Centralized pain syndromes are associated with changes within the central nervous system that amplify peripheral input and/or generate the perception of pain in the absence of a noxious stimulus. Examples of idiopathic functional disorders that are often categorized as centralized pain syndromes include fibromyalgia, chronic pelvic pain syndromes, migraine, and temporomandibular disorder. Patients often suffer from widespread pain, associated with more than one specific syndrome, and report fatigue, mood and sleep disturbances, and poor quality of life. The high degree of symptom comorbidity and a lack of definitive underlying etiology make these syndromes notoriously difficult to treat. The main purpose of this review article is to discuss potential mechanisms of centrally-driven pain amplification and how they may contribute to increased comorbidity, poorer pain outcomes, and decreased quality of life in patients diagnosed with centralized pain syndromes, as well as discuss emerging non-pharmacological therapies that improve symptomology associated with these syndromes. Abnormal regulation and output of the hypothalamic-pituitary-adrenal (HPA) axis is commonly associated with centralized pain disorders. The HPA axis is the primary stress response system and its activation results in downstream production of cortisol and a dampening of the immune response. Patients with centralized pain syndromes often present with hyper- or hypocortisolism and evidence of altered downstream signaling from the HPA axis including increased Mast cell (MC) infiltration and activation, which can lead to sensitization of nearby nociceptive afferents. Increased peripheral input via nociceptor activation can lead to “hyperalgesic priming” and/or “wind-up” and eventually to central sensitization through long term potentiation in the central nervous system. Other evidence of central modifications has been observed through brain imaging studies of functional connectivity and magnetic resonance spectroscopy and are shown to contribute to the widespreadness of pain and poor mood in patients with fibromyalgia and chronic urological pain. Non-pharmacological therapeutics, including exercise and cognitive behavioral therapy (CBT), have shown great promise in treating symptoms of centralized pain. Chronic pain, or pain lasting or recurring for more than 3 to 6 months  and 2 (CRF2) are G-protein coupled receptors that play a prominent role in HPA axis regulation by binding CRF and its related ligands, Urocortin (Ucn) 1–3. Once activated, CRF1 and CRF2 work in opposition to one another to enhance and reduce HPA output, respectively  are a critical part of the innate immune system and are highly responsive to activation of the HPA axis, as they express five isoforms of the CRFMCs are observed adjacent to unmyelinated nerves throughout the body, including the skin , and physical and mental fatigue associated with the disorder  and sound (phonophobia), nausea, fatigue, irritability, muscle tenderness, and cutaneous allodynia including extracephalic allodynia , formerly referred to as diffuse noxious inhibitory control (DNIC). CPM is a “pain-inhibits-pain” mechanism and represents a measure of the function of descending analgesic pathways. This system has been shown to be defective in chronic pain patients  and inhibitory (GABA) neurotransmitters in the CNS  and LTP  network, have greatly increased our knowledge of phenotypic and central changes that occur in patients with centralized pain syndromes (Clemens et al., Centralized pain syndromes are often comorbid with one another and are accompanied by fatigue, mood and sleep disturbances, and poor quality of life scores Clauw, . This hiOCE-S, ALN and JAC: equal contribution for the literature search and article preparation. All authors contributed towards the development, research, and writing of this review.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.


Routine data collection efforts are a necessary, often underappreciated, component of nearly all cancer research and prevention efforts. Public health cancer surveillance data are crucial for identifying needs, planning interventions, directing public health resources, and evaluating the overall effectiveness of initiatives aimed at preventing or treating cancer and its negative health consequences. As the nation’s health protection agency, the Centers for Disease Control and Prevention (CDC) provides resources for disease surveillance systems to help protect our nation against expensive and dangerous health threats, including cancer. Therefore, public health surveillance is a core function of CDC. In this article we briefly describe CDC’s approach to cancer surveillance in our public health programs and other federal initiatives to monitor cancer-related outcomes. We also describe our premier cancer incidence surveillance system, the National Program of Cancer Registries, and discuss uses and applications of the program’s critical cancer data. Cancer is the second leading cause of death in the United States  and therThe World Health Organization defines public health surveillance as the continuous, systematic collection, analysis, and interpretation of health-related data needed for the planning, implementation, and evaluation of public health practice . This coConducting public health surveillance is one of CDC’s core functions, yet no comprehensive review of the agency’s heterogeneous public health cancer surveillance activities has been conducted. This article summarizes the key components of CDC’s cancer surveillance approach with a special emphasis on cancer incidence data collected through our National Program of Cancer Registries (NPCR). CDC compiles extensive data with direct and indirect implications for cancer, either collected directly or in collaboration with funded or unfunded partners. We focus on surveillance data used by CDC programs for planning, implementation, and evaluation of public health practice.www.cdc.gov/brfss/questionnaires/index.htm).CDC’s Division of Cancer Prevention and Control (DCPC) provides resources and technical expertise for cancer-related questions included in the Behavioral Risk Factor Surveillance System (BRFSS) . Questiowww.cdc.gov/nchs/nhis/supplements_cosponsors.htm).DCPC collaborates with the National Center for Health Statistics (NCHS) and the National Cancer Institute (NCI) to support questions and special supplements on the National Health Interview Survey (NHIS). The core cancer questions provide data on self-reported cancer prevalence, various cancer-associated health behaviors, and access to and use of cancer-related health. DCPC and NCI support the NHIS Cancer Control Supplement, which periodically presents a focused examination of issues pertaining to cancer-related behaviors, screening, and risk assessment. The cancer-related questions vary across years to reflect emerging needs. DCPC-sponsored NHIS questions have been asked in 2000, 2003, 2005, 2008, 2010, 2013, and 2015. More information about NHIS supplements is available on the NHIS website (www.cdc.gov/nchs/nhanes/index.htm), the Youth Risk Behavior Surveillance System , the Medical Expenditure Panel Survey (https://meps.ahrq.gov/mepsweb/), and program-specific clinical data collection initiatives supported through the National Breast and Cervical Cancer Early Detection Program (NBCCEDP)   and the NBCCEDP) .DCPC collects data on new cancer cases diagnosed each year through NPCR covering 96% of the United States  10). Wh. Wh10). CDC’s cancer incidence data come from NPCR, which was established by Congress in 1992. From 2012 through 2017, CDC’s NPCR funded central cancer registries in 45 states, the District of Columbia, Puerto Rico, and the US Pacific Island jurisdictions. Central cancer registries are responsible for collecting, processing, and analyzing complex data from medical facilities on every in situ and invasive cancer  diagnosed among residents in their geographic catchment area . Consequently, data in the state or territorial central registries represent everyone diagnosed or treated for cancer. A brief summary of the data items collected by all central cancer registries is shown in The central cancer registry also links data with state and national databases to supplement and improve the quality of data. Every central cancer registry routinely links cancer data with that of its state death files, NBCCEDP, the National Death Index, and the Indian Health Service. Some registries optionally link with other data sources, such as Medicare and Medicaid claims files to address gaps identified in their data or improve the usefulness of the data for local cancer control activities. Because the data in a single record come from various sources, the central registry is responsible for consolidating the information into a single record on each cancer case and submitting a subset of its data to CDC annually, including any updates from previous years.To ease the burden of such a complex data collection system, CDC has several surveillance informatics initiatives to automate processes and use electronic data exchange in cancer reporting. Examples include cancer reporting from ambulatory providers to registries for Stage 2 Meaningful Use and the development of a natural language processing web-based repository to facilitate analytic data extraction from text-based records ,14.https://wonder.cdc.gov/), CDC’s Environmental Public Health Tracking Network (www.cdc.gov/nceh/tracking/), and State Cancer Profiles (https://statecancerprofiles.cancer.gov/). NPCR analytic data sets are also available to researchers interested in using these data (https://www.cdc.gov/cancer/npcr/public-use/). Through careful coordination and collaborations with our cancer surveillance partners, NPCR data are comparable with those of other countries and are included in the Cancer Incidence in Five Continents (http://ci5.iarc.fr/Default.aspx) series providing information on the global burden of cancer.NPCR uses North American Association of Central Cancer Registries uniform data standards  and workIncidence data from NPCR and SEER and cancer mortality data from NCHS NVSS are the basis for nearly all cited cancer statistics and projections, including the Annual Report to the Nation on the Status of Cancer  and the Established in 1998, the National Comprehensive Cancer Control Program (NCCCP) supports strategic approaches to preventing or minimizing the impact of cancer in communities .The NBCCEDP is a nationwide, comprehensive public health program that provides uninsured and underserved women access to timely breast and cervical cancer screening and diagnostic services . The NBCGuide to Community Preventive Services. This approach allows grantees to implement targeted evidence-based interventions and supporting strategies on a feasible scale and collect program-level and patient-specific clinical data that show the program’s impact. In 2015, CRCCP supported 24 state health departments, 6 universities, and 1 American Indian tribe. Six grantees were also funded to provide screening to uninsured and underinsured people; as in the NBCCEDP, these 6 grantees also report standardized clinical data for people screened.CDC’s Colorectal Cancer Control Program (CRCCP) helps states and tribes across the United States increase colorectal cancer screening rates among men and women aged 50 to 75 years . The prowww.healthypeople.gov/) provides quantifiable national objectives for improving the health of all Americans. For cancer, HP2020 aims to reduce the number of new cancer cases and the illness, disability, and death caused by cancer. The 27 cancer objectives support monitoring trends in incidence, death, and survival and reflect the importance of promoting evidence-based screening for cervical, colorectal, and breast cancer by measuring the use of screening tests recommended by the USPSTF. The cancer-related HP2020 objectives are measured through various CDC-supported data systems  ( systems .Several projects have used central cancer registries to recruit participants for research studies. Population-based cancer registries are useful in identifying samples of participants who meet criteria for certain cancers. For example, one study assessed health-related quality of life and health behaviors among colorectal cancer survivors recruited through the California Cancer Registry demonstrating that the cancer registry can be a valuable source for identifying and recruiting study participants ,23. CancDCPC is committed to continuously improving the accuracy, efficiency, and timeliness of all cancer surveillance efforts it directly funds or supports. One way cancer registries are doing this is by remaining on the cutting edge of health information technology by facilitating more electronic reporting and automated data management techniques. Through work with the cancer registry community and other key partners, such as the Office of the National Coordinator and the Centers for Medicare & Medicaid Services, NPCR has made great progress in developing a robust capability for electronic exchange of certain cancer data. However, there is much work to do. Sustained local, state, and federal cancer registry commitments are needed to continue to develop new tools and software for the development and acceptance of additional electronic cancer records. Through these efforts, the cost-effectiveness and timeliness of cancer surveillance is expected to improve in the long term as registry staff spend less time engaged in visual review, coding, and data entry and more time in quality assurance to improve the quality, completeness, and timeliness of the data. CDC’s NPCR will continue to build the necessary infrastructure for electronic reporting so that these efficiencies can be realized in the future. Cancer surveillance data are the core of cancer epidemiology and outcomes in clinical cancer research. CDC is dedicated to remaining a diligent steward of population-based cancer surveillance and maintaining complete capabilities in cancer incidence surveillance throughout the entire nation to support state and local activities. We also remain steadfast in making all CDC data useful and available to those who need them, particularly for program planning and monitoring, resource allocation, and state and federal accountability.


United States–Russia tensions over the hostilities in Ukraine, collapsed cease-fires and chemical weapons use in Syria, and accusations of alleged cyberattacks may require a diplomatic reset. To help ease growing strains and restore dialogue and cooperation, it is worth looking to a productive and extraordinary historical record of international scientific collaborations.Throughout the last half of the 20th century, the United States and Soviet Union managed a complex Cold War foreign policy relationship by opening and maintaining channels in sports, the arts, literature, and other humanitarian endeavors. One of the most productive engagements was through a mostly clandestine joint initiative to develop, test, and deliver life-saving vaccines that targeted the ancient scourges of humankind. Ultimately, through Cold War vaccine diplomacy, smallpox was eradicated, and polio was mostly eliminated .In 1956, a year before the Sputnik launch, the US State Department and its counterpart in the Soviet Union facilitated links between the American virologist Dr. Albert Sabin and two Soviet virologists, Drs. Mikhail Chumakov and Anatoli Smorodintsev, to collaborate in producing the oral polio vaccine at a scale suitable for testing it first on millions of Soviet citizens . WatchedThe vaccine was scaled up and produced in Chumakov’s laboratory, but clinical testing required him to bypass an obstructionist Soviet Minister of Health and go directly to the Kremlin leadership for large-scale trials to proceed . ThroughOn the heels of the polio vaccine licensure, Soviet scientists developed a unique process for preserving the smallpox vaccine in harsh environments to produce hundreds of millions of doses of freeze-dried vaccine. This proved to be a key enabling technology for the American public health physician D. A. Henderson (who passed away in 2016) to lead a celebrated campaign that eradicated smallpox by 1977 .Throughout the late 20th century, joint US–Soviet or US–Russian health activities continued, with a major focus on HIV/AIDS prevention, as well as the prevention of other sexually transmitted diseases and tuberculosis (TB) . Then, iHowever, these important efforts still fall short of the compelling stories offered by the joint vaccine science diplomacy that led to the oral polio vaccine now leading to global eradication efforts. Could Cold War lessons in this arena ease today’s escalating tensions between the US and Russian governments? Hostilities between the United States and Russia may be nowhere near our confrontations during the 1950s, 1960s, and 1970s, but extraordinary opportunities remain to meld our scientific activities to eliminate the world’s major neglected and emerging diseases .Within the last five years, we have seen the rise or emergence of several catastrophic infectious diseases for which we have no vaccine. They include Middle East Respiratory Syndrome (MERS), Ebola, and Zika virus infections, just to name a few. To help provide global financing schemes for such a vaccine, a new Coalition for Epidemic Preparedness Innovations (CEPI) is being established as an international funding organization akin to the Global Fund to Fight AIDS, Tuberculosis and Malaria . Russia In addition to regional conflicts, another factor promoting the rise of neglected tropical infections is poverty. Previously, I pointed out the rise of poverty in selected areas of Russia . AccordiAs a consequence of poverty, possibly together with other factors such as climate change and human migrations now also affecting southern Europe , we may Plasmodium vivax-caused malaria if both countries committed scientific effort and resources to make it happen. A joint US–Russian initiative to develop new neglected disease vaccines is an achievable goal and one that could begin through the nonprofit Sabin Vaccine Institute, which has already launched similar US-led initiatives with Muslim-majority countries in the Middle East and North Africa, as well as Malaysia [It is feasible to develop and test innovative vaccines for diseases such as leishmaniasis, WNV, TB, and Malaysia .Since the 1950s, joint US–Russian cooperation has shown a dual track record of improving both foreign relations and scientific collaborations. Vaccine science diplomacy is not a panacea for heightened tensions between the US and Russia, but the approach has proven valuable for promoting joint humanitarian efforts while simultaneously producing life-saving vaccines.S1 File(PDF)Click here for additional data file.


Childhood sexual abuse (CSA) remains a critical public health issue among black and Latino men who have sex with men (MSM), as it is associated with multiple negative outcomes including substance misuse, poor mental health, revictimization, and high-risk sexual behavior. Most CSA research with MSM relies on quantitative assessment that often precludes consideration of cultural variations in how formative sexual experiences are understood and is based on inconsistent or overly restrictive definitions of abuse, and therefore may fail to detect certain abusive experiences , which can have harmful health consequences if they remain unrecognized.The objective of this study is to overcome existing limitations in the literature by drawing on perspectives of black and Latino MSM and men who have sex with men and women (MSMW), as well as relevant service providers to better understand the role of, and the need to include, sexual abuse histories  in treatment and counseling settings, with the long-term goal of improving assessment and health outcomes.We will conduct mixed-methods interviews, framed by an intersectionality approach, with 80 black and Latino men (40 MSM and 40 MSMW) in New York City (NYC), exploring appraisals of their formative sexual experiences, including those described as consensual but meeting criteria for CSA. We will also interview 30 local service providers representing substance abuse treatment, mental health care, and HIV prevention and outreach.The study was launched in May 2017.This formative research will inform testable approaches to assessing and incorporating sexual abuse history into substance abuse treatment and other health and mental health services used by men with such histories. Childhood sexual abuse (CSA) is nearly five times greater among men who have sex with men (MSM) than in the general male population , with prAppraisals of CSE  are influenced by social environmental factors including gender and culture. Men may be less likely than women to define certain CSE as abusive because their socialization into masculine gender roles leads them to fear that they will be perceived as homosexual or as victims ,38,39. BThis study recognizes female perpetrators in the early sexual experiences of MSM and MSMW. To our knowledge, this is the first study to investigate formative sexual experiences of black and Latino MSM/W involving older female partners relative to their sexual identity development, adult sexual relationships, masculine and cultural norms, and psychosocial health outcomes. The majority of CSA research with men, specifically gay and bisexual men, would suggest that perpetrators are typically male. Female perpetrators are rarely accounted for in either research designs or analyses. Indeed, several studies have failed to report the gender or sex of perpetrators ,29,33,53However, there are a few exceptions ,32,35. IThere is a need for qualitative research on CSE of black and Latino MSM/W. An in-depth qualitative exploration can yield a better understanding of the meanings that individuals assign to CSE ,33 and tFew studies have explored CSE with MSMW beyond quantitative assessment ,50,52,55Service providers, including substance use counselors and HIV outreach workers, may not be adequately prepared to recognize or safely address CSA with male clients. Male survivors of CSA, often overlooked as health care consumers, have unique clinical and psychological needs that warrant critical scientific inquiry . KnowingTo our knowledge, very few studies focus specifically on understanding formative sexual histories, particularly those experiences occurring before the age of 16 years , of black and Latino MSM and MSMW. We are conducting mixed-methods interviews with 80 black and Latino men (40 MSM and 40 MSMW) in New York City (NYC), exploring appraisals of their formative sexual experiences, including those described as consensual but meeting criteria for abuse . We are To address the need for better recognition of CSA at multiple levels, we will do the following: (1) investigate appraisals of CSE among black and Latino MSM and MSMW and evaluate these experiences using established criteria for defining sexual abuse; (2) examine appraisals of CSE relative to sexual identity formation, adult sexual relationships and behaviors, concealment of same-sex behavior, alcohol and drug use, psychological and emotional functioning, and cultural ideologies of masculinity among black and Latino MSM and MSMW; and (3) examine perspectives of black and Latino MSM and MSMW and relevant service providers to understand the role of, and the need to include, sexual history in treatment and counseling settings and to determine service providers’ preparedness to address CSE in treatment and counseling settings.This study employs an intersectionality framework to examine appraisal and interpretation of CSE. Multiple social identities  “intersect at the micro level of individual experience to reflect interlocking systems of privilege and oppression at the macro level” -73. ThisThrough an intersectionality lens, and relying on an indirect approach to assessing CSE, this study will use mixed methods to consider how current appraisals of first sexual experiences are shaped by intersecting social identities . These iThis cross-sectional study will include in-person interviews with 80 black and Latino men (40 MSM and 40 MSMW) with a history of CSE, and interviews with 30 service providers about their preparedness to address issues of abuse with clients.Participants of any HIV status must: (a) be biologically male and identify himself as male; (b) be 18-50 years of age; (c) be black non-Hispanic or Hispanic/Latino; (d) have had sex with a man within the past 12 months; (e) have had at least one sexual experience before age 16 with a man or woman who was at least 18 years of age at the time; (f) be fluent in English; and (g) live in the NYC area.The study team will recruit a minimum of 30 men (38%) with a history of CSE with older female partners. This quota falls between estimates from our work with black MSMW   and thosWe employ multiple recruitment methods  based on our experience in working with stigmatized populations ,76-78. RThe research team is utilizing social  and sexual networking websites to recruit participants who may or may not openly identify as having sex with men. Advertisements target users in our study population. Facebook has been used to recruit MSM ,82 and yWe are using relationships with local organizations to generate participant referrals  by postiWe screen for eligibility via a brief internet and mobile survey . The stuAfter providing informed consent, participants complete a short interviewer-administered questionnaire to verify information collected during screening . Participants also complete a short series of survey measures to assess sexual orientation, concealment of same-sex behavior, HIV and STI testing history, substance use, psychological distress, suicidality, post-traumatic stress symptoms, cultural estrangement, masculinity, and history of intimate partner violence (estimated time is 25 min), see We conduct semi-structured (focused) interviews  using a Researchers have called for more in-depth exploration of CSE among MSM and MSMW ,32,37,50This is not to deny the value in definitions of CSA generated by quantitative research. On the contrary, a framework of agreed-upon variables to reinterpret men’s narratives of their experiences enables investigators to detect discrepancies that can be further addressed.Our approach: (1) allows men to discuss formative sexual experiences occurring before age 16 without imposing terminology that is commonly associated with abuse; (2) allows men to discuss why they appraise these experiences as abusive or consensual; and (3) allows researchers to systematically (re)appraise certain experiences as abusive based on details provided by the participant  without influencing the narrative ,34. ThisFor Aim 3, we are interviewing 30 NYC-based service providers (concurrently with the MSM and MSMW interviews) recruited through provider training networks and local organizations that specialize in substance abuse treatment, HIV prevention and counseling services, and mental health and other health-related services. Interviews are audio-recorded and take approximately 1.5 hours; providers receive $30 compensation. We begin with a few structured questions ; estimated time is 15 min. The remainder of the meeting focuses on perceived preparedness to incorporate sexual history and issues of sexuality into treatment or counseling and issues of trauma-informed care, including whether and how providers screen for CSA and what they do with this information as they learn it from clients. We present vignettes  derived from previous research  to ascerAim 1) [Aim 2)—for example, current relationships with women (IG8), identification with masculinity norms (IG7), and CSE with an older female (IG3).Interviews with black and Latino MSM/W will be transcribed before coding and thematic analysis ,108. TheAim 1) ,35,50. TInterviews with service providers will be transcribed and coded before analysis. We will analyze and integrate provider data in several ways. First, using data from both providers and MSM/W, we will compare perceptions of the need to incorporate sexual history into treatment and counseling settings. We will also examine acceptable intervention formats with sexual abuse issues from the perspectives of potential clients and providers (IG13-IG15). Second, provider responses to vignettes will reveal patterns in perceived abuse and preliminary findings as to the acceptability of using an indirect approach to assessing CSE . Third, using provider accounts of their experiences with client sexual histories, in conjunction with how they respond to the vignettes, we will derive a preliminary assessment of the level of preparedness to address issues of abuse and sexuality in diverse treatment and counseling settings.The study aims will be primarily addressed through qualitative analyses. However, the proposed sample (N=80 black and Latino MSM and MSMW) will allow for some supplemental quantitative analyses . ValiditAppraisals of CSE are a critical outcome of the proposed study. Power calculations for this outcome (example below) are based on estimates from our previous study with nongay-identified MSMW . In thatWe will employ “Best Practices” for mixed methods research  to integThe study received Institutional Review Board approval and was launched in May 2017. Data collection is underway and results are forthcoming.We recognize that this formative study will not have sufficient resources to recruit a truly representative sample. For example, nonspeakers of English will not be included. Moreover, recruitment methods favor those with internet access, but this may be somewhat offset by recruitment from community-based organizations. Much of the data will be retrospective and despite measures that we have incorporated to minimize recall bias, the possibility remains that some accounts may suffer from memory suppression.Findings will inform an R01 proposal to develop and test an alternative CSA instrument accompanied by a training curriculum for use in health services and research settings. Specifically, data from black and Latino MSM/W will be translated into a preliminary set of testable questions to indirectly detect sexual abuse perpetrated against male participants or clients. Study findings from service providers will offer insight into how qualitative assessments of sexual history can be used in conjunction with substance use measures and mental health screenings to better understand the impact of abuse; inform strategies to improve linkage to care; elucidate the degree of acceptability, preparedness, and potential discomfort among service providers in taking childhood sexual histories; and inform training in the use of this alternative instrument.


The Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop was held on July 25 and 26, 2016 at the National Institutes of Health. The workshop brought together a diverse group of researchers including pediatric neurosurgeons, neurologists, and neuropsychologists with scientists in the fields of brain injury and development, cerebrospinal and interstitial fluid dynamics, and the blood–brain and blood–CSF barriers. The goals of the workshop were to identify areas of opportunity in posthemorrhagic hydrocephalus research and encourage scientific collaboration across a diverse set of fields. This report details the major themes discussed during the workshop and research opportunities identified for posthemorrhagic hydrocephalus. The primary areas include (1) preventing intraventricular hemorrhage, (2) stopping primary and secondary brain damage, (3) preventing hydrocephalus, (4) repairing brain damage, and (5) improving neurodevelopment outcomes in posthemorrhagic hydrocephalus. The Hydrocephalus Association hosted a workshop on July 25 and 26, 2016 at the National Institutes of Health, Neuroscience Center, to build research capacity and identify areas of opportunity for research around posthemorrhagic hydrocephalus (PHH). The Hydrocephalus Association was founded in 1983 by parents of children with hydrocephalus and developed a research program in 2009. Since then the Association has committed over $7 million to research, making it the largest non-profit, non-governmental funder of hydrocephalus research in the United States. The mission of the Hydrocephalus Association is to promote a cure for hydrocephalus and improve the lives of those affected by the condition. The Association strives to accomplish this mission by collaborating with patients, caregivers, researchers and industry, raising awareness, and funding innovative, high impact research to prevent, treat, and ultimately cure hydrocephalus.The 2016 Hydrocephalus Association PHH Workshop was developed through the Hydrocephalus Association PHH Initiative, a multiyear initiative focused on increasing research efforts focused on PHH. The workshop agenda was developed by the workshop planning committee which was led by Hydrocephalus Association staff and included both an investigator in the Hydrocephalus Clinical Research Network (HCRN) and a family member of a person with hydrocephalus. The workshop brought together a diverse group of researchers including pediatric neurosurgeons, neurologists, and neuropsychologists together with scientists in the fields of brain injury and development, cerebrospinal and interstitial fluid dynamics, and the blood–brain and blood–CSF barriers. Workshop attendees also included Hydrocephalus Association staff and family members of people affected by hydrocephalus.The primary focus of the workshop was on PHH of prematurity, although PHH can develop at any age, including in utero, after preterm birth, and in children and adults who have had a brain hemorrhage . PHH devAdvances in neonatology have improved survival rates for preterm neonates in recent decades . In the PHH of prematurity is a common form of pediatric hydrocephalus, accounting for 20% of the shunted hydrocephalus cases in the United States  and is aPHH of prematurity is a common and particularly insidious form of pediatric hydrocephalus . During Many maternal factors can alter the risk of IVH in premature neonates. Some protective factors are related to health care including access to prenatal care, administration of antenatal corticosteroid regimens, and cesarean delivery . MaternaNeonates born at term rarely develop IVH or PHH . For prePremature neonates are especially vulnerable to IVH within the subependymal germinal matrix, a highly vascularized region consisting of neural and glial precursor cells , 37, 38.In preterm neonates, the germinal matrix is susceptible to hemorrhaging due to the immaturity of the vasculature, , 42, 43 Hydrocephalus represents an alteration in fluid balance within the brain and cranial cavity. It is traditionally held that under normal conditions cerebrospinal fluid (CSF) is primarily secreted into the cerebral ventricles by the choroid plexus (site of the blood–CSF barrier) and moves via bulk flow through the ventricular system and subarachnoid space before being absorbed at the arachnoid villi/granulations although it should be noted that these develop at about week 35 and 39, respectively . In addiSecondary injury mechanisms occur following ventriculomegaly (reviewed in –60). A dAs detailed above, the pathophysiology of hydrocephalus is multifactorial in nature, and the precise mechanisms underlying PHH of prematurity remain unclear . PHH is Multiple theories have been proposed to explain the development of “communicating” hydrocephalus after IVH including blockage of the arachnoid villi and arachnoid granulations due to microthrombi  or scarrSurprisingly, there have also been very few studies addressing the impact of IVH on the choroid plexus . One recex vacuo, in which the ventricles expand subsequent to impaired neurogenesis and neuronal differentiation [In contrast, there is much evidence that IVH damages the ependymal cells that line the cerebral ventricles. Alterations in this CSF–brain interface may impact bulk fluid flow via ciliopathy and disrupt neurodevelopment by exposing the subventricular zone to CSF. An emerging mechanism appears to involve impaired junctional proteins, such as N-cadherin and connexin that not only provide structure for the ependymal lining of the ventricles but also influence progenitor cell proliferation, migration, and differentiation –70. Recentiation .Treatments for PHH of prematurity fall into one of three categories: temporary non-surgical, temporary surgical, and permanent surgical. Temporary non-surgical treatments, including thrombolytic agents and diuretics, have been tested –77; howeEmerging treatments include endoscopic lavage with early removal of IVH. In one study, Schulz et al. reported a decrease in the rates of hydrocephalus and need for permanent shunt placement . HoweverIf hydrocephalus persists despite temporary CSF diversion, placement of a ventriculoperitoneal (VP) shunt has been the treatment of choice. VP shunting has been the mainstay of long-term surgical management of hydrocephalus for over six decades. However, VP shunts frequently fail. In children, approximately 30-50% of shunts fail within the first 2 years –84 and 8Past clinical trials inform future clinical, translational, and basic science research. The workshop, reviewed clinical trials conducted in both premature neonates and adults with intracranial hemorrhage to identify areas of promise and obstacles that limit our ability to interpret and compare results.Premature and/or (extremely) low birth weight neonates are vulnerable populations at risk for multiple co-morbidities such as IVH and neurological deficits. To improve survival rates and decrease such co-morbidities, interventions based on a variety of biological mechanisms have been tested and adopted by the medical community. These interventions can be broadly grouped into antenatal interventions, birth-related procedural interventions, and postnatal interventions Table .Table 1SAntenatal interventions include administration of corticosteroids, phenobarbital, magnesium sulfate, and vitamin K. Antenatal corticosteroids administration is perhaps the most established intervention and has been shown to reduce severe grades of IVH as well as reduce mortality and respiratory distress syndrome , 92. In Procedural interventions occurring at or close to the time of birth include mode of delivery and the timing of umbilical cord clamping. In many studies comparing vaginal and cesarean deliveries in preterm and very low birth weight infants, there did not appear to be IVH risk reduction associated with one form of delivery over the other –101. By Postnatal interventions that decrease the risk of IVH, but may not improve long-term neurological outcomes, include treatment with prophylactic indomethacin, ibuprofen, inositol, or ethamsylate , 109–114Other postnatal interventions, such as inhaled nitrous oxide, phenobarbital, prophylactic surfactant, and corticosteroids, have had no effect on IVH rates , 126–129Pharmaceutical agents, drainage and irrigation of the ventricles, and temporizing devices have been tested to stop the development or progression of PHH after IVH. In these studies, the primary outcome is usually permanent shunt placement.To date, pharmaceutical treatments have not been effective in stopping the development of PHH or its neurological disability , 135. Th®, human umbilical cord blood derived mesenchymal stem cells, in preterm infants with grade III–IV IVH was completed. The primary outcome is unexpected death or anaphylactic shock and the secondary outcome is death or the development of shunt dependent hydrocephalus; results are pending (NCT02274428). The same group is now enrolling infants in a follow up study (NCT02673788). In related work, multiple clinical trials are underway or being analyzed to determine the effects of mesenchymal stem cells on the development of bronchopulmonary dysplasia in preterm infants .Recently, a phase one clinical trial for the use of PNEUMOSTEMIn contrast to pharmaceutical treatments, trials that have attempted to physically wash out blood and other substances have shown more positive results , 142. DrAt this time, short-term temporizing procedures are often the first step in the clinical treatment of PHH, since the longevity of the condition may still be in question and, from a technical standpoint, the size of the neonate may preclude longer-term strategies such as permanent CSF shunting. Temporary surgical treatments include VADs, EVDs, VSG shunts, and lumbar punctures. Many studies have compared these treatment options but no clear results have emerged . AIn future studies, morbidity, mortality, permanent shunt placement, and infection risk should all be considered as important factors. However, the timing of these interventions may have a greater impact on outcomes than the type of treatment. In one study, early treatment (based on ventricular index) with either reservoir placement or lumbar puncture was safe, effective, resulted in lower rates of permanent shunt placement, and reduced moderate-to-severe disability . The resIn adults, IVH occurs as an extension of an initial intracerebral hemorrhage (ICH) with IVH occurring in about 40% of ICH cases , 148. IVIn adults, ICH/IVH treatment has focused on three main approaches: limiting bleeding, clot removal, and reducing secondary brain injury. Hemostatic therapy  and reducing blood pressure  have undergone clinical trials to limit continued bleeding (clot expansion) in the early phase (< 24 h) after ICH. Although some of these studies have reported statistically significant effects on limiting bleeding, there has yet to be definitive evidence of improved outcomes –160.The second therapeutic approach has centered on parenchymal or intraventricular clot removal. For ICH, standard surgical evacuation has not shown statistical benefit  and there is interest in using minimally invasive surgery (MIS) with or without tissue rtPA to lyse the clot  –163. EviAs in the premature population, a number of trials for adult ICH patients with IVH have combined EVD placement with administration of thrombolytic agents. A number of systematic meta-analyses have reported decreased mortality using this combination versus external ventricular drain (EVD) alone , 165. KhOther newer minimally invasive approaches to adult IVH studied in small clinical trials include endoscopic surgery and controlled lumbar drainage for prevention of permanent shunt dependency. A randomized trial of combined IVT with lumbar drainage vs. IVT alone for prevention of permanent shunt dependency after ICH with severe IVH was stopped following interim analysis after 30 patients due to significant efficacy of the tested intervention . A meta-Compared to cerebral ischemia , there hWith the exception of early clot expansion, where there is little data in the neonate, there are similarities in the approaches being examined in the adult and neonate. It is hoped that information from each age group may help in devising better ways for hematoma removal and reducing the impact of clot-induced, or derived, harmful factors.The development of PHH of prematurity involves a series of events resulting in multiple, simultaneous injury processes. Correctly predicting who is at risk, determining key time-points and targets for early interventions, and understanding the long-term effects of PHH are essential for preventing, minimizing, or reversing the development of hydrocephalus and improving long-term outcomes. During the workshop, key areas for research and interventions were identified and discussed Fig. .Fig. 2KeTo optimize clinical management, it is essential to identify the premature neonates who are at highest risk of developing IVH and subsequently PHH. This is a key area for future research Table . Many dePremature neonates are uniquely susceptible to germinal matrix hemorrhage (GMH) and the germinal matrix vasculature is a major target for research Table . DetermiOnce IVH occurs, blood and blood-derived products cause damage to the surrounding tissue. Developing methods to reduce such injury is a major research target Table . MultiplCareful time-series experimentation will be required to determine if there is a critical time window post-IVH in which these therapies are effective and if the timing can be achieved in a clinical setting. In addition, early blood evacuation with or without the use of thrombolytic agents may reduce damage and improve outcomes. Forthcoming results from the ELVIS trial should help clinical decision making. Active clearance of the blood clot remains a promising avenue for research. It may also be possible to speed up endogenous processes, such as macrophage clearance of the clot, that do not result in the release of additional blood products.Prevention or reduction of secondary injury processes and the damage caused by hydrocephalus are active areas of research, with multiple research targets Table , and mayRecent studies have focused on reducing subarachnoid fibrosis and periventricular astrogliosis by targeting inflammatory and other signaling cascades and have had positive results in animal models , 203–205For treatment of both blood-induced injury and secondary injuries, the specificity of the compounds, mode of administration, dosing, toxicity, and proof of target engagement will become extremely important as therapies move toward first in human trials  and hydrocephalus can cause additional damage through hypoxia, ischemia, and mechanical stress , 207–214Although much research is still needed on CSF dynamics Table , IVH andPremature neonates with Grade III or IV IVH are at a higher risk of poor neurodevelopmental and cognitive outcomes than preterm neonates without IVH or who have Grade I or II IVH , 230. ItFor the PHH population, improving long-term neurodevelopmental and cognitive outcomes is very important and should be a primary focus in clinical trials . UnderstImproving functional outcomes is a priority for the hydrocephalus community and must become a priority in research . LongituFocus on the clinical management of preterm neonates has intensified in recent years in parallel with advances in obstetrics and newborn medicine. Identifying and implementing best practices as well as testing the benefit, or lack thereof, of new techniques and therapies is an essential part of this process. However, in published work, substantial variability exists in the study populations as well as diagnosis and treatment thresholds, making comparisons between studies difficult.Standardizing clinical protocols through quality improvement methodologies and/or clinical trials has become a priority for the field but more work needs to be done. An early report from the HCRN demonstrated substantial variation in the treatment of PHH, even within this coordinated network . In 2014Study protocols also need to be standardized. Currently, research groups use different study populations and inclusion criteria  as well as different diagnosis and treatment thresholds. As a first step, common classification data including gestational age at birth, weight at birth, and IVH grade should be collected in every study and, when possible, standard inclusion and exclusion criteria should be used.Establishing standardized criteria for PHH diagnosis and treatment thresholds  will also help simplify the interpretation of comparative effectiveness research examining available treatments  and studies testing emerging therapeutics. Outcome measures  also need to be standardized and used consistently.Standardizing clinical management and study protocols for preterm neonates is essential as new surgical and non-surgical strategies are developed. With powerful, multi-institutional and multi-dimensional clinical trial infrastructure, the collective efforts of committed investigators can be leveraged to address critical clinical questions relevant to the diagnosis and treatment of PHH over both the short- and long-term. Research priorities in relation to clinical management and clinical studies after IVH are given in Table The workshop was designed to identify areas of opportunity and spur research efforts for PHH of prematurity, but the ultimate goal is to prevent IVH and PHH of prematurity or prevent associated brain injury. The process of moving basic science discoveries into clinical trials and then standard clinical practice, however, is slow and inefficient. During the workshop, participants identified multiple areas that could be improved and opportunities to speed up the transition from basic research to clinical trials.There is a wide range of animal models used for research in PHH of prematurity and germinal matrix hemorrhage , aThere is a paucity of studies on non-surgical therapies in PHH and one goal is to increase this number and move these therapies into clinical trial. However, the literature is littered with clinical trials that proved to be costly failures. To avoid these mistakes, it is imperative that investigators conduct preclinical research at the highest standards of scientific rigor and demonstrate robust reproducibility. It is difficult for one lab or investigator to conduct all of the experiments necessary, but it is possible to streamline these efforts through the use of standardized protocols and active collaboration. In addition, publication of negative data would benefit the entire research community.In addition to the success or failure of an experiment or series of experiments, there are other common stumbling blocks in the development of novel treatments. Many are related to the compound itself including its safety profile, metabolism, and tissue distribution. Mode of delivery can also prevent promising therapies from moving forward. On the business side, compound manufacturing, licensing, and commercialization are issues in which many investigators are not versed but can prevent a therapy from coming to market , 265. Eahttps://www.nih.gov/research-training/rigor-reproducibility/principles-guidelines-reporting-preclinical-research). The RIGOR guidelines and Stroke Therapy Academic Industry Roundtable (STAIR) recommendations have been developed for preclinical studies focused on stroke therapies [Private and public organizations provide useful resources to guide preclinical research. The Operation Brain Trauma Therapy (OBTT) consortium has published a framework for preclinical drug screening and could be a useful model for PHH research . In addiherapies –269. Thehttps://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research). For early-stage development, NINDS has created the IGNITE  Program that include: (1) funding opportunities for assay development and screening potential therapeutic agents, (2) therapeutic agent characterization  the development and validation of animal models, model systems and/or pharmacodynamic markers. Additional information about this program can be found here: https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/Funding-Programs-Researchers/IGNITE.The National Institute of Neurological Disorders and Stroke (NINDS) has also developed programs to streamline preclinical therapeutic development . For later-stage drug development, NIH established the NIH Blueprint Neurotherapeutics Network (BPN) providing support for small molecule discovery and development (https://neuroscienceblueprint.nih.gov/bpdrugs/).For later-stage biologic and biotechnology products, NINDS has established the CREATE Bio  program that includes an optimization track (agent optimizations) and a development track  funding opportunities (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58). Researchers should understand the guidelines and work with their institutions to establish GLP practices early in the drug development process. Resources are also available through the Alzheimer’s Drug Discovery Foundation that cover topics from central nervous system drug discovery through commercialization (https://www.scienceexchange.com/group/addf-access/resources#catList).The Food and Drug Administration (FDA) also provides guidelines for good laboratory practices (GLP) which need to be followed for medical product development for preclinical trials , institutional human research protection offices, and federal agencies such as the NIH and FDA.https://www.neuronext.org/). The standardized and accessible infrastructure of NeuroNext was designed to efficiently and rapidly conduct exploratory phase I and II clinical trials as well as biomarker validation studies.Despite its high prevalence within newborn medicine and hydrocephalus in general, PHH is relatively uncommon at any individual institution. Multi-institutional platforms are therefore critical to conducting meaningful human studies research in PHH. In addition to the HA-supported HCRN, the NIH has worked to develop infrastructure for clinical studies for conditions like PHH. NINDS established the Network for Excellence in Neuroscience Clinical Trials (NeuroNext) that consists of one Clinical Coordinating Center (CCC), a Data Coordinating Center (DCC), and 25 Clinical Sites located throughout the United States . For example, the Molecular Libraries Small Molecule Repository (MLSMR) has over 350,000 compounds. Taking advantage of these resources can accelerate the process of therapy development.Through the National Center for Advancing Translational Sciences (NCATS), the NIH also has important resources for early and late phase studies designed to repurpose drugs developed for other conditions  and Adult HCRN (AHCRN.org), the basic and translational researchers involved with the HA Network for Discovery Science , and the patient community through the HA Patient Powered Interactive Engagement Registry . HANDS is designed to support basic and translational research by directly funding research studies, building shared infrastructure, and convening workshops and conferences. HANDS is also a platform for improving communication between researchers and developing new research collaborations. HAPPIER is a patient reported database. The survey data generated through HAPPIER can be used by researchers. In addition, researchers can work with HA to send out new surveys and also to recruit patients for clinical trials. The HA will continue to develop and modify research programs to best serve the hydrocephalus research community as well as continue advocacy efforts to increase the availability of federal funding for hydrocephalus research.Intraventricular hemorrhage and posthemorrhagic hydrocephalus is a potentially devastating condition in premature neonates with no effective non-surgical therapies. The Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop identified many important areas for future research to help produce a pathway for reducing the occurrence and effects of PHH.


Emergency Medicine (EM) is a relatively young speciality, and in just the last few decades has experienced impressive adaptations and radical changes in its graduate medical education (GME) landscape. EM physicians are considered to be forward thinking, flexible and early adopters in education and as clinicians. With rapidly changing graduate medical education needs, educators require new understandings of adult learning that bridges generational differences.At the 2007 Academic Emergency Medicine Consensus Conference on knowledge translation in emergency medicine, leading EM researchers and educators concluded that graduating physicians require specific skills to bridge the gap between basic knowledge and clinical practice, specifically, with regard to the principles of evidence-based medicine (EBM).-,,, In 2009, The Accreditation Council for Graduate Medical Education (ACGME) challenged educators to adopt learner-centeredIn 2015, the Association of American Medical Colleges (AAMC) investigated workforce trends for healthcare providers and reported an estimated physician shortfall between 40,800 and 104,900 physicians by 2030.  Analysis of potential unmet needs by “patient race and ethnicity, region of the United States, and patient residence in metropolitan area” identified specific areas and specialities of need.,Amid physician shortages, healthcare access challenges, rising educational costs and skyrocketing healthcare costs, the 2015 Institute of Medicine Report on GME, emphasized the need for a new GME model to increase educational program quality and lower costs to the public in accordance with market consolidation, fiscal pressures, and payers’ new focus on the operating model for academic medicine.Concerns from EM educators and Florida’s community EM physicians, as discussed in an open town hall forum at the Florida College of Emergency Physicians Symposium By the Sea 2017, include dilution of educator talent, dilution of quality learning experiences , and  local workforce saturation with program geographic concentration. EM as a speciality strives to meet the needs of our learners and patients in creative ways while continuing to monitor our progress.Emergency Medicine physicians have been shown to readily adapt to changing environments and new educational demands. While not comfortable or easy, EM educators have demonstrated commitment to developing the best educational environment for future emergency physicians. With changing financial support systems directly affecting GME,EM continues to be the innovators of medical education and still strives to balance the needs of our learners, the future needs of our patients and the financial burden of medical education.The author declares that there are no conflicts of interest.


Center for Biologics Evaluation and Research enhances and supports regulatory decision-making and policy development. This work contributes to our regulatory mission, advances medical product development, and supports Food and Drug Administration’s regulatory response to public health crises. This review presents some examples of our diverse scientific work undertaken in recent years to support our regulatory and public health mission. The Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA) has regulatory oversight of blood, tissues, and complex medical products that include vaccines, allergenic products, blood-derived products, certain diagnostics and devices, live biotherapeutics, and novel medical products, such as stem cell-derived products, and other cell and gene therapies.(1)The challenge of ensuring product sterility, i.e., the absence of unwanted infectious agents, is compounded with the use of biological materials  in the manufacture of biological products. Many of the products that CBER regulates comprise components of, or intact, biologically active cells, tissues, viruses, or bacteria. In most cases, this means that they cannot be subject to terminal sterilization. Quite often, other means of inactivating or removing potentially contaminating infectious agents also cannot be applied without compromising the biological activity of the product.(2)There may not be a clear strategy for characterizing a manufactured product to verify that it is safe and potent before exposing study subjects in investigational clinical trials. Biological materials are generally not amenable to the type of straightforward analytical evaluation that might be used with a chemical drug for which the molecular structure is known and can be verified. Biological products by their very nature are complex mixtures.(3)Biological products often elicit immune responses that, depending on the product, might be a desired outcome of the intervention  or an unwanted outcome . Preclinical models might not predict these effects in humans.(4)The product’s mechanism of action might not be sufficiently understood to identify appropriate biomarkers of clinical effect and/or to develop appropriate potency assays.(5)Clinical trial designs need to optimize data collection that enables regulatory evaluation of safety and efficacy. Design must balance the desire to reduce the time and cost of product development with collection of sufficient data, while incorporating patient input and “real world evidence,” as feasible and relevant. These issues are particularly difficult when conducting clinical trials of novel treatments for rare disease where the available pool of patients, and thus the clinical trial group sizes, is quite small.(6)Evaluation of biological product safety and efficacy does not stop at licensure. Rather, it requires the development of means to accurately identify those post-licensure safety signals that might not have been apparent during clinical investigation, while also collecting additional supporting data on efficacy.(7)The products within CBER’s regulatory portfolio are often used to defend the public against emerging infectious disease (EID) outbreaks or acts of bioterrorism or burn/blast events. When addressing the threat of an EID, CBER must evaluate the risks to protect and maintain a robust and safe blood supply. CBER must also identify and develop tools to facilitate development and rapid deployment of promising investigational vaccines.(8)Often the medical products for responding to EID or acts of bioterrorism cannot be ethically or practically evaluated in human clinical trials for efficacy, for ethical or practical reasons. This necessitates development of robust preclinical models for efficacy evaluation.The complex biological products regulated by CBER present a variety of challenges:To meet these challenges, CBER relies on the best available science in its application of relevant laws through regulations and guidance. CBER engages the expertise and ingenuity of its intramural researcher–reviewers to identify and address major scientific gaps. The knowledge acquired facilitates regulatory evaluation and thus fosters development of innovative medical products. The outcomes of these efforts are made available to the public and product developers by publishing the results in peer-reviewed journals. In addition, CBER incorporates knowledge derived from its intramural research program into both informal and formal guidance to sponsors, other policy and regulatory decisions, and development of reference materials and standards to facilitate product evaluation by product developers.Center for Biologics Evaluation and Research supports the science-based regulation of this diverse and complex product portfolio through a similarly diverse applied research program. The aim of this program is to fill knowledge gaps and develop more effective tools for regulatory decision-making and policy development. The unique perspective of scientists within this regulatory agency facilitates solutions to scientific problems that might benefit an entire class of products, rather than a specific product developed by a single sponsor.Center for Biologics Evaluation and Research facilitates successful translation of early-stage medical product development into licensed safe and effective therapies. The results help to improve product manufacturing and identifying potential adverse events in marketed drugs and devices.Center for Biologics Evaluation and Research has four major research goals through which they advance the scientific basis for regulation of biologics, human tissues, and blood.Here, we provide recent examples from our diverse portfolio of research to demonstrate how CBER’s research contributes to each goal.Center for Biologics Evaluation and Research regulators must review the processes used in the manufacture of biologics and critically evaluate their quality and consistency, to ensure that they meet defined standards of safety, purity, and potency . This requires the use of validated methods and standards for evaluating products, including in-process and lot release tests.Center for Biologics Evaluation and Research develops new methods and models to evaluate regulated medical products, evaluates or improves existing methods, and develops reagents, such as reference materials for assessing the reproducibility, sensitivity, and specificity of these test methods. The following examples illustrate our efforts to develop and evaluate models, methods, and reference materials and standards.Many biological medical products are live viruses, bacteria, or mammalian cells. This means they are labile, and therefore, cannot be subjected to processes used for traditional biotechnology products, such as pathogen inactivation or removal; nor can they be subjected to terminal sterilization. Therefore, the raw materials and the products themselves must be thoroughly tested to ensure absence of contaminating infectious agents (adventitious agents). CBER scientists evaluated a technique for improving the sensitivity of detecting adventitious viruses. The technique, called tangential flow filtration, concentrates viruses from large volumes of cell substrate as a preliminary step before testing. The use of tangential flow filtration increases the ability to detect low level contaminants  and can Center for Biologics Evaluation and Research regulates live biotherapeutic products when they are used to treat a specific condition. One of the challenges of determining the safety and purity of these products is that the live bacteria intended to have a beneficial therapeutic effect can interfere with testing for pathogenic contaminating microorganisms. To address this problem, CBER scientists developed a novel approach that uses viruses (bacteriophages) to selectively target and kill biotherapeutic bacteria in test samples, allowing unwanted pathogenic microbes to grow unimpeded. This enables use of standard laboratory methods to detect the harmful contaminants .Many of CBER’s products are complex and difficult to characterize. In fact, the critical attributes that correlate with safety, purity, and potency may not be known. Stem-cell-based therapies are an emerging class of products that are particularly challenging in this regard. Stem cell research holds the promise of innovative medical treatments for a variety of diseases, but also poses unique challenges to regulatory decision-making.One major challenge facing regulators and industry is that we do not know the key, measurable properties of stem cells that correlate with specific, desired clinical outcomes. Several years ago, CBER assembled a consortium of scientists charged with addressing this challenge. The consortium uses different methods in an effort to identify critical stem cell attributes. In addition to evaluating some standard approaches, such as traditional flow cytometry for cell surface markers, CBER scientists are also developing new methods and using technological approaches such as proteomics, single-cell RT-PCR, epigenetics, and microarray.in vivo or in vitro models of wound repair, quantitative differentiation capacity, or immunosuppression  to assess EID rates and risksDeveloping reference materials to facilitate evaluation of new assays to screen for EIDs.During an outbreak of an emerging transfusion-transmitted infectious disease (TTID), there is a delicate balance of priorities between maintaining the availability of blood for life-saving transfusions and reducing or eliminating the risk of TTID. In such situations, CBER uses a multipronged strategy to facilitate the complex decision-making required to ensure the availability of safe blood:Babesia microti, dengue virus, and most recently, Ebola and Zika viruses.In the last 15 years, the safety of the blood supply has been threatened by the agents of transmissible spongiform encephalopathy including variant Creutzfeldt–Jakob disease, as well as emerging and re-merging viruses and other pathogens: West Nile virus, chikungunya virus (ChikV), Center for Biologics Evaluation and Research develops RNA reference standards that sponsors use to evaluate the sensitivity, specificity, and reproducibility of their nucleic acid-based tests intended for clinical diagnosis or blood screening for emerging and reemerging TT viruses. CBER typically characterizes these reference materials through multi-laboratory studies, such as those recently performed for West Nile virus , dengue In spring 2016, CBER participated in a coordinated public health response to the emerging Zika virus outbreak. CBER scientists developed and coordinated a multi-laboratory effort to generate Zika virus RNA reference materials that were adopted by the World Health Organization. Other international standards organizations, such as the National Institute for Biological Standards and Control, have also adopted and distributed them worldwide.(1)Early serology testing of circulating strains to identify strain prevalence(2)Generation of candidate vaccine strains(3)Generation of reagents that are distributed to manufacturers for lot release testing(4)Independent verification of lot release testing results.In addition to protecting the blood supply from the risk of TTIDs, CBER laboratories actively support the development and lot release testing of seasonal and pandemic influenza vaccines in many ways :(1)EarlCenter for Biologics Evaluation and Research prepares reagents to test influenza vaccine potency and ensure standardization of vaccine quality made by manufacturers. Traditionally, the vaccine strain is grown in eggs; bromelain is then used to purify the HA, which is used to immunize sheep. This technique is successful with most virus strains. However, in 2013, when novel H7N9 viruses emerged in China, the Center faced a major, unexpected bottleneck in preparing vaccine reagents when the traditional approach yielded substandard results. CBER scientists overcame that bottleneck by expressing H7N9 HA glycoprotein as a virus-like particle (VLP) using a vaccinia vector—a technique previously developed in our laboratories. Boosting sheep with the VLPs instead of the traditional HA yielded antiserum that significantly improved the quality of lot release assay results .This type of innovation at CBER enables timely reagent production and might overcome future potential bottlenecks in influenza vaccine production that have occurred in the past for both seasonal and pandemic strains.in silico predictive models, as well as in vitro assays and in vivo animal models.Food and Drug Administration relies on data from non-clinical models and methods to support regulatory decisions on first-in-human clinical trials. In particular, before human, phase 1 clinical studies are initiated, the primary focus of FDA review is on safety. Non-clinical studies may identify candidates that should not proceed to human clinical trials. However, there are products for which issues are identified only after they progress into clinical testing, or even wider scale use on the market  can be life threatening. To ensure product developers consider this risk, FDA issued guidance for industry (“Immunogenicity Assessment for Therapeutic Products”). The guidance—a collaboration between CBER and Center for Drugs Evaluation and Research (CDER)—incorporates knowledge and improved mechanistic understanding gained from clinical trials, post-marketing adverse events, and laboratory and research –19.The studies that informed the guidance continue today, providing improved mechanistic insights that lead to new ways to estimate risks of immunogenicity posed by recombinant protein products. Recently, CBER scientists began using a bioengineered analog of the clotting Factor VIIa to identify how neo-sequences introduced into protein drug analogs might induce development of antidrug antibodies (ADA). The work includes developing an approach to identify patients most likely to be affected by this adverse event. ADA impair the drug’s therapeutic benefit and can also be life-threatening themselves. Therefore, improved methods to predict development of ADA can enhance safety and efficacy of innovative medical products.in vitro to bind avidly to one of the peptides with the same mutations as found in the analog. However, only 44% of patients without ADAs had an HLA allele specific for peptides from vatreptacog alfa  forms complexes with the coagulation factor X (FX) that shield the vector from antibodies and complement. This shield facilitates vector transduction of hepatocytes. In contrast, vectors unable to form complexes with FX showed significantly lower levels of infection of and gene expression in, the liver and lung  in the past decade, CBER developed a baboon model. The model is being used for studies aimed at improving the safety and effectiveness of pertussis vaccines.Following introduction of the whole-cell pertussis vaccine in the 1950s, the occurrence of pertussis in the US decreased by over 90%. However, whole-cell pertussis vaccine caused soreness at the injection site and fevers in children (described as reactogenicity). Therefore, the US replaced whole-cell pertussis vaccine with the acellular pertussis (ACP) vaccine in 1997. Subsequently, there was a steady rise in cases, which peaked at nearly 50,000 in 2012, according to the Centers for Disease Control and Prevention.To investigate the cause of this rising trend of pertussis cases in the face of ACP vaccination, CBER developed the first animal model to recapitulate the disease and provide scientific evidence of airborne transmission . StudiesBordetella pertussis, from the nose and throat. Moreover, whole-cell vaccines boosted production of the immune system protein IL-17, which suggests this molecule plays a role in clearing the infection  of adaptive design proposals from product sponsors. The paper provides recommendations to sponsors for developing such proposals, with the aim of encouraging optimal design .In another project, CBER statisticians used a novel version of a Bayesian two-stage adaptive design to analyze a hypothetical Phase II trial of immune globulin —an antibody-based product used as replacement therapy in patients with humoral immunodeficiencies. The study confirmed the validity of using this statistical technique to end a clinical trial early due to either treatment futility or efficacy, an approach that can save developers of novel medical products both time and money .Center for Biologics Evaluation and Research also works to improve safety surveillance using large databases, such as the US Vaccine Adverse Event Reporting System and the FDA Adverse Event Reporting System for drugs. Optimal use of these databases requires automated retrieval of information useful for reviewer analysis. The current natural language processing systems are often hampered by low quality text . CBER developed an algorithm for analyzing low quality texts that is minimally dependent on grammatical and syntactic information . This wiAdditionally, a major limitation to timely tracking of vaccine adverse events using reporting databases, such as those used in the FDA’s Sentinel System, is that the most recent data are 6–9 months old. While these “mature” data give a broad, long-term view of events, it does not allow for timely regulatory responses to adverse events. CBER developed a way to access, use, and evaluate “fresh” data for timely influenza vaccine safety surveillance in the Sentinel System. This approach is now being used to develop an infrastructure that works for other FDA-regulated medical products, such as blood products, that require faster access to safety information and a review response that is closer to “real-time.” .Changes in science and technology are occurring rapidly, impacting many of the products CBER regulates. This means that the Center’s research program must evolve and anticipate, when feasible, developments that are likely to yield innovative medical products.As resources permit, CBER expands capabilities in key technologies, such as high resolution analytical instrumentation (NMR and mass spectrometry), “next-generation sequencing” (NGS), multiparameter analytic and sorting flow cytometry, high resolution microimaging of fixed and living cells and tissues, and tools for sequential imaging of living animals, such as digital X-ray, ultrasound, and a 4.7 T MRI.In addition, CBER developed hardware infrastructure and a bioinformatics team to support transfer, storage, and analysis of large, complex datasets. This high-performance integrated virtual environment (HIVE) supports analysis of NGS data generated not only by our own researchers but also provided by sponsors in regulatory submissions. In addition, CBER is adopting the advanced computational platform provided by HIVE for analysis of other complex data, such as high resolution mass spectra, and integration of product, preclinical, and clinical data. These new tools enable improved regulatory evaluation of medical products. The underlying code supporting HIVE is open source,Vaccine development for emerging pathogens Using the microbiome to treat infection with antibiotic-resistant bacterial pathogensUsing microphysiologic systems to improve safety and effectiveness of tissue-engineered medical productsMechanistic studies of cellular differentiation of induced pluripotent stem cells (iPSCs)Effects of the gene editing endonucleases  on genome integrity and function of human iPSCsFactors that influence T cell activation and how that might inform evaluation of CAR-T cell-based therapies (chimeric antigen receptor)To keep pace with new technology and to anticipate innovative product development, CBER needs scientists with state-of-the-art knowledge. CBER recruits scientists to develop and establish new research programs that respond to emerging public health challenges, new technology, and regulatory needs. New programs that have been initiated in the past 3 years include the following:Center for Biologics Evaluation and Research makes critical contributions to FDA’s efforts to fulfill its regulatory mission. The Center’s active intramural research program provides three important capabilities: (1) rapid responses to urgent public health needs, such as a newly identified post-marketing safety signal or EID outbreak; (2) development and evaluation of new methods to advance development of products by providing better tools for evaluating safety, effectiveness, or product quality; (3) preparation for future products by evaluating potential safety concerns or developing new methods and models to characterize complex new products that enhance effectiveness and product quality.Center for Biologics Evaluation and Research’s scientists play a dual role: they not only perform applied research relevant to key regulatory needs but also participate in the review of submitted regulatory files, perform inspections, participate and organize timely advisory committees and workshops, and inform development of guidance and regulatory decision-making. This dual role of the researcher–reviewer allows CBER to rapidly incorporate the findings of our research program into daily informal guidance provided to sponsors. It also enables the center to share the outcome of our research with both the public and the scientific and regulated communities by publishing in peer-reviewed scientific journals and presenting our research findings at public workshops, advisory committees, and relevant scientific and professional meetings. Essentially, the capabilities resulting from an active intramural research program enable CBER to be prepared, flexible, proactive, and responsive in support of its regulatory mission and its efforts to facilitate development of safer and more effective innovative medical products.MK and EB: provided input into the overall organization, content, and approach for the article. Provided substantive input into the draft of the article at each stage. Wrote initial drafts of some sections of the article. CW: primary author who wrote the initial draft of the article, coordinating input from coauthors, and finalized the article for submission.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.


The rising prevalence of maternal overweight/obesity and excessive gestational weight gain poses a serious public health concern due to the contribution of these factors to increased risk of negative health outcomes for both mother and child. Scant intervention research has indicated moderate short-term improvement in maternal diet and gestational weight gain, with little evidence of long-term behavior change, in parallel with findings from interventions outside of pregnancy. Recent laboratory-based findings from neuroscience implicate aberrant reward processing of food at the brain level  as a contributor to eating beyond energy needs. However, scant research has examined the influence of these processes on weight change in population-based settings, and the relevance of these processes to pregnancy-related weight change has not been explored. The purpose of the Pregnancy Eating Attributes Study (PEAS) is to examine the role of food reward sensitivity in maternal diet and weight change during pregnancy and postpartum. The study examines the interplay of food reward sensitivity with behavioral control, home food environment, and related aspects of eating behavior in the context of weight-related biomedical, psychosocial, genetic and behavioral factors including physical activity, stress, sleep and depression.Women of varying baseline weight status (n = 450) are enrolled early in pregnancy and followed, along with their infants, until 1 year postpartum. Assessments occur during each trimester of pregnancy, and postpartum at approximately 2 months, 6 months, 9 months and 12 months. Maternal food reward, self-control, home food environment, eating behaviors, dietary intake, health behaviors, and anthropometrics are assessed along with maternal and infant clinical and biological data, infant anthropometrics, and feeding practices. Primary exposures of interest include food reward sensitivity, behavioral control, and home food environment. Primary outcomes include gestational weight gain, postpartum weight retention and maternal diet quality.With increasing evidence suggesting the relevance of food reward sensitivity for understanding eating behavior, PEAS aims to advance understanding of the determinants of eating behavior during pregnancy, informing future interventions for improving maternal diet and weight change, and leading to improved maternal and child health and weight trajectories.Clinicaltrials.gov, NCT02217462. Date of registration: August 13, 2014 Approximately two-thirds of women of reproductive age are overweight or obese , and acrThe problem of obesity and weight gain in pregnancy is linked to the larger epidemic of obesity in the US which, along with poor diet quality, contributes to numerous adverse health outcomes, including reduced fecundity and fertility and chronic diseases such as cardiovascular disease, sleep disorders, and many cancers . The pooThe most proximal cause for excess body weight is eating beyond energetic needs. An emerging hypothesis for widespread excess energy intake leading to weight gain and increased adiposity is excess “hedonically motivated food intake” , which pEvidence suggests that the neural reward response to food stimuli is dependent on a number of food attributes, indicating that highly palatable foods may be more likely than others to contribute to hedonically-driven overeating. Neural reward response is positively associated with perceived energy content of food in images –49, and Basic, behavioral, and neuroimaging research has identified a number of important factors associated with inter-individual differences in the neural reward response to food stimuli and its plasticity. Repeated over-eating of highly palatable foods is hypothesized to be a function of individuals’ amplified reward response to highly palatable foods and/or associated food cues – 67. StuIn addition to the contributions of reward responsivity and food reinforcement value to eating behavior, evidence also indicates that decreased self-regulation may be a risk factor for overeating and excess weight gain. Both self-report and laboratory measures of impulsivity correlate positively with caloric intake , 77 and Previous interventions to improve dietary intake and promote healthy body weight based on current health behavior theories have yielded minimal success, suggesting the need for a more comprehensive understanding of the determinants of eating behavior. The reward-driven motivation to eat, culminating in widespread susceptibility to the influence of high food reinforcement value  on overeating, may be a central factor that has been absent from interventions to influence eating behaviors and weight change. Progress in understanding determinants of GWG and postpartum weight change may be advanced by extending recent findings from lab-based research on the neural reward response to highly palatable food cues to large-scale population-based research. Unique aspects of pregnancy further support the scientific utility of investigating the role of these constructs in diet and weight change. The period of pregnancy and postpartum is a bounded time of expected weight change, offering a window during which influences on weight change may be investigated. An increase in dietary intake is socially normative , and consequently, efforts to restrain intake may be relaxed. Additionally, because many women do not return to their pre-pregnancy weight, excess GWG and postpartum weight retention represent important risk factors for long-term excess weight. The proposed research investigates the influence of food reward sensitivity, home food environment, and behavioral control on maternal dietary intake and weight outcomes during pregnancy and postpartum. The study will further explore these constructs in the context of other aspects of eating behavior such as dietary restraint and motivation for healthful eating, as well as weight-related biomedical, psychosocial and behavioral factors including genetics, physical activity, stress, sleep and depression.The hypothesized core conceptual model  underlyiFood reward sensitivity is a within-person characteristic posited to influence dietary intake and body weight outcomes. All else held constant, individuals with higher food reward sensitivity are hypothesized to consume more food, leading to excess energy intake and increased risk of excessive weight gain and overweight/obesity.Behavioral control (self-regulation) is the other key personal factor influencing dietary intake and weight outcomes –83. IndiThe primary environmental factor included in this model is the reinforcement value of foods in the home. The degree to which food environments are predominated by foods sufficiently high in reinforcement value so as to induce hedonic overeating is hypothesized to influence the relationship between food reward sensitivity, behavioral control, dietary intake and weight outcomes . IndividMore distal influences assessed in this study but not included in the conceptual model include personal factors such as stress, sleep and depression, which are hypothesized to influence food reward sensitivity, behavioral control and dietary intake directly. Consequently, these factors also impact dietary intake and weight outcomes through indirect pathways. Physical activity is hypothesized to influence energy expenditure and weight outcomes directly. Genes are hypothesized to have direct effects on all interpersonal model components.The overarching aim of this research is to examine the role of food reward sensitivity, food reinforcement value, and behavioral control in maternal weight change and dietary intake during pregnancy and postpartum. Primary research questions include the association of food reward sensitivity with maternal dietary intake and weight outcomes; the moderating role of behavioral control and the availability of high-reinforcement value foods in the home environment; and differences in food reinforcement value of fruits and vegetables in their natural form versus highly processed sweet and savory snacks. Secondary research questions include examination of the interplay of food reward sensitivity, self-control, and the home food environment with other eating-related behaviors; the role of maternal food reward sensitivity and dietary intake on infant feeding behavior and body composition, and the roles of maternal sleep, stress and depression as potential moderators of the effect of food reward sensitivity on dietary intake, and change in body weight and body composition.2), overweight (BMI 25–29.9 kg/m2) and obese (BMI ≥30 kg/m2). Women are followed through pregnancy and until 1-year postpartum, along with their infants from birth to 1 year, with collection of anthropometrics, blood, stool, and urine specimens, previous and current medical and demographic information, and dietary intake and eating and physical activity behaviors. We anticipated an 11 % attrition rate from enrollment to delivery and another 12 % attrition rate from delivery to 1 year postpartum for a total sample size of approximately 350 women-child dyads.PEAS is a prospective observational study of 450 women without evidence of psychiatric or eating disorders, recruited in early pregnancy (≤12 weeks gestation), including those of normal weight ; multiple pregnancy; participant-reported eating disorder; any fetal anomaly requiring surgery with hospital admission following delivery ; any medical condition contraindicating participation in the study such as chronic illnesses or use of medication that could affect diet or weight ; psychosocial condition contraindicating participation in the study . Recruitment of participants was initiated November 2014 and expected to be completed by December 2016.Participants are recruited from women obtaining prenatal care at the obstetrics clinics at the University of North Carolina (UNC) at Chapel Hill Healthcare System with two locations, one in the hospital and the other off campus – Timberlyne. Inclusion criteria include the following: confirmed pregnant ≤12 weeks gestation at enrollment; uncomplicated singleton pregnancy anticipated; age ≥18 and <45 at screening; willingness to undergo study procedures and provide informed consent for her participation and assent for the baby’s participation; BMI ≥18.5 kg/mPotential participants are identified through the electronic clinical appointments and medical records database. These women are approached regarding the study by research staff and provided with information regarding study participation, including referral to information on the study website. All participants provide signed informed consent to participate in the study. After delivery, participants additionally provide signed informed consent for their child’s participation. Follow-up comprises designated data collection at scheduled clinic visits for the mother during pregnancy and postpartum, and for the baby after delivery, as well as self-report assessments that the participant completes online by secure connection at the study website. Certain specified medical history, medication use, laboratory data and pregnancy complications are extracted from the electronic medical record system post-delivery. Study procedures were approved by the UNC Institutional Review Board.Study assessments are conducted prenatally at each trimester of pregnancy, and postpartum at approximately 2 months, 6 months, 9 months and 12 months. A summary of the data collection schedule is provided in Outcome measures include maternal anthropometrics , maternal dietary intake assessed using 24-hour dietary recalls , 92, infIndividual’s food reward sensitivity is measured using several validated questionnaires , 97–99. Self-regulation is measured using two validated questionnaires , 107. ThPower analyses are based on examination of the association of food reward sensitivity with GWG, energy intake, and diet quality. For analysis of GWG, the null hypothesis to be tested is that a subject’s weight gain during pregnancy is independent of the subject’s food reward sensitivity, using a regression model with weight gain as the dependent variable and food reward sensitivity score as the independent variable. The null hypothesis is then the regression coefficient beta in the model is zero. For the power calculation, we assume a mean food reward sensitivity score of 2.28 with standard deviation of 0.76, an overall mean GWG of 29.7 pounds with standard deviation of 11.7, both measured at three time points during pregnancy, and utilizing the average of the three measurements. Further assuming a correlation between two food reward sensitivity measurements of 0.7, with a standard deviation of the average score of 0.68, taking retention into account, and an effective sample size of 400 women, with a two-sided significance level of 0.05, the power will be at least 90 % to detect a regression coefficient of 2.76, interpreted as the estimated gain in gestational weight for every unit increase in the food reward sensitivity score.For analysis of energy intake, the null hypothesis to be tested is that a subject’s energy intake is independent of the subject’s food reward sensitivity, using a regression model with energy intake as the dependent variable and food reward sensitivity as the independent variable. The null hypothesis is then the regression coefficient beta in the model is zero. Assuming energy intake has a mean of 2296 kcal and standard deviation of 453 kcal, and an effective sample size of 400, with a two-sided significance level of 0.05, the power will be at least 90 % to detect a regression coefficient of 106.83 kcal, interpreted as the estimated increase of dietary intake for every unit increase in the food reward sensitivity score.The Healthy Eating Index-2010 (HEI-2010) is the primary indicator of diet quality. The HEI2010 score measures conformance to the 2010 Dietary Guidelines for Americans, and is comprised of 12 component scores corresponding to dietary guidelines for intake of total fruit, whole fruit, total vegetables, greens and beans, whole grains, dairy, total protein foods, seafood and plant proteins, fatty acids, refined grains, sodium, and empty calories . The nulThree substudies are embedded within the PEAS observational cohort study in order to examine food reward sensitivity and related constructs in greater depth than could be conducted in the main study. Substudies include focus groups, an experimental study using an eating in the absence of hunger paradigm, and functional magnetic resonance imaging (fMRI) of neural response to food stimuli.A series of focus groups is conducted to provide indepth exploration of participants’ perceptions relevant to food reward value and other influences on eating during pregnancy. Participants are recruited from the main cohort, including participants of normal weight, overweight, and obese weight categories, for a total of approximately 80 women. Inclusion/exclusion criteria are the same as those used for the main study.This substudy involves a behavioral experiment that investigates hedonic eating using an eating in the absence of hunger (EAH) paradigm. Aims of the substudy include examining the relationship of food reward sensitivity and BMI with EAH and the potential modifying role of self-control. Participants are recruited from the main cohort, to include participants from the normal weight, overweight, and obese weight categories, for a total of approximately 50 women. Women participate in the behavioral experiment at any point during the window of their second trimester. Inclusion/exclusion criteria are the same as those used for the main study. Additionally, eligible women must have no allergies or aversions to foods served in the substudy protocol.This substudy will evaluate brain response to multiple types of food stimuli, varied on hedonic value, as well as an examination of possible weight related differences in resting state functional connectivity and brain network organization using functional magnetic resonance imaging (fMRI). Specifically, this substudy will examine the relationship of brain response to food stimuli  with current weight status and GWG, test for the ability of brain response to food stimuli to predict postpartum weight retention (prospectively), evaluate between-food differences in brain response to food stimuli, as well as test for associations of brain response to food stimuli with survey and behavioral measures of food reward sensitivity. Approximately 75 participants, including normal weight, over-weight, and obese women, are recruited from the PEAS cohort to participate at their six-month postpartum study visit and undergo behavioral and survey assessments of food reward, executive functioning and one fMRI session.The problem of maternal overweight, obesity, and excessive GWG is a critical public health concern. Findings from basic research in animals and humans indicate the reward-driven motivation to eat culminating in wide-spread susceptibility to the influence of highly palatable foods on overeating may be a central factor that is absent from current predominant theoretical frameworks explaining eating behavior. Research on the neurobiology of eating behavior has raised important unanswered questions that must be addressed in order to enable the translation to population-based research. The degree to which food reward sensitivity is associated with dietary intake and weight change during pregnancy is not well-understood, nor is the interplay of food reward sensitivity with other relevant constructs including self-control, the food environment, and other eating and health-related behaviors. This observational study addresses important knowledge gaps by examining the implications of food reward sensitivity for maternal diet and weight change. PEAS aims to advance understanding of the determinants of eating behavior and weight change, informing future interventions for improving maternal diet and obesity risk, and leading to improved maternal and child health trajectories.