Maternal mortality in the United States: research gaps, opportunities, and priorities.

Maternal mortality and severe maternal morbidity are urgent issues in the United States. It is important to establish priority areas to address these public health crises. On April 8, 2019, and May 2 to 3, 2019, the Eunice Kennedy Shriver National Institute of Child Health and Human Development organized and invited experts with varied perspectives to 2 meetings, a community engagement forum and a scientific workshop, to discuss underlying themes involved in the rising incidence of maternal mortality in the United States. Experts from diverse disciplines reviewed current data, ongoing activities, and identified research gaps focused on data measurement and reporting, obstetrical and health system factors, social determinants and disparities, and the community perspective and engagement. Key scientific opportunities to reduce maternal mortality and severe maternal morbidity include improved data quality and measurement, understanding the populations affected as well as the numerous etiologies, clinical research to confirm preventive and interventional strategies, and engagement of community participation in research that will lead to the reduction of maternal mortality in the United States. This article provides a summary of the workshop presentations and discussions.

Adolescent Interventions to Manage Self-Regulation in Type 1 Diabetes (AIMS-T1D): randomized control trial study protocol.

BACKGROUND: Self-regulation (SR), or the capacity to control one's thoughts, emotions, and behaviors in order to achieve a desired goal, shapes health outcomes through many pathways, including supporting adherence to medical treatment regimens. Type 1 Diabetes (T1D) is one specific condition that requires SR to ensure adherence to daily treatment regimens that can be arduous and effortful (e.g., monitoring blood glucose). Adolescents, in particular, have poor adherence to T1D treatment regimens, yet it is essential that they assume increased responsibility for managing their T1D as they approach young adulthood. Adolescence is also a time of rapid changes in SR capacity and thus a compelling period for intervention. Promoting SR among adolescents with T1D may thus be a novel method to improve treatment regimen adherence. The current study tests a behavioral intervention to enhance SR among adolescents with T1D. SR and T1D medical regimen adherence will be examined as primary and secondary outcomes, respectively. METHODS: We will use a randomized control trial design to test the impact of a behavioral intervention on three SR targets: Executive Functioning (EF), Emotion Regulation (ER), and Future Orientation (FO); and T1D medical regimen adherence. Adolescents with T1D (n = 94) will be recruited from pediatric endocrinology clinics and randomly assigned to treatment or control group. The behavioral intervention consists of working memory training (to enhance EF), biofeedback and relaxation training (to enhance ER), and episodic future thinking training (to enhance FO) across an 8-week period. SR and treatment regimen adherence will be assessed at pre- and post-test using multiple methods (behavioral tasks, diabetes device downloads, self- and parent-report). We will use an intent-to-treat framework using generalized linear mixed models to test our hypotheses that: 1) the treatment group will demonstrate greater improvements in SR than the control group, and 2) the treatment group will demonstrate better treatment regimen adherence outcomes than the control group. DISCUSSION: If successful, SR-focused behavioral interventions could improve health outcomes among adolescents with T1D and have transdiagnostic implications across multiple chronic conditions requiring treatment regimen adherence. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03688919; registered September 28, 2018.

Resistance to the most common optic neuropathy is associated with systemic mitochondrial efficiency.

Glaucomatous optic neuropathy, an important neurodegenerative condition and the commonest optic neuropathy in humans, is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with ageing and raised intraocular pressure (IOP). Using glaucomatous optic neuropathy as an exemplar for neurodegeneration, this study investigates putative factors imparting resistance to neurodegeneration. Systemic mitochondrial function, oxidative stress and vascular parameters were compared from isolated lymphocytes, whole blood and urine samples between 30 patients who have not developed the neuropathy despite being exposed for many years to very high IOP ('resistant'), 30 fast deteriorating glaucoma patients despite having low IOP ('susceptible'), and 30 age-similar controls. We found that 'resistant' individuals showed significantly higher rates of ADP phosphorylation by mitochondrial respiratory complexes I, II and IV, hyperpolarised mitochondrial membrane potential, higher levels of mitochondrial DNA, and enhanced capacity to deal with cytosolic calcium overload and exogenous oxidative stress, as compared to both controls and glaucoma patients. While it has been known for some years that mitochondrial dysfunction is implicated in neurodegeneration, this study provides a fresh perspective to the field of neurodegeneration by providing, for the first time, evidence that systemic mitochondrial efficiency above normal healthy levels is associated with an enhanced ability to withstand optic nerve injury. These results demonstrate the importance of cellular bioenergetics in glaucomatous disease progression, with potential relevance for other neurodegenerative disorders, and raise the possibility for new therapeutic targets in the field of neurodegeneration.

Changing Work and Work-Family Conflict: Evidence from the Work, Family, and Health Network*

Schedule control and supervisor support for family and personal life are work resources that may help employees manage the work-family interface. However, existing data and designs have made it difficult to conclusively identify the effects of these work resources. This analysis utilizes a group-randomized trial in which some units in an information technology workplace were randomly assigned to participate in an initiative, called STAR, that targeted work practices, interactions, and expectations by (a) training supervisors on the value of demonstrating support for employees' personal lives and (b) prompting employees to reconsider when and where they work. We find statistically significant, though modest, improvements in employees' work-family conflict and family time adequacy and larger changes in schedule control and supervisor support for family and personal life. We find no evidence that this intervention increased work hours or perceived job demands, as might have happened with increased permeability of work across time and space. Subgroup analyses suggest the intervention brings greater benefits to employees more vulnerable to work-family conflict. This study advances our understanding of the impact of social structures on individual lives by investigating deliberate organizational changes and their effects on work resources and the work-family interface with a rigorous design.

Why Definitional Clarity Matters: Implications for the Operationalization of Emotional Well-Being.

The National Institutes of Health (NIH) is increasingly prioritizing research on health-promoting processes. Park et al. (this issue) respond to a call made by NIH to advance the study of emotional well-being (EWB) and to increase understanding of the fundamental constituents of EWB across the lifespan and among diverse subgroups. They propose a definition of EWB that provides an organizing framework for research on 'psychological aspects of well-being' and health. We commend this important first step and urge consideration of three important issues related to operationalization - the process by which an abstract concept is transformed into variables that can be measured - in future research on EWB. We expect that an iterative process of construct refinement and empirical validation will advance the study of EWB, producing scientific discoveries that can be leveraged to enhance health across the lifespan.

Professor P. K. Thomas: clinician, investigator, editor and leader--a retrospective appreciation.

P. K. Thomas (1926-2008) occupied a prominent place in British and world neurology during the second half of the 20th century. Here, his lasting achievements as clinical neurologist, clinician scientist and experimentalist, editor of monographs and journals and leader of professional developments in the UK and elsewhere are assessed.

Loss of phosphatidylinositol 4-kinase 2alpha activity causes late onset degeneration of spinal cord axons.

Phosphoinositide (PI) lipids are intracellular membrane signaling intermediates and effectors produced by localized PI kinase and phosphatase activities. Although many signaling roles of PI kinases have been identified in cultured cell lines, transgenic animal studies have produced unexpected insight into the in vivo functions of specific PI 3- and 5-kinases, but no mammalian PI 4-kinase (PI4K) knockout has previously been reported. Prior studies using cultured cells implicated the PI4K2alpha isozyme in diverse functions, including receptor signaling, ion channel regulation, endosomal trafficking, and regulated secretion. We now show that despite these important functions, mice lacking PI4K2alpha kinase activity initially appear normal. However, adult Pi4k2a(GT/GT) animals develop a progressive neurological disease characterized by tremor, limb weakness, urinary incontinence, and premature mortality. Histological analysis of aged Pi4k2a(GT/GT) animals revealed lipofuscin-like deposition and gliosis in the cerebellum, and loss of Purkinje cells. Peripheral nerves are essentially normal, but massive axonal degeneration was found in the spinal cord in both ascending and descending tracts. These results reveal a previously undescribed role for aberrant PI signaling in neurological disease that resembles autosomal recessive hereditary spastic paraplegia.

Ndrg1 in development and maintenance of the myelin sheath.

CMT4D disease is a severe autosomal recessive demyelinating neuropathy with extensive axonal loss leading to early disability, caused by mutations in the N-myc downstream regulated gene 1 (NDRG1). NDRG1 is expressed at particularly high levels in the Schwann cell (SC), but its physiological function(s) are unknown. To help with their understanding, we characterise the phenotype of a new mouse model, stretcher (str), with total Ndrg1 deficiency, in comparison with the hypomorphic Ndrg1 knock-out (KO) mouse. While both models display normal initial myelination and a transition to overt pathology between weeks 3 and 5, the markedly more severe str phenotype suggests that even low Ndrg1 expression results in significant phenotype rescue. Neither model replicates fully the features of CMT4D: although axon damage is present, regenerative capacity is unimpaired and the mice do not display the early severe axonal loss typical of the human disease. The widespread large fibre demyelination coincides precisely with the period of rapid growth of the animals and the dramatic (160-500-fold) increase in myelin volume and length in large fibres. This is followed by stabilisation after week 10, while small fibres remain unaffected. Gene expression profiling of str peripheral nerve reveals non-specific secondary changes at weeks 5 and 10 and preliminary data point to normal proteasomal function. Our findings do not support the proposed roles of NDRG1 in growth arrest, terminal differentiation, gene expression regulation and proteasomal degradation. Impaired SC trafficking failing to meet the considerable demands of nerve growth, emerges as the likely pathogenetic mechanism in NDRG1 deficiency.

Future directions of the National Institutes of Health Science of Behavior Change Program.

BACKGROUND: The National Institutes of Health Science of Behavior Change Common Fund Program has accelerated the investigation of mechanisms of behavior change applicable to multiple health behaviors and outcomes and facilitated the use of the experimental medicine approach to behavior change research. PURPOSE: This commentary provides a brief background of the program, plans for its next phase, and thoughts about how the experimental medicine approach to behavior change research can inform future directions in two areas of science-reproductive health and COVID-19 vaccine uptake. CONCLUSIONS: The incorporation of a mechanisms-based approach into behavior intervention research offers new opportunities for improving health.

The membrane attack complex of the complement system is essential for rapid Wallerian degeneration.

The complement (C) system plays an important role in myelin breakdown during Wallerian degeneration (WD). The pathway and mechanism involved are, however, not clear. In a crush injury model of the sciatic nerve, we show that C6, necessary for the assembly of the membrane attack complex (MAC), is essential for rapid WD. At 3 d after injury, pronounced WD occurred in wild-type animals, whereas the axons and myelin of C6-deficient animals appeared intact. Macrophage recruitment and activation was inhibited in C6-deficient rats. However, 7 d after injury, the distal part of the C6-deficient nerves appeared degraded. As a consequence of a delayed WD, more myelin breakdown products were present than in wild-type nerves. Reconstitution of the C6-deficient animals with C6 restored the wild-type phenotype. Treatment with rhC1INH (recombinant human complement 1 inhibitor) blocked deposition of activated C-cleaved products after injury. These experiments demonstrate that the classical pathway of the complement system is activated after acute nerve trauma and that the entire complement cascade, including MAC deposition, is essential for rapid WD and efficient clearance of myelin after acute peripheral nerve trauma.

Social and economic aspects of immigration.

The absolute size of the foreign-born U.S. population is at a historical high, but neither the share of the population that is foreign born nor the share of children in immigrant families is high compared with the beginning of the 20th century. While poverty rates for immigrants and children in immigrant families are substantial, poverty is concentrated among certain groups, particularly Hispanics and blacks, non-citizens, and recent arrivals. The general economic well-being of immigrants improves with the move to the United States and as time in the United States increases. However, immigrants remain disadvantaged in terms of health insurance coverage. The economic situation of children in immigrant families has declined since the late 1960s, despite the high labor force participation of immigrant men and the lower prevalence of single-parent households among immigrant families. Still, children in immigrant families are at least as healthy as children in native families and are less likely to engage in risky behaviors. With socioeconomic factors taken into account, children in immigrant families do as well as other children in school. Analyses of the socioeconomic well-being of immigrants have been hampered by lack of information in major data sets about legal status and about the visa status of legally present immigrants, as well as by limited availability of longitudinal data.

Data analysis of the U-Pb geochronology and Lu-Hf system in zircon and whole-rock Sr, Sm-Nd and Pb isotopic systems for the granitoids of Thailand.

This data article provides zircon U-Pb and Lu-Hf isotopic information along with whole-rock Sm-Nd, Sr and Pb isotopic geochemistry from granitoids in Thailand. The U-Pb ages are described and the classification of crystallisation and inherited ages are explained. The petrography of the granitoid samples is detailed. The data presented in this article are interpreted and discussed in the research article entitled "Probing into Thailand's basement: New insights from U-Pb geochronology, Sr, Sm-Nd, Pb and Lu-Hf isotopic systems from granitoids" (Dew et al., 2018).

The NIH Science of Behavior Change Program: Transforming the science through a focus on mechanisms of change.

The goal of the NIH Science of Behavior Change (SOBC) Common Fund Program is to provide the basis for an experimental medicine approach to behavior change that focuses on identifying and measuring the mechanisms that underlie behavioral patterns we are trying to change. This paper frames the development of the program within a discussion of the substantial disease burden in the U.S. attributable to behavioral factors, and details our strategies for breaking down the disease- and condition-focused silos in the behavior change field to accelerate discovery and translation. These principles serve as the foundation for our vision for a unified science of behavior change at the NIH and in the broader research community.

Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I).

Hereditary sensory and autonomic neuropathy type I (HSAN I) is the most frequent type of hereditary neuropathy that primarily affects sensory neurons. The genetic locus for HSAN I has been mapped to chromosome 9q22.1-22.3 and recently the gene was identified as SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1. Sequencing in HSAN I families have previously identified mutations in exons 5, 6 and 13 of this gene. We analysed the SPTLC1 gene for mutations in 8 families with HSAN I, 60 individuals with sporadic sensory neuropathy, 6 HSAN II families, 20 Charcot-Marie-Tooth type I families and 20 families with Charcot-Marie-Tooth type II. Six HSAN I families and a single sporadic neuropathy case had an identical SPTLC1 mutation. No mutations were found in the other groups. Genetic haplotyping across the HSAN I critical region in 5 families and the sporadic case suggested a common founder. Several characteristics, previously not widely recognized were identified, including lack of penetrance of the SPTLC1 mutation in some individuals, variability in age of onset along with an earlier age of onset in younger generations, in some patients surprisingly early and often severe motor involvement and an earlier onset characterized by motor involvement with demyelinating features in males compared to females in 4 families. The sensory findings were often disassociated with prominent pain and temperature loss. Neurophysiology mainly showed a sensory axonal neuropathy but in many individuals there was electrical evidence of demyelination. Sural nerve biopsies from six affected individuals and the post-mortem findings in 1 case showed mainly axonal loss. This in depth study on the phenotype of HSAN I in 6 families and a single sporadic case with a common founder identifies a number of poorly recognized features in this disorder and highlights the clinical heterogeneity both within and between families suggesting the influence of other genetic and acquired factors.

Brachial plexus hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy.

We present the clinical, imaging and neuropathological findings in three patients with predominant brachial plexus neuropathy. MR scanning was key to determining the brachial plexus involvement. Biopsy of the brachial plexus was performed in one patient. The appearances of the brachial plexus on MRI, in conjunction with the clinical presentations of these patients, suggest that they are unusual variants within the spectrum of chronic inflammatory demyelinating polyradiculoneuropathy.

Clinical spectrum of CMT4C disease in patients homozygous for the p.Arg1109X mutation in SH3TC2.

We investigated the manifestations of CMT4C disease in a genetically homogeneous group of patients homozygous for the recently identified Gypsy founder mutation p.Arg1109X in SH3TC2. We observed a surprising degree of variation in age at onset, rate of progression, extent and severity of motor and sensory involvement, scoliosis, and cranial nerve involvement, suggesting that the phenotypic spectrum of CMT4C disease is much broader than the classical diagnostic criteria. Phenotype similarity in first degree relatives and increasing heterogeneity in more distantly related subjects point to the involvement of genetic modifiers, possibly variants in the genes encoding protein partners interacting with SH3TC2.

Changing contaminant mobility in a dredged canal sediment during a three-year phytoremediation trial.

Metal mobility and degradation of organic pollutants were investigated in a contaminated canal sediment in NW England. Sediment was dredged and exposed above the water surface, planted with multiple taxa of Salix, Populus and Alnus and monitored over 32 months. Short-term metal fractionation and phytotoxicity during sediment oxidation were also evaluated in separate laboratory studies. Zinc and Pb redistributed into more mobile fractions, which increased toxicity of the sediment to plants in the laboratory. In contrast, at the canal site, mobility of most elements decreased and total concentrations of Zn, Pb, Cu and Cd fell. Petroleum hydrocarbon concentrations decreased, but the tree-planted treatments appeared less effective at reducing PAH concentrations than treatments colonised by invasive plants. Tree survivorship decreased over time, suggesting increasing phytotoxicity of the exposed sediment in the longer term. Trees provided little benefit in terms of sediment remediation. Options for future management of the sediment are evaluated.

Supply of and demand for assisted reproductive technologies in the United States: clinic- and population-based data, 1995-2010.

OBJECTIVE: To study national-level trends in assisted reproduction technology (ART) treatments and outcomes as well as the characteristics of women who have sought this form of infertility treatment. DESIGN: Population-based study. SETTING: Not applicable. PATIENT(S): For CDC: All reporting clinics from 1996-2010. For NSFG: for the logistic analysis, sample comprising 2,325 women aged 22-44 years who have ever used medical help to get pregnant, excluding women who used only miscarriage prevention services. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): CDC data (number of cycles, live birth deliveries, live births, patient diagnoses); and NSFG data (individual use of ART procedures). RESULT(S): Between 1995 and 2010, use of ART increased. Parity and age are strong predictors of using ART procedures. The other correlates are higher education, having had tubal surgery, and having a current fertility problem. CONCLUSION(S): The two complementary data sets highlight the trends of ART use. An increase in the use of ART services over this time period is seen in both data sources. Nulliparous women aged 35-39 years are the most likely to have ever used ART services.