We sought to review the state of the science for research on multiple gestations. A literature search was performed with the use of PubMed for studies to quantify the representation of multiple ...gestations for a sample period (2012–2016) that were limited to phase III and IV randomized controlled trials, that were written in English, and that addressed at least 1 of 4 major pregnancy complications: fetal growth restriction or small-for-gestational-age fetus, gestational diabetes mellitus, preeclampsia, and preterm delivery.
Of the 226 studies that are included in the analysis, multiple pregnancies were most represented in studies of preterm delivery: 17% of trials recruited both singleton and multiple pregnancies; another 18% of trials recruited only multiple pregnancies. For trials that studied preeclampsia, fetal growth restriction, and gestational diabetes mellitus, 17%, 8%, and 2%, respectively, recruited both singleton and multiple gestations. None of the trials on these 3 topics were limited to women with a multiple pregnancy.
Women with a multiple pregnancy are at risk for complications similar to those of women with singleton pregnancies, but their risk is usually higher. Also, the pathophysiologic condition for some complications differs in multiple gestations from those that occur in singleton gestations. Conditions that are unique to multiple pregnancies include excess placenta, placental crowding or inability of the uteroplacental unit to support the normal growth of multiple fetuses, or suboptimal placental implantation sites with an increased risk of abnormal placental location. Other adverse outcomes in multiple gestations are also influenced by twin-specific risk factors, most notably chorionicity.
Although twins have been well represented in many studies of preterm birth, these studies have failed to identify adequate predictive tests (short cervical length established over 2 decades ago remains the single best predictor), to establish effective interventions, and to differentiate the underlying pathophysiologic condition of twin preterm birth.
Questions about fetal growth also remain. Twin growth deviates from that of singleton gestations starting at approximately 32 weeks of gestation; however, research with long-term follow-up is needed to better distinguish pathologic and physiologic growth deviations, which include growth discordance among pairs (or more). There are virtually no clinical trials that are specific to twins for gestational diabetes mellitus or preeclampsia, and subgroups for multiple pregnancies in existing trials are not large enough to allow definite conclusions. Another important area is the determination of appropriate maternal nutrition or micronutrient supplementation to optimize pregnancy and child health.
There are also unique aspects to consider for research design in multiple gestations, such as designation and tracking of the correct fetus prenatally and through delivery. The correct statistical methods must be used to account for correlated data because multiple fetuses share the same mother and intrauterine environment.
In summary, multiple gestations often are excluded from research studies, despite a disproportionate contribution to national rates of perinatal morbidity, mortality, and health-care costs. It is important to consider the enrollment of multifetal pregnancies in studies that target mainly women with singleton gestations, even when sample size is inadequate, so that insights that are specific to multiple gestations can be obtained when results of smaller studies are pooled together. The care of pregnant women with multiple gestations presents unique challenges; unfortunately, evidence-based clinical management that includes the diagnosis and treatment of common obstetrics problems are not well-defined for this population.
Acceptance and willingness to pay for the COVID-19 vaccine are unknown.
We compared attitudes toward COVID-19 vaccination in people suffering from depression or anxiety disorder and people without ...mental disorders, and their willingness to pay for it.
Adults with depression or anxiety disorder (
= 79) and healthy controls (
= 134) living in Chongqing, China, completed a cross-sectional study between 13 and 26 January 2021. We used a validated survey to assess eight aspects related to attitudes toward the COVID-19 vaccines. Psychiatric symptoms were assessed by the 21-item Depression, Anxiety and Stress Scale.
Seventy-six people with depression or anxiety disorder (96.2%) and 134 healthy controls (100%) reported willingness to receive the COVID-19 vaccine. A significantly higher proportion of people with depression or anxiety disorder (64.5%) were more willing to pay for the COVID-19 vaccine than healthy controls (38.1%) (
≤ 0.001). After multivariate adjustment, severity of depression and anxiety was significantly associated with willingness to pay for COVID-19 vaccination among psychiatric patients (
= 0.048). Non-healthcare workers (
= 0.039), health insurance (
= 0.003), living with children (
= 0.006) and internalised stigma (
= 0.002) were significant factors associated with willingness to pay for COVID-19 vaccine in healthy controls.
To conclude, psychiatric patients in Chongqing, China, showed high acceptance and willingness to pay for the COVID-19 vaccine. Factors associated with willingness to pay for the COVID-19 vaccine differed between psychiatric patients and healthy controls.
BACKGROUND:Heart failure is a leading cause of mortality and morbidity, and the search for novel therapeutic approaches continues. In the monogenic disease mucopolysaccharidosis VI, loss-of-function ...mutations in arylsulfatase B lead to myocardial accumulation of chondroitin sulfate (CS) glycosaminoglycans, manifesting as myriad cardiac symptoms. Here, we studied changes in myocardial CS in nonmucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling.
METHODS:Healthy and diseased human and rat left ventricles were subjected to histological and immunostaining methods to analyze glycosaminoglycan distribution. Glycosaminoglycans were extracted and analyzed for quantitative and compositional changes with Alcian blue assay and liquid chromatography–mass spectrometry. Expression changes in 20 CS-related genes were studied in 3 primary human cardiac cell types and THP-1–derived macrophages under each of 9 in vitro stimulatory conditions. In 2 rat models of pathological remodeling induced by transverse aortic constriction or isoprenaline infusion, recombinant human arylsulfatase B (rhASB), clinically used as enzyme replacement therapy in mucopolysaccharidosis VI, was administered intravenously for 7 or 5 weeks, respectively. Cardiac function, myocardial fibrosis, and inflammation were assessed by echocardiography and histology. CS-interacting molecules were assessed with surface plasmon resonance, and a mechanism of action was verified in vitro.
RESULTS:Failing human hearts displayed significant perivascular and interstitial CS accumulation, particularly in regions of intense fibrosis. Relative composition of CS disaccharides remained unchanged. Transforming growth factor–β induced CS upregulation in cardiac fibroblasts. CS accumulation was also observed in both the pressure-overload and the isoprenaline models of pathological remodeling in rats. Early treatment with rhASB in the transverse aortic constriction model and delayed treatment in the isoprenaline model proved rhASB to be effective at preventing cardiac deterioration and augmenting functional recovery. Functional improvement was accompanied by reduced myocardial inflammation and overall fibrosis. Tumor necrosis factor–α was identified as a direct binding partner of CS glycosaminoglycan chains, and rhASB reduced tumor necrosis factor–α—induced inflammatory gene activation in vitro in endothelial cells and macrophages.
CONCLUSIONS:CS glycosaminoglycans accumulate during cardiac pathological remodeling and mediate myocardial inflammation and fibrosis. rhASB targets CS effectively as a novel therapeutic approach for the treatment of heart failure.
The maintenance of precise cell volume is critical for cell survival. Changes in extracellular osmolarity affect cell volume and may impact various cellular processes such as mitosis, mitochondrial ...functions, DNA repair as well as cell migration and proliferation. Much of what we know about the mechanisms of cell osmoregulation comes from in vitro two-dimensional (2D) assays that are less physiologically relevant than three-dimensional (3D) in vitro or in vivo settings. Here, we developed a microfluidic model to study the impact of hyper-osmotic stress on the migration, proliferation and ion channel/transporter expression changes of three metastatic cell lines (MDA-MB-231, A549, T24) in 2D versus 3D environments. We observed a global decrease in cell migration and proliferation upon hyper-osmotic stress treatment, with similar responses between 2D and 3D conditions. Specific ion channels/aquaporins are over-expressed in metastatic cells and play a central role during osmo-regulation. Therefore, the effects of hyper-osmotic stress on two transporters, aquaporin 5 (AQP5) and the transient receptor potential cation channel (TRPV4), was investigated. While hyper-osmotic stress had no major impact on the transporters of cells cultured in 2D, cells embedded in collagen gel (3D) decreased their AQP5 expression and exhibited a reduction in intra-cellular translocation of TRPV4. Furthermore, cell dispersion from T24 aggregates embedded in 3D collagen gel decreased with higher levels of hyper-osmotic stress. In conclusion, this study provides evidence on the impact of hyper-osmotic stress on various aspects of metastatic cell progression and highlights the importance of having a 3D cell culture platform in investigating molecular players involved in cancer cell migration.
Cirrhosis-related hepatic and renal endothelial dysfunction is characterized by macrophage-endothelium adhesion-mediated inflammation, glycocalyx/barrier damage, and impaired vasodilation. Activation ...of adenosine A2A receptor (A2AR) protects cirrhotic rats from impairment of hepatic microcirculation post hepatectomy. This study evaluates the effects of A2AR activation on the cirrhosis-related hepatic and renal endothelial dysfunction in biliary cirrhotic rats receiving two weeks of A2AR agonist PSB0777 bile duct ligated (BDL)+PSB0777 treatment.
Endothelial dysfunction in cirrhotic liver, renal vessels, and kidney is characterized by downregulation of the A2AR expressions, decreased vascular endothelial vasodilatory (p-eNOS)/anti-inflammatory (IL-10/IL-10R)/barrier VE-cadherin (CDH5) and β-catenin (CTNNB1)/glycocalyx syndecan-1 (SDC1) and hyaluronan synthase-2 (HAS2) markers, and increased leukocyte-endothelium adhesion molecules (F4/80, CD68, ICAM-1, and VCAM-1). In BDL rats, PSB0777 treatment improves hepatic and renal endothelial dysfunction, ameliorates portal hypertension, and attenuates renal hypoperfusion by restoring of the vascular endothelial anti-inflammatory, barrier, glycocalyx markers and vasodilatory response as well as inhibiting the leukocyte-endothelium adhesion. In an in vitro study, conditioned medium (CM) of bone marrow-derived macrophage (BMDM) of BDL rats BMDM-CM (BDL) induced barrier/glycocalyx damage, which was reversed by the PSB0777 pre-treatment. The A2AR agonist is a potential agent that can simultaneously correct cirrhosis-related hepatic and renal endothelial dysfunction, portal hypertension, renal hypoperfusion, and renal dysfunction.
Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based ...immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.
Vesicle fusion is executed via formation of an Ω-shaped structure (Ω-profile), followed by closure (kiss-and-run) or merging of the Ω-profile into the plasma membrane (full fusion). Although ...Ω-profile closure limits release but recycles vesicles economically, Ω-profile merging facilitates release but couples to classical endocytosis for recycling. Despite its crucial role in determining exocytosis/endocytosis modes, how Ω-profile merging is mediated is poorly understood in endocrine cells and neurons containing small ∼30-300 nm vesicles. Here, using confocal and super-resolution STED imaging, force measurements, pharmacology and gene knockout, we show that dynamic assembly of filamentous actin, involving ATP hydrolysis, N-WASP and formin, mediates Ω-profile merging by providing sufficient plasma membrane tension to shrink the Ω-profile in neuroendocrine chromaffin cells containing ∼300 nm vesicles. Actin-directed compounds also induce Ω-profile accumulation at lamprey synaptic active zones, suggesting that actin may mediate Ω-profile merging at synapses. These results uncover molecular and biophysical mechanisms underlying Ω-profile merging.
Objective
This paper aims to examine the efficacy of virtual reality (VR)‐enhanced cognitive behavioural therapy (CBT) in the treatment of binge‐purging type eating disorders compared to CBT.
Method
...Four electronic literature databases were searched to retrieve eligible randomised controlled trials (RCTs). The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses was used to select eligible studies. Meta‐analyses of extracted data were then conducted by RevMan 5.3 software.
Results
Six RCTs totalling 297 participants were included. Results showed significantly larger decreases in the frequency of binges in participants who underwent VR‐enhanced CBT compared to CBT. However, there was no statistically significant difference in the change in body mass index or frequency of purges. Additionally, there were significantly larger decreases in situation‐induced body dissatisfaction in participants who underwent VR‐enhanced CBT compared to CBT, but no significant difference in improvement of overall body satisfaction.
Conclusion
VR‐enhanced CBT shows greater efficacy than CBT in reducing situation‐induced body dissatisfaction and frequency of binges. Our results highlight the potential of VR in helping patients develop coping strategies to food/situational triggers. Future RCTs may benefit from recruiting more participants to reduce the impact of drop‐outs on outcome data and blinding post‐intervention assessors to reduce risk of bias.
HIGHLIGHTS
Patients who underwent VR‐enhanced CBT had a statistically significant larger decrease in situation‐induced body dissatisfaction compared to patients who underwent CBT, although there was no statistically significant difference in the increase in overall body satisfaction between the two groups
There was a larger decrease in frequency of binges for patients who underwent VR‐enhanced CBT, but no statistically significant decrease in frequency of purges. There appear to be no statistically significant differences between the physical outcomes of patients undergoing VR‐enhanced CBT and CBT
Further research needs to be done on the evaluation of long‐term physical, behavioural and psychological outcome measures of VR‐enhanced CBT, but current results show promise in the potential of using VR to help patients develop coping strategies to food and situational triggers
Changes in active layer thickness (ALT) over northern high‐latitude permafrost regions have important impacts on the surface energy balance, hydrologic cycle, carbon exchange between the atmosphere ...and the land surface, plant growth, and ecosystems as a whole. This study examines the 20th century variations of ALT for the Ob, Yenisey, and Lena River basins. ALT is estimated from historical soil temperature measurements from 17 stations (1956–1990, Lena basin only), an annual thawing index based on both surface air temperature data (1901–2002) and numerical modeling (1980–2002). The latter two provide spatial fields. Based on the thawing index, the long‐term average (1961–1990) ALT is about 1.87 m in the Ob, 1.67 in the Yenisey, and 1.69 m in the Lena basin. Over the past several decades, ALT over the three basins shows positive trends, but with different magnitudes. Based on the 17 stations, ALT increased about 0.32 m between 1956 and 1990 in the Lena. To the extent that results based on the soil temperatures represent ground “truth,” ALT obtained from both the thawing index and numerical modeling is underestimated. It is widely believed that ALT will increase with global warming. However, this hypothesis needs further refinement since ALT responds primarily to summer air temperature while observed warming has occurred mainly in winter and spring. It is also shown that ALT exhibits complex and inconsistent responses to variations in snow cover.
Docetaxel and cabazitaxel are taxane chemotherapy treatments for metastatic castration-resistant prostate cancer (CRPC). However, therapeutic resistance remains a major issue. MicroRNAs are short ...non-coding RNAs that can silence multiple genes, regulating several signalling pathways simultaneously. Therefore, synthetic microRNAs may have therapeutic potential in CRPC by regulating genes involved in taxane response and minimise compensatory mechanisms that cause taxane resistance. To identify microRNAs that can improve the efficacy of taxanes in CRPC, we performed a genome-wide screen of 1280 microRNAs in the CRPC cell lines PC3 and DU145 in combination with docetaxel or cabazitaxel treatment. Mimics of miR-217 and miR-181b-5p enhanced apoptosis significantly in PC3 cells in the presence of these taxanes. These mimics downregulated at least a thousand different transcripts, which were enriched for genes with cell proliferation and focal adhesion functions. Individual knockdown of a selection of 46 genes representing these transcripts resulted in toxic or taxane sensitisation effects, indicating that these genes may be mediating the effects of the microRNA mimics. A range of these genes are expressed in CRPC metastases, suggesting that these microRNA mimics may be functional in CRPC. With further development, these microRNA mimics may have therapeutic potential to improve taxane response in CRPC patients.
PDF
