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The Eyes Absent family (EYA1-4) are a group of dual function proteins that act as both tyrosine phosphatases and transcriptional co-activators. EYA proteins play a vital role in development, but are also aberrantly overexpressed in cancers, where they often confer an oncogenic effect. Precisely how the EYAs impact cell biology is of growing interest, fuelled by the therapeutic potential of an expanding repertoire of EYA inhibitors. Recent functional studies suggest that the EYAs are important players in the regulation of genome maintenance pathways including DNA repair, mitosis, and DNA replication. While the characterized molecular mechanisms have predominantly been ascribed to EYA phosphatase activities, EYA co-transcriptional activity has also been found to impact the expression of genes that support these pathways. This indicates functional convergence of EYA phosphatase and co-transcriptional activities, highlighting the emerging importance of the EYA protein family at the intersection of genome maintenance mechanisms. In this review, we discuss recent progress in defining EYA protein substrates and transcriptional effects, specifically in the context of genome maintenance. We then outline future directions relevant to the field and discuss the clinical utility of EYA inhibitors., 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., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Background: Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality among US infants. A child's calendar birth month determines their age at first exposure(s) to RSV. We estimated birth month-specific risk of medically attended (MA) RSV lower respiratory tract infection (LRTI) among infants during their first RSV season and first year of life (FYOL)., Methods: We analyzed infants born in the USA between July 2016 and February 2020 using three insurance claims databases (two commercial, one Medicaid). We classified infants' first MA RSV LRTI episode by the highest level of care incurred (outpatient, emergency department, or inpatient), employing specific and sensitive diagnostic coding algorithms to define index RSV diagnoses. In our main analysis, we focused on infants' first RSV season. In our secondary analysis, we compared the risk of MA RSV LRTI during infants' first RSV season to that of their FYOL., Results: Infants born from May through September generally had the highest risk of first-season MA RSV LRTI-approximately 6-10% under the specific RSV index diagnosis definition and 16-26% under the sensitive. Infants born between October and December had the highest risk of RSV-related hospitalization during their first season. The proportion of MA RSV LRTI events classified as inpatient ranged from 9% to 54% (specific) and 5% to 33% (sensitive) across birth month and comorbidity group. Through the FYOL, the overall risk of MA RSV LRTI is comparable across birth months within each claims database (6-11% under the specific definition, 17-30% under the sensitive), with additional cases progressing to care at outpatient or ED settings., Conclusions: Our data support recent national recommendations for the use of nirsevimab in the USA. For infants born at the tail end of an RSV season who do not receive nirsevimab, a dose administered prior to the onset of their second RSV season could reduce the incidence of outpatient- and ED-related events., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Telomeres are repetitive nucleoprotein complexes at chromosomal termini essential for maintaining genome stability. Telomeric RNA, or TERRA, is a previously presumed long noncoding RNA of heterogeneous lengths that contributes to end-capping structure and function, and facilitates telomeric recombination in tumors that maintain telomere length via the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. Here, we investigated TERRA in the radiation-induced DNA damage response (DDR) across astronauts, high-altitude climbers, healthy donors, and cellular models. Similar to astronauts in the space radiation environment and climbers of Mt. Everest, in vitro radiation exposure prompted increased transcription of TERRA, while simulated microgravity did not. Data suggest a specific TERRA DDR to telomeric double-strand breaks (DSBs), and provide direct demonstration of hybridized TERRA at telomere-specific DSB sites, indicative of protective TERRA:telomeric DNA hybrid formation. Targeted telomeric DSBs also resulted in accumulation of TERRA foci in G2-phase, supportive of TERRA's role in facilitating recombination-mediated telomere elongation. Results have important implications for scenarios involving persistent telomeric DNA damage, such as those associated with chronic oxidative stress (e.g., aging, systemic inflammation, environmental and occupational radiation exposures), which can trigger transient ALT in normal human cells, as well as for targeting TERRA as a therapeutic strategy against ALT-positive tumors., (© 2024. The Author(s).)

Background: Bronchiolitis due to respiratory syncytial virus (RSV) is the leading cause of hospitalization among American infants. The overall burden of RSV among infants has been historically under-estimated due to variable testing practices, particularly in the outpatient setting. Universal masking and social distancing implemented during the coronavirus disease 2019 (COVID-19) pandemic altered RSV seasonality, however potential consequences on RSV testing practices across different healthcare settings and sociodemographic groups have not been described. Variable testing practices could also affect accurate assessment of the effects of two recently approved RSV preventative agents targeting infants., Methods: Utilizing real-time clinical and viral surveillance, we examined RSV testing practices among infants with bronchiolitis within four United States healthcare systems across different healthcare settings and sociodemographic groups pre- and post-COVID-19., Results: RSV testing among infants with bronchiolitis increased since 2015 within each healthcare system across all healthcare settings and sociodemographic groups, with a more dramatic increase since the COVID-19 pandemic. Outpatient testing remained disproportionately low compared to hospital-based testing, although there were no major differences in testing frequency among sociodemographic groups in either setting., Conclusions: Although RSV testing increased among infants with bronchiolitis, relatively low outpatient testing rates remain a key barrier to accurate RSV surveillance., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christopher Nelson reports financial support was provided by Sanofi Pasteur Inc. Christopher Nelson reports financial support was provided by AstraZeneca. Christopher Nelson reports a relationship with Sanofi that includes: employment. Emmanuel Walter reports a relationship with Pfizer Inc that includes: funding grants. Emmanuel Walter reports a relationship with Moderna Inc that includes: funding grants. Emmanuel Walter reports a relationship with Sequiris that includes: funding grants. Emmanuel Walter reports a relationship with Najit Technologies that includes: funding grants. Emmanuel Walter reports a relationship with Clinetic that includes: funding grants. Emmanuel Walter reports a relationship with Vaxcyte Inc. that includes: consulting or advisory. Emmanuel Walter reports a relationship with ILiAD Biotechnologies LLC that includes: consulting or advisory. Joseph Domachowske reports a relationship with Pfizer Inc that includes: funding grants. Joseph Domachowske reports a relationship with Moderna Inc that includes: consulting or advisory and funding grants. Joseph Domachowske reports a relationship with GlaxoSmithKline Inc that includes: consulting or advisory and funding grants. Joseph Domachowske reports a relationship with Sanofi that includes: funding grants. Joseph Domachowske reports a relationship with AstraZeneca that includes: consulting or advisory and funding grants. Joseph Domachowske reports a relationship with Clinetic that includes: funding grants. Claudia Espinosa reports a relationship with Sanofi that includes: consulting or advisory and funding grants. Claudia Espinosa reports a relationship with AstraZeneca that includes: funding grants. Claudia Espinosa reports a relationship with Clinetic that includes: funding grants. Mina Suh reports a relationship with EpidStrategies that includes: employment. Heidi Reichert reports a relationship with EpidStrategies that includes: employment. Jon Fryzek reports a relationship with EpidStrategies that includes: employment. Naimisha Movva reports a relationship with EpidStrategies that includes: employment. If there are other authors, they 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Respiratory syncytial virus (RSV) is a substantial cause of infant morbidity and mortality due to seasonal peaks of bronchiolitis across the United States. Clinical and viral surveillance plays a pivotal role in helping hospital systems prepare for expected surges in RSV bronchiolitis. Existing surveillance efforts have shown a geographic pattern of RSV positivity across the United States, with cases typically starting in the southeast and spreading north and west. Public health measures implemented due to the COVID-19 pandemic disrupted viral transmission across the nation and altered the expected seasonality of RSV. The impact of these changes on the geographic progression of infant RSV bronchiolitis across the United States has not been described., Methods: Here, we used clinical and viral surveillance data from four health care systems located in different regions of the United States to describe the geographic progression of infant RSV bronchiolitis across the country from 2015 to 2023., Results: Prior to widespread circulation of SARS-CoV-2, infant RSV bronchiolitis followed an established geographic pattern associated with seasonal epidemics originating in Florida and spreading north (North Carolina and New York) and later westward (Nevada). Although public health and social measures implemented during the COVID-19 pandemic disrupted the seasonality of RSV disease, infant RSV bronchiolitis epidemics progressed across the nation in a pattern identical to the prepandemic era., Conclusions: Our findings highlight the importance of ongoing clinical and viral surveillance to optimally track the onset of RSV epidemics and allow health care systems to prepare for expected RSV bronchiolitis surges., (© 2024 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

The ATR-CHK1 DNA damage response pathway becomes activated by the exposure of RPA-coated single-stranded DNA (ssDNA) that forms as an intermediate during DNA damage and repair, and as a part of the replication stress response. Here, we identify ZNF827 as a component of the ATR-CHK1 kinase pathway. We demonstrate that ZNF827 is a ssDNA binding protein that associates with RPA through concurrent binding to ssDNA intermediates. These interactions are dependent on two clusters of C2H2 zinc finger motifs within ZNF827. We find that ZNF827 accumulates at stalled forks and DNA damage sites, where it activates ATR and promotes the engagement of homologous recombination-mediated DNA repair. Additionally, we demonstrate that ZNF827 depletion inhibits replication initiation and sensitizes cancer cells to the topoisomerase inhibitor topotecan, revealing ZNF827 as a therapeutic target within the DNA damage response pathway., (© 2024. The Author(s).)

The Eyes Absent proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour-promoting across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as an interactor and phosphatase substrate of EYA4 and EYA1, with pY445 on PLK1 being the primary target site. Dephosphorylation of pY445 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and PLK1-activation complexes. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a phosphotyrosine signalling network governing PLK1 and mitosis., (© 2024. The Author(s).)

Following prolonged cell division, mesenchymal stem cells enter replicative senescence, a state of permanent cell cycle arrest that constrains the use of this cell type in regenerative medicine applications and that in vivo substantially contributes to organismal ageing. Multiple cellular processes such as telomere dysfunction, DNA damage and oncogene activation are implicated in promoting replicative senescence, but whether mesenchymal stem cells enter different pre-senescent and senescent states has remained unclear. To address this knowledge gap, we subjected serially passaged human ESC-derived mesenchymal stem cells (esMSCs) to single cell profiling and single cell RNA-sequencing during their progressive entry into replicative senescence. We found that esMSC transitioned through newly identified pre-senescent cell states before entering into three different senescent cell states. By deconstructing this heterogeneity and temporally ordering these pre-senescent and senescent esMSC subpopulations into developmental trajectories, we identified markers and predicted drivers of these cell states. Regulatory networks that capture connections between genes at each timepoint demonstrated a loss of connectivity, and specific genes altered their gene expression distributions as cells entered senescence. Collectively, this data reconciles previous observations that identified different senescence programs within an individual cell type and should enable the design of novel senotherapeutic regimes that can overcome in vitro MSC expansion constraints or that can perhaps slow organismal ageing., (© 2023. Crown.)

Alternative lengthening of telomeres (ALT) is a homology-directed repair mechanism that becomes activated in a subset of cancers to maintain telomere length. One of the defining features of ALT cells is the prevalence of extrachromosomal telomeric repeat (ECTR) DNA. Here, we identify that ALT cells engage in two modes of telomere synthesis. Non-productive telomere synthesis occurs during the G2 phase of the cell cycle and is characterized by newly synthesized internal telomeric regions that are not retained in the subsequent G1, coinciding with an induction of ECTR DNA. Productive telomere synthesis occurs specifically during the transition from G2 to mitosis and is defined as the extension of the telomere termini. While many proteins associated with break-induced telomere synthesis function in both non-productive and productive telomere synthesis, POLH specifically promotes productive telomere lengthening and suppresses non-productive telomere synthesis. These findings delineate the mechanism and cell cycle regulation of ALT-mediated telomere synthesis and extension., Competing Interests: H.A.P. is a founder of Tesellate Bio and a member of its scientific advisory board., (© 2023 The Author(s).)

Background: Respiratory syncytial virus (RSV) bronchiolitis is the leading cause of hospitalizations among infants in the United States. Unpredictability in RSV seasonality has occurred following the onset of the coronavirus disease 2019 (COVID-19) pandemic. Local surveillance networks can enhance the ability to appropriately time prophylaxis when exposure risk is highest., Methods: A retrospective, cohort study was conducted to describe the epidemiologic patterns of RSV disease among outpatient, emergency department and inpatient encounters in children <5 years in Central New York before and after the onset of the COVID-19 pandemic. Local data were collected from October 2015 to January 2023 and compared to state-level data. Linear regression models were used to identify clinical and sociodemographic differences before and after the pandemic., Results: Local variation in RSV seasonality was noted prior to the COVID-19 pandemic, however highly atypical circulation patterns appeared in the post-COVID-19 era. Since March 2020, patterns for local and state-defined RSV seasons have remained atypical (local season onset in 2021: week 27 and 2022: week 27; state season onset in 2021: week 31 and 2022: week 38). After adjusting for increases in testing, RSV bronchiolitis cases were not significantly different during pre- and post-pandemic eras. In comparison to the 2021 bronchiolitis season, the 2022 season had a higher proportion of RSV cases despite decreased testing., Conclusions: Temporal patterns for RSV have shifted during the COVID-19 pandemic. Local surveillance networks may be advantageous in trending community-level RSV activity to optimize prophylaxis administration. Changes in RSV testing patterns occurred throughout the study period and should be accounted for when describing infant and childhood RSV disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: New extended half-life antibodies for the single-dose prevention of medically attended (MA) respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) have been developed for administration to all infants before or during their first RSV season. For infants born during the season, administration as soon as feasible after birth would provide optimal protection and minimize access disparities. The objective of this study was to assess the time from birth hospitalization discharge to the first outpatient visit (FOV) among US infants in order to determine optimal site of administration for the extended half-life antibody., Material and Methods: This retrospective, observational, time-to-event analysis uses the Merative™ MarketScan® Commercial and Multi-State Medicaid Databases. Time to FOV is reported separately for the COVID-19 and recent pre-COVID-19 eras and for commercially insured and Medicaid infants., Results: Overall, 73.8 % of Medicaid infants had an FOV within 5 days as compared to 84.7 % of commercially insured infants. Estimates were higher during the COVID-19 era. Urban commercially insured infants had much higher FOV completion than their counterparts. Among Medicaid infants, urban Black and rural White infants were least likely to complete their FOV within 5 days of birth hospitalization discharge., Discussion and Conclusion: FOV within 5 days after birth hospitalization discharge for Medicaid infants is substantially lower than that of commercially insured infants. Approximately 1 in 4 Medicaid infants and 1 in 8 infants with commercial insurance did not have an outpatient visit within 5 days of birth hospitalization discharge. For US infants born during the RSV season, administration of extended half-life RSV antibodies in the newborn nursery prior to discharge would ensure optimal uptake and minimize access disparities., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Policymakers need data about the burden of respiratory syncytial virus (RSV) lower respiratory tract infections (LRTI) among infants. This study estimates quality of life (QoL) for otherwise healthy term US infants with RSV-LRTI and their caregivers, previously limited to premature and hospitalized infants, and corrects for selective testing., Methods: The study enrolled infants <1 year with a clinically diagnosed LRTI encounter between January and May 2021. Using an established 0-100 scale, the 36 infants' and caregivers' QoL at enrollment and quality-adjusted life year losses per 1000 LRTI episodes (quality-adjusted life years [QALYs]/1000) were validated and analyzed. Regression analyses examined predictors of RSV-testing and RSV-positivity, creating modeled positives., Results: Mean QoL at enrollment in outpatient ( n  = 11) LRTI-tested infants (66.4) was lower than that in not-tested LRTI infants (79.6, p  = 0.096). For outpatient LRTI infants ( n  = 23), median QALYs/1000 losses were 9.8 and 0.25 for their caregivers. RSV-positive outpatient LRTI infants ( n  = 6) had significantly milder QALYs/1000 losses (7.0) than other LRTI-tested infants ( n  = 5)(21.8, p  = 0.030). Visits earlier in the year were more likely to be RSV-positive than later visits ( p  = 0.023). Modeled RSV-positivity (51.9%) was lower than the observed rate (55.0%). Infants' and caregivers' QALYs/1000 loss were positively correlated (rho = 0.34, p  = 0.046), indicating that infants perceived as sicker imposed greater burdens on caregivers., Conclusions: The overall median QALYs/1000 losses for LRTI (9.0) and RSV-LRTI (5.6) in US infants are substantial, with additional losses for their caregivers (0.25 and 0.20, respectively). These losses extend equally to outpatient episodes. This study is the first reporting QALY losses for infants with LRTI born at term or presenting in nonhospitalized settings, and their caregivers., Competing Interests: Christopher B. Nelson is an employee of Sanofi and may hold shares and/or stock options in the company. All other authors received grant funding from Sanofi and AstraZeneca (through Sanofi). Kimberley A. Fisher, Charles T. Wood, William F. Malcolm received grant funding for this study from Sanofi and AstraZeneca through Clinetic. Donald S. Shepard has received financial support from Abbott, Inc, Takeda Vaccines, Inc. and Trustees of Columbia University, New York, in the past 36 months. Dhwani Hariharan, William H. Crown and V.S. Senthil Kumar have received financial support from Bill & Melinda Gates Foundation and The Global Fund to Fight AIDS, Tuberculosis and Malaria, in the past 36 months., (© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Erdafitinib, an anticancer drug, was synthesized in a three-step two-pot sequence involving ppm levels of Pd catalyst run under aqueous micellar conditions enabled by a biodegradable surfactant. This process features both pot- and time-economies and eliminates egregious organic solvents and toxic reagents associated with existing routes.

Background: The World Health Organization (WHO) recommended 'pre-vaccination screening' as its preferred implementation strategy when using the licensed dengue vaccine (CYD-TDV; Dengvaxia, Sanofi), so that only individuals with previous dengue infection are vaccinated. The US Centers for Disease Control and Prevention (CDC) recommended use of CYD-TDV to prevent dengue in children with previous laboratory-confirmed dengue infection in regions where dengue is endemic. Here, we evaluate the public health impact and cost-effectiveness of a 'pre-vaccination screening' strategy in Puerto Rico., Methods: The current analysis builds upon a previously published transmission model used to assess the benefits/risks associated with dengue vaccination. For 'pre-vaccination screening', three alternative testing methods were assessed: one using an immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) dengue serotest, another with dengue serotesting using a rapid diagnostic test (RDT), and one using both sequentially (as recommended in Puerto Rico). The time horizon considered was 10 years., Results: In Puerto Rico, the disability-adjusted life years (DALYs) averted for 'pre-vaccination screening' with an ELISA-based program, RDT-based program, and both sequentially would be a median 1,192 (95% CI: 716-2,232), 2,812 (95% CI: 1,579-5,019), and 1,017 (95% CI: 561-1,738), respectively. These benefits would arise from the reduction in cases: median 24,961 (95% CI: 17,480-36,782), 58,273 (95% CI: 40,729-84,796), 20,775 (95% CI: 14,637-30,374) fewer cases, respectively. The cost per DALY averted from a payer perspective would be US$12,518 (95 %CI: US$4,749-26,922), US$10,047 (95% CI: US$3,350-23,852), and US$12,334 (95% CI: US$4,965-26,444), respectively. All three strategies would be cost saving from a societal perspective., Conclusions: Our study supports the WHO and CDC 'pre-vaccination screening' guidance for CYD-TDV implementation. In Puerto Rico, regardless of the testing strategy and even with a relatively low rate of testing, it would be cost-effective from a payer perspective and cost saving from a societal perspective., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ET, LC, RM, MM, CN, and AC are employees of Sanofi Pasteur and may hold shares and/or stock options in the company., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To understand physician preferences for various attributes of pediatric combination vaccines., Methods: An online survey was completed by 400 US physicians (pediatricians and family physicians) who routinely administer vaccines to infants aged 1-12 months in outpatient settings. Respondents completed a discrete choice experiment (DCE) by selecting their preferred options from different hypothetical vaccine profiles with systematic variation in the levels of five attributes: vaccine presentation, number of injections administered at a single visit, completion rates, timeliness rates (within 30 days of recommended age), and years of availability for routine use, assuming similar cost, safety, and efficacy. Odds ratios and relative attribute importance scores were estimated using a random parameters logit model., Results: Physicians (mean age 50.4 years, 52.5% women) preferred combination vaccines that reduced the number of injections administered at a single visit, facilitated higher completion and timeliness rates for the primary DTaP series, were available as a pre-filled syringe rather than a vial needing reconstitution and had been available for routine use for more than 1 year. All odds ratios were statistically significant. Physicians were twice as likely to prefer administering three injections in a single visit instead of four. The most important attribute was the number of injections administered at a single visit (relative importance 38%), followed by timeliness, completion rates, and vaccine presentation; years a vaccine has been available was the least important attribute., Conclusion: US physicians prefer pediatric combination vaccines that enable fewer injections to be administered at a single visit, facilitate higher completion and timeliness rates, are offered as a pre-filled syringe, and have been available for routine use for more than 1 year. The most important attribute of pediatric combination vaccines was a reduction in the number of injections administered at a single visit.

Background: Respiratory syncytial virus (RSV) is the leading cause of hospitalizations in United States infants aged <1 year, but research has focused on select populations., Methods: National (Nationwide) Inpatient Sample and National Emergency Department (ED) Sample data (2011-2019) were used to report RSV hospitalization (RSVH), bronchiolitis hospitalization (BH), and ED visit counts, percentage of total hospitalizations/visits, and rates per 1000 live births along with inpatient mortality, mechanical ventilation (MV), and total charges (2020 US dollars)., Results: Average annual RSVH and RSV ED visits were 56 927 (range, 43 845-66 155) and 131 999 (range, 89 809-177 680), respectively. RSVH rates remained constant over time (P = .5), whereas ED visit rates increased (P = .004). From 2011 through 2019, Medicaid infants had the highest average rates (RSVH: 22.3 [95% confidence interval {CI}, 21.5-23.1] per 1000; ED visits: 55.9 [95% CI, 52.4-59.4] per 1000) compared to infants with private or other/unknown insurance (RSVH: P < .0001; ED visits: P < .0001). From 2011 through 2019, for all races and ethnicities, Medicaid infants had higher average RSVH rates (up to 7 times) compared to infants with private or other/unknown insurance. RSVH mortality remained constant over time (P = .8), whereas MV use (2019: 13% of RSVH, P < .0001) and mean charge during hospitalization (2019: $21 513, P < .0001) increased. Bronchiolitis patterns were similar., Conclusions: This study highlights the importance of ensuring access to RSV preventive measures for all infants., Competing Interests: Potential conflicts of interest. EpidStrategies received a grant from Sanofi for this research. M. S., N. M., X. J., H. R., L. C. B., and J. P. F. are employees of EpidStrategies. C. B. N. is an employee of Sanofi and may hold shares and/or stock options in the company. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Respiratory syncytial virus (RSV), a leading cause of lower respiratory tract infection in US children, reduces quality of life (QOL) of children, their caregivers, and families., Methods: We conducted a systematic literature review in PubMed, EconLit, and other databases in the United States of articles published since 2000, derived utility lost per RSV episode from cohort studies, and performed a systematic analysis., Results: From 2262 unique citations, 35 received full-text review and 7 met the inclusion criteria (2 cohort studies, 4 modeling studies, and 1 synthesis). Pooled data from the 2 cohort studies (both containing only hospitalized premature infants) gave quality-adjusted life-year (QALY) losses per episode of 0.0173 at day 38. From the cohort study that also assessed caregivers' QOL, we calculated net QALYs lost directly attributable to RSV per nonfatal episode from onset to 60 days after onset for the child, caregiver, child-and-caregiver dyad of 0.0169 (167% over prematurity alone), 0.0031, and 0.0200, respectively., Conclusion: Published data on QOL of children in the United States with RSV are scarce and consider only premature hospitalized infants, whereas most RSV episodes occur in children who were born at term and were otherwise healthy. QOL studies are needed beyond hospitalized premature infants., Competing Interests: Potential conflicts of interest. E. L. G., D. H., D. M. B., R. M. G., K. R. R., and D. S. S. were supported under an agreement between Sanofi and Brandeis University, but none received any direct funding nor in-kind support from the sponsors. C. B. N. is an employee of Sanofi and may hold shares and/or stock options in the company. L. B. declared no conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The target populations and financing mechanisms for a new health technology may affect health inequalities in access and impact. We projected the distributional consequences of introducing nirsevimab for prevention of respiratory syncytial virus in a US birth cohort of infants through alternative reimbursement pathway scenarios. Using the RSV immunization impact model, we estimated that a vaccine-like reimbursement pathway would cover 32% more infants than a pharmaceutical pathway. The vaccine pathway would avert 30% more hospitalizations and 39% more emergency room visits overall, and 44% and 44%, respectively, in publicly insured infants. The vaccine pathway would benefit infants from poorer households., Competing Interests: Potential conflicts of interest. G. B. G., C. R., C. B. N., and S. S. C. are employees of Sanofi, a company which makes Nirsevimab, a monoclonal antibody for RSV prevention, and may own Sanofi shares. Sanofi employees were involved in all aspects of data collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. D. S. S. received grant funding from Sanofi. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Surveillance in 2020-2021 showed that seasonal respiratory illnesses were below levels seen during prior seasons, with the exception of interseasonal respiratory syncytial virus (RSV)., Methods: Electronic health record data of infants aged <1 year visiting the Duke University Health System from 4 October 2015 to 28 March 2020 (pre-COVID-19) and 29 March 2020 to 30 October 2021 (COVID-19) were assessed. International Classification of Diseases-Tenth Revision (ICD-10) codes for RSV (B97.4, J12.1, J20.5, J21.0) and bronchiolitis (RSV codes plus J21.8, J21.9) were used to detail encounters in the inpatient (IP), emergency department (ED), outpatient (OP), urgent care (UC), and telemedicine (TM) settings., Results: Pre-COVID-19, 88% of RSV and 92% of bronchiolitis encounters were seen in ambulatory settings. During COVID-19, 94% and 93%, respectively, occurred in ambulatory settings. Pre-COVID-19, the highest RSV proportion was observed in December-January (up to 38% in ED), while the peaks during COVID-19 were seen in July-September (up to 41% in ED) across all settings. RSV laboratory testing among RSV encounters was low during pre-COVID-19 (IP, 51%; ED, 51%; OP, 41%; UC, 84%) and COVID-19 outside of UC (IP, 33%; ED, 47%; OP, 47%; UC, 87%). Full-term, otherwise healthy infants comprised most RSV encounters (pre-COVID-19, up to 57% in OP; COVID-19, up to 82% in TM)., Conclusions: With the interruption of historical RSV epidemiologic trends and the emergence of interseasonal disease during COVID-19, continued monitoring of RSV is warranted across all settings as the changing RSV epidemiology could affect the distribution of health care resources and public health policy., Competing Interests: Potential conflicts of interest. N. M., M. S., H. R., and J. P. F. are employees of EpidStrategies. K. F., C. T. W., and W. F. M. are employees of Duke University Health System. Z. W., S. C., and T. K. are employees of Clinetic. EpidStrategies, Duke University Health System, and Clinetic received funding from Sanofi for this research. B. H. and M. P. S. are employees of Duke Institute for Health Innovation. Duke Institute for Health Innovation received funding from Clinetic for this research. M. W. and C. B. N. are employees of Sanofi and may hold shares and/or stock options in the company., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Limited data are available on the economic costs of respiratory syncytial virus (RSV) infections among infants and young children in the United States., Methods: We performed a systematic literature review of 10 key databases to identify studies published between 1 January 2014 and 2 August 2021 that reported RSV-related costs in US children aged 0-59 months. Costs were extracted and a systematic analysis was performed., Results: Seventeen studies were included. Although an RSV hospitalization (RSVH) of an extremely premature infant costs 5.6 times that of a full-term infant ($10 214), full-term infants accounted for 82% of RSVHs and 70% of RSVH costs. Medicaid-insured infants were 91% more likely than commercially insured infants to be hospitalized for RSV treatment in their first year of life. Medicaid financed 61% of infant RSVHs. Paying 32% less per hospitalization than commercial insurance, Medicaid paid 51% of infant RSVH costs. Infants' RSV treatment costs $709.6 million annually, representing $187 per overall birth and $227 per publicly funded birth., Conclusions: Public sources pay for more than half of infants' RSV medical costs, constituting the highest rate of RSVHs and the highest expenditure per birth. Full-term infants are the predominant source of infant RSVHs and costs., Competing Interests: Potential conflicts of interest. D. M. B., K. R. R., D. H., R. M. G., Y. H.-R., and E. L. G. were supported in part under an agreement between Sanofi and Brandeis University, but none received any direct funding nor in-kind support from the sponsors. C. B. N. is an employee of Sanofi and may hold shares and/or stock options in the company. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Infant mortality due to respiratory syncytial virus (RSV) in the United States is not well understood., Methods: From 1999 to 2018, RSV, bronchiolitis, and influenza deaths were described for infants <1 year using linked birth/death datasets from the National Vital Statistics System. Mortality was described overall and by infant birth and death characteristics. Bronchiolitis was included as the plausible upper limit of RSV, while influenza served as a comparator., Results: Total infant deaths were 561 RSV, 1603 bronchiolitis, and 504 influenza, and rates were 6.9 (95% confidence interval [CI], 6.4-7.5), 19.8 (95% CI, 18.9-20.8), and 6.2 (95% CI, 5.7-6.8) per 1 000 000 live births, respectively. The highest RSV rates were observed among <29 weeks' gestational age infants (103.5; 95% CI, 81.8-129.1), American Indian/Alaskan Native (20.3; 95% CI, 11.6-33.0), and Medicaid-insured (7.3; 95% CI, 5.9-8.9). However, RSV mortality burden was greatest in full-term (53.7%), white (44.9%), and Medicaid-insured (61.7%) infants. Deaths outside the inpatient setting were 21% and 54% for RSV and bronchiolitis; more Medicaid- (58%) and other/unknown-insured (69%) infants with bronchiolitis died outside of the inpatient setting, compared to privately insured infants (48%) (P = .0327)., Conclusions: These national estimates emphasize the importance of considering all infants across all healthcare settings when describing RSV mortality., Competing Interests: Potential conflicts of interest. EpidStrategies received a grant from Sanofi for this research. H. R., M. S., X. J., N. M., L. C. B., and J. P. F. are employees of EpidStrategies. C. B. N. is an employee of Sanofi and may hold shares and/or stock options in the company. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The burden and health care utilization (HCU) of respiratory syncytial virus (RSV) in US infants aged <1 year across health care settings are not well characterized., Methods: We systematically reviewed studies of RSV and bronchiolitis published 2000-2021 (data years, 1979-2020). Outcomes included RSV hospitalization (RSVH)/bronchiolitis hospitalization rates, emergency department (ED)/outpatient (OP) visit rates, and intensive care unit (ICU) admissions or mechanical ventilation (MV) use among RSV-/bronchiolitis-hospitalized infants. Study quality was determined using standard tools., Results: We identified 141 good-/fair-quality studies. Five national studies reported annual average RSVH rates (range, 11.6 per 1000 per year among infants aged 6-11 months in 2006 to 50.1 per 1000 per year among infants aged 0-2 months in 1997). Two national studies provided RSVH rates by primary diagnosis for the entire study period (range, 22.0-22.7 per 1000 in 1997-1999 and 1997-2000, respectively). No national ED/OP data were available. Among 11 nonnational studies, RSVH rates varied due to differences in time, populations (eg, prematurity), and locations. One national study reported that RSVH infants with high-risk comorbidities had 5-times more MV use compared to non-high-risk infants in 1997-2012., Conclusions: Substantial data variability was observed. Nationally representative studies are needed to elucidate RSV burden and HCU., Competing Interests: Potential conflicts of interest. EpidStrategies received a grant from Sanofi for this research. M. S., N. M., L. C. B., and J. P. F. are employees of EpidStrategies. C. B. N. is an employee of Sanofi and may hold shares and/or stock options in the company. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Competing Interests: Potential conflicts of interest. E. N. H. and C. B. N. are employees of Sanofi and may own Sanofi shares. M. W. was a contracted employee with Sanofi at the time the work was done and has no conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Background: This study describes leading causes of hospitalization, including respiratory syncytial virus (RSV), in United States infants (<1 year) from 2009 through 2019., Methods: Within the National (Nationwide) Inpatient Sample (NIS) data, hospitalizations were determined by primary diagnosis using International Classification of Diseases, Ninth or Tenth Revision codes. RSV was defined as 079.6, 466.11, 480.1, B97.4, J12.1, J20.5, or J21.0. Bronchiolitis was defined as 466.19, J21.8, or J21.9. Leading causes overall and by sociodemographic variables were identified. The Kids' Inpatient Database (KID) was used for confirmatory analyses., Results: Acute bronchiolitis due to RSV (code 466.11 or J21.0) was the leading primary diagnosis, accounting for 9.6% (95% confidence interval [CI], 9.4%-9.9%) and 9.3% (95% CI, 9.0%-9.6%) of total infant hospitalizations from January 2009 through September 2015 and October 2015 through December 2019, respectively; it was the leading primary diagnosis in every year accounting for >10% of total infant hospitalizations from December through March, reaching >15% in January-February. From 2009 through 2011, acute bronchiolitis due to RSV was the leading primary diagnosis in every birth month. Acute bronchiolitis due to RSV was the leading cause among all races/ethnicities, except Asian/Pacific Islanders, and all insurance payer groups. KID analyses confirmed these results., Conclusions: Acute bronchiolitis due to RSV is the leading cause of US infant hospitalizations., Competing Interests: Potential conflicts of interest. M. S., N. M., X. J., L. C. B., H. R., and J. P. F. are employees of EpidStrategies. C. B. N. is an employee of Sanofi and may hold shares and/or stock options in the company. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: A systematic literature review was conducted to summarize the mortality (overall and by disease severity factors) of US infants and children aged <5 years with respiratory syncytial virus (RSV) or all-cause bronchiolitis (ACB)., Methods: Comprehensive, systematic literature searches were conducted; articles were screened using prespecified eligibility criteria. A standard risk of bias tool was used to evaluate studies. Mortality was extracted as the rate per 100 000 or the case fatality ratio (CFR; proportion of deaths among RSV/ACB cases)., Results: Among 42 included studies, 36 evaluated inpatient deaths; 10 used nationally representative populations updated through 2013, and only 2 included late-preterm/full-term otherwise healthy infants and children. The RSV/ACB definition varied across studies (multiple International Classification of Diseases [ICD] codes; laboratory confirmation); no study reported systematic testing for RSV. No studies reported RSV mortality rates, while 3 studies provided ACB mortality rates (0.57-9.4 per 100 000). CFRs ranged from 0% to 1.7% for RSV (n = 15) and from 0% to 0.17% for ACB (n = 6); higher CFRs were reported among premature, intensive care unit-admitted, and publicly insured infants and children., Conclusions: RSV mortality reported among US infants and children is variable. Current, nationally representative estimates are needed for otherwise healthy, late-preterm to full-term infants and children., Competing Interests: Potential conflicts of interest. EpidStrategies received a grant from Sanofi for this research. L. C. B., M. S., N. M., and J. P. F. are employees of EpidStrategies. C. B. N. is an employee of Sanofi and may hold shares and/or stock options in the company. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Respiratory syncytial virus (RSV) is a leading cause of infant hospitalization in the United States. Preterm infants and those with select comorbidities are at highest risk of RSV-related complications. However, morbidity due to RSV infection is not confined to high-risk infants. We estimated the burden of medically attended (MA) RSV-associated lower respiratory tract infection (LRTI) among infants in the United States., Methods: We analyzed commercial (MarketScan Commercial [MSC], Optum Clinformatics [OC]), and Medicaid (MarketScan Medicaid [MSM]) insurance claims data for infants born between April 2016 and February 2020. Using both specific and sensitive definitions of MA RSV LRTI, we estimated the burden of MA RSV LRTI during infants' first RSV season, stratified by gestational age, comorbidity status, and highest level of medical care associated with the MA RSV LRTI diagnosis., Results: According to the specific definition 75.0% (MSC), 78.6% (MSM), and 79.6% (OC) of MA RSV LRTI events during infants' first RSV season occurred among term infants without known comorbidities., Conclusions: Term infants without known comorbidities account for up to 80% of the MA RSV LRTI burden in the United States during infants' first RSV season. Future prevention efforts should consider all infants., Competing Interests: Potential conflicts of interest . J. R. G., A. R. Z., and D. A. S. receive research funding support from Sanofi. N. Z. and B. L. are employees of IBM Watson Health, who was contracted by Sanofi to perform analyses included in this paper. S. S. C., W. V. L. V., C. B. N., C. R., and R. vA. are employees of Sanofi. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Respiratory syncytial virus (RSV) can cause serious illness in those aged <5 years in the United States, but uncertainty remains around which populations receive RSV testing. We conducted a systematic literature review of RSV testing patterns in studies published from 2000 to 2021., Methods: Studies of RSV, medically attended RSV lower respiratory tract infections (LRTIs), and bronchiolitis were identified using standard methodology. Outcomes were clinical decisions to test for RSV, testing frequency, and testing incidence proportions in inpatient (IP), emergency department (ED), outpatient (OP), and urgent care settings., Results: Eighty good-/fair-quality studies, which reported data from the period 1988-2020, were identified. Twenty-seven described the clinical decision to test, which varied across and within settings. Two studies reported RSV testing frequency for multiple settings, with higher testing proportions in IP (n = 2, range: 83%-85%, 1996-2009) compared with ED (n = 1, 25%, 2006-2009) and OP (n = 2, 15%-25%, 1996-2009). Higher RSV testing incidence proportions were observed among LRTI infant populations in the ED (n = 1, 74%, 2007-2008) and OP (n = 2, 54%-69%, 1995-2008). Incidence proportions in LRTI populations were not consistently higher in the IP setting (n = 13). Across studies and time, there was heterogeneity in RSV testing patterns, which may reflect varying detection methods, populations, locations, time periods, and healthcare settings., Conclusions: Not all infants and children with LRTI are tested for RSV, highlighting underestimation of RSV burden across all settings., Competing Interests: Potential conflicts of interest . N. M., M. S., L. C. B., and J. P. F. are employees of EpidStrategies. C. B. N. is an employee of Sanofi and may hold shares and/or stock options in the company. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The burden of respiratory syncytial virus (RSV)-associated acute respiratory illnesses among healthy infants (<1 year) in the inpatient setting is well established. The focus on RSV-associated illnesses in the outpatient (OP) and emergency department (ED) settings are however understudied. We sought to determine the spectrum of RSV illnesses in infants at three distinct healthcare settings., Methods: From 16 December 2019 through 30 April 2020, we performed an active, prospective RSV surveillance study among infants seeking medical attention from an inpatient (IP), ED, or OP clinic. Infants were eligible if they presented with fever and/or respiratory symptoms. Demographics, clinical characteristics, and illness histories were collected during parental/guardian interviews, followed by a medical chart review and illness follow-up surveys. Research nasal swabs were collected and tested for respiratory pathogens for all enrolled infants., Results: Of the 627 infants screened, 475 were confirmed eligible; 360 were enrolled and research tested. Within this final cohort, 101 (28%) were RSV-positive (IP = 37, ED = 18, and OP = 46). Of the RSV-positive infants, the median age was 4.5 months and 57% had ⩾2 healthcare encounters. The majority of RSV-positive infants were not born premature (88%) nor had underlying medical conditions (92%). RSV-positive infants, however, were more likely to have a lower respiratory tract infection than RSV-negative infants (76% vs 39%, p  < 0.001). Hospitalized infants with RSV were younger, 65% required supplemental oxygen, were more likely to have lower respiratory tract symptoms, and more often had shortness of breath and rales/rhonchi than RSV-positive infants in the ED and OP setting., Conclusion: Infants with RSV illnesses seek healthcare for multiple encounters in various settings and have clinical difference across settings. Prevention measures, especially targeted toward healthy, young infants are needed to effectively reduce RSV-associated healthcare visits., Competing Interests: Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: NH receives funding from Sanofi Pasteur, Quidel, and speaker compensation from an education grant supported by Genentech. CBN is an employee of Sanofi Pasteur and may hold shares and/or stock options in the company. JF, MS, and DSS received funding from Sanofi Pasteur for this and other contracted work. All other authors report no other conflicts of interest., (© The Author(s), 2022.)

Background: Seasonal influenza vaccine (SIV) uptake in the United States remains suboptimal, requiring new and innovative strategies., Objective: To evaluate the impact of a behavioral peer comparison (PC) intervention on SIV uptake in community pharmacies across the United States., Methods: A cluster randomized study was conducted across a national network of Walmart community pharmacies (> 4500 sites) during the 2019-2020 influenza season. The clusters consisted of 416 markets, each containing an average of 11 pharmacies. All pharmacies in a market were randomly assigned to either no intervention or the PC intervention, a software-delivered communication informing on-site staff, including pharmacists and pharmacy technicians, of their pharmacy's weekly performance, measured as SIV doses administered, compared with that of peer pharmacies within their market. The outcome was the pharmacy-level cumulative SIV doses administered during the intervention period (September 1, 2019,-February 29, 2020). Linear regression models were used to estimate the PC impact, with multiway cluster-robust SEs estimated by market and state., Results: A total of 4589 pharmacies were enrolled in the study, with 2297 (50.1%) randomized to the control group and 2292 (49.9%) randomized to the PC intervention group. Overall, compared with the control pharmacies, the PC pharmacies administered 3.7% (95% CI -0.3% to 7.9%) additional SIV doses. Among large-format pharmacies, the PC pharmacies administered 4.1% (95% CI 0.1%-8.3%) additional SIV doses compared with the controls. Historically low-performing large-format PC pharmacies administered 6.1% (95% CI 0.5%-11.9%) additional SIV doses compared with the controls. No statistically significant treatment effects were observed among small-format pharmacies., Conclusion: Our findings demonstrate that PCs can improve SIV uptake among large-format community pharmacies, with historically low-performing pharmacies potentially exhibiting the greatest relative impact. Wide-scale implementation of PCs in community pharmacies may help to further improve SIV uptake in these settings., (Copyright © 2021 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Telomeres, repetitive nucleoprotein complexes that protect chromosomal termini and prevent them from activating inappropriate DNA damage responses (DDRs), shorten with cell division and thus with aging. Here, we characterized the human cellular response to targeted telomeric double-strand breaks (DSBs) in telomerase-positive and telomerase-independent alternative lengthening of telomere (ALT) cells, specifically in G1 phase. Telomeric DSBs in human G1 cells elicited early signatures of a DDR; however, localization of 53BP1, an important regulator of resection at broken ends, was not observed at telomeric break sites. Consistent with this finding and previously reported repression of classical non-homologous end-joining (c-NHEJ) at telomeres, evidence for c-NHEJ was also lacking. Likewise, no evidence of homologous recombination (HR)-dependent repair of telomeric DSBs in G1 was observed. Rather, and supportive of rapid truncation events, telomeric DSBs in G1 human cells facilitated formation of extensive tracks of resected 5' C-rich telomeric single-stranded (ss)DNA, a previously proposed marker of the recombination-dependent ALT pathway. Indeed, induction of telomeric DSBs in human ALT cells resulted in significant increases in 5' C-rich (ss)telomeric DNA in G1, which rather than RPA, was bound by the complementary telomeric RNA, TERRA, presumably to protect these exposed ends so that they persist into S/G2 for telomerase-mediated or HR-dependent elongation, while also circumventing conventional repair pathways. Results demonstrate the remarkable adaptability of telomeres, and thus they have important implications for persistent telomeric DNA damage in normal human G1/G0 cells (e.g., lymphocytes), as well as for therapeutically relevant targets to improve treatment of ALT-positive tumors., 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 © 2021 Nelson, Alturki, Luxton, Taylor, Maranon, Muraki, Murnane and Bailey.)

The Veterans Health Administration (VHA) developed Psychosocial Rehabilitation and Recovery Centers (PRRCs) to enhance recovery-oriented mental health services to large populations of veterans diagnosed with serious mental illness (e.g., psychotic disorders, bipolar disorder) and significant functional challenges. Psychosocial Rehabilitation and Recovery Centers were designed to support a rehabilitation framework to help veterans obtain needed skills and support to integrate into meaningful, self-determined community roles. This study used data collected as part of VHA's development and implementation of a national system to monitor PRRC performance with the purpose of evaluating the psychometric properties and latent structure of outcome measures used in PRRCs. Baseline self-report data from 5,086 veterans and their assigned PRRC staff providers were collected and reviewed. Exploratory factor analyses were used to evaluate the psychometric properties of the Veteran-Rated Psychiatric Symptom Items (VR-PSI), the Clinician-Rated Psychiatric Symptom Items (CR-PSI), and the Internalized Stigma of Mental Illness 10-item scale (ISMI-10). Four latent factors were identified for the VR-PSI and CR-PSI for the total sample, while the ISMI-10 was reduced to 8-items to assess self-stigma as a unitary measure. All measures demonstrated good psychometric properties. This study provides initial support for the latent factor structures and psychometric properties of measures used to assess national VHA PRRC performance. Implications and limitations are discussed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Telomeres are repetitive regions of DNA bound by specialized proteins at the termini of linear chromosomes that prevent the natural chromosome ends from being recognized as DNA double strand breaks. Telomeric DNA is gradually eroded with each round of cell division, resulting in the accumulation of critically short or dysfunctional telomeres that eventually trigger cellular senescence. Consequently, telomere length is indicative of the proliferative capacity of a cell. Multiple methods exist to measure telomere length and telomere content, but a simple and reliable technique to accurately measure individual telomere lengths is currently lacking. We have developed the Telomere length Combing Assay (TCA) to measure telomere length on stretched DNA fibers. We used TCA to measure telomere erosion in primary human fibroblasts, and to detect telomere lengthening in response to activation of telomere maintenance pathways. TCA was also used to accurately measure telomere length in healthy individuals, and to identify critically short telomeres in patients with telomere biology disorders. TCA is performed on isolated DNA, negating the need for cycling cells. TCA is amenable to semi-automated image analysis, and can be fully automated using the Genomic Vision molecular combing platform. This not only precludes sampling bias, but also provides the potential for high-throughput applications and clinical development. TCA is a simple and versatile technique to measure the distribution of individual telomere lengths in a cell population, offering improved accuracy, and more detailed biological insight for telomere length measurement applications., (Copyright © 2020 Kahl, Allen, Nelson, Sobinoff, Lee, Kilo, Vasireddy and Pickett.)

A conference on «ARBOVIRUSES, A GLOBAL PUBLIC HEALTH THREAT» was organized on June 20-22, 2018 at the Merieux Foundation Conference Center in Veyrier du Lac, France, to review and raise awareness to the global public health threat of epidemic arboviruses, and to advance the discussion on the control and prevention of arboviral diseases. The presentations by scientists and public health officials from Asia, the Americas, Europe and Africa strengthened the notion that arboviral diseases of both humans and domestic animals are progressively becoming dominant public health problems in the world. The repeated occurrence of recent deadly epidemics strongly reinforces the call for action against these viral diseases, and the need for developing effective vaccines, drugs, vector control tools and strong prevention programs., 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 © 2020.)

Objective: This study tested whether computerized cognitive-behavioral therapy for depression supported by a peer specialist with lived experience of depression (PS-cCBT) improves mental health-related outcomes for primary care patients., Methods: In the U.S. Department of Veterans Affairs, primary care patients with a new diagnosis of depression (N=330) were randomly assigned to 3 months of PS-cCBT or a usual-care control condition. Linear mixed-effects models were used to assess differences in depression symptoms, general mental health status, quality of life, and mental health recovery measured at baseline and 3 and 6 months., Results: In adjusted analyses, participants who received PS-cCBT experienced 1.4 points' (95% confidence interval [CI]=0.3-2.5, p=0.01) greater improvement in depression symptoms on the Quick Inventory of Depression Symptomatology-Self Report at 3 months, compared with the control group, but no significant difference was noted at 6 months. PS-cCBT recipients also had 2.6 points' (95% CI=0.5-4.8, p=0.02) greater improvement in quality of life at 3 months on the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form and greater improvement in recovery on the Recovery Assessment Scale at 3 months (3.6 points; 95% CI=0.9-6.2, p=0.01) and 6 months (4.5 points; 95% CI=1.2-7.7, p=0.01)., Conclusions: PS-cCBT is an effective option for improving short-term depression symptoms and longer-term recovery among primary care patients newly diagnosed as having depression.

Mental illness is a major public health concern negatively affecting persons across multiple domains. To address this, health care systems have prioritized access to care and use of empirically supported treatments to better serve those with psychiatric concerns. Rates of dropout from psychotherapy are high, especially in routine clinical settings. Peer support has been promulgated as fostering treatment engagement and completion due to a connection forged from common experience (e.g., military service, psychiatric diagnosis, etc.). As such, the Veterans Health Administration has invested heavily in peer support, although there is limited direct evidence that it enhances treatment engagement or completion. The current study advances upon prior research, showing positive effects of a Cognitive Behavioral Therapy-Pretreatment Intervention (CBT-PTI) on individual therapy outcomes (Lusk, Lyubkin, Chermack, Sanborn, & Bowersox, 2016), by comparing CBT-PTI initial engagement and completion among 352 veterans who met with either a Peer Support Specialist or a Program Support Assistant. Logistic regressions were used to assess the effects of significant unadjusted predictors on CBT-PTI initial engagement and completion, and Mann-Whitney tests were used to further describe differences between veterans who met with PSA versus PSS. Support for the role of PSS was found for CBT-PTI completion, and there was a trend for engagement, although further research is needed. This study provides preliminary support for the use of PSS in fostering CBT-PTIs in routine clinical settings, although further study is warranted to confirm and expand support. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The collapse of stalled replication forks is a major driver of genomic instability. Several committed mechanisms exist to resolve replication stress. These pathways are particularly pertinent at telomeres. Cancer cells that use Alternative Lengthening of Telomeres (ALT) display heightened levels of telomere-specific replication stress, and co-opt stalled replication forks as substrates for break-induced telomere synthesis. FANCM is a DNA translocase that can form independent functional interactions with the BLM-TOP3A-RMI (BTR) complex and the Fanconi anemia (FA) core complex. Here, we demonstrate that FANCM depletion provokes ALT activity, evident by increased break-induced telomere synthesis, and the induction of ALT biomarkers. FANCM-mediated attenuation of ALT requires its inherent DNA translocase activity and interaction with the BTR complex, but does not require the FA core complex, indicative of FANCM functioning to restrain excessive ALT activity by ameliorating replication stress at telomeres. Synthetic inhibition of FANCM-BTR complex formation is selectively toxic to ALT cancer cells.

Zinc oxide (ZnO) in the form of nanoparticles (NPs) is an important nanomaterial due to its catalytic and optoelectronic properties. An interesting aspect of ZnO is that its crystal structure is anisotropic, which leads to a strong 2nd order nonlinear response, such as frequency doubling or second harmonic generation (SHG). In this article we show that not only the bulk but the surface of ZnO NPs in contact with a liquid medium can contribute to the overall SHG. We have developed and applied a synergistic combination of tight binding (TB) theory and optical SHG spectroscopy to determine the surface second order susceptibilities of nearly spherical 33 ± 13 nm crystalline ZnO NPs dispersed in acetonitrile. The corresponding χ and χ were determined to be 0.86 × 10 -8 esu and 1.72 × 10 -8 esu for the O-terminated surface and 3.28 × 10 -8 esu and 6.64 × 10 -8 esu for the Zn-terminated surface. A further application of the TB-SHG approach revealed that adsorption of coumarin based dye, which forms a bidentate attachment between the carboxyl and Zn-terminated surface, does not restructure the NP surface significantly to manifest a change in the SHG polarization profile. However, if the dye acts as an independent source of SHG, its orientation on the surface dictates the overall change in the observed SHG. The results highlighted here bear a strong potential to further our knowledge of molecular interactions at the solid-liquid interface of crystalline nanostructures.

There is an enhanced focus on considering the full public health value (FPHV) of vaccination when setting priorities, making regulatory decisions and establishing implementation policy for public health activities. Historically, a therapeutic paradigm has been applied to the evaluation of prophylactic vaccines and focuses on an individual benefit-risk assessment in prospective and individually-randomized phase III trials to assess safety and efficacy against etiologically-confirmed clinical outcomes. By contrast, a public health paradigm considers the population impact and encompasses measures of community benefits against a range of outcomes. For example, measurement of the FPHV of vaccination may incorporate health inequity, social and political disruption, disruption of household integrity, school absenteeism and work loss, health care utilization, long-term/on-going disability, the development of antibiotic resistance, and a range of non-etiologically and etiologically defined clinical outcomes. Following an initial conference at the Fondation Mérieux in mid-2015, a second conference (December 2016) was held to further describe the efficacy of using the FPHV of vaccination on a variety of prophylactic vaccines. The wider scope of vaccine benefits, improvement in risk assessment, and the need for partnership and coalition building across interventions has also been discussed during the 2014 and 2016 Global Vaccine and Immunization Research Forums and the 2016 Geneva Health Forum, as well as in numerous publications including a special issue of Health Affairs in February 2016. The December 2016 expert panel concluded that while progress has been made, additional efforts will be necessary to have a more fully formulated assessment of the FPHV of vaccines included into the evidence-base for the value proposition and analysis of unmet medical need to prioritize vaccine development, vaccine licensure, implementation policies and financing decisions. The desired outcomes of these efforts to establish an alternative framework for vaccine evaluation are a more robust vaccine pipeline, improved appreciation of vaccine value and hence of its relative affordability, and greater public access and acceptance of vaccines., (Copyright © 2017.)

The enrichment of putative CD44(+)/CD24(-/low) breast stem cell populations following exposure to ionizing radiation (IR) has been ascribed to their inherent radioresistance and an elevated frequency of symmetric division during repopulation. However, recent studies demonstrating radiation-induced phenotypic reprogramming (the transition of non-CD44(+)/CD24(-/low) cells into the CD44(+)/CD24(-/low) phenotype) as a potential mechanism of CD44(+)/CD24(-/low) cell enrichment have raised the question of whether a higher survival and increased self-renewal of existing CD44(+)/CD24(-/low) cells or induced reprogramming is an additional mode of enrichment. To investigate this question, we combined a cellular automata model with in vitro experimental data using both MCF-10A non-tumorigenic human mammary epithelial cells and MCF-7 breast cancer cells, with the goal of identifying the mechanistic basis of CD44(+)/CD24(-/low) stem cell enrichment in the context of radiation-induced cellular senescence. Quantitative modeling revealed that incomplete phenotypic reprogramming of pre-senescent non-stem cells (reprogramming whereby the CD44(+)/CD24(-/low) phenotype is conveyed, along with the short-term proliferation capacity of the original cell) could be an additional mode of enriching the CD44(+)/CD24(-/low) subpopulation. Furthermore, stem cell enrichment in MCF-7 cells occurs both at lower doses and earlier time points, and has longer persistence, than that observed in MCF-10A cells, suggesting that phenotypic plasticity appears to be less regulated in breast cancer cells. Taken together, these results suggest that reprogramming of pre-senescent non-stem cells may play a significant role in both cancer and non-tumorigenic mammary epithelial populations following exposure to IR, a finding with important implications for both radiation therapy and radiation carcinogenesis.

Using data from a sample of 398 veterans diagnosed with depression, the present study used principal components analysis to shorten the Mental Health Recovery Measure (MHRM) to a 10-item instrument. Results indicated the 10-item MHRM had excellent internal reliability. Construct validity for the 10-item MHRM was evidenced by correlations with measures of depression coping self-efficacy, social adjustment, hopelessness, and depression. The 10-item MHRM derived in the present study was compared with a 10-item version of the MHRM that was previously empirically derived in a sample of veterans with schizophrenia (Armstrong, Cohen, Hellemann, Reist, & Young, 2014). Results suggest that similar items represent the underlying construct of recovery for veterans with depression and veterans with schizophrenia. Veterans with depression reported lower average levels of recovery than veterans with schizophrenia. Study limitations, directions for future investigations, and the implications of routine assessment of mental health recovery in public mental health systems are discussed. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Background: Prior research found lower employment rates among working-aged patients who use the VA than among non-Veterans or Veterans who do not use the VA, with the lowest reported employment rates among VA patients with mental disorders. This study assessed employment status, employment functioning, and barriers to employment among VA patients treated in primary care settings, and examined how depression and anxiety were associated with these outcomes., Methods: The sample included 287 VA patients treated in primary care in a large Midwestern VA Medical Center. Bivariate and multivariable analyses were conducted examining associations between socio-demographic and clinical predictors of six employment domains, including: employment status, job search self-efficacy, work performance, concerns about job loss among employed Veterans, and employment barriers and likelihood of job seeking among not employed Veterans., Results: 54% of respondents were employed, 36% were not employed, and 10% were economically inactive. In adjusted analyses, participants with depression or anxiety (43%) were less likely to be employed, had lower job search self-efficacy, had lower levels of work performance, and reported more employment barriers. Depression and anxiety were not associated with perceived likelihood of job loss among employed or likelihood of job seeking among not employed., Limitations: Single VA primary care clinic; cross-sectional study., Discussion: Employment rates are low among working-aged VA primary care patients, particularly those with mental health conditions. Offering primary care interventions to patients that address mental health issues, job search self-efficacy, and work performance may be important in improving health, work, and economic outcomes., (Published by Elsevier B.V.)