Author Correction: Regulation of transposable elements by DNA modifications.

The originally published article contained an error in Figure 2a: for the left side of the figure part (showing piRNA-directed DNA methylation of mouse transposable elements), DNMT3A/B should have been DNMT3C. The article has now been corrected online.

Regulation of transposable elements by DNA modifications.

Maintenance of genome stability requires control over the expression of transposable elements (TEs), whose activity can have substantial deleterious effects on the host. Chemical modification of DNA is a commonly used strategy to achieve this, and it has long been argued that the emergence of 5-methylcytosine (5mC) in many species was driven by the requirement to silence TEs. Potential roles in TE regulation have also been suggested for other DNA modifications, such as N6-methyladenine and oxidation derivatives of 5mC, although the underlying mechanistic relationships are poorly understood. Here, we discuss current evidence implicating DNA modifications and DNA-modifying enzymes in TE regulation across different species.

Insights into plant regeneration: cellular pathways and DNA methylation dynamics.

Plants, known for their immobility, employ various mechanisms against stress and damage. A prominent feature is the formation of callus tissue-a cellular growth phenomenon that remains insufficiently explored, despite its distinctive cellular plasticity compared to vertebrates. Callus formation involves dedifferentiated cells, with a subset attaining pluripotency. Calluses exhibit an extraordinary capacity to reinitiate cellular division and undergo structural transformations, generating de novo shoots and roots, thereby developing into regenerated plants-a testament to the heightened developmental plasticity inherent in plants. In this way, plant regeneration through clonal propagation is a widely employed technique for vegetative reproduction. Thus, exploration of the biological components involved in regaining pluripotency contributes to the foundation upon which methods of somatic plant propagation can be advanced. This review provides an overview of the cellular pathway involved in callus and subsequent de novo shoot formation from already differentiated plant tissue, highlighting key genes critical to this process. In addition, it explores the intricate realm of epigenetic regulatory processes, emphasizing the nuanced dynamics of DNA methylation that contribute to plant regeneration. Finally, we briefly discuss somaclonal variation, examining its relation to DNA methylation, and investigating the heritability of epigenomic changes in crops.

The DME demethylase regulates sporophyte gene expression, cell proliferation, differentiation, and meristem resurrection.

The flowering plant life cycle consists of alternating haploid (gametophyte) and diploid (sporophyte) generations, where the sporophytic generation begins with fertilization of haploid gametes. In Arabidopsis, genome-wide DNA demethylation is required for normal development, catalyzed by the DEMETER (DME) DNA demethylase in the gamete companion cells of male and female gametophytes. In the sporophyte, postembryonic growth and development are largely dependent on the activity of numerous stem cell niches, or meristems. Analyzing Arabidopsis plants homozygous for a loss-of-function dme-2 allele, we show that DME influences many aspects of sporophytic growth and development. dme-2 mutants exhibited delayed seed germination, variable root hair growth, aberrant cellular proliferation and differentiation followed by enhanced de novo shoot formation, dysregulation of root quiescence and stomatal precursor cells, and inflorescence meristem (IM) resurrection. We also show that sporophytic DME activity exerts a profound effect on the transcriptome of developing Arabidopsis plants, including discrete groups of regulatory genes that are misregulated in dme-2 mutant tissues, allowing us to potentially link phenotypes to changes in specific gene expression pathways. These results show that DME plays a key role in sporophytic development and suggest that DME-mediated active DNA demethylation may be involved in the maintenance of stem cell activities during the sporophytic life cycle in Arabidopsis.

H2A.X promotes endosperm-specific DNA methylation in Arabidopsis thaliana.

BACKGROUND: H2A.X is an H2A variant histone in eukaryotes, unique for its ability to respond to DNA damage, initiating the DNA repair pathway. H2A.X replacement within the histone octamer is mediated by the FAcilitates Chromatin Transactions (FACT) complex, a key chromatin remodeler. FACT is required for DEMETER (DME)-mediated DNA demethylation at certain loci in Arabidopsis thaliana female gametophytes during reproduction. Here, we sought to investigate whether H2A.X is involved in DME- and FACT-mediated DNA demethylation during reproduction. RESULTS: H2A.X is encoded by two genes in Arabidopsis genome, HTA3 and HTA5. We generated h2a.x double mutants, which displayed a normal growth profile, whereby flowering time, seed development, and root tip organization, S-phase progression and proliferation were all normal. However, h2a.x mutants were more sensitive to genotoxic stress, consistent with previous reports. H2A.X fused to Green Fluorescent Protein (GFP) under the H2A.X promoter was highly expressed especially in newly developing Arabidopsis tissues, including in male and female gametophytes, where DME is also expressed. We examined DNA methylation in h2a.x developing seeds and seedlings using whole genome bisulfite sequencing, and found that CG DNA methylation is decreased genome-wide in h2a.x mutant endosperm. Hypomethylation was most striking in transposon bodies, and occurred on both parental alleles in the developing endosperm, but not the embryo or seedling. h2a.x-mediated hypomethylated sites overlapped DME targets, but also included other loci, predominately located in heterochromatic transposons and intergenic DNA. CONCLUSIONS: Our genome-wide methylation analyses suggest that H2A.X could function in preventing access of the DME demethylase to non-canonical sites. Overall, our data suggest that H2A.X is required to maintain DNA methylation homeostasis in the unique chromatin environment of the Arabidopsis endosperm.

The catalytic core of DEMETER guides active DNA demethylation in Arabidopsis.

The Arabidopsis DEMETER (DME) DNA glycosylase demethylates the maternal genome in the central cell prior to fertilization and is essential for seed viability. DME preferentially targets small transposons that flank coding genes, influencing their expression and initiating plant gene imprinting. DME also targets intergenic and heterochromatic regions, but how it is recruited to these differing chromatin landscapes is unknown. The C-terminal half of DME consists of 3 conserved regions required for catalysis in vitro. We show that this catalytic core guides active demethylation at endogenous targets, rescuing dme developmental and genomic hypermethylation phenotypes. However, without the N terminus, heterochromatin demethylation is significantly impeded, and abundant CG-methylated genic sequences are ectopically demethylated. Comparative analysis revealed that the conserved DME N-terminal domains are present only in flowering plants, whereas the domain architecture of DME-like proteins in nonvascular plants mainly resembles the catalytic core, suggesting that it might represent the ancestral form of the 5mC DNA glycosylase found in plant lineages. We propose a bipartite model for DME protein action and suggest that the DME N terminus was acquired late during land plant evolution to improve specificity and facilitate demethylation at heterochromatin targets.

FACT complex is required for DNA demethylation at heterochromatin during reproduction in Arabidopsis.

The DEMETER (DME) DNA glycosylase catalyzes genome-wide DNA demethylation and is required for endosperm genomic imprinting and embryo viability. Targets of DME-mediated DNA demethylation reside in small, euchromatic, AT-rich transposons and at the boundaries of large transposons, but how DME interacts with these diverse chromatin states is unknown. The STRUCTURE SPECIFIC RECOGNITION PROTEIN 1 (SSRP1) subunit of the chromatin remodeler FACT (facilitates chromatin transactions), was previously shown to be involved in the DME-dependent regulation of genomic imprinting in Arabidopsis endosperm. Therefore, to investigate the interaction between DME and chromatin, we focused on the activity of the two FACT subunits, SSRP1 and SUPPRESSOR of TY16 (SPT16), during reproduction in Arabidopsis We found that FACT colocalizes with nuclear DME in vivo, and that DME has two classes of target sites, the first being euchromatic and accessible to DME, but the second, representing over half of DME targets, requiring the action of FACT for DME-mediated DNA demethylation genome-wide. Our results show that the FACT-dependent DME targets are GC-rich heterochromatin domains with high nucleosome occupancy enriched with H3K9me2 and H3K27me1. Further, we demonstrate that heterochromatin-associated linker histone H1 specifically mediates the requirement for FACT at a subset of DME-target loci. Overall, our results demonstrate that FACT is required for DME targeting by facilitating its access to heterochromatin.

Control of DEMETER DNA demethylase gene transcription in male and female gamete companion cells in Arabidopsis thaliana.

The DEMETER (DME) DNA glycosylase initiates active DNA demethylation via the base-excision repair pathway and is vital for reproduction in Arabidopsis thaliana DME-mediated DNA demethylation is preferentially targeted to small, AT-rich, and nucleosome-depleted euchromatic transposable elements, influencing expression of adjacent genes and leading to imprinting in the endosperm. In the female gametophyte, DME expression and subsequent genome-wide DNA demethylation are confined to the companion cell of the egg, the central cell. Here, we show that, in the male gametophyte, DME expression is limited to the companion cell of sperm, the vegetative cell, and to a narrow window of time: immediately after separation of the companion cell lineage from the germline. We define transcriptional regulatory elements of DME using reporter genes, showing that a small region, which surprisingly lies within the DME gene, controls its expression in male and female companion cells. DME expression from this minimal promoter is sufficient to rescue seed abortion and the aberrant DNA methylome associated with the null dme-2 mutation. Within this minimal promoter, we found short, conserved enhancer sequences necessary for the transcriptional activities of DME and combined predicted binding motifs with published transcription factor binding coordinates to produce a list of candidate upstream pathway members in the genetic circuitry controlling DNA demethylation in gamete companion cells. These data show how DNA demethylation is regulated to facilitate endosperm gene imprinting and potential transgenerational epigenetic regulation, without subjecting the germline to potentially deleterious transposable element demethylation.

Screening for Urinary Incontinence in Women: A Recommendation From the Women's Preventive Services Initiative.

Description: Recommendation on screening for urinary incontinence in women by the Women's Preventive Services Initiative (WPSI), a national coalition of women's health professional organizations and patient representatives. The WPSI's recommendations are intended to guide clinical practice and coverage of services for the Health Resources and Services Administration and other stakeholders. The target audience for this recommendation includes all clinicians providing preventive health care for women, particularly in primary care settings. This recommendation applies to women of all ages, as well as adolescents. Methods: The WPSI developed this recommendation after evaluating evidence regarding the benefits and harms of screening for urinary incontinence in women. The evaluation included a systematic review of the accuracy of screening instruments and the benefits and harms of treatments. Indirect evidence was used to link screening and health outcomes in the chain of evidence that might support screening in the absence of direct evidence. The WPSI also considered the effect of screening on symptom progression and avoidance of costly and complex treatments, as well as implementation factors. Recommendation: The WPSI recommends screening women for urinary incontinence annually. Screening ideally should assess whether women experience urinary incontinence and whether it affects their activities and quality of life. The WPSI recommends referring women for further evaluation and treatment if indicated.

What happens during early outpatient palliative care consultations for persons with newly diagnosed advanced cancer? A qualitative analysis of provider documentation.

BACKGROUND: Early outpatient palliative care consultations are recommended by clinical oncology guidelines globally. Despite these recommendations, it is unclear which components should be included in these encounters. AIM: Describe the evaluation and treatment recommendations made in early outpatient palliative care consultations. DESIGN: Outpatient palliative care consultation chart notes were qualitatively coded and frequencies tabulated. SETTING/PARTICIPANTS: Outpatient palliative care consultations were automatically triggered as part of an early versus delayed randomized controlled trial (November 2010 to April 2013) for patients newly diagnosed with advanced cancer living in the rural Northeastern US. RESULTS: In all, 142 patients (early = 70; delayed = 72) had outpatient palliative care consultations. The top areas addressed in these consultations were general evaluations-marital/partner status (81.7%), spirituality/emotional well-being (80.3%), and caregiver/family support (79.6%); symptoms-mood (81.7%), pain (73.9%), and cognitive/mental status (68.3%); general treatment recommendations-counseling (39.4%), maintaining current medications (34.5%), and initiating new medication (23.9%); and symptom-specific treatment recommendations-pain (22.5%), constipation (12.7%), depression (12.0%), advanced directive completion (43.0%), identifying a surrogate (21.8%), and discussing illness trajectory (21.1%). Compared to the early group, providers were more likely to evaluate general pain ( p = 0.035) and hospice awareness ( p = 0.005) and discuss/recommend hospice ( p = 0.002) in delayed group participants. CONCLUSION: Outpatient palliative care consultations for newly diagnosed advanced cancer patients can address patients' needs and provide recommendations on issues that might not otherwise be addressed early in the disease course. Future prospective studies should ascertain the value of early outpatient palliative care consultations that are automatically triggered based on diagnosis or documented symptom indicators versus reliance on oncologist referral.

Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American College of Physicians and the American Academy of Family Physicians.

Description: The American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) jointly developed this guideline to present the evidence and provide clinical recommendations based on the benefits and harms of higher versus lower blood pressure targets for the treatment of hypertension in adults aged 60 years or older. Methods: This guideline is based on a systematic review of published randomized, controlled trials for primary outcomes and observational studies for harms only (identified through EMBASE, the Cochrane Database of Systematic Reviews, MEDLINE, and ClinicalTrials.gov), from database inception through January 2015. The MEDLINE search was updated through September 2016. Evaluated outcomes included all-cause mortality, morbidity and mortality related to stroke, major cardiac events (fatal and nonfatal myocardial infarction and sudden cardiac death), and harms. This guideline grades the evidence and recommendations using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method. Target Audience and Patient Population: The target audience for this guideline includes all clinicians, and the target patient population includes all adults aged 60 years or older with hypertension. Recommendation 1: ACP and AAFP recommend that clinicians initiate treatment in adults aged 60 years or older with systolic blood pressure persistently at or above 150 mm Hg to achieve a target systolic blood pressure of less than 150 mm Hg to reduce the risk for mortality, stroke, and cardiac events. (Grade: strong recommendation, high-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient. Recommendation 2: ACP and AAFP recommend that clinicians consider initiating or intensifying pharmacologic treatment in adults aged 60 years or older with a history of stroke or transient ischemic attack to achieve a target systolic blood pressure of less than 140 mm Hg to reduce the risk for recurrent stroke. (Grade: weak recommendation, moderate-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient. Recommendation 3: ACP and AAFP recommend that clinicians consider initiating or intensifying pharmacologic treatment in some adults aged 60 years or older at high cardiovascular risk, based on individualized assessment, to achieve a target systolic blood pressure of less than 140 mm Hg to reduce the risk for stroke or cardiac events. (Grade: weak recommendation, low-quality evidence). ACP and AAFP recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient.

National Partnership for Maternal Safety: Consensus Bundle on Severe Hypertension During Pregnancy and the Postpartum Period.

Complications arising from hypertensive disorders of pregnancy are among the leading causes of preventable severe maternal morbidity and mortality. Timely and appropriate treatment has the potential to significantly reduce hypertension-related complications. To assist health care providers in achieving this goal, this patient safety bundle provides guidance to coordinate and standardize the care provided to women with severe hypertension during pregnancy and the postpartum period. This is one of several patient safety bundles developed by multidisciplinary work groups of the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care. These safety bundles outline critical clinical practices that should be implemented in every maternity care setting. Similar to other bundles that have been developed and promoted by the Partnership, the hypertension safety bundle is organized into four domains: Readiness, Recognition and Prevention, Response, and Reporting and Systems Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged. This commentary provides information to assist with bundle implementation.

Nucleoporin MOS7/Nup88 is required for mitosis in gametogenesis and seed development in Arabidopsis.

Angiosperm reproduction is characterized by alternate diploid sporophytic and haploid gametophytic generations. Gametogenesis shares similarities with that of animals except for the formation of the gametophyte, whereby haploid cells undergo several rounds of postmeiotic mitosis to form gametes and the accessory cells required for successful reproduction. The mechanisms regulating gametophyte development in angiosperms are incompletely understood. Here, we show that the nucleoporin Nup88-homolog MOS7 (Modifier of Snc1,7) plays a crucial role in mitosis during both male and female gametophyte formation in Arabidopsis thaliana. Using a mutagenesis screen, we identify the mos7-5 mutant allele, which causes ovule and pollen abortion in MOS7/mos7-5 heterozygous plants, and preglobular stage embryonic lethality in homozygous mos7-5 seeds. During interphase, we show that MOS7 is localized to the nuclear membrane but, like many nucleoporins, is associated with the spindle apparatus during mitosis. We detect interactions between MOS7 and several nucleoporins known to control spindle dynamics, and find that in pollen from MOS7/mos7-5 heterozygotes, abortion is accompanied by a failure of spindle formation, cell fate specification, and phragmoplast activity. Most intriguingly, we show that following gamete formation by MOS7/mos7-5 heterozygous spores, inheritance of either the MOS7 or the mos7-5 allele by a given gamete does not correlate with its respective survival or abortion. Instead, we suggest a model whereby MOS7, which is highly expressed in the Pollen- and Megaspore Mother Cells, enacts a dosage-limiting effect on the gametes to enable their progression through subsequent mitoses.

Engaging patients and families to create a feasible clinical trial integrating palliative and heart failure care: results of the ENABLE CHF-PC pilot clinical trial.

BACKGROUND: Early palliative care (EPC) is recommended but rarely integrated with advanced heart failure (HF) care. We engaged patients and family caregivers to study the feasibility and site differences in a two-site EPC trial, ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers). METHODS: We conducted an EPC feasibility study (4/1/14-8/31/15) for patients with NYHA Class III/IV HF and their caregivers in academic medical centers in the northeast and southeast U.S. The EPC intervention comprised: 1) an in-person outpatient palliative care consultation; and 2) telephonic nurse coach sessions and monthly calls. We collected patient- and caregiver-reported outcomes of quality of life (QOL), symptom, health, anxiety, and depression at baseline, 12- and 24-weeks. We used linear mixed-models to assess baseline to week 24 longitudinal changes. RESULTS: We enrolled 61 patients and 48 caregivers; between-site demographic differences included age, race, religion, marital, and work status. Most patients (69%) and caregivers (79%) completed all intervention sessions; however, we noted large between-site differences in measurement completion (38% southeast vs. 72% northeast). Patients experienced moderate effect size improvements in QOL, symptoms, physical, and mental health; caregivers experienced moderate effect size improvements in QOL, depression, mental health, and burden. Small-to-moderate effect size improvements were noted in patients' hospital and ICU days and emergency visits. CONCLUSIONS: Between-site demographic, attrition, and participant-reported outcomes highlight the importance of intervention pilot-testing in culturally diverse populations. Observations from this pilot feasibility trial allowed us to refine the methodology of an in-progress, full-scale randomized clinical efficacy trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT03177447 (retrospectively registered, June 2017).

"There were more decisions and more options than just yes or no": Evaluating a decision aid for advanced cancer patients and their family caregivers.

OBJECTIVE: Few decision aids are available for patients with a serious illness who face many treatment and end-of-life decisions. We evaluated the Looking Ahead: Choices for Medical Care When You're Seriously Ill® patient decision aid (PtDA), one component of an early palliative care clinical trial. METHOD: Our participants included individuals with advanced cancer and their caregivers who had participated in the ENABLE (Educate, Nurture, Advise, Before Life Ends) early palliative care telehealth randomized controlled trial (RCT) conducted in a National Cancer Institute-designated cancer center, a U.S. Department of Veterans Affairs medical center, and affiliated outreach clinics in rural New England. ENABLE included six weekly patient and three weekly family caregiver structured sessions. Participants watched the Looking Ahead PtDA prior to session 3, which covered content on decision making and advance care planning. Nurse coaches employed semistructured interviews to obtain feedback from consecutive patient and caregiver participants approximately one week after viewing the Looking Ahead PtDA program (booklet and DVD). RESULTS: Between April 1, 2011, and October 31, 2012, 57 patients (mean age = 64), 42% of whom had lung and 23% gastrointestinal cancer, and 20 caregivers (mean age = 59), 80% of whom were spouses, completed the PtDA evaluation. Participants reported a high degree of satisfaction with the PtDA format, as well as with its length and clarity. They found the format of using patient interviews "validating." The key themes were: (1) "the earlier the better" to view the PtDA; (2) feeling empowered, aware of different options, and an urgency to participate in advance care planning. SIGNIFICANCE OF RESULTS: The Looking Ahead PtDA was well received and helped patients with a serious illness realize the importance of prospective decision making in guiding their treatment pathways. We found that this PtDA can help seriously ill patients prior to the end of life to understand and discuss future healthcare decision making. However, systems to routinely provide PtDAs to seriously ill patients are yet not well developed.

National Partnership for Maternal Safety: Consensus Bundle on Venous Thromboembolism.

Obstetric venous thromboembolism is a leading cause of severe maternal morbidity and mortality. Maternal death from thromboembolism is amenable to prevention, and thromboprophylaxis is the most readily implementable means of systematically reducing the maternal death rate. Observational data support the benefit of risk-factor-based prophylaxis in reducing obstetric thromboembolism. This bundle, developed by a multidisciplinary working group and published by the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care, supports routine thromboembolism risk assessment for obstetric patients, with appropriate use of pharmacologic and mechanical thromboprophylaxis. Safety bundles outline critical clinical practices that should be implemented in every maternity unit. The safety bundle is organized into four domains: Readiness, Recognition, Response, and Reporting and Systems Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged.

Cell-autonomous-like silencing of GFP-partitioned transgenic Nicotiana benthamiana.

We previously reported the novel partitioning of regional GFP-silencing on leaves of 35S-GFP transgenic plants, coining the term "partitioned silencing". We set out to delineate the mechanism of partitioned silencing. Here, we report that the partitioned plants were hemizygous for the transgene, possessing two direct-repeat copies of 35S-GFP. The detection of both siRNA expression (21 and 24 nt) and DNA methylation enrichment specifically at silenced regions indicated that both post-transcriptional gene silencing (PTGS) and transcriptional gene silencing (TGS) were involved in the silencing mechanism. Using in vivo agroinfiltration of 35S-GFP/GUS and inoculation of TMV-GFP RNA, we demonstrate that PTGS, not TGS, plays a dominant role in the partitioned silencing, concluding that the underlying mechanism of partitioned silencing is analogous to RNA-directed DNA methylation (RdDM). The initial pattern of partitioned silencing was tightly maintained in a cell-autonomous manner, although partitioned-silenced regions possess a potential for systemic spread. Surprisingly, transcriptome profiling through next-generation sequencing demonstrated that expression levels of most genes involved in the silencing pathway were similar in both GFP-expressing and silenced regions although a diverse set of region-specific transcripts were detected.This suggests that partitioned silencing can be triggered and regulated by genes other than the genes involved in the silencing pathway.

Return on investment: a fuller assessment of the benefits and cost savings of the US publicly funded family planning program.

UNLABELLED: Policy Points: The US publicly supported family planning effort serves millions of women and men each year, and this analysis provides new estimates of its positive impact on a wide range of health outcomes and its net savings to the government. The public investment in family planning programs and providers not only helps women and couples avoid unintended pregnancy and abortion, but also helps many thousands avoid cervical cancer, HIV and other sexually transmitted infections, infertility, and preterm and low birth weight births. This investment resulted in net government savings of $13.6 billion in 2010, or $7.09 for every public dollar spent. CONTEXT: Each year the United States' publicly supported family planning program serves millions of low-income women. Although the health impact and public-sector savings associated with this program's services extend well beyond preventing unintended pregnancy, they never have been fully quantified. METHODS: Drawing on an array of survey data and published parameters, we estimated the direct national-level and state-level health benefits that accrued from providing contraceptives, tests for the human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs), Pap tests and tests for human papillomavirus (HPV), and HPV vaccinations at publicly supported family planning settings in 2010. We estimated the public cost savings attributable to these services and compared those with the cost of publicly funded family planning services in 2010 to find the net public-sector savings. We adjusted our estimates of the cost savings for unplanned births to exclude some mistimed births that would remain publicly funded if they had occurred later and to include the medical costs for births through age 5 of the child. FINDINGS: In 2010, care provided during publicly supported family planning visits averted an estimated 2.2 million unintended pregnancies, including 287,500 closely spaced and 164,190 preterm or low birth weight (LBW) births, 99,100 cases of chlamydia, 16,240 cases of gonorrhea, 410 cases of HIV, and 13,170 cases of pelvic inflammatory disease that would have led to 1,130 ectopic pregnancies and 2,210 cases of infertility. Pap and HPV tests and HPV vaccinations prevented an estimated 3,680 cases of cervical cancer and 2,110 cervical cancer deaths; HPV vaccination also prevented 9,000 cases of abnormal sequelae and precancerous lesions. Services provided at health centers supported by the Title X national family planning program accounted for more than half of these benefits. The gross public savings attributed to these services totaled approximately $15.8 billion-$15.7 billion from preventing unplanned births, $123 million from STI/HIV testing, and $23 million from Pap and HPV testing and vaccines. Subtracting $2.2 billion in program costs from gross savings resulted in net public-sector savings of $13.6 billion. CONCLUSIONS: Public expenditures for the US family planning program not only prevented unintended pregnancies but also reduced the incidence and impact of preterm and LBW births, STIs, infertility, and cervical cancer. This investment saved the government billions of public dollars, equivalent to an estimated taxpayer savings of $7.09 for every public dollar spent.