Objective: To assess the real-world use of home health services (HHS) among patients with major depressive disorder (MDD) with and without treatment-resistant depression (TRD).
Methods: Adults ...(18-64 years) from a commercial claims database (07/2009 to 03/2015) were categorized into three cohorts: "TRD"(N = 6411), "non-TRD MDD"(N = 33,068), "non-MDD"(N = 149,884) stratified based on use of HHS (HHS vs. no-HHS). Healthcare resource utilization (HRU) and costs were evaluated up to two years following the first antidepressant pharmacy claim using descriptive statistics. HRU (e.g. inpatient, outpatient, emergency department visits) and costs were measured per-patient-per-year (PPPY) in 2015 USD.
Results: During the follow-up period, 18.0% of TRD, 12.4% of non-TRD MDD, and 6.5% of non-MDD patients received HHS. Mean all-cause healthcare costs PPPY were numerically higher among patients with HHS use. Among the TRD cohort, patients using HHS had healthcare costs of $40,040 PPPY while patients with TRD and no-HHS had healthcare costs of $12,272 PPPY. Within the non-TRD MDD cohort, HHS users incurred healthcare costs of $28,767 PPPY and non-HHS users incurred costs of $7227 PPPY. Patients without MDD who used HHS had annual healthcare costs of $22,340 while non-MDD patients who did not use HHS had healthcare costs of $3479 PPPY. However, among HHS users, HHS costs represented a relatively small proportion of total healthcare costs.
Conclusions: The high proportion of TRD patients using HHS suggests it is a utilized healthcare delivery pathway by TRD patients.
Evaluate the feasibility and acceptability of routine aspirin in low-risk women, compared with screening-test indicated aspirin for the prevention of pre-eclampsia and fetal growth restriction.
...Multicentre open-label feasibility randomised controlled trial.
Two tertiary maternity hospitals in Dublin, Ireland.
546 low-risk nulliparous women completed the study.
Women underwent computerised randomisation to: Group 1-routine aspirin 75 mg from 11 until 36 weeks; Group 2-no aspirin and; Group 3-aspirin based on the Fetal Medicine Foundation screening test. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Proportion agreeing to participate; (2) compliance with protocol; (3) proportion where first trimester uterine artery Doppler was obtainable and; (4) time taken to issue a screening result. Secondary outcomes included rates of pre-eclampsia and small-for-gestational-age fetuses.
546 were included in the routine aspirin (n=179), no aspirin (n=183) and screen and treat (n=184) groups. 546 of 1054 were approached (51.8%) and enrolled. Average aspirin adherence was 90%. The uterine artery Doppler was obtained in 98.4% (181/184) and the average time to obtain a screening result was 7.6 (0-26) days. Of those taking aspirin, vaginal spotting was greater; n=29 (15.1%), non-aspirin n=28 (7.9%), OR 2.1 (95% CI 1.2 to 3.6). Postpartum haemorrhage >500 mL was also greater; aspirin n=26 (13.5%), no aspirin n=20 (5.6%), OR 2.6 (95% CI 1.4 to 4.8).
Low-risk nulliparous women are open to taking aspirin in pregnancy and had high levels of adherence. Aspirin use was associated with greater rates of vaginal bleeding. An appropriately powered randomised controlled trial is now required to address the efficacy and safety of universal low-dose aspirin in low-risk pregnancy compared with a screening approach.
ISRCTN (15191778); Post-results.
The HBS1L-MYB intergenic region (chr6q23) regulates erythroid cell proliferation, maturation, and fetal hemoglobin (HbF) expression. An enhancer element within this locus, highlighted by a 3-bp ...deletion polymorphism (rs66650371), is known to interact with the promoter of the neighboring gene, MYB, to increase its expression, thereby regulating HbF production. RNA polymerase II binding and a 50-bp transcript from this enhancer region reported in ENCODE datasets suggested the presence of a long noncoding RNA (lncRNA). We characterized a novel 1283bp transcript (HMI-LNCRNA; chr6:135,096,362–135,097,644; hg38) that was transcribed from the enhancer region of MYB. Within erythroid cells, HMI-LNCRNA was almost exclusively present in nucleus, and was much less abundant than the mRNA for MYB. HMI-LNCRNA expression was significantly higher in erythroblasts derived from cultured adult peripheral blood CD34+ cells which expressed more HBB, compared to erythroblasts from cultured cord blood CD34+ cells which expressed much more HBG. Down-regulation of HMI-LNCRNA in HUDEP-2 cells, which expressed mostly HBB, significantly upregulated HBG expression both at the mRNA (200-fold) and protein levels, and promoted erythroid maturation. No change was found in the expression of BCL11A and other key transcription factors known to modulate HBG expression. HMI-LNCRNA plays an important role in regulating HBG expression, and its downregulation can result in a significant increase in HbF. HMI-LNCRNA might be a potential therapeutic target for HbF induction treatment in sickle cell disease and β-thalassemia.
Preterm labour occurs in approximately 10% of pregnancies and is a major cause of infant morbidity and mortality. However, the pathways involved in regulating contractility in normal and preterm ...labour are not fully elucidated. Our aim was to utilise a human myometrial contractility model to investigate the effect of a number of uterine specific contractility agents in this system. Therefore, we investigated the contractile response of human primary uterine smooth muscle cells or immortalised myometrial smooth muscle cells cultured within collagen lattices, to known mediators of uterine contractility, which included thrombin, the ROCK-1 inhibitor Y-27632, tumour necrosis factor alpha (TNF alpha) and the non-steroidal anti-inflammatory indomethacin.
Cell contractility was calculated over time, with the collagen gel contraction assay, utilising human primary uterine smooth muscle cells (hUtSMCs) and immortalised myometrial smooth muscle cells (hTERT-HM): a decrease in collagen gel area equated to an increase in contractility. RNA was isolated from collagen embedded cells and gene expression changes were analysed by real time fluorescence reverse transcription polymerase chain reaction. Scanning electron and fluorescence microscopy were employed to observe cell morphology and cell collagen gel interactions. Statistical analysis was performed using ANOVA followed by Tukey's post hoc tests.
TNF alpha increased collagen contractility in comparison to the un-stimulated collagen embedded hUtSMC cells, which was inhibited by indomethacin, while indomethacin alone significantly inhibited contraction. Thrombin augmented the contractility of uterine smooth muscle cell and hTERT-HM collagen gels, this effect was inhibited by the thrombin specific inhibitor, hirudin. Y-27632 decreased both basal and thrombin-induced collagen contractility in the hTERT-HM embedded gels. mRNA expression of the thrombin receptor, F2R was up-regulated in hUtSMCs isolated from collagen gel lattices, following thrombin-stimulated contractility.
TNF alpha and thrombin increased uterine smooth muscle cell collagen contractility while indomethacin had the opposite effect. Thrombin-induced collagen contractility resulted in F2R activation which may in part be mediated by the ROCK-1 pathway. This study established the in vitro human myometrial model as a viable method to assess the effects of a range of uterotonic or uterorelaxant agents on contractility, and also permits investigation of the complex regulatory pathways involved in mediating myometrial contractility at labour.
•A trend toward increasing morbidity was observed with increasing Genesis risk score.•A trend toward increasing rate of operative vaginal delivery was also observed.•The Genesis nomogram has the ...potential to estimate maternal and neonatal morbidity.
In the prospective multicenter Genesis study, we developed a prediction model for Cesarean delivery (CD) in term nulliparous women. The objective of this secondary analysis was to determine whether the Genesis model has the potential to predict maternal and neonatal morbidity associated with vaginal delivery.
The national prospective Genesis trial recruited 2,336 nulliparous women with a vertex presentation between 39 + 0- and 40 + 6-weeks’ gestation from seven tertiary centers. The prediction model used five parameters to assess the risk of CD: maternal age, maternal height, body mass index, fetal head circumference and fetal abdominal circumference. Simple and multiple logistic regression analyses were used to develop the Genesis model. The risk score calculated using this model were correlated with maternal and neonatal morbidity in women who delivered vaginally: postpartum hemorrhage (PPH), obstetric anal sphincter injury (OASI), shoulder dystocia, one- and five-minute Apgar score ≤ 7, neonatal intensive care (NICU) admission, cephalohematoma, fetal laceration, nerve palsy and fractures. The morbidities associated with spontaneous vaginal delivery were compared with those associated with operative vaginal delivery (OVD). The likelihood ratios for composite morbidity and the morbidity associated with OVD based on the Genesis risk scores were also calculated.
A total of 1,845 (79%) nulliparous women had a vaginal delivery. A trend of increasing intervention and morbidity was observed with increasing Genesis risk score, including OVD (p < 0.001), PPH (p < 0.008), NICU admission (p < 0.001), low Apgar score at one-minute (p < 0.001) and OASI (p = 0.009). The morbidity associated with OVD was significantly higher compared to spontaneous vaginal delivery, including NICU admission (p < 0.001), PPH (p = 0.022), birth injury (p < 0.001), shoulder dystocia (p = 0.002) and Apgar score of<7 at one-minute (p < 0.001). The positive likelihood ratios for composite outcomes (where the OVD was excluded) increases with increasing risk score from 1.005 at risk score of 5% to 2.507 for risk score of>50%.
In women who ultimately achieved a vaginal birth, we have shown more maternal and neonatal morbidity in the setting of a Genesis nomogram-determined high-risk score for intrapartum CD. Therefore, the Genesis prediction tool also has the potential to predict a more morbid vaginal delivery.
Post-term pregnancy is associated with an increased risk of maternal complications, respiratory distress and trauma to the neonate. Amniotic membrane sweeping has been recommended as a simple ...procedure to promote the spontaneous onset of labour. However, despite its widespread use, there is an absence of evidence on (a) its effectiveness and (b) its optimal timing and frequency. The primary aim of the MILO Study is to inform the optimal design of a future definitive randomised trial to evaluate the effectiveness (including optimal timing and frequency) of membrane sweeping to prevent post-term pregnancy. We will also assess the acceptability and feasibility of the proposed trial interventions to clinicians and women (through focus group interviews).
Multicentre, pragmatic, parallel-group, pilot randomised controlled trial with an embedded factorial design. Pregnant women with a live, singleton foetus ≥ 38 weeks gestation; cephalic presentation; longitudinal lie; intact membranes; English speaking and ≥ 18 years of age will be randomised in a 2:1 ratio to membrane sweep versus no membrane sweep. Women allocated randomly to a sweep will then be randomised further (factorial component) to early (from 39 weeks) versus late (from 40 weeks) sweep commencement and a single versus weekly sweep. The proposed feasibility study consists of four work packages, i.e. (1) a multicentre, pilot randomised trial; (2) a health economic analysis; (3) a qualitative study; and (4) a study within the host trial (a SWAT). Outcomes to be collected include recruitment and retention rates, compliance with protocol, randomisation and allocation processes, attrition rates and cost-effectiveness. Focus groups will be held with women and clinicians to explore the acceptability and feasibility of the proposed intervention, study procedures and perceived barriers and enablers to recruitment.
The primary aim of the MILO Study is to inform the optimal design of a future definitive randomised trial to evaluate the effectiveness (including optimal timing and frequency) of membrane sweeping to prevent post-term pregnancy. Results will inform whether and how the design of the definitive trial as originally envisaged should be delivered or adapted.
ClinicalTrials.gov NCT04307199 . Registered on 12 March 2020.
To evaluate the natural fetal and neonatal outcome for pregnancies with an established prenatal diagnosis of fetal trisomy 18, and a parental decision for continuation of the pregnancy.
The obstetric ...and neonatal outcome data for 23 such pregnancies, diagnosed at a single referral Fetal Medicine Centre, were retrospectively obtained.
The overall intrauterine fetal death rate was 61%, with a progressive decline in live fetuses up to 39 weeks gestation. For fetuses diagnosed before 20 weeks gestation, there was a trend towards a higher intrauterine fetal death rate (88%), in comparison to those diagnosed after this period (44%) (p=0.06). For live births, the preterm delivery rate was 44%. All infants born alive died within 48 h of birth.
These data provide reliable information for parental counselling pertaining to risk of intrauterine death when trisomy 18 is diagnosed prenatally. These findings suggest that long-term survival implications for trisomy 18 are different when it is diagnosed prenatally.
The human DEK gene is frequently overexpressed and sometimes amplified in human cancer. Consistent with oncogenic functions, Dek knockout mice are partially resistant to chemically induced papilloma ...formation. Additionally, DEK knockdown in vitro sensitizes cancer cells to DNA damaging agents and induces cell death via p53-dependent and -independent mechanisms. Here we report that DEK is important for DNA double-strand break repair. DEK depletion in human cancer cell lines and xenografts was sufficient to induce a DNA damage response as assessed by detection of γH2AX and FANCD2. Phosphorylation of H2AX was accompanied by contrasting activation and suppression, respectively, of the ATM and DNA-PK pathways. Similar DNA damage responses were observed in primary Dek knockout mouse embryonic fibroblasts (MEFs), along with increased levels of DNA damage and exaggerated induction of senescence in response to genotoxic stress. Importantly, Dek knockout MEFs exhibited distinct defects in non-homologous end joining (NHEJ) when compared to their wild-type counterparts. Taken together, the data demonstrate new molecular links between DEK and DNA damage response signaling pathways, and suggest that DEK contributes to DNA repair.
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