clearing storage including GPDs. Therefore, ARPE-19 CLN3-KO cells represent a human cell model for CLN3 disease showing many of the described core lysosomal deficits, some of which can be improved using TRPML1 agonists., (© 2024. The Author(s).)

Objectives. To identify sociodemographic shifts among unsheltered Latino people experiencing homelessness (PEH) between 2020-2022. Methods. We examined differences in characteristics reported in demographic surveys for Latino PEH older than 25 years from 2020 (n = 1215) and 2022 (n = 1395) in Los Angeles County, California, using weighted bivariate χ 2 tests. Results. From 2020 to 2022, there was a 25% increase in the number of unsheltered Latino individuals. The share of Latino PEH who were unemployed increased (57% to 67%). The increase in homelessness occurred largely among individuals living in vehicles (14% to 33%), rather than in tents or on sidewalks. Latino PEH were significantly less likely to report mental illness (24% vs 18%) and had higher rates of first entry into homelessness in the past 2 years than non-Latino respondents. Conclusions. Our results are consistent with the effects of increasing socioeconomic vulnerability, likely related to COVID-19, in driving the increase in Latino PEH. Policy Implications. The rise in homelessness among economically vulnerable yet healthy Latinos suggests a need to bolster social safety nets and increase homelessness prevention programs. ( Am J Public Health . 2024;114(S6):S510-S514. https://doi.org/10.2105/AJPH.2024.307717) [Formula: see text].

Unsheltered homelessness is an increasingly prevalent phenomenon in major cities that is associated with adverse health and mortality outcomes. This creates a need for spatial estimates of population denominators for resource allocation and epidemiological studies. Gaps in the timeliness, coverage, and spatial specificity of official Point-in-Time Counts of unsheltered homelessness suggest a role for geospatial data from alternative sources to provide interim, neighborhood-level estimates of counts and trends. We use citizen-generated data from homeless-related 311 requests, provider-based administrative data from homeless street outreach cases, and expert reports of unsheltered count to predict count and emerging hotspots of unsheltered homelessness in census tracts across the City of Los Angeles for 2019 and 2020. Our study shows that alternative data sources can contribute timely insights into the state of unsheltered homelessness throughout the year and inform the delivery of interventions to this vulnerable population., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Labor migration has a profound effect on families, but evidence documenting the impact of migration on women left behind is still lacking. Utilizing the Matlab Health and Socioeconomic Surveys, we examined the roles of migration and families in four domains of empowerment for women in Bangladesh. We found that women with international migrant spouses saw significant improvements in economic empowerment, mobility, and decision-making relative to women with coresident spouses (p < .0001). However, women who lived in multigenerational households with their parents or in-laws experienced significant reductions in empowerment across these three domains. Both having a migrant spouse and living in a multigenerational household had negative effects on beliefs about gender equivalence and reduced joint decision-making for women. Results, which were robust to migration selection controls (including propensity approaches), indicate that the benefits of migration for women left behind might be diluted by family structures that perpetuate unequal gender dynamics., (Copyright © 2024 The Authors.)

Organ-specific gene expression datasets that include hundreds to thousands of experiments allow the reconstruction of organ-level gene regulatory networks (GRNs). However, creating such datasets is greatly hampered by the requirements of extensive and tedious manual curation. Here, we trained a supervised classification model that can accurately classify the organ-of-origin for a plant transcriptome. This K-Nearest Neighbor-based multiclass classifier was used to create organ-specific gene expression datasets for the leaf, root, shoot, flower, and seed in Arabidopsis thaliana . A GRN inference approach was used to determine the: i. influential transcription factors (TFs) in each organ and, ii. most influential TFs for specific biological processes in that organ. These genome-wide, organ-delimited GRNs (OD-GRNs), recalled many known regulators of organ development and processes operating in those organs. Importantly, many previously unknown TF regulators were uncovered as potential regulators of these processes. As a proof-of-concept, we focused on experimentally validating the predicted TF regulators of lipid biosynthesis in seeds, an important food and biofuel trait. Of the top 20 predicted TFs, eight are known regulators of seed oil content, e.g., WRI1, LEC1, FUS3. Importantly, we validated our prediction of MybS2, TGA4, SPL12, AGL18, and DiV2 as regulators of seed lipid biosynthesis. We elucidated the molecular mechanism of MybS2 and show that it induces purple acid phosphatase family genes and lipid synthesis genes to enhance seed lipid content. This general approach has the potential to be extended to any species with sufficiently large gene expression datasets to find unique regulators of any trait-of-interest., Competing Interests: Competing interests statement:The authors have applied for a patent based on the results in this manuscript at Purdue University.

Background: US military veterans who have experienced homelessness often have high rates of housing transition. Disruptions caused by these transitions likely exacerbate this population's health problems and interfere with access to care and treatment engagement. Individuals experiencing homelessness increasingly use smartphones, contributing to improved access to medical and social services. Few studies have used smartphones as a data collection tool to systematically collect information about the daily life events that precede and contribute to housing transitions, in-the-moment emotions, behaviors, geographic movements, and perceived social support., Objective: The study aims to develop and test a smartphone app to collect longitudinal data from veterans experiencing homelessness (VEH) and to evaluate the feasibility and acceptability of using the app in a population that is unstably housed or homeless., Methods: This study's design had 3 phases. Phase 1 used ethnographic methods to capture detailed data on day-to-day lived experiences of up to 30 VEH on topics such as housing stability, health, and health behaviors. Phase 2 involved focus groups and usability testing to develop and refine mobile phone data collection methods. Phase 3 piloted the smartphone mobile data collection with 30 VEH. We included mobile ethnography, real-time surveys through an app, and the collection of GPS data in phase 3., Results: The project was launched in June 2020, and at this point, some data collection and analysis for phases 1 and 2 are complete. This project is currently in progress., Conclusions: This multiphase study will provide rich data on the context and immediate events leading to housing transitions among VEH. This study will ensure the development of a smartphone app that will match the actual needs of VEH by involving them in the design process from the beginning. Finally, this study will offer important insights into how best to develop a smartphone app that can help intervene among VEH to reduce housing transitions., International Registered Report Identifier (irrid): DERR1-10.2196/53022., (©Marva Foster, Gemmae M Fix, Justeen Hyde, Shawn Dunlap, Thomas H Byrne, Naomi F Sugie, Randall Kuhn, Sonya Gabrielian, Jill S Roncarati, Shibei Zhao, D Keith McInnes. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 22.04.2024.)

Introduction: Puerto Rico (PR) has an ambiguous status within Centers for Disease Control and Prevention (CDC) public health monitoring and surveillance systems. However, as a U.S. territory, PR relies on federal health resource allocation processes that are informed by these data sources. This study sought to quantify the coverage of PR within CDC-supported systems compared with the 50 states, describe coverage across critical system-types, and assess the availability of data collection instruments in Spanish., Methods: This cross-sectional observational study employed the method of data curation by identifying, collecting, and categorizing data primarily from web-based sources maintained by the CDC. Data were originally collected and coded from August 2021 to March 2022 and reviewed by two additional coders from October 2022 to March 2023. Each curated system was assessed to determine coverage of PR across five system-types (probability-based, case-based, administrative, registry, and multiple-source) compared with the 50 states. The availability of data collection instruments in Spanish was also assessed., Results: Of 93 active CDC-supported systems assessed, results revealed that PR was not covered in 54% of CDC-supported systems. Comparatively, inclusive coverage of all 50 states was only lacking in 33% of CDC-supported systems. Of the 32 CDC-supported systems in PR that could be coded for language, only 53% had data collection instruments in Spanish., Conclusions: There are significant gaps in the coverage of PR within CDC-supported systems. Future efforts must be made to identify the reasons for this exclusion and increase the territory's representation within these essential public health data systems., (Copyright © 2023 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: The transition towards remote healthcare has been rapidly accelerated in recent years due to a number of factors, including the COVID-19 pandemic, however, few studies have explored service users' views of remote mental healthcare, particularly in community mental health settings., Methods: As part of a larger study concerned with the development of a remotely delivered psychosocial intervention, a survey was conducted with service users with psychosis ( N  = 200) from six NHS trusts across England to gain cross-sectional data about service users' opinions and attitudes towards remote interventions and explore how digital access varies across different demographic groups and geographical localities., Results: The majority of service users had access to technological devices and a quiet space to receive care. Age was a key factor in motivation to engage with remote care as older participants had less access to technological devices and the internet, and reported less confidence to learn how to use new technologies compared to younger participants. Differences in access and attitudes towards remote care were found across the different geographical localities. Over half of the participants (53.1%) preferred a hybrid model (i.e., mixture of face-to-face and remotely delivered treatment), with only 4.5% preferring remote treatment exclusively. Factors that both encourage and deter service users from engaging with remote care were identified., Conclusions: The findings of this study provide important information about the environmental and clinical barriers that prevent, or limit, the uptake of remotely delivered care for people with psychotic disorders. Although service users often have the ability and capacity to receive remote care, providers need to be cognisant of factors which may exacerbate digital exclusion and negatively impact the therapeutic alliance., Competing Interests: The authors declare that this research was conducted for the purpose of developing a novel remotely delivered healthcare software called Remote DIALOG+. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Kuhn, Abdel-Halim, Healey, Bird, Elliot and McNamee.)

Purpose: We examined the impact of duration and number of homelessness episodes on health outcomes for unsheltered homeless young adults., Methods: We analyzed the 2018/2019 Los Angeles County homeless youth demographic surveys. We addressed five summary health outcomes: physical health, mental health, substance use disorder, tri-morbidity, and any condition. Respondents were classified into three homeless trajectory groups: (1) short-term-homeless < 1 year in one episode, (2) episodic-homeless < 1 year and multiple episodes, and (3) long-term-homeless continuously for > 1 year. Weighted bivariate and multivariate logistic regression models tested the relationship between homeless trajectory group and health, with controls for sociodemographic factors and structural exposures., Results: Mental health and substance use were high among unsheltered young adults compared to national rates. Long-term homeless respondents were significantly more likely than short-term to report a mental health condition (53.3% vs. 39.8%, p < .001), substance use disorder (25.5% vs. 18.3%, p < .001), and physical conditions (26.0% vs. 15.6%, p = .008). Episodic respondents were more likely to report a mental health condition (50.5%, p < .001). In multivariate models, long-term respondents had twice the odds of tri-morbidity (odds ratio [OR] = 2.14, p < .05) and any health condition (OR 2.00, p < .01) as short term and significantly higher odds of a physical health condition (OR = 1.64, p < .05)., Discussion: Youth with longer durations and more frequent episodes of homelessness have substantially poorer health outcomes. The association of longer duration to poorer health persisted in multivariate models. Longer duration of unsheltered homelessness may drive the onset of physical and mental health problems., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

As the field of synthetic biology expands, the need to grow and train science, technology, engineering, and math (STEM) practitioners is essential. However, the lack of access to hands-on demonstrations has led to inequalities of opportunity and practice. In addition, there is a gap in providing content that enables students to make their own bioengineered systems. To address these challenges, we develop four shelf-stable cell-free biosensing educational modules that work by simply adding water and DNA to freeze-dried crude extracts of non-pathogenic Escherichia coli . We introduce activities and supporting curricula to teach the structure and function of the lac operon, dose-responsive behavior, considerations for biosensor outputs, and a "build-your-own" activity for monitoring environmental contaminants in water. We piloted these modules with K-12 teachers and 130 high-school students in their classrooms─and at home─without professional laboratory equipment. This work promises to catalyze access to interactive synthetic biology education opportunities.

Improving health and healthcare for people experiencing homelessness (PEH) has become a national research priority. It is critical for research related to homelessness to be guided by input from PEH themselves. We are a group of researchers and individuals who have personally experienced homelessness collaborating on a study focused on homelessness and housing. In this Fresh Focus, we describe our partnership, lessons learned from our work together, what we have gained from our collaboration, and considerations for future homelessness research-lived experience partnerships., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Motivation: The maturation of systems immunology methodologies requires novel and transparent computational frameworks capable of integrating diverse data modalities in a reproducible manner., Results: Here, we present the ePlatypus computational immunology ecosystem for immunogenomics data analysis, with a focus on adaptive immune repertoires and single-cell sequencing. ePlatypus is an open-source web-based platform and provides programming tutorials and an integrative database that helps elucidate signatures of B and T cell clonal selection. Furthermore, the ecosystem links novel and established bioinformatics pipelines relevant for single-cell immune repertoires and other aspects of computational immunology such as predicting ligand-receptor interactions, structural modeling, simulations, machine learning, graph theory, pseudotime, spatial transcriptomics, and phylogenetics. The ePlatypus ecosystem helps extract deeper insight in computational immunology and immunogenomics and promote open science., Availability and Implementation: Platypus code used in this manuscript can be found at github.com/alexyermanos/Platypus., (© The Author(s) 2023. Published by Oxford University Press.)

In >100,000 observations across Swiss acute-care hospitals, hand hygiene (HH) adherence significantly increased during the first coronavirus disease 2019 (COVID-19) wave. However, despite persisting COVID-19 activity, HH adherence returned to prepandemic levels over a 2-year observation period. These results indicate that training and support remains challenging.

Over the last three decades, out-migration has become a stable source of income for more than 12 million Bangladeshis. Of those migrants, 90% are men. Due to patriarchal cultural norms in Bangladeshi society, the migration of a male spouse may have significant consequences for the social well-being and health of left-behind women. In this study, we examine the impact of external (out of country) and internal (rural to urban) spousal migration on the perinatal healthcare utilization of left-behind women. We used data from the 2012 Matlab Health and Socioeconomic Survey (MHSS2) to examine use of antenatal care, presence of a medically qualified attendant at birth, and delivery at a healthcare facility for live births that occurred between 2007 and 2014 for currently married women aged 15-45 (N = 1,458 births among 1,180 women). Adjusted regression models indicated that for births occurring to women with a migrant spouse, odds of receiving antenatal care were significantly higher (OR: 4.1 for births to women with a domestic urban migrant spouse and 4.6 for births to women with an international migrant spouse, p < 0.01). Spousal migration was not linked to having a medically qualified attendant at birth or delivery at a clinic or hospital. Results suggest that spousal migration may be beneficial for receiving health care during a pregnancy, but not for the type of attendant or place of delivery at birth., (© 2023. The Author(s).)

Background: Permanent supportive housing (PSH) is an evidence-based practice to address homelessness that is implemented using 2 distinct approaches. The first approach is place-based PSH (PB-PSH), or single-site housing placement, in which an entire building with on-site services is designated for people experiencing homelessness. The second approach is scatter-site PSH (SS-PSH), which uses apartments rented from a private landlord while providing mobile case management services., Objective: This paper describes the protocols for a mixed methods comparative effectiveness study of 2 distinct approaches to implementing PSH and the patient-centered quality of life, health care use, and health behaviors that reduce COVID-19 risk., Methods: People experiencing homelessness who are placed in either PB-PSH or SS-PSH completed 6 monthly surveys after move-in using smartphones provided by the study team. A subsample of participants completed 3 qualitative interviews at baseline, 3 months, and 6 months that included photo elicitation interviewing. Two stakeholder advisory groups, including one featuring people with lived experience of homelessness, helped guide study decisions and interpretations of findings., Results: Study recruitment was supposed to occur over 6 months starting in January 2021 but was extended due to delays in recruitment. These delays included COVID-19 delays (eg, recruitment sites shut down due to outbreaks and study team members testing positive) and delays that may have been indirectly related to the COVID-19 pandemic, including high staff turnover or recruitment sites having competing priorities. In end-July 2022, in total, 641 people experiencing homelessness had been referred from 26 partnering recruitment sites, and 563 people experiencing homelessness had enrolled in the study and completed a baseline demographic survey. Of the 563 participants in the study, 452 had recently moved into the housing when they enrolled, with 272 placed in PB-PSH and 180 placed in SS-PSH. Another 111 participants were approved but are still waiting for housing placement. To date, 49 participants have been lost to follow-up, and 12% of phones (70 of the initial 563 distributed) were reported lost by participants., Conclusions: Recruitment during the pandemic, while successful, was challenging given that in-person contact was not permitted at times either by program sites or the research institutions during COVID-19 surges and high community transmission, which particularly affected homelessness programs in Los Angeles County. To overcome recruitment challenges, flexible strategies were used, which included extending the recruitment period and the distribution of cell phones with paid data plans. Given current recruitment numbers and retention rates that are over 90%, the study will be able to address a gap in the literature by considering the comparative effectiveness of PB-PSH versus SS-PSH on patient-centered quality of life, health care use, and health behaviors that reduce COVID-19 risk, which can influence future public health approaches to homelessness and infectious diseases., Trial Registration: ClinicalTrials.gov NCT04769349; https://clinicaltrials.gov/ct2/show/NCT04769349., International Registered Report Identifier (irrid): DERR1-10.2196/46782., (©Benjamin F Henwood, Randall Kuhn, Howard Padwa, Roya Ijadi-Maghsoodi, Gisele Corletto, Alex Lawton, Jessie Chien, Ricky Bluthenthal, Michael R Cousineau, Melissa Chinchilla, Bikki Tran Smith, Katherine D Vickery, Taylor Harris, Maria Patanwala, Whitney Akabike, Lillian Gelberg. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 28.04.2023.)

Latinx represent a growing population in the United States (US) that continue to experience a disproportionate burden of disease. However, health disparities vary across Latinx subgroups, including Mexican, Puerto Rican, and Cuban communities, particularly when assessing self-rated health. Given the nature of political exclusion in the US, these differences may be associated with underexplored political factors, or political determinants of health, within the social environment that distinctly shape health among racial and ethnic minorities. To explore potential pathways that connect the political environment to individual-level health outcomes among Latinx subgroups, political efficacy (or one's perceptions about one's power to influence political affairs) was assessed as a correlate of self-rated health. We used secondary data from the 2016 Collaborative Multiracial Post-election Survey to conduct ordered logistic regression analysis to determine whether two domains of political efficacy, internal and external political efficacy, were correlates of self-rated health among Mexican, Puerto Rican, and Cuban subgroups as compared to non-Latinx whites in the US. We also tested for differential associations across Latinx subgroups as compared to non-Latinx whites. The sample consisted of 3156 respondents (1486 Mexicans, 484 Puerto Ricans, 159 Cubans and 1027 non-Latinx whites). Among Puerto Ricans, results revealed that lower levels of internal political efficacy were associated with higher levels of self-rated health. Conversely, among other subgroups, positive associations between internal political efficacy and self-rated health were observed. This study provides empirical evidence of a relationship between internal political perceptions and health perceptions that has not previously been established within the Latinx health disparities literature. Future investigations should continue to examine pathways that connect political determinants to individual-level health outcomes, particularly among communities that disproportionately experience political exclusion., Competing Interests: None., (© 2023 The Authors.)

B cells contribute to the pathogenesis of both cellular- and humoral-mediated central nervous system (CNS) inflammatory diseases through a variety of mechanisms. In such conditions, B cells may enter the CNS parenchyma and contribute to local tissue destruction. It remains unexplored, however, how infection and autoimmunity drive transcriptional phenotypes, repertoire features, and antibody functionality. Here, we profiled B cells from the CNS of murine models of intracranial (i.c.) viral infections and autoimmunity. We identified a population of clonally expanded, antibody-secreting cells (ASCs) that had undergone class-switch recombination and extensive somatic hypermutation following i.c. infection with attenuated lymphocytic choriomeningitis virus (rLCMV). Recombinant expression and characterisation of these antibodies revealed specificity to viral antigens (LCMV glycoprotein GP), correlating with ASC persistence in the brain weeks after resolved infection. Furthermore, these virus-specific ASCs upregulated proliferation and expansion programs in response to the conditional and transient induction of the LCMV GP as a neo-self antigen by astrocytes. This class-switched, clonally expanded, and mutated population persisted and was even more pronounced when peripheral B cells were depleted prior to autoantigen induction in the CNS. In contrast, the most expanded B cell clones in mice with persistent expression of LCMV GP in the CNS did not exhibit neo-self antigen specificity, potentially a consequence of local tolerance induction. Finally, a comparable population of clonally expanded, class-switched, and proliferating ASCs was detected in the cerebrospinal fluid of relapsing multiple sclerosis (RMS) patients. Taken together, our findings support the existence of B cells that populate the CNS and are capable of responding to locally encountered autoantigens., (© 2023. The Author(s).)

Although new genomics-based pipelines have potential to augment antibody discovery, these methods remain in their infancy due to an incomplete understanding of the selection process that governs B cell clonal selection, expansion, and antigen specificity. Furthermore, it remains unknown how factors such as aging and reduction of tolerance influence B cell selection. Here we perform single-cell sequencing of antibody repertoires and transcriptomes of murine B cells following immunizations with a model therapeutic antigen target. We determine the relationship between antibody repertoires, gene expression signatures, and antigen specificity across 100,000 B cells. Recombinant expression and characterization of 227 monoclonal antibodies revealed the existence of clonally expanded and class-switched antigen-specific B cells that were more frequent in young mice. Although integrating multiple repertoire features such as germline gene usage and transcriptional signatures failed to distinguish antigen-specific from nonspecific B cells, other features such as immunoglobulin G (IgG) subtype and sequence composition correlated with antigen specificity., Competing Interests: S.T.R. is a co-founder and holds shares of Engimmune Therapeutics AG. S.T.R. may hold shares of Alloy Therapeutics. S.T.R. is on the scientific advisory board of Engimmune Therapeutics and Alloy Therapeutics. T.C, D.S. and D.J.L. are or were employees of UCB Pharma. D.J.L. holds stock and/or stock options in UCB Pharma., (© 2023 The Author(s).)

Objectives: The primary objective of this study was to compare the occurrence of acute kidney injury (AKI) in patients with cystic fibrosis (CF) receiving intravenous (IV) vancomycin monitored through single serum trough concentrations and two-point estimated area under the curve (AUC). Time to next exacerbation and return to baseline lung function were also assessed., Methods: A retrospective review was conducted in patients of all ages with CF admitted to the University of Kentucky who received IV vancomycin between October 2015 and January 2021. Patients were excluded if they received less than 5 days of IV vancomycin therapy., Results: A total of 113 adults and 42 pediatric encounters met the inclusion criteria. There was no statistically significant difference in occurrence of AKI, however, all grade 2-3 AKIs were in the serum through the monitoring group. Adult patients monitored with AUC also had a higher return to baseline lung function over trough monitoring (86% vs. 57%) (p = 0.002). There was not a statistically significant difference in time to the next exacerbation in either group., Conclusions: Adult patients with CF experienced less severe AKIs when monitored with AUC versus trough. The results of this study indicate that AUC monitoring may enhance the efficacy of IV vancomycin in adult patients with CF., (© 2022 Wiley Periodicals LLC.)

With the advent of continuous direct compression (CDC) process, it becomes increasingly desirable to characterize inherent powder blend heterogeneity at a small batch scale for a robust and CDC-amenable formulation. To accomplish this goal, a near infrared spectroscopy (NIRS)-based characterization approach was developed and implemented on multiple direct compression (DC) blends in this study, with the intended purpose of complementing existing formulation development tools and enabling to build an early CMC data package for late-phased process analytical technology (PAT) method development. Three fumaric acid DC blends, designed to harbor varied degrees of inherent blend heterogeneity, were employed. Near infrared spectral data were collected on a kg-scale batch blender via both time- and angle-based triggering modes. The time-triggered data were used to investigate the blending heterogeneity with respect to rotation angles, while the angle-triggered data were used to provide blending variability characterization and compare against off-line HPLC-based results. The time-triggered data revealed that the greatest blend variability was observed between revolutions, while the blending variability within a single revolution stayed relatively low with respect to rotation angles. This confirmed earlier literature findings that the bottom layer of powder blends tends to move with the blender within each revolution, and the most intense powder mixing takes place across revolutions. This also indicates the use of blending speed and the number of co-adds are not able to increase sampling volume to improve signal-to-noise ratio under a tumble-bin blender as what were typically done in a feedframe application. The angle-triggered data showed that there is a consistent trend between NIRS and HPLC-based methods on characterizing blend heterogeneity across the blends at a given sample size. This study contributes to establishing NIRS as a potential characterization approach for inherent powder blend heterogeneity for early R&D. It also highlights the promise of continuous characterization of inherent powder blend heterogeneity from gram scale to mini-batch CDC scale., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Importance: Few studies have used precise age-specific data to construct age-standardized estimates of the relative risks (RRs) of COVID-19 mortality for people experiencing homelessness (PEH) vs the general population, and none to date has addressed race and ethnicity and sex variations in COVID-19 mortality among PEH with COVID-19 infection., Objective: To measure age-standardized mortality rate ratios for PEH vs the general population overall and by sex and race and ethnicity., Design, Setting, and Participants: In this cross-sectional study, crude and age-specific COVID-19 mortality rates per 100 000 people were calculated using 5-year age groups and standardized mortality ratios for PEH and the general population aged 25 years and older, assessing differences by race and ethnicity and sex, from January 1, 2020, to November 1, 2021. Mortality and population estimates came from COVID-19 mandatory case reporting conducted by the Los Angeles County Department of Public Health, the annual point-in-time homeless count, and the US Census., Main Outcomes and Measures: The main outcome was COVID-19 deaths sourced from clinician reports, death certificates, medical examiner reports, and vital records deaths. PEH status was determined using the US Department of Housing and Urban Development definitions for homelessness at the time of COVID-19 diagnosis or symptom onset., Results: The study population included 25 441 deaths among an estimated 6 382 402 general population individuals and 256 deaths among an estimated 52 015 PEH. The race and ethnicity of the PEH sample was as follows: 15 539 Black (29.9%), 18 057 Hispanic (34.7%), 14 871 female (28.6%), 37 007 male (71.3%), and 3380 aged 65 years or older (6.5%), compared with the estimated general population of 6 382 402, which was 591 003 Black (9.3%), 2 854 842 Hispanic (44.7%), 3 329 765 female (52.2%), 3 052 637 male (47.8%), and 1 190 979 aged 65 years or older (18.7%). Crude death rates were 0.49% for PEH and 0.40% for the general population, but PEH experienced age-specific COVID-19 mortality risk 2.35 (95% CI, 2.08-2.66) times higher than the general population. There was significant risk associated with PEH status compared with their counterparts in the general population for Black PEH (RR, 1.69; 95% CI, 1.31-2.18), Hispanic PEH (RR, 2.34; 95% CI, 1.96-2.79), White PEH (RR, 8.33; 95% CI, 6.37-10.88), female PEH (RR, 3.39; 95% CI, 2.56-4.48), and male PEH (RR, 1.74; 95% CI, 1.52-2.00)., Conclusions and Relevance: This cross-sectional study of COVID-19 mortality among PEH with COVID-19 infection provides evidence suggesting excess risk of age-adjusted COVID-19 mortality among PEH compared with the general population. This study furthers understanding of the intersectional association between homelessness and race and ethnicity, as higher levels of mortality but narrower racial disparities among PEH than in the general population were observed.

A secure web-based electronic tool was developed and implemented to record adherence to hand hygiene during routine care and to provide direct feedback including anonymized benchmarking. It was found suitable for documenting hand hygiene improvements in a local campaign and following rollout to other institutions in 2013, the tool is currently used in >100 hospitals in Switzerland and will play a major part in upcoming national hand hygiene campaigns., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: In recent years, cities across the world have seen widespread growth in unsheltered homelessness, in which a person sleeps in a place not meant for human habitation such as cars, parks, sidewalks, and abandoned buildings. It is widely understood that people experiencing homelessness have poorer health outcomes than the general population. Less is known about the health of people who are unsheltered, yet they may be exposed to greater health risks than their sheltered counterparts. The purpose of this literature review is to evaluate and summarize the evidence on unsheltered homelessness and health., Evidence Acquisition: A literature search was conducted using PubMed to identify publications on unsheltered homelessness and health. A total of 42 studies were included for review., Evidence Synthesis: Unsheltered populations experience higher rates of chronic disease, serious mental illness, and substance abuse than sheltered populations. Unsheltered homelessness is strongly associated with chronic homelessness that exacerbates serious mental illness and substance use, which is often co-occurring. Despite having large unmet health needs, unsheltered populations have lower healthcare utilization and often lack health insurance., Conclusions: Evaluating the impact of shelter status on health outcomes has important implications for the allocation of housing and health services. Longitudinal studies are needed to examine the relationship between the duration of sheltered and unsheltered homelessness and health outcomes and explore the mediating mechanisms that lead to poor health among unsheltered populations. Despite these limitations, our results also suggest an urgent need to address the unique and severe challenges facing unsheltered populations and the need for intervention approaches that are sensitive to these unique disease burdens., (© 2022 The Author(s).)

Motivation: Single-cell sequencing now enables the recovery of full-length immune receptor repertoires [B cell receptor (BCR) and T cell receptor (TCR) repertoires], in addition to gene expression information. The feature-rich datasets produced from such experiments require extensive and diverse computational analyses, each of which can significantly influence the downstream immunological interpretations, such as clonal selection and expansion. Simulations produce validated standard datasets, where the underlying generative model can be precisely defined and furthermore perturbed to investigate specific questions of interest. Currently, there is no tool that can be used to simulate single-cell datasets incorporating immune receptor repertoires and gene expression., Results: We developed Echidna, an R package that simulates immune receptors and transcriptomes at single-cell resolution with user-tunable parameters controlling a wide range of features such as clonal expansion, germline gene usage, somatic hypermutation, transcriptional phenotypes and spatial location. Echidna can additionally simulate time-resolved B cell evolution, producing mutational networks with complex selection histories incorporating class-switching and B cell subtype information. We demonstrated the benchmarking potential of Echidna by simulating clonal lineages and comparing the known simulated networks with those inferred from only the BCR sequences as input. Finally, we simulated immune repertoire information onto existing spatial transcriptomic experiments, thereby generating novel datasets that could be used to develop and integrate methods to profile clonal selection in a spatially resolved manner. Together, Echidna provides a framework that can incorporate experimental data to simulate single-cell immune repertoires to aid software development and bioinformatic benchmarking of clonotyping, phylogenetics, transcriptomics and machine learning strategies., Availability and Implementation: The R package and code used in this manuscript can be found at github.com/alexyermanos/echidna and also in the R package Platypus (Yermanos et al. , 2021). Installation instructions and the vignette for Echidna is described in the Platypus Computational Ecosystem (https://alexyermanos.github.io/Platypus/index.html). Publicly available data and corresponding sample accession numbers can be found in Supplementary Tables S2 and S3., Supplementary Information: Supplementary data are available at Bioinformatics Advances online., (© The Author(s) 2022. Published by Oxford University Press.)

Adaptive immune repertoires are composed by the ensemble of B and T-cell receptors within an individual, reflecting both past and current immune responses. Recent advances in single-cell sequencing enable recovery of the complete adaptive immune receptor sequences in addition to transcriptional information. Here, we recovered transcriptome and immune repertoire information for polyclonal T follicular helper cells following lymphocytic choriomeningitis virus (LCMV) infection, CD8+ T cells with binding specificity restricted to two distinct LCMV peptides, and B and T cells isolated from the nervous system in the context of experimental autoimmune encephalomyelitis. We could relate clonal expansion, germline gene usage, and clonal convergence to cell phenotypes spanning activation, memory, naive, antibody secretion, T-cell inflation, and regulation. Together, this dataset provides a resource for immunologists that can be integrated with future single-cell immune repertoire and transcriptome sequencing datasets., (© 2022. The Author(s).)

Objectives: To analyze the records of the pregnancies of 2283 Australian women with epilepsy in the Australian Register of Antiepileptic Drugs in Pregnancy database to identify neurological factors relevant to the Cesarean sections carried out in these pregnancies., Results: The Cesarean section rate in Australian women overall increased by an average of 0.59% annually over 20 years, from 26.0% to its calculated 2020 value of 37.3%. For the operations in women with epilepsy, the corresponding figures were 0.71% annually, and 34.4% and 48.7%. The average annual rate of increase for pre-labor operations was 0.89% to a 2020 value of 39.1%, the annual rate for operations during labor showing no statistically significant change. Multivariate regression analysis identified a number of characteristics of women with epilepsy that were statistically significantly associated with an increased likelihood of Cesarean section, but of these only seizures continuing to occur in the third trimester and having chronic illness, in particular migraine, were neurological ones. In 70 migraine-affected women, the Cesarean section rate was 51.4%, compared with 39% in the remaining pregnancies (P < 0.05)., Conclusions: Having seizures in the final trimester of pregnancy and having chronic neurological illness, especially migraine, favored Cesarean section being carried out in Australian women with epilepsy, but did not adequately account for the increasing rates of occurrence of the operation over the past 20 years., Competing Interests: Conflicts of interest F.J.E. Vajda has received research support for the Australian Pregnancy Register from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Epilepsy Action, Sanofi-Aventis, Eisai, UCB Pharma, and Sci-Gen. T. O’Brien has received research support from the Epilepsy Society of Australia, NHMRC, RMH Neuroscience Foundation, Sanofi-Aventis, UCB Pharma, and Sci-Gen and Eisai. P. Perucca is supported by an Early Career Fellowship from the National Health and Medical Research Council (APP1163708), the Epilepsy Foundation, the Royal Australasian College of Physicians, The University of Melbourne, Monash University, the Weary Dunlop Medical Research Foundation, Brain Australia, and the Norman Beischer Medical Research Foundation. He has received speaker honoraria or consultancy fees to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma, outside the submitted work. He is an Associate Editor for Epilepsia Open. J.E. Graham, A.A. Hitchcock, R. Kuhn, C.M. Lander, and M.J. Eadie have no relevant conflicts of interest to declare. They have not received any personal funding from outside bodies in relation to their roles in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The capacity of humoral B cell-mediated immunity to effectively respond to and protect against pathogenic infections is largely driven by the presence of a diverse repertoire of polyclonal antibodies in the serum, which are produced by plasma cells (PCs). Recent studies have started to reveal the balance between deterministic mechanisms and stochasticity of antibody repertoires on a genotypic level (i.e., clonal diversity, somatic hypermutation, and germline gene usage). However, it remains unclear if clonal selection and expansion of PCs follow any deterministic rules or are stochastic with regards to phenotypic antibody properties (i.e., antigen-binding, affinity, and epitope specificity). Here, we report on the in-depth genotypic and phenotypic characterization of clonally expanded PC antibody repertoires following protein immunization. We find that clonal expansion drives antigen specificity of the most expanded clones (top ∼10), whereas among the rest of the clonal repertoire antigen specificity is stochastic. Furthermore, we report both on a polyclonal repertoire and clonal lineage level that antibody-antigen binding affinity does not correlate with clonal expansion or somatic hypermutation. Last, we provide evidence for convergence toward targeting dominant epitopes despite clonal sequence diversity among the most expanded clones. Our results highlight the extent to which clonal expansion can be ascribed to antigen binding, affinity, and epitope specificity, and they have implications for the assessment of effective vaccines.

CD8+ T cells play a crucial role in the control and resolution of viral infections and can adopt a wide range of phenotypes and effector functions depending on the inflammatory context and the duration and extent of antigen exposure. Similarly, viral infections can exert diverse selective pressures on populations of clonally related T cells. Technical limitations have nevertheless made it challenging to investigate the relationship between clonal selection and transcriptional phenotypes of virus-specific T cells. We therefore performed single-cell T cell receptor (TCR) repertoire and transcriptome sequencing of virus-specific CD8 T cells in murine models of acute, chronic and latent infection. We observed clear infection-specific populations corresponding to memory, effector, exhausted, and inflationary phenotypes. We further uncovered a mouse-specific and polyclonal T cell response, despite all T cells sharing specificity to a single viral epitope, which was accompanied by stereotypic TCR germline gene usage in all three infection types. Persistent antigen exposure during chronic and latent viral infections resulted in a higher proportion of clonally expanded T cells relative to acute infection. We furthermore observed a relationship between transcriptional heterogeneity and clonal expansion for all three infections, with highly expanded clones having distinct transcriptional phenotypes relative to less expanded clones. Together our work relates clonal selection to gene expression in the context of viral infection and further provides a dataset and accompanying software for the immunological community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kuhn, Sandu, Agrafiotis, Hong, Shlesinger, Neimeier, Merkler, Oxenius, Reddy and Yermanos.)

Plasma cells and their secreted antibodies play a central role in the long-term protection against chronic viral infection. However, due to experimental limitations, a comprehensive description of linked genotypic, phenotypic, and antibody repertoire features of plasma cells (gene expression, clonal frequency, virus specificity, and affinity) has been challenging to obtain. To address this, we performed single-cell transcriptome and antibody repertoire sequencing of the murine BM plasma cell population following chronic lymphocytic choriomeningitis virus infection. Our single-cell sequencing approach recovered full-length and paired heavy- and light-chain sequence information for thousands of plasma cells and enabled us to perform recombinant antibody expression and specificity screening. Antibody repertoire analysis revealed that, relative to protein immunization, chronic infection led to increased levels of clonal expansion, class-switching, and somatic variants. Furthermore, antibodies from the highly expanded and class-switched (IgG) plasma cells were found to be specific for multiple viral antigens and a subset of clones exhibited cross-reactivity to nonviral and autoantigens. Integrating single-cell transcriptome data with antibody specificity suggested that plasma cell transcriptional phenotype was correlated to viral antigen specificity. Our findings demonstrate that chronic viral infection can induce and sustain plasma cell clonal expansion, combined with significant somatic hypermutation, and can generate cross-reactive antibodies., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Roundup® is the brand name for herbicide solutions containing glyphosate, which specifically inhibits the 5-enolpyruvyl-shikimate-3-phosphate (EPSP) synthase of the shikimate pathway. The inhibition of the EPSP synthase causes plant death because EPSP is required for biosynthesis of aromatic amino acids. Glyphosate also inhibits the growth of archaea, bacteria, Apicomplexa, algae and fungi possessing an EPSP synthase. Here, we have characterized two glyphosate-resistant bacteria from a Roundup solution. Taxonomic classification revealed that the isolates 1CH1 and 2CH1 are Burkholderia anthina and Burkholderia cenocepacia strains respectively. Both isolates cannot utilize glyphosate as a source of phosphorus and synthesize glyphosate-sensitive EPSP synthase variants. Burkholderia. anthina 1CH1 and B. cenocepacia 2CH1 tolerate high levels of glyphosate because the herbicide is not taken up by the bacteria. Previously, it has been observed that the exposure of soil bacteria to herbicides like glyphosate promotes the development of antibiotic resistances. Antibiotic sensitivity testing revealed that the only the B. cenocepacia 2CH1 isolate showed increased resistance to a variety of antibiotics. Thus, the adaptation of B. anthina 1CH1 and B. cenocepacia 2CH1 to glyphosate did not generally increase the antibiotic resistance of both bacteria. However, our study confirms the genomic adaptability of bacteria belonging to the genus Burkholderia., (© 2021 The Authors. Environmental Microbiology Reports published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Spray-drying dispersion (SDD) is a well-established manufacturing technique used to prepare amorphous solid dispersions (ASDs), allowing for poorly soluble drugs to have improved bioavailability. However, the process of spray-drying with multiple factors and numerous variables can lead to a lengthy development timeline with intense resource requirements, which becomes the main obstacle limiting spray-drying development at the preclinical stage. The purpose of this work was to identify optimized preset parameters for spray-drying to support the early development of ASDs suitable for most circumstances rather than individual optimization. First, a mini-DoE (Design of Experiment) study was designed to evaluate the critical interplay of two key variables for spray-drying using a BUCHI B-290 mini spray dryer: solid load and atomizing spray gas flow. The critical quality attributes (CQAs) of the ASDs, including yield, particle size, morphology, and in vitro release profile, were taken into account to identify the impact of the key variables. The mini-DoE results indicated that a 5% solid load (w/v %) and 35 mm height atomizing spray gas flow were the most optimized parameters. These predefined values were further verified using different formulation compositions, including various polymers (Eudragit L100-55, HPMCAS-MF, PVAP, and PVP-VA64) and drugs (G-F, GEN-A, Indomethacin, and Griseofulvin), a range of drug loading (10 to 40%), and scale (200 mg to 200 g). Using these predefined parameters, all ASD formulations resulted in good yields as well as consistent particle size distribution. This was despite the differences in the formulations, making this a valuable and rapid approach ideal for early development. This strategy of leveraging the preset spray-drying parameters was able to successfully translate into a reproducible and efficient spray-drying platform while also saving material and reducing developmental timelines in early-stage formulation development., (© 2021. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background: Women left behind by migration represent a unique and growing population yet remain understudied as key players in the context of migration and development. Using a unique longitudinal survey of life in Bangladesh, the Matlab Health and Socioeconomic Surveys, we examined the role of spousal migration in healthcare utilization for women. The objective of this study was to assess realized access to care (do women actually get healthcare when it is needed) and consider specific macrostructural, predisposing, and resource barriers to care that are related to migration., Methods and Findings: In a sample of 3,187 currently married women, we estimated multivariate logistic and multinomial regression models controlling for a wide range of baseline sociodemographic factors measured as far back as 1982. Our analyses also controlled for selection effects and explored two mechanisms through which spousal migration can affect healthcare utilization for women, remittances and frequent contact with spouses. We found that women with migrant spouses were approximately half as likely to lack needed healthcare compared to women whose spouses remained in Bangladesh (predicted probability of not getting needed healthcare 11.7% vs. 21.8%, p<0.001). The improvements in access (logistic regression coefficient for lacking care for left-behind women -0.761 p<0.01) primarily occurred through a reduction in financial barriers to care for women whose spouses were abroad., Conclusions: Wives of international migrants showed significantly better access to healthcare even when accounting for selection into a migrant family. While the overall story is one of positive migration effects on healthcare access due to reductions in financial barriers to care, results also showed an increase in family-related barriers such as not being permitted to get care by a family member or travel alone to a facility, indicating that some of the benefits of migration for women left behind may be diluted by gendered family structures., Competing Interests: The authors have declared that no competing interests exist.

Day laborers are a highly vulnerable population, due to their contingent work arrangements, low socioeconomic position, and precarious immigration status. Earlier studies posited day labor as a temporary bridge for recent immigrants to achieve more stable employment, but recent studies have observed increasing duration of residence in the United States among foreign-born day laborers. This article draws on 170 qualitative interviews and a multi-venue, year-long street corner survey of 411 day laborers in the Denver metropolitan area to analyze how duration in the United States affects day laborers' wages, work, and wage theft experiences. Compared to recent immigrants, foreign-born day laborers with longer duration in the United States, we found, worked fewer hours and had lower total earnings but also had higher hourly wages and lower exposure to wage theft. We draw on qualitative interviews to address whether this pattern represented weathering, negative selection, or greater discernment. Rather than upward or downward mobility, long duration immigrant day labors had more jagged incorporations experiences. Interviews suggest that day laborers draw on experience to mitigate the risk of wage theft but that the value of experience is undercut by the fierce competition of daily recruitment, ultimately highlighting the compounding vulnerabilities facing longer duration and older immigrant day laborers. The article highlights duration as an understudied precarity factor which can adversely impact the economic assimilation of long duration immigrants who persist in contingent markets like day labor., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Spray dried amorphous solid dispersions (ASDs) stand as one of the most effective formulation strategies to address issues of low aqueous solubility when developing new chemical entities.An emerging research topic focusing on the formation of amorphous nanoparticles or nanodroplets from ASD formulations has attracted attention recently. These ASD nanoparticlescan be highly beneficial and able to further increase oral bioavailability. The incorporation of surfactants in ASD formulations has been shown to facilitate the formation of these nanoparticles. Therefore, understanding the mechanism of surfactant-promoted nanoparticle formation becomes critical for the rational design of ASD formulations. This work demonstrated the importance of inclusion of the surfactant within the ASD composition for nanoparticle formation. In contrast, when a surfactant is added externally (e.g., by inclusion in the dosing vehicle), only a limited degree of nanoparticle formation was observed even at the optimized surfactant-to-drug ratios. A variety of different surfactants were also assessed for understanding their impact on ASD nanoparticle formation. The spray drying systems containing nonionic surfactants, Tween 80 and Vitamin E TPGS, produced higher amounts of in situ ASD nanoparticles when compared to an anionic surfactant, sodium lauryl sulfate (SLS). The ASD nanoparticles produced by the Genentech developmental compound, GDC-0334, were highly stable and retained their original particle size and amorphous feature for at least 18 h under biorelevant conditions. The high degree of nanoparticle formation from spray dried GDC-0334 containing Tween 80 combined with the superior physical stability of the nanoparticles also translated to enhanced in vivo performance in a rat pharmacokinetics study., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using 1 H-NMR, 13 C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE 6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC 50 value of 160 nM. Compound 13b exhibited an enzyme IC 50 value of 4.9 µM. However, it exhibited a potent antiviral EC 50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC 50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site.

People experiencing homelessness (PEH) are at high risk for COVID-19 complications and fatality, and have been prioritized for vaccination in many areas. Yet little is known about vaccine acceptance in this population. The objective of this study was to determine the level of vaccine hesitancy among PEH in Los Angeles, CA and to understand the covariates of hesitancy in relation to COVID-19 risk, threat perception, self-protection and information sources. A novel mobile survey platform was deployed to recruit PEH from a federally qualified health center (FQHC) in Los Angeles to participate in a monthly rapid response study of COVID-19 attitudes, behaviors, and risks. Of 90 PEH surveyed, 43 (48%) expressed some level of vaccine hesitancy based either on actual vaccine offers (17/90 = 19%) or a hypothetical offer (73/90 = 81%). In bivariate analysis, those with high COVID-19 threat perception were less likely to be vaccine hesitant (OR = 0.34, P = 0.03), while those who frequently practiced COVID-19 protective behaviors were more likely to be vaccine hesitant (OR = 2.21, P = 0.08). In a multivariate model, those with high threat perception (AOR = 0.25, P = 0.02) were less likely to be hesitant, while those engaging in COVID-19 protective behaviors were more hesitant (AOR = 3.63, P = 0.02). Those who trusted official sources were less hesitant (AOR = 0.37, P = 0.08) while those who trusted friends and family for COVID-19 information (AOR = 2.70, P = 0.07) were more likely to be hesitant. Findings suggest that targeted educational and social influence interventions are needed to address high levels of vaccine hesitancy among PEH., Competing Interests: Authors MK and KM are employees of Akido Labs. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Family planning programs are believed to have substantial long-term benefits for women's health and well-being, yet few studies have established either extent or direction of long-term effects. The Matlab, Bangladesh, maternal and child health/family planning (MCH/FP) program afforded a 12-y period of well-documented differential access to services. We evaluate its impacts on women's lifetime fertility, adult health, and economic outcomes 35 y after program initiation. We followed 1,820 women who were of reproductive age during the differential access period (born 1938-1973) from 1978 to 2012 using prospectively collected data from the Matlab Health and Demographic Surveillance System and the 1996 and 2012 Matlab Health and Socioeconomic Surveys. We estimated intent-to-treat single-difference models comparing treatment and comparison area women. MCH/FP significantly increased contraceptive use, reduced completed fertility, lengthened birth intervals, and reduced age at last birth, but had no significant positive impacts on health or economic outcomes. Treatment area women had modestly poorer overall health (+0.07 SD) and respiratory health (+0.12 SD), and those born 1950-1961 had significantly higher body mass index (BMI) in 1996 (0.76 kg/m 2 ) and 2012 (0.57 kg/m 2 ); fewer were underweight in 1996, but more were overweight or obese in 2012. Overall, there was a +2.5 kg/m 2 secular increase in BMI. We found substantial changes in lifetime contraceptive and fertility behavior but no long-term health or economic benefits of the program. We observed modest negative health impacts that likely result from an accelerated nutritional transition among treated women, a transition that would, in an earlier context, have been beneficial., Competing Interests: The authors declare no competing interest.

Introduction: The Infectious Diseases Society of America (IDSA) recommends a minimum of 5 days of antibiotic therapy in stable patients who have community-acquired pneumonia (CAP). However, excessive duration of therapy (DOT) is common. Define, measure, analyze, improve, and control (DMAIC) is a Lean Six Sigma methodology used in quality improvement efforts, including infection control; however, the utility of this approach for antimicrobial stewardship initiatives is unknown. To determine the impact of a prospective physician-driven stewardship intervention on excess antibiotic DOT and clinical outcomes of patients hospitalized with CAP. Our specific aim was to reduce excess DOT and to determine why some providers treat beyond the IDSA minimum DOT., Methods: A single-center, quasi-experimental quality improvement study evaluating rates of excess antimicrobial DOT before and after implementing a DMAIC-based antimicrobial stewardship intervention that included education, prospective audit, and feedback from a physician peer, and daily tracking of excess DOT on a Kaizen board. The baseline period included retrospective CAP cases that occurred between October 2018 and February 2019 (control group). The intervention period included CAP cases between October 2019 and February 2020 (intervention group)., Results: A total of 123 CAP patients were included (57 control and 66 intervention). Median antibiotic DOT per patient decreased (8 versus 5 days; p < 0.001), and the proportion of patients treated for the IDSA minimum increased (5.3% versus 56%; p < 0.001) after the intervention. No differences in mortality, readmission, length of stay, or incidence of Clostridioides difficile infection were observed between groups. Almost half of the caregivers surveyed were aware that as few as 5 days of antibiotic treatment could be appropriate., Conclusions: A physician-driven antimicrobial quality improvement initiative designed using DMAIC methodology led to reduced DOT and increased compliance with the IDSA treatment guidelines for hospitalized patients with CAP reduced without negatively affecting clinical outcomes., Competing Interests: Conflict of Interest: None., (© Innovative Healthcare Institute.)

Aminophosphonates such as aminotris(methylenephosphonic acid) (ATMP) are common constituents of antiscalants. In nanofiltration (NF) and reverse osmosis (RO) processes, ATMP prevents inorganic scaling leading to more stable membrane performance. So far, little attention has been paid to the possible permeation of aminophosphonates through NF and RO membranes. We have investigated the permeability of these membrane types for ATMP and its potential metabolites iminodi(methylenephosphonic acid) (IDMP) and amino(methylenephosphonic acid) (AMPA) with two different NF membranes (TS40 and TS80) and one RO membrane (ACM2) and three different water compositions (ultra-pure water, synthetic tap water and local tap water). We found traces of phosphonates in all investigated permeates. The highest phosphonate rejection occurred with local tap water for all three membranes investigated. Filtration experiments with a technical antiscalant formulation containing ATMP indicated similar trends of phosphonate permeability through all three membranes. We assume that the separation mechanisms of the membranes are the results of a very complex relationship between physico-chemical properties such as Donnan exclusion, feed pH, feed ionic strength and feed concentration, as well as solute-solute interactions.

Glyphosate is a nonselective herbicide that kills weeds and other plants competing with crops. Glyphosate specifically inhibits the 5-enolpyruvyl-shikimate-3-phosphate (EPSP) synthase, thereby depleting the cell of EPSP serving as a precursor for biosynthesis of aromatic amino acids. Glyphosate is considered to be toxicologically safe for animals and humans. Therefore, it became the most-important herbicide in agriculture. However, its intensive application in agriculture is a serious environmental issue because it may negatively affect the biodiversity. A few years after the discovery of the mode of action of glyphosate, it has been observed that bacteria evolve glyphosate resistance by acquiring mutations in the EPSP synthase gene, rendering the encoded enzyme less sensitive to the herbicide. The identification of glyphosate-resistant EPSP synthase variants paved the way for engineering crops tolerating increased amounts of the herbicide. This review intends to summarize the molecular mechanisms underlying glyphosate resistance in bacteria. Bacteria can evolve glyphosate resistance by (i) reducing glyphosate sensitivity or elevating production of the EPSP synthase, by (ii) degrading or (iii) detoxifying glyphosate and by (iv) decreasing the uptake or increasing the export of the herbicide. The variety of glyphosate resistance mechanisms illustrates the adaptability of bacteria to anthropogenic substances due to genomic alterations., (© 2021 The Authors. Environmental Microbiology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Constrained peptides (CPs) have emerged as attractive candidates for drug discovery and development. To fully unlock the therapeutic potential of CPs, it is crucial to understand their physical stability and minimize the formation of aggregates that could induce immune responses. Although amyloid like aggregates have been researched extensively, few studies have focused on aggregates from other peptide scaffolds (e.g., CPs). In this work, a streamlined approach to effectively profile the nature and formation pathway of CP aggregates was demonstrated. Aggregates of various sizes were detected and shown to be amorphous. Though no major changes were found in peptide structure upon aggregation, these aggregates appeared to have mixed natures, consisting of primarily non-covalent aggregates with a low level of covalent species. This co-existence phenomenon was also supported by two kinetic pathways observed in time- and temperature-dependent aggregation studies. Furthermore, a stability study with 8 additional peptide variants exhibited good correlation between aggregation propensity and peptide hydrophobicity. Therefore, a dual aggregation pathway was proposed, with the non-covalent aggregates driven by hydrophobic interactions, whereas the covalent ones formed through disulfide scrambling. Overall, the workflow presented here provides a powerful strategy for comprehensive characterization of peptide aggregates and understanding their mechanisms of formation., (Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)