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Challenges remain with the implementation of preconception care, as many women do not plan their pregnancies and clinicians do not initiate preconception consultations. However, the interconception period may present a more opportune time to address health issues that impact on pregnancy outcomes and may influence future conceptions. It is also an important time to focus on pregnancy complications that may influence a person's health trajectory. This review discusses the evidence pointing to a need for greater attention on interconception health and focuses on five areas of care that may be particularly important in affecting equitable access to good care before a subsequent pregnancy: interpregnancy intervals, contraception, weight, nutrition, and gestational diabetes follow-up. Several programs internationally have developed models of care for interconception health and this review presents one such model developed in the United States that explicitly seeks to reach vulnerable populations of women who may otherwise not receive preconception care.

Each year, 3% of infants in the Unites States (US) are born with congenital anomalies, including 3000 with neural tube defects. Multivitamins (MVIs) including folic acid reduce the incidence of these birth defects. Most women do not take recommended levels of folic acid prior to conception or during the interconception period. The Interventions to Minimize Preterm and Low Birth Weight Infants through Continuous Improvement Techniques (IMPLICIT) ICC model was implemented to screen mothers who attend well child visits (WCVs) for their children aged 0–24 months. Mothers were queried for maternal behavioral risks known to affect pregnancy including multivitamin use and use of family planning methods to enhance birth spacing. When appropriate, interventions targeted at those at risk behaviors are offered. A mixed effects logistic regression model was used to calculate the odds ratio (OR) of behavior change in MVI use among mothers who reported not using MVIs. 37.7% of mothers reported not using MVIs at WCVs. 64.0% of mothers received an intervention to improve MVI use in this model. Mothers who received an intervention were more likely to report taking an MVI at the subsequent WCV if they received advice to take MVIs (OR 1.64) or directly received MVI samples (OR 3.09). Dedicated maternal counseling during pediatric WCVs is an opportunity to influence behavioral change in women at risk of becoming pregnant. Direct provision of MVIs increases the odds that women will report taking them at a higher rate than provider advice or no counseling at all.

The amygdala is vulnerable to multiple or "mixed" mis-aggregated proteins associated with neurodegenerative conditions that can manifest clinically with amnestic dementia; the amygdala region is often affected even at earliest disease stages. With the original intent of identifying novel dementia-associated proteins, the detergent-insoluble proteome was characterized from the amygdalae of 40 participants from the University of Kentucky Alzheimer's Disease Center autopsy cohort. These individuals encompassed a spectrum of clinical conditions (cognitively normal to severe amnestic dementia). Polypeptides from the detergent-insoluble fraction were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. As anticipated, portions of peptides previously associated with neurologic diseases were enriched from subjects with dementia. Among all detected peptides, Apolipoprotein E (ApoE) stood out: even more than the expected Tau, APP/Aβ, and α-Synuclein peptides, ApoE peptides were strongly enriched in dementia cases, including from individuals lacking the APOE ε4 genotype. The amount of ApoE protein detected in detergent-insoluble fractions was robustly associated with levels of complement proteins C3 and C4. Immunohistochemical staining of APOE ε3/ε3 subjects' amygdalae confirmed ApoE co-localization with C4 in amyloid plaques. Thus, analyses of human amygdala proteomics indicate that rather than being only an "upstream" genetic risk factor, ApoE is an aberrantly aggregated protein in its own right, and show that the ApoE protein may play active disease-driving mechanistic roles in persons lacking the APOE ε4 allele.

AIMS: The heterotetrameric assembly protein complex 2 (AP-2) is a central hub for clathrin-dependent endocytosis. The AP-2 α-adaptin subunit has two major isoforms, encoded by two separate genes: AP2A1 and AP2A2. Endocytosis has been implicated in the pathogenesis of neurodegenerative disease, and recent studies linked α-adaptins (gene variants, splicing defects, and altered expression) with late-onset Alzheimer’s disease (LOAD) risk. Here, we used multiple antibodies to investigate α-adaptin isoforms and their localization in human brains. METHODS: The specificities of ten different α-adaptin antibodies were evaluated using immunoblots after human AP2A1 and AP2A2 plasmid transfection in cultured cells. Additional immunoblot analyses were then performed on protein homogenates from control and LOAD subjects. Formalin-fixed, paraffin-embedded brain sections from control and LOAD subjects were immunohistochemically stained, and immunofluorescence experiments were performred for quantitation of colocalization with digital image analysis. RESULTS: Eight of the ten evaluated antibodies recognized transfected α-adaptin proteins on immunoblots. The α-adaptin subspecies were relatively uniformly expressed in five different human brain regions. The α-adaptins were present in the detergent-insoluble fraction from cognitively impaired, but less so in control, brains. Immunohistochemical analyses showed colocalization of AP2A1 with tau pathology in LOAD brains. By contrast, AP2A2 colocalized with microglial cells. CONCLUSIONS: These observations provide evidence of isoform-specific changes of α-adaptins in the brains of LOAD subjects. Antibodies that were verified to recognize AP2A1, but not AP2A2, labelled neurofibrillary tangles of LOAD patients. The findings extend our understanding of AP-2 proteins in the human brain in healthy and diseased states.

Each year, 3% of infants in the Unites States (US) are born with congenital anomalies, including 3000 with neural tube defects. Multivitamins (MVIs) including folic acid reduce the incidence of these birth defects. Most women do not take recommended levels of folic acid prior to conception or during the interconception period.The Interventions to Minimize Preterm and Low Birth Weight Infants through Continuous Improvement Techniques (IMPLICIT) ICC model was implemented to screen mothers who attend well child visits (WCVs) for their children aged 0-24 months. Mothers were queried for maternal behavioral risks known to affect pregnancy including multivitamin use and use of family planning methods to enhance birth spacing. When appropriate, interventions targeted at those at risk behaviors are offered. A mixed effects logistic regression model was used to calculate the odds ratio (OR) of behavior change in MVI use among mothers who reported not using MVIs.37.7% of mothers reported not using MVIs at WCVs. 64.0% of mothers received an intervention to improve MVI use in this model. Mothers who received an intervention were more likely to report taking an MVI at the subsequent WCV if they received advice to take MVIs (OR 1.64) or directly received MVI samples (OR 3.09).Dedicated maternal counseling during pediatric WCVs is an opportunity to influence behavioral change in women at risk of becoming pregnant. Direct provision of MVIs increases the odds that women will report taking them at a higher rate than provider advice or no counseling at all.

Introduction: Adequate maternal nutrition before pregnancy is important to reduce the risk of poor birth outcomes. However, patients report suboptimal intake of multivitamins with folic acid (MVIs). Methods: We conducted a quality improvement study to identify predictors of insufficient multivitamin use in women of childbearing age at five University of Pittsburgh Medical Center (UPMC) family health centers that implemented the IMPLICIT interconception care (ICC) model of maternal health screenings during well-child visits (WCVs). We derived this analysis from a retrospective chart review of patient-reported demographic information and physician documented maternal behaviors of 758 women who accompanied their children to 2,706 total well-child visits. Insufficient multivitamin use was defined as having one or more visits where the mother reported that she was not taking multivitamins. Results: Insufficient multivitamin use at these health centers was associated with younger age (OR 0.96, 95% CI 0.92, 0.98), less than high school education (OR 3.3, 95% CI 1.56-6.80), public insurance (OR 1.56, 95% CI 1.05-2.34), and increased number of well-child visits attended (OR 1.46, 95% CI 1.31-1.61). Conclusion: Among women who received screening, younger, low-income, and less educated women are likely to benefit from targeted interventions to improve multivitamin use during the interconception period. Findings also suggest that WCVs are a viable access point to assess and address multivitamin use and other desired maternal health behaviors.

The DEAH/RHA helicase DHX36 has been linked to cellular RNA and DNA quadruplex structures and to AU-rich RNA elements. In vitro, DHX36 remodels DNA and RNA quadruplex structures and unwinds DNA duplexes in an ATP-dependent manner. DHX36 contains the superfamily 2 helicase core and several auxiliary domains that are conserved in orthologs of the enzyme. The role of these auxiliary domains for the enzymatic function of DHX36 is not well understood. Here, we combine structural and biochemical studies to define the function of three auxiliary domains that contact nucleic acid. We first report the crystal structure of mouse DHX36 bound to ADP. The structure reveals an overall architecture of mouse DHX36 that is similar to previously reported architectures of fly and bovine DHX36. In addition, our structure shows conformational changes that accompany stages of the ATP-binding and hydrolysis cycle. We then examine the roles of the DHX36-Specific Motif (DSM), the OB-fold, and a conserved β-hairpin (β-HP) in mouse DHX36 in the remodeling of RNA structures. We then demonstrate and characterize RNA duplex unwinding for DHX36 and examine the remodeling of inter- and intramolecular RNA quadruplex structures. We find that the DSM functions not only as a quadruplex binding adaptor, but also promotes the remodeling of RNA duplex and quadruplex structures. The OB-fold and the β-HP contribute to RNA binding. Both domains are also essential for remodeling RNA quadruplex and duplex structures. Our data reveal roles of auxiliary domains for multiple steps of the nucleic acid remodeling reactions.

Chromosome ends are protected by guanosine-rich telomere DNA that forms stable G-quadruplex (G4) structures. The heterodimeric POT1-TPP1 complex interacts specifically with telomere DNA to shield it from illicit DNA damage repair and to resolve secondary structure that impedes telomere extension. The mechanism by which POT1-TPP1 accomplishes these tasks is poorly understood. Here, we establish the kinetic framework for POT1-TPP1 binding and unfolding of telomere G4 DNA. Our data identify two modes of POT1-TPP1 destabilization of G4 DNA that are governed by protein concentration. At low concentrations, POT1-TPP1 passively captures transiently unfolded G4s. At higher concentrations, POT1-TPP1 proteins bind to G4s to actively destabilize the DNA structures. Cancer-associated POT1-TPP1 mutations impair multiple reaction steps in this process, resulting in less efficient destabilization of G4 structures. The mechanistic insight highlights the importance of cell cycle dependent expression and localization of the POT1-TPP1 complex and distinguishes diverse functions of this complex in telomere maintenance.

Introduction: Short interpregnancy periods increase the likelihood of preterm delivery and low birth weight,1 both of which are significant causes of infant morbidity and mortality.2 Since nearly half of pregnancies in the United States are unplanned,3 opportunities exist to better understand barriers to contraceptive services. Studying these barriers as perceived by clinical staff can better guide programs to improve interpregnancy spacing. Methods: Between September and November 2017, 76 staff and 95 primary care clinicians from two family medicine residency practices (Highland Family Medicine (HFM) in Rochester, New York and St Margaret Family Medicine (SM) in Pittsburgh, Pennsylvania) completed surveys. Questions assessed perceived barriers to providing contraceptive services, contraception knowledge, and opportunities for improvement. Survey-based analysis focused on comparative descriptive statistics between staff and provider responses. Results: Clinicians ranked side effects and patient lack of awareness and misconceptions about contraceptive methods more highly than staff (P=0.0073 and P=0.0001, respectively). Staff identified childcare and work absence as more significant barriers (P=0.0114 and P=0.0380, respectively). Providers felt appointment timing was the largest constraint to contraceptive care. Staff perceived financial limitations and scheduling to be the top barriers. Nonclinician staff exhibited significant knowledge gaps regarding contraception. Conclusions: Numerous modifiable barriers contribute to difficulty providing contraceptive services. Providers and staff largely agree on the perceived barriers, but there is a significant gap in nonclinician staff knowledge of contraception. Education can address one of the leading concerns, but improvement efforts should also address areas such as availability of devices, scheduling issues, and resident supervision.

Background Preterm birth, birth defects, and unintended pregnancy are major sources of infant and maternal morbidity, mortality, and associated resource use in American health care. Interconception Care (ICC) is recommended as a strategy to improve birth outcomes by modifying maternal risks between pregnancies, but no established model currently exists. The Interventions to Minimize Preterm and Low Birth Weight Infants through Continuous Improvement Techniques (IMPLICIT) Network developed and implemented a unique approach to ICC by assessing mothers during their baby's well-child visits (WCVs) up to 24 months. Methods Mothers who accompanied their children to WCVs at eleven eastern US family medicine residency programs underwent screening for four risk factors (tobacco use, depression risk, contraception use to avoid unintended pregnancy and prolong interpregnancy interval, and use of a multivitamin with folic acid). Positive screens in women were addressed through brief interventions or referrals to treatment. Results Mothers accompanied their babies to 92.7% of WCVs. At more than half of WCVs (69.1%), mothers were screened for presence of ICC behavioral risks, although significant practice variation existed. Risk factors were identified at significant rates (tobacco use, 16.2%; depression risk, 8.1%; lack of contraception use, 28.2%; lack of multivitamin use, 45.4%). Women screened positive for 1 or more ICC risk factor at 64.6% of WCVs. Rates of documented interventions for women who screened positive were also substantial (tobacco use, 80.0%; depression risk, 92.8%; lack of contraception use, 76.0%; lack of multivitamin use, 58.2%). Conclusion WCVs provide a reliable point of contact with mothers and a unique opportunity to assess and address behavioral risks for future poor birth outcomes.

SummaryMany steps in nuclear RNA processing, surveillance, and degradation require TRAMP, a complex containing the poly(A) polymerase Trf4p, the Zn-knuckle protein Air2p, and the RNA helicase Mtr4p. TRAMP polyadenylates RNAs designated for decay or trimming by the nuclear exosome. It has been unclear how polyadenylation by TRAMP differs from polyadenylation by conventional poly(A) polymerase, which produces poly(A) tails that stabilize RNAs. Using reconstituted S. cerevisiae TRAMP, we show that TRAMP inherently suppresses poly(A) addition after only 3–4 adenosines. This poly(A) tail length restriction is controlled by Mtr4p. The helicase detects the number of 3′-terminal adenosines and, over several adenylation steps, elicits precisely tuned adjustments of ATP affinities and rate constants for adenylation and TRAMP dissociation. Our data establish Mtr4p as a critical regulator of polyadenylation by TRAMP and reveal that an RNA helicase can control the activity of another enzyme in a highly complex fashion and in response to features in RNA.

We present single-molecule high-resolution optical trapping measurements of RNA unwinding by the Ski2-like nuclear helicase Mtr4p both alone and within the Trf4/Air2/Mtr4 polyadenylation (TRAMP) complex. RNA helicases such as Mtr4p play key roles in RNA metabolism. Mtr4p is thought to assist RNA degradation by the exosome presumably by unwinding RNA structures. In addition, the TRAMP complex appends short 3′ poly(A) tails to RNA meant for degradation by the exosome. Mtr4p within the TRAMP complex plays a crucial role in regulating the polyadenylation activity, limiting the poly(A) tail length. The unwinding activity of Mtr4p is required and indeed within the TRAMP complex, Mtr4p unwinds duplex RNA 10x faster than when alone. However, the dynamic details of the RNA unwinding activity and interaction of Mtr4p and TRAMP and indeed the Ski2-like family of RNA helicases are unknown. We have performed high-resolution RNA hairpin unwinding experiments for both Mtr4p and TRAMP. We find that Mtr4p unwinds RNA duplexes in a single or multiple bursts with a mean step size of 9 base pairs. The unwinding is irreversible suggesting that Mtr4p remains stably bound after unwinding the duplex, preventing re-annealing. TRAMP unwinding experiments reveal a faster molecular recognition by the Mtr4p helicase when in complex as well as enhanced RNA duplex unwinding dynamics. Combined high-resolution trapping and fluorescence experiments underway may reveal how the competition within TRAMP between the 3′-to-5′ Mtr4p helicase and the 5′-to-3′ Trf4p polymerase is resolved dynamically.

ContextDiagnosis of Parkinson disease (PD) remains challenging. An accurate diagnosis is important because effective symptomatic treatment for PD is available.ObjectiveTo systematically review the literature for information on the precision and accuracy of the clinical examination for diagnosing PD.Data SourcesMEDLINE database was searched for all English-language articles related to the diagnosis of PD published from January 1966 through April 2001. The reference lists of all articles retrieved were searched for additional relevant sources.Study SelectionStudies in which patients presented with 1 or more typical features of PD were included if the final diagnosis was confirmed by a suitable criterion standard and data could be extracted to determine the accuracy of 1 or more symptoms or signs. Variability in descriptions of symptoms and signs made it impossible to combine data across existing studies for most findings.Data SynthesisWe identified 6 studies that met our criteria. The positive (presence) likelihood ratios (LRs) for tremor as a symptom of PD ranged from 1.3 to 17 (range of negative [absence] LRs, 0.24 to 0.60). Tremor as a sign of PD produced a range of positive LRs from 1.3 to 1.5 (negative LRs, 0.47 to 0.61). Clinical features useful in the diagnosis of PD include a history of the combination of symptoms of rigidity and bradykinesia (positive LR, 4.5; negative LR, 0.12); a history of loss of balance (range of positive LRs, 1.6 to 6.6; range of negative LRs, 0.29 to 0.35), symptoms of micrographia (range of positive LRs, 2.8 to 5.9; range of negative LRs, 0.30 to 0.44), and a history of shuffling gait (range of positive LRs, 3.3 to 15; range of negative LRs, 0.32 to 0.50). Trouble with certain tasks such as turning in bed (positive LR, 13; negative LR, 0.56), opening jars (positive LR, 6.1; negative LR, 0.26), and rising from a chair (range of positive LRs, 1.9 to 5.2; range of negative LRs, 0.39 to 0.58). Useful signs include the glabella tap test (positive LR, 4.5; negative LR, 0.13), difficulty walking heel-to-toe (positive LR, 2.9; negative LR, 0.32), and rigidity (range of positive LRs, 0.53 to 2.8; range of negative LRs, 0.38 to 1.6). Significant selection bias was detected in all studies included for review.ConclusionsSymptoms of tremor, rigidity, bradykinesia, micrographia, shuffling gait, and difficulty with the tasks of turning in bed, opening jars, and rising from a chair should be carefully reviewed in all patients with suspected PD. The glabella tap and heel-to-toe tests also should be assessed.