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Declining Insulin Requirement in the Late First Trimester of Diabetic Pregnancy Lois Jovanovic , MD 1 , Robert H. Knopp , MD 2 , Zane Brown , MD 3 , Mary R. Conley , MA 4 , Eunsik Park , PHD, MD 4 , James L. Mills , MD 4 , Boyd E. Metzger , MD 5 , Jerome H. Aarons , MD 6 , Lewis B. Holmes , MD 7 , Joe L. Simpson , MD 8 and and the National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study Group 1 Sansum Medical Research Institute, Santa Barbara, California 2 Northwest Lipid Research Clinic, and the 3 Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington 4 Epidemiology and Biometry Branches, National Institute of Child Health and Human Development, Bethesda, Maryland 5 Northwestern University Medical School, Chicago, Illinois 6 Department of Medicine, Magee Women’s Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 7 Genetics and Teratology Unit, Massachusetts General Hospital, Boston, Massachusetts 8 Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas Abstract OBJECTIVE —To investigate whether pregnancies complicated by type 1 diabetes are associated with a decrease in first-trimester insulin requirement. RESEARCH DESIGN AND METHODS —We examined the weekly insulin requirement (as units per kilogram per day) during the first trimester of pregnancy in diabetic women in the Diabetes in Early Pregnancy Study (DIEP) with accurate gestational dating, regular glucose monitoring, daily insulin-dose recording, and monthly glycohemoglobin measurements. RESULTS —In pregnancies that resulted in live-born full-term singleton infants, a significant 18% increase in mean weekly dosage was observed between weeks 3 and 7 ( P = 0.000), followed by a significant 9% decline from week 7 through week 15 ( P = 0.000). Further testing localized a significant change in insulin dose in the interval beginning weeks 7–8 and ending weeks 11–12 ( P = 0.014). Within this interval, the maximum decrease was between weeks 9 and 10 (mean), 10 and 11 (median), and 8 and 9 (most frequent maximal decrease). To determine whether prior poor glucose control exaggerated these trends, we categorized the women based on their glycohemoglobin values: <2 SDs above the mean of a normal population (subgroup 1), 2–4 SDs (subgroup 2), and >4 SDs (subgroup 3) at baseline. Late first-trimester declines in dosage were statistically significant in subgroup 2 ( P = 0.002) and subgroups 2 and 3 together ( P = 0.003). Similarly, women with BMI >27.0 had a greater initial insulin rise and then fall compared with leaner women. CONCLUSIONS —Observations in the DIEP cohort disclose a mid–first-trimester decline in insulin requirement in type 1 diabetic pregnant women. Possible explanations include overinsulinization of previously poorly controlled diabetes, a transient decline in progesterone secretion during the late first-trimester luteo-placental shift in progesterone secretion, or other hormonal shifts. Clinicians should anticipate a clinically meaningful reduction in insulin requirement in the 5-week interval between weeks 7 and 12 of gestation. ASI, aggressive subcutaneous insulin CSII, continuous subcutaneous insulin infusion DIEP, Diabetes in Early Pregnancy Study NICHD, National Institute of Child Health and Human Development Footnotes Address correspondence and reprint requests to Lois Jovanovic, MD, Sansum Medical Research Institute, 2219 Bath St., Santa Barbara, CA 93105. E-mail: ljovanovic{at}sansum.org . Received for publication 22 September 2000 and accepted in revised form 7 March 2001. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

To the Editor: Mastenbroek et al. (July 5 issue) 1 report a detrimental effect of preimplantation genetic screening, performed in women of advanced maternal age, on rates of ongoing pregnancy and live birth. We believe this outcome is explained by problems with the authors' methods, both for biopsy and for diagnosis. As Mastenbroek and colleagues note, pregnancy rates after in vitro fertilization (IVF) steadily decline with increasing maternal age, while rates of pregnancy loss concurrently increase. These observations are attributed mostly to chromosome abnormalities in embryos obtained after follicular stimulation (which range from 50% among young patients to nearly 80% among . . .

Preterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce preterm birth and adverse neonatal outcomes. We did a systematic review of randomised trials comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth. We identified published and unpublished trials that completed primary data collection before July 30, 2016, (12 months before data collection began), by searching MEDLINE, Embase, CINAHL, the Maternity and Infant Care Database, and relevant trial registers between inception and July 30, 2019. Trials of progestogen to prevent early miscarriage or immediately-threatened preterm birth were excluded. Individual participant data were requested from investigators of eligible trials. Outcomes included preterm birth, early preterm birth, and mid-trimester birth. Adverse neonatal sequelae associated with early births were assessed using a composite of serious neonatal complications, and individually. Adverse maternal outcomes were investigated as a composite and individually. Individual participant data were checked and risk of bias assessed independently by two researchers. Primary meta-analyses used one-stage generalised linear mixed models that incorporated random effects to allow for heterogeneity across trials. This meta-analysis is registered with PROSPERO, CRD42017068299. Initial searches identified 47 eligible trials. Individual participant data were available for 30 of these trials. An additional trial was later included in a targeted update. Data were therefore available from a total of 31 trials (11 644 women and 16185 offspring). Trials in singleton pregnancies included mostly women with previous spontaneous preterm birth or short cervix. Preterm birth before 34 weeks was reduced in such women who received vaginal progesterone (nine trials, 3769 women; relative risk [RR] 0·78, 95% CI 0·68–0·90), 17-OHPC (five trials, 3053 women; 0·83, 0·68–1·01), and oral progesterone (two trials, 183 women; 0·60, 0·41–0·90). Results for other birth and neonatal outcomes were consistently favourable, but less certain. A possible increase in maternal complications was suggested, but this was uncertain. We identified no consistent evidence of treatment interaction with any participant characteristics examined, although analyses within subpopulations questioned efficacy in women who did not have a short cervix. Trials in multifetal pregnancies mostly included women without additional risk factors. For twins, vaginal progesterone did not reduce preterm birth before 34 weeks (eight trials, 2046 women: RR 1·01, 95% CI 0·84–1·20) nor did 17-OHPC for twins or triplets (eight trials, 2253 women: 1·04, 0·92–1·18). Preterm premature rupture of membranes was increased with 17-OHPC exposure in multifetal gestations (rupture <34 weeks RR 1·59, 95% CI 1·15–2·22), but we found no consistent evidence of benefit or harm for other outcomes with either vaginal progesterone or 17-OHPC. Vaginal progesterone and 17-OHPC both reduced birth before 34 weeks' gestation in high-risk singleton pregnancies. Given increased underlying risk, absolute risk reduction is greater for women with a short cervix, hence treatment might be most useful for these women. Evidence for oral progesterone is insufficient to support its use. Shared decision making with woman with high-risk singleton pregnancies should discuss an individual's risk, potential benefits, harms and practicalities of intervention. Treatment of unselected multifetal pregnancies with a progestogen is not supported by the evidence. Patient-Centered Outcomes Research Institute.

To determine how much insulin-dependent diabetes increases a woman's risk of giving birth to a malformed infant and how that risk is influenced by metabolic control, we followed 347 diabetic and 389 control women who enrolled in the study within 21 days of conception (the early-entry group) and 279 diabetic women who entered later (the late-entry group). We detected major malformations in the infants of 4.9 percent of the early-entry diabetic women, 2.1 percent of the controls, and 9.0 percent of the late-entry diabetic women. Malformation rates were significantly higher among offspring of early-entry diabetic women than among those of controls (odds ratio, 2.45; lower one-sided 95 percent confidence limit, 1.12; P = 0.027), and higher among late-entry than among early-entry diabetic women (odds ratio, 1.91; lower one-sided 95 percent confidence limit, 1.07; P = 0.032). Mean blood glucose and glycosylated hemoglobin levels during organogenesis were not significantly higher in women whose infants were malformed. Hypoglycemia (glucose, ≤50 mg per deciliter [2.8 mmol per liter]) was not significantly more common in the same group. Hyperglycemia and glycosylated hemoglobin were not correlated with malformation. The data suggest that more sensitive measures are needed to identify the teratogenic mechanisms, or that not all malformation can be prevented by good glycemic control. Despite the increased malformation rate among infants of the early-entry diabetic women, as compared with the controls, the more favorable outcome seen in the former group as compared with the late-entry group justifies the attempt to achieve good metabolic control around the time of conception. (N Engl J Med 1988; 318:671–6.) MAJOR malformations are said to be two to three times more common in infants whose mothers had insulin-dependent diabetes mellitus at conception. 1 The recognition that these diabetes-associated malformations occur in the first six weeks after conception 2 led us to investigate the relation between diabetic control during organogenesis and malformation. The National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study, which began in 1980, was designed for two purposes: to quantify the risk of malformation in offspring of insulin-dependent diabetic women as compared with a nondiabetic control population, and to identify the factor or factors associated with . . .

OBJECTIVES: The purpose of this study was to determine prospectively whether unplanned pregnancies are associated with adverse pregnancy outcomes among users of natural family planning. METHODS: Women who became pregnant while using natural family planning were identified in five centers worldwide: there were 373 unplanned and 367 planned pregnancies in this cohort. The subjects were followed up at 16 and 32 weeks' gestation and after delivery. The risks of spontaneous abortion, low birth-weight, and preterm birth were estimated after adjustment by logistic regression. RESULTS: The women with unplanned pregnancies were more likely to be at the extremes of age, to report more medical problems before and during the index pregnancy, and to seek antenatal care later in gestation than the women with planned pregnancies. However, women with planned pregnancies reported a higher rate of spontaneous abortion in previous pregnancies (28.8%) than did women with unplanned pregnancies (12.9%). There were no significant differences in the rates of spontaneous abortion, low birthweight, or preterm birth between the two groups. CONCLUSIONS: No increased risk of adverse pregnancy outcomes was observed among women who experienced an unplanned pregnancy while using natural family planning.

To the Editor: We wish to report a midtrimester prenatal diagnosis by ultrasonography of congenital muscular dystrophy producing arthrogryposis. The proband was a 2875-g female infant born at term to healthy, unrelated parents of Northern European origin. The pregnancy had been uncomplicated except for the mother's recollection of the absence of fetal movement. The infant was delivered by cesarean section because of fetal distress. She had Apgar scores of 3 and 4 at one and five minutes, respectively, had multiple external compression deformities and contractures, and died of respiratory failure two hours after birth. At autopsy, skeletal muscle was found . . . No extract is available for articles shorter than 400 words.

CAMBRIA HEIGHTS The Rev. John H. Boyd Sr., who served as senior pastor at the New Greater Bethel Ministries in southeast Queens, died Wednesday. He was 85. City Councilman Leroy Comrie (D-St. Albans) mourned his loss, noting that Boyd \"worked meticulously to help those less fortunate.\" \"Under the direction of Rev. Boyd, Greater Bethel started programs such as the Lord's Food Pantry and Soup Kitchen, and the Inmate Community Improvement Program,\" Comrie said in a statement.

This large, systematic study of prenatal diagnosis shows that chromosomal microarray analysis provided additional, clinically significant cytogenetic information as compared with karyotyping but did not identify triploidies and balanced translocations. The development of array-based molecular cytogenetic techniques has improved the detection of small genomic deletions and duplications (called copy-number variants) that are not routinely seen on karyotyping, the standard cytogenetic analysis performed. Copy-number variants result in a variation from the expected number of copies of a segment of DNA (i.e., the number in a normal genome). Copy-number variants can be either benign or pathogenic, depending on their location and genetic content. They are identified with the use of chromosomal microarray analysis in which a test sample of DNA from the patient is compared directly or indirectly with a reference (normal) . . .

There has been re-emerging interest and significant work dedicated to investigating the metabolic effects of high intensity interval training (HIIT) in recent years. HIIT is considered to be a time efficient alternative to classic endurance training (ET) that elicits similar metabolic responses in skeletal muscle. However, there is a lack of information on the impact of HIIT on cardiac muscle in disease. Therefore, we determined the efficacy of ET and HIIT to alter cardiac muscle characteristics involved in the development of diastolic dysfunction, such as ventricular hypertrophy, fibrosis and angiogenesis, in a well-established rodent model of hypertension-induced heart failure before the development of overt heart failure. ET decreased left ventricle fibrosis by ~40% (P < 0.05), and promoted a 20% (P<0.05) increase in the left ventricular capillary/fibre ratio, an increase in endothelial nitric oxide synthase protein (P<0.05), and a decrease in hypoxia inducible factor 1 alpha protein content (P<0.05). In contrast, HIIT did not decrease existing fibrosis, and HIIT animals displayed a 20% increase in left ventricular mass (P<0.05) and a 20% decrease in cross sectional area (P<0.05). HIIT also increased brain natriuretic peptide by 50% (P<0.05), in the absence of concomitant angiogenesis, strongly suggesting pathological cardiac remodeling. The current data support the longstanding belief in the effectiveness of ET in hypertension. However, HIIT promoted a pathological adaptation in the left ventricle in the presence of hypertension, highlighting the need for further research on the widespread effects of HIIT in the presence of disease.

Assessing global progress on human adaptation to climate change is an urgent priority. Although the literature on adaptation to climate change is rapidly expanding, little is known about the actual extent of implementation. We systematically screened >48,000 articles using machine learning methods and a global network of 126 researchers. Our synthesis of the resulting 1,682 articles presents a systematic and comprehensive global stocktake of implemented human adaptation to climate change. Documented adaptations were largely fragmented, local and incremental, with limited evidence of transformational adaptation and negligible evidence of risk reduction outcomes. We identify eight priorities for global adaptation research: assess the effectiveness of adaptation responses, enhance the understanding of limits to adaptation, enable individuals and civil society to adapt, include missing places, scholars and scholarship, understand private sector responses, improve methods for synthesizing different forms of evidence, assess the adaptation at different temperature thresholds, and improve the inclusion of timescale and the dynamics of responses.Determining progress in adaptation to climate change is challenging, yet critical as climate change impacts increase. A stocktake of the scientific literature on implemented adaptation now shows that adaptation is mostly fragmented and incremental, with evidence lacking for its impact on reducing risk.