Publications by authors named "Gordon Smith"

877 Publications

Fentanyl and other opioid involvement in methamphetamine-related deaths.

Am J Drug Alcohol Abuse 2021 Nov 9:1-9. Epub 2021 Nov 9.

School of Public Health, West Virginia University, Morgantown, WV, USA.

Background: Methamphetamine-related deaths have been rising along with those involving synthetic opioids, mostly fentanyl and fentanyl analogs (FAs). However, the extent to which methamphetamine involvement in deaths differs from those changes occurring in synthetic opioid involvement is unknown.

Objectives: To determine the patterns and temporal changes in methamphetamine-related deaths with and without other drug involvement.

Methods: Data from all methamphetamine-related deaths in West Virginia from 2013 to 2018 were analyzed. Quasi-Poisson regression analyses over time were conducted to compare the rates of change in death counts among methamphetamine and fentanyl//FA subgroups.

Results: A total of 815 methamphetamine-related deaths were analyzed; 572 (70.2%) were male and 527 (64.7%) involved an opioid. The proportion of methamphetamine only deaths stayed relatively flat over time although the actual numbers of deaths increased. Combined fentanyl/FAs and methamphetamine were involved in 337 deaths (41.3%) and constituted the largest increase from 2013 to 2018. The modeling of monthly death counts in 2017-2018 found that the average number of deaths involving fentanyl without methamphetamine significantly declined (rate of change -0.025, < .001), while concomitant fentanyl with methamphetamine and methamphetamine only death counts increased significantly (rate of change 0.056 and 0.057, respectively, < .001).

Conclusions: Fentanyl and FAs played an increasingly significant role in methamphetamine-related deaths. The accelerating number of deaths involving fentanyl/FAs and methamphetamine indicates the importance of stimulants and opioids in unintentional deaths. Comprehensive surveillance efforts should continue to track substance use patterns to ensure that appropriate prevention programs are undertaken.
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http://dx.doi.org/10.1080/00952990.2021.1981919DOI Listing
November 2021

Iatrogenic Delivery for Suspected Fetal Growth Restriction and Childhood School Outcomes.

Authors:
Gordon C S Smith

JAMA 2021 11;326(18):1870-1871

Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, England.

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http://dx.doi.org/10.1001/jama.2021.15516DOI Listing
November 2021

Dietary management of obesity-associated neuropathy: Implications for clinical practice and trial design.

Obesity (Silver Spring) 2021 Dec 8;29(12):1990-1991. Epub 2021 Nov 8.

Department of Neurology, University of Utah, Salt Lake City, Utah, USA.

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http://dx.doi.org/10.1002/oby.23304DOI Listing
December 2021

Predicting increases in COVID-19 incidence to identify locations for targeted testing in West Virginia: A machine learning enhanced approach.

PLoS One 2021 3;16(11):e0259538. Epub 2021 Nov 3.

West Virginia Clinical and Translational Science Institute, Morgantown, West Virginia, United States of America.

During the COVID-19 pandemic, West Virginia developed an aggressive SARS-CoV-2 testing strategy which included utilizing pop-up mobile testing in locations anticipated to have near-term increases in SARS-CoV-2 infections. This study describes and compares two methods for predicting near-term SARS-CoV-2 incidence in West Virginia counties. The first method, Rt Only, is solely based on producing forecasts for each county using the daily instantaneous reproductive numbers, Rt. The second method, ML+Rt, is a machine learning approach that uses a Long Short-Term Memory network to predict the near-term number of cases for each county using epidemiological statistics such as Rt, county population information, and time series trends including information on major holidays, as well as leveraging statewide COVID-19 trends across counties and county population size. Both approaches used daily county-level SARS-CoV-2 incidence data provided by the West Virginia Department Health and Human Resources beginning April 2020. The methods are compared on the accuracy of near-term SARS-CoV-2 increases predictions by county over 17 weeks from January 1, 2021- April 30, 2021. Both methods performed well (correlation between forecasted number of cases and the actual number of cases week over week is 0.872 for the ML+Rt method and 0.867 for the Rt Only method) but differ in performance at various time points. Over the 17-week assessment period, the ML+Rt method outperforms the Rt Only method in identifying larger spikes. Results show that both methods perform adequately in both rural and non-rural predictions. Finally, a detailed discussion on practical issues regarding implementing forecasting models for public health action based on Rt is provided, and the potential for further development of machine learning methods that are enhanced by Rt.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0259538PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565789PMC
November 2021

Post-partum psychosis and its association with bipolar disorder in the UK: a case-control study using polygenic risk scores.

Lancet Psychiatry 2021 12 26;8(12):1045-1052. Epub 2021 Oct 26.

MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK; National Centre for Mental Health, Cardiff University, Cardiff, UK.

Background: For more than 150 years, controversy over the status of post-partum psychosis has hindered research and caused considerable confusion for clinicians and women, with potentially negative consequences. We aimed to explore the hypothesis that genetic vulnerability differs between women with first-onset post-partum psychosis and those with bipolar disorder more generally.

Methods: In this case-control study on first-onset post-partum psychosis and bipolar disorder in the UK, we included 203 women with first-onset post-partum psychosis (defined as a manic, mixed, or psychotic depression episode within 6 weeks of delivery without a psychiatric history) and 1225 parous women with a history of bipolar disorder. Information on women with bipolar disorder was obtained from the Bipolar Disorder Research Network database, and participants were recruited through screening community mental health teams across the UK and via the media and patient support organisations. All were assessed using a semistructured face-to-face psychiatric interview and psychiatric case note review. 2809 women from the general population were recruited via the national UK Blood Services and the 1958 Birth Cohort (UK National Child Development Study) as controls and matched to cases according to genetic ancestry. All self-reported their ethnicity as White and were recruited from across the UK. Polygenic risk scores (PRSs) were generated from discovery genome-wide association studies of schizophrenia, bipolar disorder, and major depression. Logistic regression was used to model the effect of each PRS on diagnosis, and the RRs and ORs presented were adjusted for ten principal components of genetic variation to account for population stratification.

Findings: 203 women with first-onset post-partum psychosis (median age at interview: 46 years [IQR 37-55]) and 1225 women with bipolar disorder (49 years [41-58]) were recruited between September, 1991, and May, 2013, as well as 2809 controls. Women with first-onset post-partum psychosis had similar bipolar disorder and schizophrenia PRSs to women with bipolar disorder, which were significantly higher than those of controls. When compared with controls, women with first-onset post-partum psychosis had an adjusted relative risk ratio (RR) for bipolar disorder PRSs of 1·71 (95% CI 1·56-1·86, p<0·0001) and for schizophrenia PRSs of 1·82 (1·66-1·97, p<0·0001). The effect sizes were similar when comparing women with bipolar disorder to controls (adjusted RR 1·77 [1·69-1·84], p<0·0001 for bipolar disorder PRSs; 2·00 (1·92-2·08), p<0·0001 for schizophrenia PRSs). Although women with bipolar disorder also had higher major depression PRSs than did controls (1·24 [1·17-1·31], p<0·0001), women with first-onset post-partum psychosis did not differ from controls in their polygenic liability to major depression (0·97 (0·82-1·11), p=0·63).

Interpretation: Our study supports the recognition of first-onset post-partum psychosis as a separate nosological entity within the bipolar disorder spectrum both in research and clinical settings.

Funding: Wellcome Trust and Medical Research Council.
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http://dx.doi.org/10.1016/S2215-0366(21)00253-4DOI Listing
December 2021

Predicting increases in COVID-19 incidence to identify locations for targeted testing in West Virginia: A machine learning enhanced approach.

medRxiv 2021 Oct 7. Epub 2021 Oct 7.

West Virginia Clinical and Translational Science Institute, Morgantown, West Virginia.

During the COVID-19 pandemic, West Virginia developed an aggressive SARS-CoV-2 testing strategy which included utilizing pop-up mobile testing in locations anticipated to have near-term increases in SARS-CXoV-2 infections. In this study, we describe and compare two methods for predicting near-term SARS-CoV-2 incidence in West Virginia counties. The first method, R Only, is solely based on producing forecasts for each county using the daily instantaneous reproductive numbers, R The second method, ML+ R , is a machine learning approach that uses a Long Short-Term Memory network to predict the near-term number of cases for each county using epidemiological statistics such as Rt, county population information, and time series trends including information on major holidays, as well as leveraging statewide COVID-19 trends across counties and county population size. Both approaches used daily county-level SARS-CoV-2 incidence data provided by the West Virginia Department Health and Human Resources beginning April 2020. The methods are compared on the accuracy of near-term SARS-CoV-2 increases predictions by county over 17 weeks from January 1, 2021-April 30, 2021. Both methods performed well (correlation between forecasted number of cases and the actual number of cases week over week is 0.872 for the ML+R method and 0.867 for the R Only method) but differ in performance at various time points. Over the 17-week assessment period, the ML+R method outperforms the R Only method in identifying larger spikes. We also find that both methods perform adequately in both rural and non-rural predictions. Finally, we provide a detailed discussion on practical issues regarding implementing forecasting models for public health action based on R , and the potential for further development of machine learning methods that are enhanced by R
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http://dx.doi.org/10.1101/2021.10.06.21264569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509102PMC
October 2021

Mass-flowering monoculture attracts bees, amplifying parasite prevalence.

Proc Biol Sci 2021 Oct 13;288(1960):20211369. Epub 2021 Oct 13.

Institute for Ecology and Evolution, University of Oregon, 272 Onyx Bridge, Eugene, OR 97403, USA.

As the global agricultural footprint expands, it is increasingly important to address the link between the resource pulses characteristic of monoculture farming and wildlife epidemiology. To understand how mass-flowering crops impact host communities and subsequently amplify or dilute parasitism, we surveyed wild and managed bees in a monoculture landscape with varying degrees of floral diversification. We screened 1509 bees from 16 genera in sunflower fields and in non-crop flowering habitat across 200 km of the California Central Valley. We found that mass-flowering crops increase bee abundance. Wild bee abundance was subsequently associated with higher parasite presence, but only in sites with a low abundance of non-crop flowers. Bee traits related to higher dispersal ability (body size) and diet breadth (pollen lecty) were also positively related to parasite presence. Our results highlight the importance of non-crop flowering habitat for supporting bee communities. We suggest monoculture alone cannot support healthy bees.
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http://dx.doi.org/10.1098/rspb.2021.1369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511775PMC
October 2021

Clinical and demographic factors associated with stimulant use disorder in a rural heart failure population.

Drug Alcohol Depend 2021 Sep 24;229(Pt A):109060. Epub 2021 Sep 24.

West Virginia University School of Medicine, Morgantown, WV 26506, USA.

Background: Heart failure is becoming increasingly common among patients under 50 years of age, particularly in African Americans and patients with stimulant use disorder. Yet the sources of these disparities remain poorly understood. This study identified key demographic and clinical factors associated with stimulant use disorder in a largely rural heart failure patient registry.

Methods: Patient records reporting a diagnosis of heart failure between January 2008 and March 2020 were requested from West Virginia University Hospital Systems (n=37,872). Odds of stimulant use disorder were estimated by demographic group (age, race, sex), insurance carrier, and clinical comorbidities using logistic regression.

Results: Multivariable regression analysis identified higher odds of stimulant use disorder among Black/African Americans (1.95 [1.32, 2.77]) and patients who report drinking one or more alcoholic drinks per week (2.23 [1.72, 2.88]). Lower odds of stimulant use disorder were identified among patients with hypertension (0.59 [0.47, 0.73]), or diabetes (0.65 [0.52, 0.81]).. Likewise, lower odds of stimulant use disorder were noted among females, patients older than 30 years of age and those not enrolled in Medicaid.

Conclusion: These results highlight the alarming extent to which Medicaid enrollees, Black/African Americans, people aged 18-24 and 25-44, or persons with a past alcohol use disorder diagnosis are associated with stimulant use disorder among heart failure populations living in largely rural areas. Additionally, they emphasize the need to develop policies and refine clinical care that affects this vulnerable population's prognoses.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.109060DOI Listing
September 2021

Visual processing: Systematic variation in light-dark bias across visual space.

Curr Biol 2021 Sep;31(18):R1095-R1097

Optical Imaging and Brain Science Medical Discovery Team, Department of Neuroscience, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

Detecting changes in luminance is a fundamental property of the visual system. A new study shows that lights and darks are represented differently across visual space, with strong OFF bias in central vision and balanced ON/OFF in the periphery.
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http://dx.doi.org/10.1016/j.cub.2021.07.057DOI Listing
September 2021

Acute Kidney Injury in Extracorporeal Membrane Oxygenation Patients: National Analysis of Impact of Age.

Blood Purif 2021 Sep 7:1-10. Epub 2021 Sep 7.

Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: The aim of this study was to determine epidemiology and outcomes of acute kidney injury (AKI) in patients on extracorporeal membrane oxygenation (ECMO) and to assess if age modifies the effect of AKI on mortality.

Methods: Using National (Nationwide) Inpatient Sample Database for hospitalizations in the USA from 2003 to 2014, we identified adult patients on ECMO support. Using International Classification of Diseases 9th Revision, we assessed the rates of AKI and AKI requiring dialysis (AKI-D) among them and associated survival. We used a multivariable logistic regression to identify risk factors of and differential effect of age on mortality from AKI.

Results: AKI was seen in 63.9% of 17,942 ECMO hospitalizations: 21.9% of those with AKI required dialysis. The percentage of those with AKI increased steadily. Mortality was higher in those with AKI, with highest in those with AKI-D (70.8% vs. 61.7%; p < 0.001). While both age and AKI were independent predictors of mortality, age was neither a risk factor for AKI nor did it modify the effect of AKI on mortality.

Conclusions: AKI is common and is increasing among patients on ECMO support. Patients on ECMO have high mortality and AKI is an independent predictor of mortality. Though age is also an independent predictor of mortality in patients on ECMO, it is neither a predictor of AKI nor does not modify the relationship between AKI and mortality.
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http://dx.doi.org/10.1159/000518346DOI Listing
September 2021

Circulating maternal placental growth factor responses to low-molecular-weight heparin in pregnant patients at risk of placental dysfunction.

Am J Obstet Gynecol 2021 Aug 27. Epub 2021 Aug 27.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Ontario, Canada. Electronic address:

Background: Patients at high risk of severe preeclampsia and fetal growth restriction have low circulating levels of placental growth factor and features of maternal vascular malperfusion placental pathology at delivery. Multimodal screening and commencement of aspirin prophylaxis at 11 to 13 weeks' gestation markedly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low-molecular-weight heparin and mechanisms of action remain uncertain. Because low-molecular-weight heparin augments the production and release of placental growth factor in vitro by both placental villi and vascular endothelium, it may be effective to suppress the risk of severe preeclampsia in a niche group of high-risk patients with low circulating placental growth factor in the early second trimester.

Objective: This study aimed to define a gestational age-specific reference range for placental growth factor and to test the hypothesis that prophylactic low-molecular-weight heparin administered in the early second trimester may restore deficient circulating placental growth factor levels and thereby prolong pregnancy.

Study Design: Centile curves for circulating placental growth factor levels from 12 to 36 weeks' gestation were derived using quantile regression of combined data from a published cohort of 4207 unselected nulliparous patients in Cambridge, United Kingdom, at 4 sampling time points (12, 20, 28, and 36 weeks' gestation) and the White majority (n=531) of a healthy nulliparous cohort in Toronto, Canada, at 16 weeks' gestation using the same test platform. Within a specialty high-risk clinic in Toronto, a niche group of 7 patients with a circulating placental growth factor at the <10th centile in the early second trimester received daily prophylactic low-molecular-weight heparin (enoxaparin; 40 mg subcutaneously) and were followed up until delivery (group 1). Their baseline characteristics, delivery details, and placental pathologies were compared with 5 similar patients who did not receive low-molecular-weight heparin during the observation period (group 2) and further with 21 patients who delivered with severe preeclampsia (group 3) in the same institution.

Results: A gestational age-specific reference range for placental growth factor levels at weekly intervals between 12 and 36 weeks was established for White women with singleton pregnancies. Within group 1, 5 of 7 patients demonstrated a sustained increase in circulating placental growth factor levels, whereas placental growth factor levels did not increase in group 2 or group 3 patients who did not receive low-molecular-weight heparin. Group 1 patients receiving low-molecular-weight heparin therapy exhibited a later gestation at delivery, relative to groups 2 and 3 (36 weeks [33-37] vs 23 weeks [22-26] and 28 weeks [27-31], respectively), and consequently had higher birthweights (1.93 kg [1.1-2.7] vs 0.32 kg [0.19-0.39] and 0.73 kg [0.52-1.03], respectively). The incidence of stillbirth was lowest in group 1 (14% [1 of 7]), relative to groups 2 and 3 (80% [4 of 5] and 29% [6 of 21], respectively). Maternal vascular malperfusion was the most common placental pathology found in association with abnormal uterine artery Doppler.

Conclusion: In patients at high risk of a serious adverse pregnancy outcome owing to placental disease, the addition of low-molecular-weight heparin to aspirin prophylaxis in the early second trimester may restore deficient circulating placental growth factor to mediate an improved perinatal outcome. These data support the implementation of a multicenter pilot randomized control trial where patients are recruited primarily based on the assessment of placental function in the early second trimester.
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http://dx.doi.org/10.1016/j.ajog.2021.08.027DOI Listing
August 2021

Do Mass Spectrometry-Derived Metabolomics Improve the Prediction of Pregnancy-Related Disorders? Findings from a UK Birth Cohort with Independent Validation.

Metabolites 2021 Aug 10;11(8). Epub 2021 Aug 10.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.

Many women who experience gestational diabetes (GDM), gestational hypertension (GHT), pre-eclampsia (PE), have a spontaneous preterm birth (sPTB) or have an offspring born small/large for gestational age (SGA/LGA) do not meet the criteria for high-risk pregnancies based upon certain maternal risk factors. Tools that better predict these outcomes are needed to tailor antenatal care to risk. Recent studies have suggested that metabolomics may improve the prediction of these pregnancy-related disorders. These have largely been based on targeted platforms or focused on a single pregnancy outcome. The aim of this study was to assess the predictive ability of an untargeted platform of over 700 metabolites to predict the above pregnancy-related disorders in two cohorts. We used data collected from women in the Born in Bradford study (BiB; two sub-samples, = 2000 and = 1000) and the Pregnancy Outcome Prediction study (POPs; = 827) to train, test and validate prediction models for GDM, PE, GHT, SGA, LGA and sPTB. We compared the predictive performance of three models: (1) risk factors (maternal age, pregnancy smoking, BMI, ethnicity and parity) (2) mass spectrometry (MS)-derived metabolites ( = 718 quantified metabolites, collected at 26-28 weeks' gestation) and (3) combined risk factors and metabolites. We used BiB for the training and testing of the models and POPs for independent validation. In both cohorts, discrimination for GDM, PE, LGA and SGA improved with the addition of metabolites to the risk factor model. The models' area under the curve (AUC) were similar for both cohorts, with good discrimination for GDM (AUC (95% CI) BiB 0.76 (0.71, 0.81) and POPs 0.76 (0.72, 0.81)) and LGA (BiB 0.86 (0.80, 0.91) and POPs 0.76 (0.60, 0.92)). Discrimination was improved for the combined models (compared to the risk factors models) for PE and SGA, with modest discrimination in both studies (PE-BiB 0.68 (0.58, 0.78) and POPs 0.66 (0.60, 0.71); SGA-BiB 0.68 (0.63, 0.74) and POPs 0.64 (0.59, 0.69)). Prediction for sPTB was poor in BiB and POPs for all models. In BiB, calibration for the combined models was good for GDM, LGA and SGA. Retained predictors include 4-hydroxyglutamate for GDM, LGA and PE and glycerol for GDM and PE. MS-derived metabolomics combined with maternal risk factors improves the prediction of GDM, PE, LGA and SGA, with good discrimination for GDM and LGA. Validation across two very different cohorts supports further investigation on whether the metabolites reflect novel causal paths to GDM and LGA.
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http://dx.doi.org/10.3390/metabo11080530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399752PMC
August 2021

Contemporary Neuroscience Core Curriculum for Medical Schools.

Neurology 2021 Aug 16. Epub 2021 Aug 16.

Massachusetts General Hospital, Boston, MA.

Medical students need to understand core neuroscience principles as a foundation for their required clinical experiences in neurology. In fact, they need a solid neuroscience foundation for their clinical experiences in all other medical disciplines also, because the nervous system plays such a critical role in the function of every organ system. Due to the rapid pace of neuroscience discoveries, it is unrealistic to expect students to master the entire field. It is also unnecessary, as students can expect to have ready access to electronic reference sources no matter where they practice. In the pre-clerkship phase of medical school, the focus should be on providing students with the foundational knowledge to use those resources effectively and interpret them correctly. This article describes an organizational framework for teaching the essential neuroscience background needed by all physicians. This is particularly germane at a time when many medical schools are re-assessing traditional practices and instituting curricular changes such as competency-based approaches, earlier clinical immersion, and increased emphasis on active learning. This article reviews factors that should be considered when developing the pre-clerkship neuroscience curriculum, including goals and objectives for the curriculum, the general topics to include, teaching and assessment methodology, who should direct the course, and the areas of expertise of faculty who might be enlisted as teachers or content experts. These guidelines were developed by a work group of experienced educators appointed by the Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN). They were then successively reviewed, edited, and approved by the entire UES, the AAN Education Committee, and the AAN Board of Directors.
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http://dx.doi.org/10.1212/WNL.0000000000012664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520386PMC
August 2021

Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis.

Nat Commun 2021 08 10;12(1):4829. Epub 2021 Aug 10.

Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D.
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http://dx.doi.org/10.1038/s41467-021-25025-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355239PMC
August 2021

Mood episodes in pregnancy and risk of postpartum recurrence in bipolar disorder: The Bipolar Disorder Research Network Pregnancy Study.

J Affect Disord 2021 11 22;294:714-722. Epub 2021 Jul 22.

Division of Psychiatry and Clinical Neurosciences, School of Medicine, Cardiff University, UK.

Background: Women with bipolar disorder (BD) are at high risk of mania/psychosis following childbirth. The risk factors for these episodes remain poorly understood and prospective studies are rare. Here, we examine whether mood episodes occurring within pregnancy predict postpartum recurrence in women with BD using a prospective design.

Method: 128 women with DSM-5 BD were followed from week 12 of pregnancy (baseline) to 12-weeks postpartum. Semi-structured interviews, supplemented by clinician questionnaires and case-note review, assessed lifetime psychiatric history at baseline, and perinatal psychopathology at two follow-up assessments: third-trimester of pregnancy and 12-weeks postpartum.

Results: Postpartum follow-up data were obtained for 124/128 (97%) women [98 bipolar I disorder/schizoaffective-BD (BD-I/SA-BD group) and 26 bipolar II disorder/other specified BD and related disorder (BD-II/BD-OS group)]. Perinatal recurrence was high in both diagnostic groups (57% and 62% respectively). Women with BD-I/SA-BD were significantly more likely to experience mania/psychosis within 6 weeks postpartum (23%, n=22/96) compared to those with BD-II/BD-NOS (4%, n=1/25; p=0.042). In BD-I/SA-BD, mania/psychosis in pregnancy significantly elevated risk of mania/psychosis postpartum compared to remaining well (RR 7.0, p<0.001) and experiencing non-psychotic depression in pregnancy (RR 3.18, p=0.023) Limitations: Predominantly United Kingdom White sample and limited BD-II/BD-OS sample size.

Conclusions: Women with BD are at high risk of recurrence during pregnancy and the postpartum. Over and above risk conferred by a history of BD-I/SA-BD, mania/psychosis during pregnancy further increased risk of postpartum mania/psychosis in this high-risk group. These data may have important implications for prediction and management of severe postpartum recurrence of BD.
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http://dx.doi.org/10.1016/j.jad.2021.07.067DOI Listing
November 2021

Simultaneously Tuning the Defects and Surface Properties of TaN Nanoparticles by Mg-Zr Codoping for Significantly Accelerated Photocatalytic H Evolution.

J Am Chem Soc 2021 Jul 1;143(27):10059-10064. Epub 2021 Jul 1.

Research Initiative for Supra-Materials, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano-shi, Nagano 380-8553, Japan.

The simultaneous control of the defect species and surface properties of semiconducting materials is a crucial aspect of improving photocatalytic performance, yet it remains challenging. Here, we synthesized Mg-Zr-codoped single-crystalline TaN (TaN:Mg+Zr) nanoparticles by a brief NH nitridation process, exhibiting photocatalytic water reduction activity 45 times greater than that of pristine TaN under visible light. A coherent picture of the relations between the defect species (comprising reduced Ta, nitrogen vacancies and oxygen impurities), surface properties (associated with dispersion of the Pt cocatalyst), charge carrier dynamics, and photocatalytic activities was drawn. The tuning of defects and simultaneous optimization of surface properties resulting from the codoping evidently resulted in the generation of high concentrations of long-lived electrons in this material as well as the efficient migration of these electrons to evenly distributed surface Pt sites. These effects greatly enhanced the photocatalytic activity. This work highlights the importance and feasibility of improving multiple properties of a catalytic material via a one-step strategy.
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http://dx.doi.org/10.1021/jacs.1c04861DOI Listing
July 2021

Antenatal Exposure to UV-B Radiation and Preeclampsia: A Retrospective Cohort Study.

J Am Heart Assoc 2021 07 22;10(13):e020246. Epub 2021 Jun 22.

Institute of Health and Wellbeing University of Glasgow United Kingdom.

Background Risk of preeclampsia varies by month of delivery. We tested whether this seasonal patterning may be mediated through maternal vitamin D concentration using antenatal exposure to UV-B radiation as an instrumental variable. Methods and Results Scottish maternity records were linked to antenatal UV-B exposure derived from satellites between 2000 and 2010. Logistic regression analyses were used to explore the association between UV-B and preeclampsia, adjusting for the potential confounding effects of month of conception, child's sex, gestation, parity, and mean monthly temperature. Of the 522 896 eligible singleton deliveries, 8689 (1.66%) mothers developed preeclampsia. Total antenatal UV-B exposure ranged from 43.18 to 101.11 kJ/m and was associated with reduced risk of preeclampsia with evidence of a dose-response relationship (highest quintile of exposure: adjusted odds ratio, 0.57; 95% CI, 0.44-0.72; <0.001). Associations were demonstrated for UV-B exposure in all 3 trimesters. Conclusions The seasonal patterning of preeclampsia may be mediated through low maternal vitamin D concentration in winter resulting from low UV-B radiation. Interventional studies are required to determine whether vitamin D supplements or UV-B-emitting light boxes can reduce the seasonal patterning of preeclampsia.
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http://dx.doi.org/10.1161/JAHA.120.020246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403301PMC
July 2021

Developing Novel Tests to Screen for Fetal Growth Restriction.

Authors:
Gordon C S Smith

Trends Mol Med 2021 08 16;27(8):743-752. Epub 2021 Jun 16.

Department of Obstetrics and Gynaecology, University of Cambridge; NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0SW, UK. Electronic address:

Fetal growth restriction (FGR) is a major determinant of global morbidity and mortality. There is an unmet need for methods to stratify the pregnant population on the basis of FGR risk. Despite evolutionary divergence in mammalian reproduction, studies of genetically modified mice have identified biomarkers that have been validated in women, and a systematic screen for genes that control fetal growth in animals could help identify novel clinical biomarkers. Current approaches to biomarker identification using human samples include both targeted and discovery approaches (omics). Application of omic methods to the placenta and maternal blood has yielded promising results, but comes with logistical, experimental, and analytical challenges and all studies are limited by the lack of a gold standard for disease.
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http://dx.doi.org/10.1016/j.molmed.2021.05.006DOI Listing
August 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458480PMC
March 2021

Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease.

Gastroenterology 2021 Sep 15;161(3):968-981.e12. Epub 2021 May 15.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

Background And Aims: Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD.

Methods: Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N = 14); (2) obese with normal IHTG content (OB-NL; N = 28); and (3) obese with NAFLD (OB-NAFLD; N = 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants.

Results: Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes.

Conclusions: Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).
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http://dx.doi.org/10.1053/j.gastro.2021.05.008DOI Listing
September 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Coevolutionary transitions from antagonism to mutualism explained by the Co-Opted Antagonist Hypothesis.

Nat Commun 2021 05 17;12(1):2867. Epub 2021 May 17.

Dept. of Ecology and Evolutionary Biology, University of Arizona, P.O. Box 210088, Tucson, AZ, USA.

There is now good evidence that many mutualisms evolved from antagonism; why or how, however, remains unclear. We advance the Co-Opted Antagonist (COA) Hypothesis as a general mechanism explaining evolutionary transitions from antagonism to mutualism. COA involves an eco-coevolutionary process whereby natural selection favors co-option of an antagonist to perform a beneficial function and the interacting species coevolve a suite of phenotypic traits that drive the interaction from antagonism to mutualism. To evaluate the COA hypothesis, we present a generalized eco-coevolutionary framework of evolutionary transitions from antagonism to mutualism and develop a data-based, fully ecologically-parameterized model of a small community in which a lepidopteran insect pollinates some of its larval host plant species. More generally, our theory helps to reconcile several major challenges concerning the mechanisms of mutualism evolution, such as how mutualisms evolve without extremely tight host fidelity (vertical transmission) and how ecological context influences evolutionary outcomes, and vice-versa.
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http://dx.doi.org/10.1038/s41467-021-23177-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129128PMC
May 2021

The RNA landscape of the human placenta in health and disease.

Nat Commun 2021 05 11;12(1):2639. Epub 2021 May 11.

Department of Obstetrics and Gynaecology, University of Cambridge, NIHR Cambridge Biomedical Research Centre, Cambridge, UK.

The placenta is the interface between mother and fetus and inadequate function contributes to short and long-term ill-health. The placenta is absent from most large-scale RNA-Seq datasets. We therefore analyze long and small RNAs (~101 and 20 million reads per sample respectively) from 302 human placentas, including 94 cases of preeclampsia (PE) and 56 cases of fetal growth restriction (FGR). The placental transcriptome has the seventh lowest complexity of 50 human tissues: 271 genes account for 50% of all reads. We identify multiple circular RNAs and validate 6 of these by Sanger sequencing across the back-splice junction. Using large-scale mass spectrometry datasets, we find strong evidence of peptides produced by translation of two circular RNAs. We also identify novel piRNAs which are clustered on Chr1 and Chr14. PE and FGR are associated with multiple and overlapping differences in mRNA, lincRNA and circRNA but fewer consistent differences in small RNAs. Of the three protein coding genes differentially expressed in both PE and FGR, one encodes a secreted protein FSTL3 (follistatin-like 3). Elevated serum levels of FSTL3 in pregnant women are predictive of subsequent PE and FGR. To aid visualization of our placenta transcriptome data, we develop a web application ( https://www.obgyn.cam.ac.uk/placentome/ ).
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http://dx.doi.org/10.1038/s41467-021-22695-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113443PMC
May 2021

Routine Third Trimester Sonogram: Friend or Foe.

Obstet Gynecol Clin North Am 2021 Jun;48(2):359-369

Department of Obstetrics and Gynaecology, University of Cambridge, Box 223, The Rosie Hospital, Robinson Way, Cambridge CB2 0SW, United Kingdom. Electronic address:

Several risk factors for adverse pregnancy outcomes can be identified by a routine third trimester ultrasound scan. However, there is also potential for harm, anxiety, and additional health care costs through unnecessary intervention due to false positive results. The evidence base informing the balance of risks and benefits of universal screening is inadequate to fully inform decision making. However, data on the diagnostic effectiveness of universal ultrasound suggest that better methods are required to result in net benefit, with the exception of screening for presentation near term, where a clinical and economic case can be made for its implementation.
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http://dx.doi.org/10.1016/j.ogc.2021.02.006DOI Listing
June 2021

Cervical ripening at home or in-hospital-prospective cohort study and process evaluation (CHOICE) study: a protocol.

BMJ Open 2021 05 4;11(5):e050452. Epub 2021 May 4.

Edinburgh Clinical Trials Unit (ECTU) Usher Institute, University of Edinburgh, Edinburgh, UK.

Introduction: The aim of the cervical ripening at home or in-hospital-prospective cohort study and process evaluation (CHOICE) study is to compare home versus in-hospital cervical ripening to determine whether home cervical ripening is safe (for the primary outcome of neonatal unit (NNU) admission), acceptable to women and cost-effective from the perspective of both women and the National Health Service (NHS).

Methods And Analysis: We will perform a prospective multicentre observational cohort study with an internal pilot phase. We will obtain data from electronic health records from at least 14 maternity units offering only in-hospital cervical ripening and 12 offering dinoprostone home cervical ripening. We will also conduct a cost-effectiveness analysis and a mixed methods study to evaluate processes and women/partner experiences. Our primary sample size is 8533 women with singleton pregnancies undergoing induction of labour (IOL) at 39+0 weeks' gestation or more. To achieve this and contextualise our findings, we will collect data relating to a cohort of approximately 41 000 women undergoing IOL after 37 weeks. We will use mixed effects logistic regression for the non-inferiority comparison of NNU admission and propensity score matched adjustment to control for treatment indication bias. The economic analysis will be undertaken from the perspective of the NHS and Personal Social Services (PSS) and the pregnant woman. It will include a within-study cost-effectiveness analysis and a lifetime cost-utility analysis to account for any long-term impacts of the cervical ripening strategies. Outcomes will be reported as incremental cost per NNU admission avoided and incremental cost per quality adjusted life year gained.

Research Ethics Approval And Dissemination: CHOICE has been funded and approved by the National Institute of Healthcare Research Health Technology and Assessment, and the results will be disseminated via publication in peer-reviewed journals.

Trial Registration Number: ISRCTN32652461.
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http://dx.doi.org/10.1136/bmjopen-2021-050452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098973PMC
May 2021

Sex differences in the foraging behavior of a generalist hawkmoth.

Insect Sci 2021 Apr 27. Epub 2021 Apr 27.

Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona, USA.

Within-species variation in pollinator behavior is widely observed, but its causes have been minimally investigated. Pollinator sex is associated with large differences in behavior that may lead to predictable differences in flower foraging, but this expectation has not been explicitly tested. We investigate sex-associated differences in nectar-foraging behavior of the hawkmoth Hyles lineata, using pollen on the proboscis as a proxy for flower visitation. We tested two predictions emerging from the literature: (1) the sexes differ in the flower species they visit, (2) females are more specialized in flower choice. We also examined potential drivers underlying these predictions by performing field and laboratory experiments to test whether males (3) switch among flower species more frequently, or (4) fly farther and therefore encounter more species than females. Consistent with prediction (1), pollen load composition differed between the sexes, indicative of visitation differences. Contrary to prediction (2), females consistently carried more species-rich pollen loads than males. (3) Both sexes switched between flower species at similar rates, suggesting that differences in floral fidelity are unlikely to explain why females are less specialized than males. (4) Males flew longer distances than females; coupled with larger between-site differences in pollen composition for females, this result suggests that sex differences in mobility influence foraging, and that females may forage more frequently and in smaller areas than males. Together, our results demonstrate that sex-associated foraging differences can be large and consistent over time, and highlight the importance of sex as a driver of variation in pollinator behavior.
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http://dx.doi.org/10.1111/1744-7917.12926DOI Listing
April 2021

Slowing of fetal growth and elevated maternal serum sFLT1:PlGF are associated with early term spontaneous labor.

Am J Obstet Gynecol 2021 11 24;225(5):520.e1-520.e10. Epub 2021 Apr 24.

Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom; NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. Electronic address:

Background: The physiological control of human parturition at term is unknown.

Objective: This study aimed to test the hypothesis that slowing of fetal growth or elevated maternal serum levels of markers of placental hypoxia in late gestation will be associated with earlier term labor.

Study Design: We observed 2208 women having first births and performed serial blinded ultrasonography and immunoassay of soluble fms-like tyrosine kinase-1 and placenta growth factor. We estimated the probability of spontaneous delivery from 37 weeks of gestational age concerning (1) fetal growth between 20 and 36 weeks of gestational age and (2) the maternal serum soluble fms-like tyrosine kinase-1-to-placenta growth factor ratio measured at approximately 36 weeks of gestational age. Data were analyzed using logistic regression and Cox regression.

Results: Fetal size at 36 weeks of gestational age was not independently associated with the timing of delivery at term. However, there was an inverse relationship between fetal growth between 20 weeks of gestational age and 36 weeks of gestational age and the probability of spontaneous labor at 37 to 38 weeks' gestation (hazard ratio [95% confidence interval] for a 50 percentile increase in abdominal circumference growth velocity, 0.60 [0.47-0.78]; P=.0001). This association was weaker at 39 to 40 weeks' gestation (0.83 [0.74-0.93]; P=.0013), and there was no association at ≥41 weeks' gestation. Very similar associations were observed for estimated fetal weight growth velocity. There was a positive relationship between soluble fms-like tyrosine kinase-1-to-placenta growth factor ratio and the probability of spontaneous labor at 37 to 38 weeks' gestation (hazard ratio [95% confidence interval] for a 50 percentile increase in soluble fms-like tyrosine kinase-1-to-placenta growth factor ratio, 3.05 [2.32-4.02]; P<.0001). This association was weaker at 39 to 40 weeks' gestation (1.46 [1.30-1.63]; P<.0001), and there was no association at ≥41 weeks' gestation. Adjustment for maternal characteristics was without material effect on any of these associations.

Conclusion: Slowing of fetal growth and biomarkers of placental insufficiency were associated with an increased probability of early onset of spontaneous term labor. We speculated that progressive placental insufficiency may be a physiological phenomenon that occurs with advancing gestational age near and at term and promotes the initiation of labor.
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http://dx.doi.org/10.1016/j.ajog.2021.04.232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568041PMC
November 2021

Migraine associated with early onset postpartum depression in women with major depressive disorder.

Arch Womens Ment Health 2021 12 21;24(6):949-955. Epub 2021 Apr 21.

Psychological Medicine, University of Worcester, Henwick Grove, Worcester, WR2 6AJ, UK.

Major depressive disorder (MDD) and migraine are both more common among women than men. Women's reproductive years are associated with increased susceptibility to recurrence of both conditions, suggesting a potential role of sex hormones in aetiology. We examined associations between comorbid migraine and clinical features of MDD in women, including relationships with lifetime reproductive events such as childbirth. Lifetime clinical characteristics and reproductive events in a well-characterised sample of 222 UK women with recurrent MDD, with (n = 98) and without (n = 124) migraine were compared. Women had all been recruited as part of a UK-based ongoing programme of research into the genetic and non-genetic determinants of mood disorders. Multivariate analysis showed a specific association between the lifetime presence of migraine and postpartum depression (PPD) within 6 weeks of delivery (OR = 2.555; 95% CI: 1.037-6.295, p = 0.041). This association did not extend to a broader definition of PPD with onset up to 6 months postpartum. All other factors included in the analysis were not significantly associated with the presence of migraine: family history of depression, younger age at depression onset, history of suicide attempt and severe premenstrual syndrome symptoms. The finding that women with MDD and comorbid migraine may be particularly sensitive to hormonal changes early in the postpartum period leads to aetiological hypotheses and suggests this group may be useful for future studies attempting to characterise PPD and MDD phenotypes. The refinement of such phenotypes has implications for individualising risk and treatment and for future biological and genetic studies.
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http://dx.doi.org/10.1007/s00737-021-01131-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585813PMC
December 2021

Late Pregnancy Ultrasound to Screen for and Manage Potential Birth Complications in Nulliparous Women: A Cost-Effectiveness and Value of Information Analysis.

Value Health 2021 04 21;24(4):513-521. Epub 2021 Jan 21.

Department of Obstetrics and Gynaecology, University of Cambridge, NIHR Cambridge Biomedical Research Centre, Cambridge, UK.

Background: Fetal growth restriction is a major risk factor for stillbirth. A routine late-pregnancy ultrasound scan could help detect this, allowing intervention to reduce the risk of stillbirth. Such a scan could also detect fetal presentation and predict macrosomia. A trial powered to detect stillbirth differences would be extremely large and expensive.

Objectives: It is therefore critical to know whether this would be a good investment of public research funds. The aim of this study is to estimate the cost-effectiveness of various late-pregnancy screening and management strategies based on current information and predict the return on investment from further research.

Methods: Synthesis of current evidence structured into a decision model reporting expected costs, quality-adjusted life-years, and net benefit over 20 years and value-of-information analysis reporting predicted return on investment from future clinical trials.

Results: Given a willingness to pay of £20 000 per quality-adjusted life-year gained, the most cost-effective strategy is a routine presentation-only scan for all women. Universal ultrasound screening for fetal size is unlikely to be cost-effective. Research exploring the cost implications of induction of labor has the greatest predicted return on investment. A randomized, controlled trial with an endpoint of stillbirth is extremely unlikely to be a value for money investment.

Conclusion: Given current value-for-money thresholds in the United Kingdom, the most cost-effective strategy is to offer all pregnant women a presentation-only scan in late pregnancy. A randomized, controlled trial of screening and intervention to reduce the risk of stillbirth following universal ultrasound to detect macrosomia or fetal growth restriction is unlikely to represent a value for money investment.
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http://dx.doi.org/10.1016/j.jval.2020.11.005DOI Listing
April 2021

Fetal umbilical artery Doppler as a tool for universal third trimester screening: A systematic review and meta-analysis of diagnostic test accuracy.

Placenta 2021 05 22;108:47-54. Epub 2021 Mar 22.

Department of Obstetrics and Gynaecology, University of Cambridge; NIHR Cambridge Comprehensive Biomedical Research Centre, CB2 2SW, United Kingdom. Electronic address:

The objective of this study was to investigate the accuracy of universal third trimester umbilical artery (UA) Doppler to predict adverse pregnancy outcome at term. We searched Medline, EMBASE, the Cochrane library and ClinicalTrials.gov from inception to October 2020 and we also analyzed previously unpublished data from a prospective cohort study of nulliparous women, the Pregnancy Outcome Prediction (POP) study. We included studies that performed a third-trimester ultrasound scan in unselected, low or mixed risk populations, excluding studies which only included high risk pregnancies. Meta-analysis was performed using the hierarchal summary receiver operating characteristic curve (HSROC) analysis and bivariate logit-normal models. We identified 13 studies (including the POP study) involving 67,764 pregnancies which met our inclusion criteria. The overall quality was variable and only six studies (N = 5777 patients) blinded clinicians to the UA Doppler result. The summary sensitivity and positive likelihood ratio (LR) for small for gestational age (SGA; birthweight <10th centile) were 21.7% (95% CI 13.2-33.6%) and 2.65 (95% CI 1.89-3.72) respectively. The summary positive LR for NICU admission and metabolic acidosis were 1.35 (95% CI 0.93-1.97) and 1.34 (95% CI 0.86-2.08) respectively. The results were similar in the POP study: associations with SGA (positive LR 2.66 [95% CI 2.11-3.36]) and severe SGA (birthweight <3rd centile; positive LR 3.27 [95% CI 2.29-4.68]) but no statistically significant association with neonatal morbidity. We conclude that third trimester UA Doppler has moderate predictive accuracy for small for gestational age but not for indicators of neonatal morbidity in unselected and low risk pregnancies.
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http://dx.doi.org/10.1016/j.placenta.2021.03.011DOI Listing
May 2021
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