Metformin has been prescribed in pregnancy for over 40 years; for much of this time, use has been limited both in numbers and geographically, and the evidence base has been confined to observational ...studies. In early years, perceived safety concerns and lack of availability of the drug in many countries acted as a barrier to use. More recently, RCTs have begun to examine the role of metformin in pregnancy in much-needed detail. However, this evidence base has been interpreted differently in different countries, leading to very wide variation in its current application in pregnancy. In this short review, we will discuss the history of metformin in pregnancy and highlight some of the key clinical trials. We will then consider some of the remaining controversies associated with metformin use in pregnancy, most important of these being the potential for long-term ‘programming’ effects on the fetus as a result of metformin being able to cross the placenta. We will also consider clinical situations where metformin might be avoided. Finally, we will discuss some future directions for this drug as it reaches its sixtieth anniversary.
Cell migration requires coordinated formation of focal adhesions (FAs) and assembly and contraction of the actin cytoskeleton. Nonmuscle myosin II (MII) is a critical mediator of contractility and FA ...dynamics in cell migration. Signaling downstream of the small GTPase Rac1 also regulates FA and actin dynamics, but its role in regulation of MII during migration is less clear.
We found that Rac1 promotes association of MIIA with FA. Live-cell imaging showed that, whereas most MIIA at the leading edge assembled into dorsal contractile arcs, a substantial subset assembled in or was captured within maturing FA, and this behavior was promoted by active Rac1. Protein kinase C (PKC) activation was necessary and sufficient for integrin- and Rac1-dependent phosphorylation of MIIA heavy chain (HC) on serine1916 (S1916) and recruitment to FA. S1916 phosphorylation of MIIA HC and localization in FA was enhanced during cell spreading and ECM stiffness mechanosensing, suggesting upregulation of this pathway during physiological Rac1 activation. Phosphomimic and nonphosphorylatable MIIA HC mutants demonstrated that S1916 phosphorylation was necessary and sufficient for the capture and assembly of MIIA minifilaments in FA. S1916 phosphorylation was also sufficient to promote the rapid assembly of FAs to enhance cell migration and for the modulation of traction force, spreading, and migration by ECM stiffness.
Our study reveals for the first time that Rac1 and integrin activation regulates MIIA HC phosphorylation through a PKC-dependent mechanism that promotes MIIA association with FAs and acts as a critical modulator of cell migration and mechanosensing.
•Rac1 and integrin activation promotes myosin IIA localization at focal adhesions (FAs)•PKC-mediated Myo IIA HC phosphorylation is required for its localization to FAs•Phosphomutants of Myo IIA alter FA dynamics, cell migration, and mechanosensation
Pasapera et al. find that Rac1 and integrin activation regulates MIIA heavy-chain phosphorylation through a PKC-dependent mechanism that promotes MIIA association with focal adhesions, which acts as a critical modulator of cell migration and mechanosensing.
Aims/hypothesis
Maternal obesity in pregnancy is associated with cardiovascular disease and mortality rate in the offspring. We aimed to determine whether maternal obesity is also associated with ...increased incidence of type 2 and type 1 diabetes in the offspring, independently of maternal diabetes as a candidate mechanistic pathway.
Methods
Birth records of 118,201 children from 1950 to 2011 in the Aberdeen Maternity and Neonatal Databank were linked to Scottish Care Information–Diabetes, the national register for diagnosed diabetes in Scotland, to identify incident and prevalent type 1 and type 2 diabetes up to 1 January 2012. Maternal BMI was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on offspring outcomes was tested using time-to-event analysis with Cox proportional hazards regression to compare outcomes in offspring of mothers in underweight, overweight or obese categories of BMI, compared with offspring of women with normal BMI.
Results
Offspring of obese (BMI ≥30 kg/m
2
) and overweight (BMI 25–29.9 kg/m
2
) mothers had an increased hazard of type 2 diabetes compared with mothers with normal BMI, after adjustment for gestation when weight was measured, maternal history of diabetes before pregnancy, maternal history of hypertension, age at delivery, parity, socioeconomic status, and sex of the offspring: HR 3.48 (95% CI 2.33, 5.06) and HR 1.39 (1.06, 1.83), respectively.
Conclusions/interpretation
Maternal obesity is associated with increased incidence of type 2 diabetes in the offspring. Evidence-based strategies that reduce obesity among women of reproductive age and that might reduce the incidence of diabetes in their offspring are urgently required.
Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause ...mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.
The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005-2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4-3.8, p<0.001) than men (2.3: 2.0-2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2-3.0, p<0.001) in men and 2.7 (2.2-3.4, p<0.001) in women. Between 2005-2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60-69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA(1c) of <7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used.
Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed. Please see later in the article for the Editors' Summary.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Few data are available regarding the long-term mortality rate for patients receiving nocturnal home hemodialysis. Study Design Posttrial observational study. Setting & Participants ...Frequent Hemodialysis Network (FHN) Nocturnal Trial participants who consented to extended follow-up. Intervention The FHN Nocturnal Trial randomly assigned 87 individuals to 6-times-weekly home nocturnal hemodialysis or 3-times-weekly hemodialysis for 1 year. Patients were enrolled starting in March 2006 and follow-up was completed by May 2010. After the 1-year trial concluded, FHN Nocturnal participants were free to modify their hemodialysis prescription. Outcomes & Measurements We obtained dates of death and kidney transplantation through July 2011 using linkage to the US Renal Data System and queries of study centers. We used log-rank tests and Cox regression to relate mortality to the initial randomization assignment. Results Median follow-up for the trial and posttrial observational period was 3.7 years. In the nocturnal arm, there were 2 deaths during the 12-month trial period and an additional 12 deaths during the extended follow-up. In the conventional arm, the numbers of deaths were 1 and 4, respectively. In the nocturnal dialysis group, the overall mortality HR was 3.88 (95% CI, 1.27-11.79; P = 0.01). Using as-treated analysis with a 12-month running treatment average, the HR for mortality was 3.06 (95% CI, 1.11-8.43; P = 0.03). Six-month running treatment data analysis showed an HR of 1.12 (95% CI, 0.44-3.22; P = 0.7). Limitations These results should be interpreted cautiously due to a surprisingly low (0.03 deaths/patient-year) mortality rate for individuals randomly assigned to conventional home hemodialysis, low statistical power for the mortality comparison due to the small sample size, and the high rate of hemodialysis prescription changes. Conclusions Patients randomly assigned to nocturnal hemodialysis had a higher mortality rate than those randomly assigned to conventional dialysis. The implications of this result require further investigation.
Background and aims
Prescription opioid overdose is a leading cause of injury‐related morbidity and mortality in the United States. We aimed to identify characteristics associated with clinical ...severity in emergency department patients with prescription opioid overdose.
Design
This was a secondary data analysis of adult prescription opioid overdoses from a large prospective cohort of acute overdoses. We examined elements of a typical emergency department evaluation using a multivariable model to determine which characteristics were associated with clinical severity, specifically severe respiratory depression (SRD).
Setting
This study was conducted at two urban academic emergency departments in New York City, USA.
Participants
Adult patients who presented with acute prescription opioid overdose between 2009 and 2013 were included in the current study. We analyzed 307 patients (mean age = 44.7, 42% female, 2.0% mortality).
Measurements
Patient demographics, reported substances ingested, suspected intent for ingesting the substance, vital signs, laboratory data, treatments including antidotes and intubation and outcome of death were recorded by trained research assistants. Intent was categorized into four mutually exclusive categories: suicide, misuse, therapeutic error and undetermined. The primary outcome was SRD, defined as administration of either (a) naloxone or (b) endotracheal intubation (ETI).
Findings
A total of 109 patients suffered SRD with 90 patients receiving naloxone alone, nine ETI alone and 10 both naloxone and ETI. The most common opioids were oxycodone (n = 124) and methadone (n = 116). Mean age was higher in patients with SRD (51.1 versus 41.1, P < 0.001). Opioid misuse was associated with SRD in the multivariable analysis odds ratio (OR) = 2.07, 95% confidence interval (CI) = 1.21–3.55. The unadjusted relative risk of SRD was high for fentanyl (83.3% SRD) and lowest for codeine (3.6% SRD).
Conclusion
In emergency department patients in the United States with prescription opioid overdose, worse clinical severity was associated with opioid misuse, increased with age and was widely variable, depending on the specific opioid medication involved.
The human reference genome assembly plays a central role in nearly all aspects of today's basic and clinical research. GRCh38 is the first coordinate-changing assembly update since 2009; it reflects ...the resolution of roughly 1000 issues and encompasses modifications ranging from thousands of single base changes to megabase-scale path reorganizations, gap closures, and localization of previously orphaned sequences. We developed a new approach to sequence generation for targeted base updates and used data from new genome mapping technologies and single haplotype resources to identify and resolve larger assembly issues. For the first time, the reference assembly contains sequence-based representations for the centromeres. We also expanded the number of alternate loci to create a reference that provides a more robust representation of human population variation. We demonstrate that the updates render the reference an improved annotation substrate, alter read alignments in unchanged regions, and impact variant interpretation at clinically relevant loci. We additionally evaluated a collection of new de novo long-read haploid assemblies and conclude that although the new assemblies compare favorably to the reference with respect to continuity, error rate, and gene completeness, the reference still provides the best representation for complex genomic regions and coding sequences. We assert that the collected updates in GRCh38 make the newer assembly a more robust substrate for comprehensive analyses that will promote our understanding of human biology and advance our efforts to improve health.
Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three ...times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/Vurea, a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.
The role of human behavior to thwart transmission of infectious diseases like COVID-19 is evident. Psychological and behavioral science are key areas to understand decision-making processes ...underlying engagement in preventive health behaviors. Here we adapt well validated methods from behavioral economic discounting and demand frameworks to evaluate variables (e.g., delay, cost, probability) known to impact health behavior engagement. We examine the contribution of these mechanisms within a broader response class of behaviors reflecting adherence to public health recommendations made during the COVID-19 pandemic. Four crowdsourced samples (total N = 1,366) completed individual experiments probing a response class including social (physical) distancing, facemask wearing, COVID-19 testing, and COVID-19 vaccination. We also measure the extent to which choice architecture manipulations (e.g., framing, opt-in/opt-out) may promote (or discourage) behavior engagement. We find that people are more likely to socially distance when specified activities are framed as high risk, that facemask use during social interaction decreases systematically with greater social relationship, that describing delay until testing (rather than delay until results) increases testing likelihood, and that framing vaccine safety in a positive valence improves vaccine acceptance. These findings collectively emphasize the flexibility of methods from diverse areas of behavioral science for informing public health crisis management.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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