Chemoenzymatic Catalysis: Cooperativity Enables Opportunity.

The application of enzymes in synthetic organic chemistry has emerged as a powerful means to generate molecular complexity in a highly selective, efficient, and sustainable manner. While enzymes have increasingly been incorporated into synthetic sequences for numerous academic and industrial applications on their own and in sequential processes, their utility in cooperative catalysis with small molecule catalytic platforms has recently drawn increased attention across the field of organic synthesis. In this review, we present a selection of notable accomplishments in cooperative chemoenzymatic catalysis and provide a perspective on its future directions.

Building the MCH Public Health Workforce of the Future: A Call to Action from the MCHB Strategic Plan.

INTRODUCTION: In 2021, the Maternal and Child Health Bureau (MCHB) released a new strategic plan to guide its work over the next 10-15 years. The plan highlights four goals-access, equity, workforce capacity, and impact-that are essential to achieving MCHB's vision. METHODS: We present 13 recommendations to highlight opportunities for ongoing and new activities aligned with Goal 3 of the plan-"Strengthen Public Health Capacity and Workforce for MCH." RESULTS: Recommendations 1-3 highlight the need to support pathways into state and local MCH public health (PH) positions, to offer accessible and high-quality training for the practicing workforce, and to build capacity to address health and social inequities. Recommendations 4-7 discuss the need to build a racially and ethnically diverse workforce, ensure equity and anti-racism are foundational concepts in training, and strengthen engagement of community members and those with lived experience as part of the MCH PH workforce. Recommendations 8-10 outline opportunities to enhance MCH workforce data and measurement frameworks, and support practice-based research. Recommendations 11-12 discuss the importance of academic-practice partnerships and the need to spur innovation. Recommendation 13 highlights the need to define and amplify the unique skillset of the MCH PH workforce. CONCLUSIONS: The release of the MCHB strategic plan comes at a time of critical need to build and sustain a MCH PH workforce to achieve equity for MCH populations. We encourage the field to engage in dialogue around the recommendations presented in this paper, and to offer additional actions to build and support the MCH PH workforce.

The MCH training program: developing MCH leaders that are equipped for the changing health care landscape.

This article examines the success of the Maternal and Child Health (MCH) Bureau's MCH Training Program in producing the next generation of MCH leaders, equipped with interdisciplinary, leadership skills necessary for the changing health care landscape. A secondary data analysis of performance measure data (2007-2011) collected through the discretionary grant information system was performed. Grantees were grouped by grant program (n = 10) for this analysis. Outcomes of interest 5 years post-program completion included: (1) the percentage of long-term training program graduates who demonstrate field leadership; (2) the percentage of long-term trainees (LTT) who remain in MCH, work with underserved and/or vulnerable populations, or work in a public health agency/organization; and (3) the percentage of LTT working in an interdisciplinary manner to serve the MCH population. Summary output data on the number of LTT reached was also calculated. The number of LTT participating in the MCH Training Program increased between 2007 and 2011. Over 84% of LTT demonstrate field leadership 5 years after program completion, while 78.2% of LTT remain in MCH work and 83% are working with underserved or vulnerable populations. At 5-years post-program completion, over 75% of LTT are working in an interdisciplinary manner to serve the MCH population. The MCH Training Program has produced well-positioned leaders. Continued investment in the MCH Training Program is critical to ensure a well-trained pipeline of health professionals equipped to address the special health needs of MCH populations in an evolving health system.

Transformation of the title V maternal and child health services block grant.

This paper describes the transformation of the Title V Maternal and Child Health (MCH) Services Block Grant. The Maternal and Child Health Bureau of the Health Resources and Services Administration led a 21-month visioning process to engage input from MCH stakeholders and other national, state and local MCH leaders, families and other partners to improve, innovate, and transform the Title V MCH Services Block Grant. The process has helped inform the development of a new grant guidance for the next 5-year cycle beginning in fiscal year 2016. The triple aims of the transformation are to reduce burden, maintain flexibility, and increase accountability. State reporting burden is reduced by aligning and streamlining the needs assessment, annual report and application, reducing the number of forms States have to fill out, eliminating Health Systems Capacity Indicators, and prepopulating the annual report and application with State data using national data sources. State flexibility is maintained through the needs assessment process whereby State needs and priorities drive the selection of National Performance Measures and State-specific Performance Measures, and the development of State Action Plan and Evidence-based/informed Strategy Measures. Accountability is increased through the new three-tiered performance measurement framework, which will help States tell a more coherent and compelling story about the impact of Title V on the health of the Nation's mothers, children, and families. The ultimate success of the transformation will be measured by how much the transformed Title V program moves the needle in MCH in the States and for the Nation.

Decarboxylative halogenation of indoles by vanadium haloperoxidases.

Halogenated heteroarenes are key building blocks across numerous chemical industries. Here, we report that vanadium haloperoxidases are capable of producing 3-haloindoles through decarboxylative halogenation of 3-carboxyindoles. This biocatalytic method is applicable to decarboxylative chlorination, bromination, and iodination in moderate to high yields and with excellent chemoselectivity.

Developing a standard approach to examine infant mortality: findings from the State Infant Mortality Collaborative (SIMC).

States can improve pregnancy outcomes by using a standard approach to assess infant mortality. The State Infant Mortality Collaborative (SIMC) developed a series of analyses to describe infant mortality in states, identify contributing factors to infant death, and develop the evidence base for implementing new or modifying existing programs and policies addressing infant mortality. The SIMC was conducted between 2004 and 2006 among five states: Delaware, Hawaii, Louisiana, Missouri, and North Carolina. States used analytic strategies in an iterative process to investigate contributors to infant mortality. Analyses were conducted within three domains: data reporting (quality, reporting, definitional criteria, and timeliness), cause and timing of infant death (classification of cause and fetal, neonatal, and postneonatal timing), and maturity and weight at birth/maturity and birth weight-specific mortality. All states identified the SIMC analyses as useful for examining infant mortality trends. In each of the three domains, SIMC results were used to identify important direct contributors to infant mortality including disparities, design or implement interventions to reduce infant death, and identify foci for additional analyses. While each state has unique structural, political, and programmatic circumstances, the SIMC model provides a systematic approach to investigating increasing or static infant mortality rates that can be easily replicated in all other states and allows for cross-state comparison of results.

Assessment of state measures of risk-appropriate care for very low birth weight infants and recommendations for enhancing regionalized state systems.

The goal of this study was to examine state measurements and improvements in risk-appropriate care for very low birth weight (VLBW) infants. The authors reviewed state perinatal regionalization models and levels of care to compare varying definitions between states and assess mechanisms of measurement and areas for improvement. Seven states that presented at a 2009 Association of Maternal & Child Health Programs Perinatal Regionalization Meeting were included in the assessment. Information was gathered from meeting presentations, presenters, state representatives, and state websites. Comparison of state levels of care and forms of regulation were outlined. Review of state models revealed variability in the models themselves, as well as the various mechanisms for measuring and improving risk-appropriate care. Regulation of regionalization programs, data surveillance, review of adverse events, and consideration of geography and demographics were identified as mechanisms facilitating better measurement of risk-appropriate care. Antenatal or neonatal transfer arrangements, telemedicine networks, acquisition of funding, provision of financial incentives, and patient education comprised state actions for improving risk-appropriate care. The void of explicit and updated national standards led to the current variations in definitions and models among states. State regionalization models and measures of risk-appropriate care varied greatly. These variations arose from inconsistent definitions and models of perinatal regionalization. Guidelines should be collaboratively developed by healthcare providers and public health officials for consistent and suitable measures of perinatal risk-appropriate care.

The Autism Intervention Research Network on Physical Health (AIR-P) Research Agenda.

OBJECTIVES: In the United States, autistic individuals experience disproportionate physical and mental health challenges relative to non-autistic individuals, including higher rates of co-occurring and chronic conditions and lower physical, social, and psychological health-related quality of life. The Autism Intervention Research Network on Physical Health (AIR-P) is an interdisciplinary, multicenter research network for scientific collaboration and infrastructure that aims to increase the life expectancy and quality of life for autistic individuals, with a focus on underserved or vulnerable populations. The current paper describes the development of the AIR-P Research Agenda. METHODS: Development of the research agenda involved an iterative and collaborative process between the AIR-P Advisory Board, Steering Committee, and Autistic Researcher Review Board. The methodology consisted of 3 phases: (1) ideation and design, (2) literature review and synthesis; and (3) network engagement. RESULTS: Six core research priorities related to the health of autistic individuals were identified: (1) primary care services and quality, (2) community-based lifestyle interventions, (3) health systems and services, (4) gender, sexuality, and reproductive health, (5) neurology, and (6) genetics. Specific topics within each of these priorities were identified. Four cross-cutting research priorities were also identified: (1) neurodiversity-oriented care, (2) facilitating developmental transitions, (3) methodologically rigorous intervention studies, and (4) addressing health disparities. CONCLUSIONS: The AIR-P Research Agenda represents an important step forward for enacting large-scale health-promotion efforts for autistic individuals across the lifespan. This agenda will catalyze autism research in historically underrepresented topic areas while adopting a neurodiversity-oriented approach to health-promotion.

Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial.

BACKGROUND: We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. METHODS: This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per µL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [<10-4]) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. FINDINGS: Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. INTERPRETATION: BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. FUNDING: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Maternal and Child Health Bureau's Autism Research Program.

OBJECTIVES: To provide an overview and quantitatively demonstrate the reach of the Health Resources and Services Administration's Maternal and Child Health Bureau autism research program. METHODS: We reviewed program reports and internal data from 59 autism research grantees. The US federal Interagency Autism Coordinating Committee's strategic plan questions were used as a framework to highlight the contributions of the autism research program in advancing the field. RESULTS: The autism research program grantees advance research in several ways. Grantees have strengthened the evidence for autism interventions by conducting 89 studies at 79 distinct research sites. A total of 212 708 participants have enrolled in autism research program studies and 361 researchers have contributed to furthering autism research. The program addresses topics that align with the majority of the Interagency Autism Coordinating Committee's priority topic areas, including advancements in treatments and interventions, services and supports, and identifying risk factors. Grantee products include 387 peer-reviewed publications, 19 tools, and 13 practice guidelines for improving care and intervention practices. CONCLUSIONS: The autism research program has contributed to medical advances in research, leveraged innovative training platforms to provide specialized training, and provided access to health services through research-based screening and diagnostic procedures. Autism research program studies have contributed to the development of evidence-based practice guidelines, informed policy guidelines, and quality improvement efforts to bolster advancements in the field. Although disparities still exist, the Health Resources and Services Administration's Maternal and Child Health Bureau can reduce gaps in screening and diagnosis by targeting interventions to underserved populations including minority and rural communities.

Maternal and neonatal outcomes associated with infertility.

Objective: To investigate perinatal outcomes in a cohort of fertile and infertile nulliparous women. Design: Retrospective cohort study. Setting: Academic medical center. Patients: All nulliparous women delivering singletons ≥24-week gestation at our center from 1 January 2012 to 31 December 2012 were included. Women were classified into two groups - fertile and infertile - based on a chart review at the time of delivery. Outcome measure: Perinatal outcomes of interest included mode of delivery, gestational age at delivery, and birth weight. Results: A total of 3293 mother/infant dyads fulfilled the inclusion criteria. Of these, 277 women (8.4%) were classified as infertile. Infertile women were significantly older than fertile women. In bivariate analyses, infertile women were more likely to undergo cesarean delivery (51.8 versus 36.1%, p < .001) and deliver at an earlier gestational age (38.9 ± 2.3 versus 39.4 ± 1.7 weeks, p < .0001). Infertility was no longer significantly associated with cesarean delivery after adjusting for maternal age. Infertility remained associated with an earlier gestational age at delivery after adjusting for maternal age and maternal race (ß coefficient -0.42, 95%CI -0.64, -0.2). There was no difference in infant birth weight. Late preterm deliveries (34-36 completed gestational weeks) accounted for 8.3% of deliveries for infertile women compared to 4.3% for fertile women (p = .032). Conclusions: We conclude that the increased risk of cesarean section associated with infertility is driven by maternal age. Late preterm infants represent a key cohort for further evaluation in the perinatal outcomes of infertile women.

Oligohydramnios compromises lung cells size and interferes with epithelial-endothelial development.

BACKGROUND AND OBJECTIVE: Severe oligohydramnios can induce pulmonary hypoplasia. However, the mechanisms by which leaking of fluids cause lung hypoplasia are not well defined. The objective of this study was to characterize a mouse model of pulmonary hypoplasia induced by oligohydramnios. METHODS: Amniotic sacs were punctured on E14.5 of gestation. Untouched fetuses were used as control. Pregnancy was allowed to continue until E18.5 in which lung tissue was collected and evaluated for morphometry, proliferation, differentiation, apoptosis, and angiogenesis. RESULTS: Our results found that lung weight, lung to total body weight ratio, and lung water content were reduced in oligohydramnios when compared to controls. In contrast, oligohydramnios did not affect the DNA content. Morphometric studies confirmed that oligohydramnios fetuses had smaller air spaces than control. Interestingly, cells from oligohydramnios fetuses have smaller size and less regular shapes. Oligohydramnios decreased the differentiation of type I epithelial cells and compromised apoptosis and angiogenesis while proliferation was not affected. CONCLUSIONS: Although, the smaller size of the lung could be explained by a decreased of lung fluids, our data suggest that increased of external compression secondary to severe oligohydramnios can compromise cell size and interfere with epithelial and endothelial development. Type I epithelial cells could have an unrecognized key role in the differentiation of the distal lung mediated by mechanical signals. Pediatr Pulmonol. 2017;52:746-756. © 2017 Wiley Periodicals, Inc.

Impact of fertility treatment on severe maternal morbidity.

OBJECTIVE: To determine if fertility treatment is associated with increased risk of severe maternal morbidity (SMM) compared with spontaneous pregnancies. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENT(S): In 2012, 6,543 women delivered live births >20 weeks gestation at our center. Women were categorized based on mode of conception: in vitro fertilization (IVF), non-IVF fertility treatment (NIFT), or spontaneous pregnancies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The main outcome was presence of true SMM, such as eclampsia, respiratory failure, and peripartum hysterectomy. Deliveries were screened with the use of: 1) International Classification of Diseases 9 codes; 2) prolonged postpartum stay; 3) maternal intensive care unit admissions, and 4) blood transfusion. The charts of women meeting the screening criteria were reviewed to identify true SMM based on a previously validated method, recognizing that medical record review is the criterion standard. RESULT(S): Of the 6,543 deliveries, 246 (3.8%) were IVF conceptions and 109 (1.7%) NIFT conceptions. Sixty-nine cases of true SMM were identified (1.1%). In multivariate analyses, any fertility treatment (IVF + NIFT) was associated with increased risk of SMM compared with spontaneous conceptions. In a subset analysis of singletons only, the association between any fertility treatment (IVF + NIFT) and SMM was not statistically significant. CONCLUSION(S): Overall, fertility treatment increased risk for SMM events. Given the limited sample size, the negative finding with singleton gestations is inconclusive. Larger multicenter studies with accurate documentation of fertility treatment and SMM cases are needed to further clarify the risk associated with singletons.

Fathers matter: the role of paternal age in infant mortality.

Infant mortality is the most widely used indicator of a nation's health status and is associated with a plethora of maternal and socioeconomic factors. Although the association between young and old maternal age and the risk of infant mortality is well established, the link between paternal age and birth outcomes has received far less attention. This study seeks to examine the added impact of paternal age on infant mortality, above and beyond that of maternal age among married couples. Using the 2002 linked birth and infant death data set (N = 63,754), hazard odds ratios for the association between combined adolescent and adult maternal and paternal age and the risk of infant mortality were estimated. Maternal demographic characteristics, such as education and race/ethnicity were controlled. The findings indicate that, independent of maternal education and race/ethnicity, adolescent father adds additional risk, above and beyond that of maternal age, only when the mother is older (21-45 years; hazard ratio = 2.7). This study highlights that for married couples, adolescent fathers add to the risk of infant mortality when the mothers are older, providing insight into the role of paternal age in infant mortality. Implications for additional research are discussed.

Financing newborn screening: sources, issues, and future considerations.

Newborn screening (NBS) programs are population-based public health programs and are uniquely financed footline compared with many other public health programs. Since they began more than 45 years ago, the financing issues have become more complex for NBS programs. Today, almost all programs have a portion of their costs paid by fees. The fee amounts vary from program to program, with little standardization in the way they are formulated, collected, or used. We previously surveyed 37 of the 51 dried blood spot screening programs throughout the United States, and confirmed an increasing dependence on NBS fees. In this study, we have collected responses from all 51 programs (100%), including updated responses from the original 37, and updated our fee listings. Comments from those surveyed indicated that the lack of a national standardized procedural coding system for NBS contributes to billing complexities. We suggest one coding possibility for discussion and debate for such a system. Differences in Medicaid interpretations may also contribute to financing inequities across NBS programs and there may be benefit from certain clarifications at the national level. Completed survey responses accounted for few changes in the conclusions of our original survey. We confirmed that 90 percent of all NBS programs have a fee paid by parents or a third party payer. Sixty-one percent reported receiving some funds from the Maternal and Child Health Services Title V block grant, 33 percent reported some funding from state general revenue/general public health appropriations; and 24 percent reported obtaining direct reimbursement from Medicaid (without passing through a third party). A majority of programs (63%) reported budget increases between 2002 and 2005, with increases primarily from fees (72%) and to a lesser extent from Medicaid, the Title V block grant, and state general revenues.

Financing state newborn screening programs: sources and uses of funds.

BACKGROUND: Financing for newborn screening is different from virtually all other public health programs. All except 5 screening programs collect fees as the primary source of program funding. A fee-based approach to financing newborn screening has been adopted by most states, to ensure consistent funding for this critical public health activity. METHODS: Two types of data are reported here, ie, primary data from a survey of 37 state public health agencies and findings from exploratory case studies from 7 states. RESULTS: Most of the programs that participated in this survey (73%) reported that their newborn screening funding increased between 2002 and 2005, typically through increased fees and to a lesser extent through Medicaid, Title V Maternal and Child Health Services Block Grant, and state general revenue funding. All of the responding states that collect fees (n = 31) use such funds to support laboratory expenses, and most (70%) finance short-term follow-up services and program management. Nearly one half (47%) finance longer-term follow-up services, case management, or family support beyond diagnosis. Other states (43%) finance genetic or nutritional counseling and formula foods or treatment. CONCLUSIONS: Regardless of the source of funds, the available evidence indicates that states are committed to maintaining their programs and securing the necessary financing for the initial screening through diagnosis. Use of federal funding is currently limited; however, pressure to provide dedicated federal funding would likely increase if national recommendations for a uniform newborn screening panel were issued.