Targeting Astrocyte Signaling Alleviates Cerebrovascular and Synaptic Function Deficits in a Diet-Based Mouse Model of Small Cerebral Vessel Disease.

Despite the indispensable role that astrocytes play in the neurovascular unit, few studies have investigated the functional impact of astrocyte signaling in cognitive decline and dementia related to vascular pathology. Diet-mediated induction of hyperhomocysteinemia (HHcy) recapitulates numerous features of vascular contributions to cognitive impairment and dementia (VCID). Here, we used astrocyte targeting approaches to evaluate astrocyte Ca2+ dysregulation and the impact of aberrant astrocyte signaling on cerebrovascular dysfunction and synapse impairment in male and female HHcy diet mice. Two-photon imaging conducted in fully awake mice revealed activity-dependent Ca2+ dysregulation in barrel cortex astrocytes under HHcy. Stimulation of contralateral whiskers elicited larger Ca2+ transients in individual astrocytes of HHcy diet mice compared with control diet mice. However, evoked Ca2+ signaling across astrocyte networks was impaired in HHcy mice. HHcy also was associated with increased activation of the Ca2+/calcineurin-dependent transcription factor NFAT4, which has been linked previously to the reactive astrocyte phenotype and synapse dysfunction in amyloid and brain injury models. Targeting the NFAT inhibitor VIVIT to astrocytes, using adeno-associated virus vectors, led to reduced GFAP promoter activity in HHcy diet mice and improved functional hyperemia in arterioles and capillaries. VIVIT expression in astrocytes also preserved CA1 synaptic function and improved spontaneous alternation performance on the Y maze. Together, the results demonstrate that aberrant astrocyte signaling can impair the major functional properties of the neurovascular unit (i.e., cerebral vessel regulation and synaptic regulation) and may therefore represent a promising drug target for treating VCID and possibly Alzheimer's disease and other related dementias.SIGNIFICANCE STATEMENT The impact of reactive astrocytes in Alzheimer's disease and related dementias is poorly understood. Here, we evaluated Ca2+ responses and signaling in barrel cortex astrocytes of mice fed with a B-vitamin deficient diet that induces hyperhomocysteinemia (HHcy), cerebral vessel disease, and cognitive decline. Multiphoton imaging in awake mice with HHcy revealed augmented Ca2+ responses in individual astrocytes, but impaired signaling across astrocyte networks. Stimulation-evoked arteriole dilation and elevated red blood cell velocity in capillaries were also impaired in cortex of awake HHcy mice. Astrocyte-specific inhibition of the Ca2+-dependent transcription factor, NFAT, normalized cerebrovascular function in HHcy mice, improved synaptic properties in brain slices, and stabilized cognition. Results suggest that astrocytes are a mechanism and possible therapeutic target for vascular-related dementia.

Not all marketed skin cleansers' pH is optimal for atopic dermatitis.

Background: The normally acidic skin pH changes in atopic dermatitis (AD) to alkaline, which contributes to the associated skin-barrier dysfunction. Hence, acidic cleansers would be preferred, but such information is scarce. Objective: Guiding health-care providers and patients on selecting skin cleansers with a pH optimal for AD. Methods: A total of 250 products were tested: 37 soaps (32 bars, 5 liquid) and 213 syndets (14 bars, 199 liquid); 10% solutions were tested for pH by using a pH meter; pH values 6.65-7.35 were considered neutral. Results: The pH of the tested skin cleansers varied widely (3.59-10.83). All 37 soaps were highly alkaline. In the 14 syndet bars, the pH was neutral in 6, alkaline in 8, and acidic in none. In the 199 syndet liquids, the pH was acidic in 84.9%, neutral in 11.1%, and alkaline in 4.0%. The product's pH was disclosed in none of the 37 soaps and in only 32 syndets (15%) , of which 9 bars were labeled "balanced," whose measured pH was neutral in 6 and alkaline in 3. Of the other 23 syndets, the labeled pH was referred to as "balanced" in 20 whose measured pH was neutral in 2 (6.80, 6.88) and acidic in 18 (3.59-6.59). The pH in the other three syndets was 4.25-6.00. Conclusion: All tested soaps had undesirable pH, whereas 84.9% of the liquid syndets were acidic (which is desirable) and 11.1% were neutral (which could be acceptable). Only 12.8% of the products disclosed the pH, an issue in need of improvement.

Vision Loss as a Presenting Feature of Chronic Inflammatory Demyelinating Polyneuropathy: A Case Series.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated, and clinically heterogeneous demyelinating disease affecting the nerve roots and peripheral nerves. We report a series of 4 patients who presented with early and progressive vision loss in the context of new-onset CIDP: 3 due to papilledema and 1 due to optic neuropathy without papilledema. METHODS: This was a retrospective case series of 4 patients with vision loss as a presenting feature of CIDP evaluated at the Hospital of the University of Pennsylvania from January 2016 to August 2021. Demographic, clinical, diagnostic, and treatment data were collected via retrospective medical record review. RESULTS: Case 1 was a 51-year-old man with 2 months of progressive bilateral papilledema associated with reduced visual acuity (count fingers at 1 foot in each eye) and severely constricted visual fields. Case 2 was a 36-year-old man with 4 months of worsening headaches, reduced visual acuity (count fingers at 1 foot in each eye), severely constricted visual fields, and papilledema. Case 3 was a 39-year-old man with papilledema causing progressive vision loss (20/80 in both eyes), headaches, and relapsing limb sensorimotor deficits. Case 4 was a 19-year-old man with 3 months of progressive bilateral visual decline (20/400 in the right eye, 20/600 in the left eye), central scotoma, and optic disc pallor consistent with optic neuropathy without papilledema. All 4 patients met clinical and electrodiagnostic criteria of CIDP. Cases 3 and 4 each tested positive for serum neurofascin-155 IgG4 antibodies. All patients were managed with immunomodulatory therapy. Cases 1 and 2 also each required surgical intervention with bilateral optic nerve sheath fenestration and cerebrospinal fluid (CSF) shunting procedures. CONCLUSION: Vision loss from optic neuropathy with or without papilledema has rarely been reported in CIDP, and typically has been described in the context of longstanding disease. Our cases highlight how CIDP can present with early vision loss that may be profound and challenging to manage if diagnosis is delayed. CIDP should be considered in any patient with new progressive vision loss when associated with peripheral sensorimotor symptoms and elevated CSF protein. The small subgroup of CIDP patients with neurofascin-155 antibodies may be at particular risk of optic nerve involvement.

The impact of modernization on allergy and asthma development.

Background: In recent years, an increase of allergies and asthma has been observed throughout the world, more so in Western countries than in less developed ones. Although genetics may play a role in this increase, there are many other factors that may have contributed to the upsurge. Objective: The purpose of the present report was to review the many factors associated with modernization and lifestyle that may have contributed to the allergy and/or asthma epidemic, with a particular focus on those aspects that have particular relevance for the allergist/immunologist. Results: The marked rise in allergy and asthma has been significantly seen in more-developed countries, greater in urban than in rural areas, more pronounced in affluent than in poorer societies, and in individuals who have migrated from developing countries to industrialized countries. A widely accepted explanation for this rise is the "hygiene hypothesis," which postulates a critical dependence on microbial infection for maintenance of a healthy balanced immune system and that extremely clean external environments, often found in the developed world, can derail equilibrated immune development. With the control of infectious diseases, the immune system shifts from a balanced equilibrated immunologic structure to a more Th2 driven proinflammatory state often associated with IgE and eosinophil-related disorders. Conclusion: Modernization has been associated with increased development of allergies and asthma through a cleaner environment and more exposure to allergens and to multiple other contributory factors. The marked reduction in infectious diseases in recent decades permitted the immune system to switch from fighting infectious disease agents and parasites to reacting adversely (hypersensitivity) to benign environmental agents (allergens) and even to self-antigens (autoimmunity).

Identification of 22 novel BTK gene variants in B cell deficiency with hypogammaglobulinemia.

X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by pathogenic variants in the BTK gene, resulting in impaired B cell differentiation and maturation. Over 900 variants have already been described in this gene, however, new pathogenic variants continue to be identified. In this report, we describe 22 novel variants in BTK, associated with B cell deficiency with hypo- or agammaglobulinemia in male patients or in asymptomatic female carriers. Genetic data was correlated with BTK protein expression by flow cytometry, and clinical and family history to obtain a comprehensive assessment of the clinico-pathologic significance of these new variants in the BTK gene. For one novel missense variant, p.Cys502Tyr, site-directed mutagenesis was performed to determine the impact of the sequence change on protein expression and stability. Genetic data should be correlated with protein and/or clinical and immunological data, whenever possible, to determine the clinical significance of the gene sequence alteration.

NAPDH Oxidase-Specific Flow Cytometry Allows for Rapid Genetic Triage and Classification of Novel Variants in Chronic Granulomatous Disease.

PURPOSE: Chronic granulomatous disease (CGD) is an innate immune deficiency, primarily affecting the phagocytic compartment, and presenting with a diverse phenotypic spectrum ranging from severe childhood infections to monogenic inflammatory bowel disease. Dihydrorhodamine (DHR) flow cytometry is the standard diagnostic test for CGD, and correlates with NADPH oxidase activity. While there may be genotype correlation with the DHR flow pattern in some patients, in several others, there is no correlation. In such patients, assessment by flow cytometric evaluation of NADPH oxidase-specific (NOX) proteins provides a convenient and rapid means of genetic triage, though immunoblotting has long been used for this purpose. METHODS AND RESULTS: We describe the clinical utility of the NOX flow cytometry assay through assessment of X-linked and autosomal recessive CGD patients and their first-degree relatives. The assessment of specific NOX proteins was correlated with overall NADPH oxidase function (DHR flow), clinical phenotype and genotype. NOX-specific protein assessment is a valuable adjunct to DHR assessment and genotyping to classify and characterize CGD patients. CONCLUSIONS: The atypical clinical presentation of some CGD patients can make genotype-phenotype correlation with DHR flow data challenging. Genetic testing, while useful for confirmation of diagnosis, can take several weeks, and in some patients does not provide a conclusive answer. However, NADPH-oxidase-specific protein flow assessment offers a rapid alternative to identification of the underlying genetic defect in cellular subsets, and can be utilized as a reflex test to an abnormal DHR flow. Further, it can provide insight into correlation between oxidative burst relative to protein expression in granulocytes and monocytes.

Herpes simplex virus: global infection prevalence and incidence estimates, 2016.

OBJECTIVE: To generate global and regional estimates for the prevalence and incidence of herpes simplex virus (HSV) type 1 and type 2 infection for 2016. METHODS: To obtain data, we undertook a systematic review to identify studies up to August 2018. Adjustments were made to account for HSV test sensitivity and specificity. For each World Health Organization (WHO) region, we applied a constant incidence model to pooled prevalence by age and sex to estimate the prevalence and incidence of HSV types 1 and 2 infections. For HSV type 1, we apportioned infection by anatomical site using pooled estimates of the proportions that were oral and genital. FINDINGS: In 2016, an estimated 491.5 million people (95% uncertainty interval, UI: 430.4 million-610.6 million) were living with HSV type 2 infection, equivalent to 13.2% of the world's population aged 15-49 years. An estimated 3752.0 million people (95% UI: 3555.5 million-3854.6 million) had HSV type 1 infection at any site, equivalent to a global prevalence of 66.6% in 0-49-year-olds. Differing patterns were observed by age, sex and geographical region, with HSV type 2 prevalence being highest among women and in the WHO African Region. CONCLUSION: An estimated half a billion people had genital infection with HSV type 2 or type 1, and several billion had oral HSV type 1 infection. Millions of people may also be at higher risk of acquiring human immunodeficiency virus (HIV), particularly women in the WHO African Region who have the highest HSV type 2 prevalence and exposure to HIV.

Scoring systems for allergies and asthma in clinical research and practice.

Background: Scoring systems are increasingly being developed for various diseases, including asthma and allergic disorders, with the objective of improving the classification of disease severity and the assessment of efficacy of therapeutic modalities. Objective: This review provided concise summaries of published scoring systems used for allergic rhinitis, asthma, atopic dermatitis, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis, eosinophilic esophagitis, and systemic allergic reactions (anaphylaxis). Methods: We searched the medical literature between 1985 and 2018 for published scoring systems that have been developed and used in clinical trials or in practice for assessment of asthma and a variety of allergic disorders. Results: The scoring systems for each of these diseases were briefly presented in the text in chronological order of publication, and selected information was presented in the tables for easy comparisons. For more details, the reader should refer to the original relevant publications. Conclusion: Such assessment methods are useful for sound designing of clinical trials, fair comparisons of findings of studies, and objective measurements of patients' progress in clinical practice. The choice of using one scoring system over another would depend on its proven degree of validity, the purpose, and applicability.

Advancing vaccine development for gonorrhoea and the Global STI Vaccine Roadmap.

Efforts to develop vaccines against Neisseria gonorrhoeae have become increasingly important, given the rising threat of gonococcal antimicrobial resistance (AMR). Recent data suggest vaccines for gonorrhoea are biologically feasible; in particular, epidemiological evidence shows that vaccines against a closely related pathogen, serogroup B Neisseria meningitidis outer membrane vesicle (OMV) vaccines, may reduce gonorrhoea incidence. Vaccine candidates using several approaches are currently in preclinical development, including meningococcal and gonococcal OMV vaccines, a lipooligosaccharide epitope and purified protein subunit vaccines. The Global STI Vaccine Roadmap provides action steps to build on this technical momentum and advance gonococcal vaccine development. Better quantifying the magnitude of gonorrhoea-associated disease burden, for outcomes like infertility, and modelling the predicted role of gonococcal vaccines in addressing AMR will be essential for building a full public health value proposition, which can justify investment and help with decision making about future vaccine policy and programs. Efforts are underway to gain consensus on gonorrhoea vaccine target populations, implementation strategies and other preferred product characteristics that would make these vaccines suitable for use in low- and middle-income, as well as high-income, contexts. Addressing these epidemiological, programmatic and policy considerations in parallel to advancing research and development, including direct assessment of the ability of meningococcal B OMV vaccines to prevent gonorrhoea, can help bring about the development of viable gonococcal vaccines.

Correction: Prevalence of sexually transmitted infections and bacterial vaginosis among women in sub-Saharan Africa: An individual participant data meta-analysis of 18 HIV prevention studies.

[This corrects the article DOI: 10.1371/journal.pmed.1002511.].

Prevalence of sexually transmitted infections and bacterial vaginosis among women in sub-Saharan Africa: An individual participant data meta-analysis of 18 HIV prevention studies.

BACKGROUND: Estimates of sexually transmitted infection (STI) prevalence are essential for efforts to prevent and control STIs. Few large STI prevalence studies exist, especially for low- and middle-income countries (LMICs). Our primary objective was to estimate the prevalence of chlamydia, gonorrhea, trichomoniasis, syphilis, herpes simplex virus type 2 (HSV-2), and bacterial vaginosis (BV) among women in sub-Saharan Africa by age, region, and population type. METHODS AND FINDINGS: We analyzed individual-level data from 18 HIV prevention studies (cohort studies and randomized controlled trials; conducted during 1993-2011), representing >37,000 women, that tested participants for ≥1 selected STIs or BV at baseline. We used a 2-stage meta-analysis to combine data. After calculating the proportion of participants with each infection and standard error by study, we used a random-effects model to obtain a summary mean prevalence of each infection and 95% confidence interval (CI) across ages, regions, and population types. Despite substantial study heterogeneity for some STIs/populations, several patterns emerged. Across the three primary region/population groups (South Africa community-based, Southern/Eastern Africa community-based, and Eastern Africa higher-risk), prevalence was higher among 15-24-year-old than 25-49-year-old women for all STIs except HSV-2. In general, higher-risk populations had greater prevalence of gonorrhea and syphilis than clinic/community-based populations. For chlamydia, prevalence among 15-24-year-olds was 10.3% (95% CI: 7.4%, 14.1%; I2 = 75.7%) among women specifically recruited from higher-risk settings for HIV in Eastern Africa and was 15.1% (95% CI: 12.7%, 17.8%; I2 = 82.3%) in South African clinic/community-based populations. Among clinic/community-based populations, prevalence was generally greater in South Africa than in Southern/Eastern Africa for most STIs; for gonorrhea, prevalence among 15-24-year-olds was 4.6% (95% CI: 3.3%, 6.4%; I2 = 82.8%) in South Africa and was 1.7% (95% CI: 1.2%, 2.6%; I2 = 55.2%) in Southern/Eastern Africa. Across the three primary region/population groups, HSV-2 and BV prevalence was high among 25-49-year-olds (ranging from 70% to 83% and 33% to 44%, respectively). The main study limitation is that the data are not from random samples of the target populations. CONCLUSIONS: Combining data from 18 HIV prevention studies, our findings highlight important features of STI/BV epidemiology among sub-Saharan African women. This methodology can be used where routine STI surveillance is limited and offers a new approach to obtaining critical information on STI and BV prevalence in LMICs.

High-risk drug rashes.

OBJECTIVE: To provide a brief overview of the clinical presentation, common offending agents, management, prognosis, and mortality of 6 selected high-risk drug rashes, namely, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, multiple drug hypersensitivity (MDH) syndrome, acute generalized exanthematous pustulosis (AGEP), and drug-induced bullous pemphigoid (DIBP). DATA SOURCES: A review of the published literature was performed with PubMed and supplemented with our clinical experience. STUDY SELECTIONS: The most recent clinically relevant studies and older seminal works were selected. RESULTS: Most of the published data on these uncommon rashes were based on small observational series or case reports. SJS and TEN have specific genotypes association with certain drugs, have high morbidity and mortality, and require aggressive management by a team of multiple specialists. DRESS syndrome is a severe, prolonged multiorgan reaction, yet it has a better prognosis than TEN. MDH is a syndrome of repeated reactions to unrelated drugs that often imposes diagnostic and management difficulties. AGEP consists of generalized sterile small pustules, usually mistaken for infection with subsequent inappropriate treatment. Bullous pemphigoid presents with tense pruritic bullae and characteristic linear basement membrane deposition of IgG and C3. DIBP has much better prognosis than the autoimmune variety. CONCLUSION: In such high-risk drug rashes, early recognition, immediate withdrawal of the suspected drug(s), prompt individualized management, and monitoring of vital organs function are mandatory for reducing morbidity and mortality. The lack of reliable tests for identification of the causative agent imposes difficulty, particularly in patients receiving multiple medications.

The dilemma of allergy to food additives.

OBJECTIVE: To provide a brief summary on food additives and to outline a practical approach for evaluating subjects suspected of having reactions to food additives. DATA SOURCES: Information was derived from selected reviews and original articles published in peer-reviewed journals, supplemented by the clinical experience of the authors. STUDY SELECTION: Priority was given to studies that used blinded, placebo controlled, oral challenges to confirm adverse reactions to food additives. In addition, selected, appropriately evaluated case reports were included. RESULTS: A large number of food additives are widely used in the food industry. Allergic reactions to additives seem to be rare but are very likely underdiagnosed, primarily due to a low index of suspicion. A wide variety of symptoms to food additives have been reported, but a cause-and-effect relationship has not been well documented in the majority of cases. CONCLUSION: Reactions to food additives should be suspected in patients who report symptoms related to multiple foods or to a certain food when commercially prepared but not when home made. It is also prudent to investigate food additives in subjects considered to have "idiopathic" reactions. Except for a limited number of natural additives, there is a small role for skin tests or in vitro testing. Oral challenge, in stages, with commonly used additives is the definitive procedure for detecting the offending agent. Once the specific additive is identified, management is strict avoidance, which can be difficult.

Pitfalls in anaphylaxis diagnosis and management at a university emergency department.

BACKGROUND: Some previous reports revealed suboptimal management of anaphylaxis (ANX) in the emergency department (ED). OBJECTIVE: To evaluate the recorded diagnosis and management of patients who presented with ANX at our university hospital ED and to assess how the management correlated with the severity of the case and the training level of the ED staff. METHODS: A descriptive study that involved reviewing the electronic medical records of patients who presented with ANX at the ED during a period of 4 years. RESULTS: When reviewing 1341 charts of potential cases, 60 met the criteria for ANX, but only 23% were correctly coded. Inaccurate coding was noted in 77%, mainly as an "allergic reaction." Systemic corticosteroids were administered in the ED to 85% of the patients and H1-antihistamines to 73%; only 20% received epinephrine. Ten patients required hospital admission, and, on discharge, only four patients (40%) were given epinephrine autoinjector prescriptions. Of the 50 who were discharged home, 48% were given epinephrine autoinjector prescriptions and 16% were given a referral for allergy evaluation. CONCLUSION: The observed low rates of appropriate diagnostic coding of ANX, of epinephrine administration, epinephrine autoinjector prescribing at discharge, and referral for allergy evaluation call for more education on these issues. Some of these pitfalls can be partly attributed to the setting in a university ED where health providers are usually busy in rendering urgent care.

Future prospects for new vaccines against sexually transmitted infections.

PURPOSE OF REVIEW: This review provides an update on the need, development status, and important next steps for advancing development of vaccines against sexually transmitted infections (STIs), including herpes simplex virus (HSV), Neisseria gonorrhoeae (gonorrhea), Chlamydia trachomatis (chlamydia), and Treponema pallidum (syphilis). RECENT FINDINGS: Global estimates suggest that more than a million STIs are acquired every day, and many new and emerging challenges to STI control highlight the critical need for development of new STI vaccines. Several therapeutic HSV-2 vaccine candidates are in Phase I/II clinical trials, and one subunit vaccine has shown sustained reductions in genital lesions and viral shedding, providing hope that an effective HSV vaccine is on the horizon. The first vaccine candidate for genital chlamydia infection has entered Phase I trials, and several more are in the pipeline. Use of novel technological approaches will likely see viable vaccine candidates for gonorrhea and syphilis in the future. The global STI vaccine roadmap outlines key activities to further advance STI vaccine development. SUMMARY: Major progress is being made in addressing the large global unmet need for STI vaccines. With continued collaboration and support, these critically important vaccines for global sexual and reproductive health can become a reality.

Skin rash in a 2-week-old infant.

We presented a case of a male infant with annular patchy rash on his torso since 2 weeks of age. This was initially diagnosed as tinea corporis but did not respond to oral antifungal treatment. Because of the appearance of the rash and a history of a certain disease in a maternal aunt, we suspected the most probable cause of the rash and the diagnosis was confirmed by laboratory testing. Furthermore, laboratory screening of the mother, who was asymptomatic, revealed that she was seropositive for the disease and was counseled on the importance of follow-up. The infant's rash gradually improved and completely disappeared, without any sequalae by 8 months of age.

Antiepilepsy drugs and the immune system.

OBJECTIVE: To alert physicians about the peculiar adverse effects of antiepilepsy drugs (AEDs) on the immune system. DATA SOURCES: PubMed literature during the past 25 years. STUDY SELECTIONS: Reports and review articles on the hypersensitivities of AEDs and their effect on immunity. RESULTS: AEDs have significant effects on the immune system in the form of hypersensitivity or immune suppression. IgE-mediated reactions can be urticaria, angioedema, bronchospasm, or anaphylaxis. Non-IgE-mediated reactions, more commonly associated with aromatic AEDs, can be in the form of nonspecific rashes or serious reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptom syndrome, and acute generalized exanthematous pustulosis. Because of strong genetic predispositions for certain AEDs in causing severe reactions, HLA analysis before initiation of the drug is advised in certain populations. Immunoglobulin levels can be reduced to various degrees, particularly by carbamazepine, valproate, phenytoin, levetiracetam, zonisamide, and lamotrigine. Spontaneous return to normal levels can be rapid or take months to a few years, and intravenous immunoglobulin supplementation may be needed. Cellular effects can be in the form of cytopenias, inhibition of lymphocyte function, or cytokine dysregulation. CONCLUSION: When prescribing AEDs, physicians should pay special attention to their potential adverse effects on immunity or hypersensitivity, which can be severe and even fatal. For early recognition and intervention, monitoring such patients is necessary. The cornerstone of management is discontinued use of the suspected medication and avoidance of drugs of similar structure, particularly among members of the aromatic group.

Trends and patterns of sexual behaviors among adolescents and adults aged 14 to 59 years, United States.

BACKGROUND: Evaluation of sexual behaviors is essential to better understand the epidemiology of sexually transmitted infections and their sequelae. METHODS: The National Health and Nutrition Examination Surveys (NHANES) is an ongoing probability sample survey of the US population. Using NHANES sexual behavior data from 1999 to 2012, we performed the following: (1) trend analyses among adults aged 25 to 59 years by 10-year birth cohorts and (2) descriptive analyses among participants aged 14 to 24 years. Sex was defined as vaginal, anal, or oral sex. RESULTS: Among adults aged 25 to 59 years, median age at sexual initiation decreased between the 1940-1949 and 1980-1989 cohorts from 17.9 to 16.2 among females (P trend < 0.001) and from 17.1 to 16.1 among males (P trend < 0.001). Median lifetime partners increased between the 1940-1949 and 1970-1979 cohorts, from 2.6 to 5.3 among females (P trend < 0.001) and from 6.7 to 8.8 among males (P trend < 0.001). The percentage of females reporting ever having a same-sex partner increased from 5.2% to 9.3% between the 1940-1949 and 1970-1979 cohorts (P trend < 0.001). Among participants aged 14 to 24 years, the percentage having had sex increased with age, from 12.5% among females and 13.1% among males at age 14 years to more than 75% at age 19 years for both sexes. Among sexually experienced 14- to 19-year-olds, 45.2% of females and 55.0% of males had at least 3 lifetime partners; 39.4% of females and 48.6% of males had at least 2 partners in the past year. The proportion of females aged 20 to 24 years who reported ever having a same-sex partner was 14.9%. The proportion of participants aged 14-19 or 20-24 years reporting ever having sex did not differ by survey year from 1999 to 2012 for either males or females. CONCLUSIONS: Sexual behaviors changed with successive birth cohorts, with more pronounced changes among females. A substantial proportion of adolescents are sexually active and have multiple partners. These data reinforce existing recommendations for sexual health education and sexually transmitted infection prevention targeting adolescents before sexual debut.