Objective
To detect if removing the cervical mucus before performing intrauterine insemination (IUI) could improve pregnancy outcomes in patients with unexplained infertility.
Design
Prospective ...randomized study.
Setting
An Egyptian University Hospital.
Population
Seven hundred and fourteen couples with unexplained infertility who underwent intrauterine insemination (IUI) with or without cervical mucus removal.
Methods
Using computer‐generated numbers, patients were randomly allocated to cervical‐mucus‐removal (removed from both internal and external os) or non‐mucus‐removal groups. Only participants were blinded as to group assignment.
Main outcome measures
The clinical pregnancy rate.
Results
Of 714 IUI patients between November 2014 and March 2017, 361 were in the mucus removal group, and 353 in the non‐mucus‐removal group. Difficult catheterization was encountered in 17 cases out of 666 (2.6%) 12 in the cervical‐mucus‐removal group and five in the non‐mucus‐removal group). A total of 666 IUI cycles were completed while 48 were either cancelled or lost in their follow‐up. The clinical pregnancy rate was significantly higher in the mucus‐removal group 31.0% (n = 112) than in the non‐mucus‐removal group 21.8% (n = 77); P = 0.005. Ovarian hyperstimulation developed in 33 (4.6%) cases: 18 cervical mucus‐removal and 15 non‐mucus‐removal. All except one were mild and managed with outpatient care.
Conclusions
Cervical mucus removal before IUI could improve pregnancy outcomes in women with unexplained infertility.
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Cervical mucus removal before IUI can improve pregnancy outcomes.
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Cervical mucus removal before IUI can improve pregnancy outcomes.
This paper includes Author Insights, a video available at https://vimeo.com/rcog/authorinsights15003
Introduction and ObjectiveMost patients with idiopathic pulmonary fibrosis (IPF) are affected by chronic cough causing physical, emotional, and psychological stress. Cough has also been hypothesised ...as potential driver of the underlying fibrotic process. Currently, no effective treatment for cough in IPF exists. Mixed opioid agonists/antagonists may reduce chronic cough by pharmacologically acting on the opioid system at both the peripheral and central nervous system level. We report the interim analysis of a phase 2 study of an extended-release (ER) oral formulation of the dual-acting κ-opioid receptor agonist/µ-opioid receptor antagonist nalbuphine (NAL) for IPF-related chronic cough (NCT04030026).MethodsThe study was a randomised, double-blind, placebo-controlled crossover trial comprising two 22-day treatment periods (Period 1: NAL ER-placebo; Period 2: placebo-NAL ER) separated by a 2-week washout. Adult patients diagnosed with IPF and chronic cough (duration >8 weeks) were enrolled. Eligible patients were randomised to either NAL ER or placebo. The starting dose of NAL ER 27 mg once daily was titrated to NAL ER 162 mg twice daily at Day 16. The primary endpoint was the mean percent change from baseline in daytime hourly cough frequency as measured by an objective digital monitor (VitaloJAK®) and analysed with a mixed-effects model. A patient-reported outcome instrument (EXACT2) was used to assess daily cough frequency.Results45 patients were screened, and 32 were enrolled/randomised; the Period 1 full analysis set comprised 26 patients. Patients were primarily male, mean age 72 years, and with daytime cough frequency of 31/hour. Reduction in hourly cough frequency from baseline to Day 22 was 77.3% with NAL ER vs 25.7% for placebo (51.6% placebo-adjusted difference; p<0.0001). Overall, 42% of NAL ER-treated patients (vs0% for placebo) achieved a 75% reduction in cough frequency (figure 1). Preliminary analysis of EXACT2 shows patient-reported cough frequency to be consistent with VitaloJAK® data, and indicates early improvement with NAL ER vs placebo. No new safety signals related to nalbuphine were identified when compared to previous human clinical trial data.Abstract S15 Figure 1ConclusionsIn this interim analysis of phase 2 data, NAL ER shows a significant reduction in IPF-related hourly daytime chronic cough frequency vs placebo.Please refer to page A208 for declarations of interest related to this abstract.
IntroductionCough is a common symptom in patients with interstitial lung disease. Studies have previously focused on the burden of cough in idiopathic pulmonary fibrosis (IPF) and research is lacking ...in patients with hypersensitivity pneumonitis (HP). We aimed to investigate reported cough severity in subjects with HP, using an IPF cohort as disease controls.MethodsWe recruited incident cases of IPF and HP into a prospective observational study. Cough visual analogue scales (VAS, range 0–100 mm) and Leicester Cough Questionnaires (LCQ, range 3–21) were collected at baseline. Demographic details, lung function and bronchoalveolar lavage (BAL) cell differentials were collected.ResultsA total of 207 IPF and 35 HP patients were recruited. Demographic data is summarised in table 1. All subjects with IPF had never received antifibrotic therapy. Only 6/35 patients with HP had received prior steroid treatment. Median cough VAS was 29 mm in IPF and 29.5 mm in HP (Mann-Whitney U, p = 0.732). Median LCQ was 16.1 in IPF and 15.1 in HP (Mann-Whitney U, p = 0.138). FVC and TLco negatively correlated with cough VAS in both IPF and HP subgroups. While TLco positively correlated with LCQ in IPF, neither lung function parameters derived correlation with LCQ in HP. BAL percentage lymphocyte fraction was available for 46 IPF and 28 HP patients (mean 11.2% and 33.2% respectively). In the cohort as a whole an elevated BAL lymphocyte count was associated with higher cough VAS (r = 0.313; p = 0.007). To establish independent predictors of cough within our combined cohort a general linear model analysis was conducted for cough VAS and LCQ. The variables assessed in this model included smoking history, age, sex, reflux, FVC and TLco. FVC (p = 0.002) and sex (p = 0.049) were predictive of cough VAS. However, none of the independent variables were predictive of LCQ.Abstract S3 Table 1Baseline demographic data for IPF and HP cohorts. Comparison between categorical data was conducted using χ-squared test. Parametric data was compared with independent samples t-test*data available for 160 subjects Variable IPF HP P - value N 207 35 Age (years) (SD) 74 (7.3) 64 (11.4) < 0.001 Male sex (%) 171 (83) 16 (46) < 0.001 Ever smoked (%) 141 (68) 18 (51) 0.054 Symptomatic reflux (%) * 39 (24) 6 (18) 0.399 FVC% predicted (SD) 78 (14.9) 84 (19.2) 0.071 TLco% predicted (SD) 47 (13.4) 54 (16.6) 0.012 ConclusionCough burden in HP is similar to IPF, with poorer FVC seemingly a factor in predicting reported cough severity. The association between BAL lymphocytosis and cough VAS support the theory that inflammation is linked to cough.
To assess the utility of a volumetric low-dose computed tomography (CT) thorax (LDCTT) protocol at a dose equivalent to a posteroanterior (PA) and lateral chest radiograph for surveillance of cystic ...fibrosis (CF) patients.
A prospective study was undertaken of 19 adult patients with CF that proceeded to LDCTT at 12 and 24 months following initiation of ivacaftor. A previously validated seven-section, low-dose axial CT protocol was used for the 12-month study. A volumetric LDCTT protocol was developed for the 24-month study and reconstructed with hybrid iterative reconstruction (LD-ASIR) and pure iterative reconstruction (model-based IR LD-MBIR). Radiation dose was recorded for each scan. Image quality was assessed quantitatively and qualitatively, and disease severity was assessed using a modified Bhalla score. Statistical analysis was performed and p-values of <0.05 were considered statistically significant.
Volumetric LD-MBIR studies were acquired at a lower radiation dose than the seven-section studies (0.08 ± 0.01 versus 0.10 ± 0.02 mSv; p=0.02). LD-MBIR and seven-section ASIR images had significantly lower levels of image noise compared with LD-ASIR images (p<0.0001). Diagnostic acceptability scores and depiction of bronchovascular structures were found to be acceptable for axial and coronal LD-MBIR images. LD-MBIR images were superior to LD-ASIR images for all qualitative parameters assessed (p<0.0001). No significant change was observed in mean Bhalla score between 1-year and 2-year studies (p=0.84).
The use of a volumetric LDCTT protocol (reconstructed with pure IR) enabled acquisition of diagnostic quality CT images, which were considered extremely useful for surveillance of CF patients, at a dose equivalent to a PA and lateral chest radiograph.
•CF may be evaluated with CT at a radiation dose equivalent to a chest radiograph.•Low dose thoracic CT may be acquired with a mean ED of 0.08 ± 0.01mSv.•Compared with ASIR, MBIR images demonstrate superior objective image parameters.
Abstract
Conventional radar systems are often unable to produce highly accurate results for target classification and identification via linear frequency modulation (LFM) signals. The potential of ...artificial intelligence, particularly deep learning, has been applied in various fields, which promotes utilizing them in the context of target classification in radar systems. However, to train deep learning models for this task, large datasets of LFM radar signals are required, which are practically difficult to obtain due to the time, effort, and involved high cost. Therefore, the presented work spots the light on utilizing the recent one-dimensional generative adversarial network (GAN) and Wasserstein GAN (WGAN) models to synthesize a large time-series LFM signal dataset from a reference smaller one. Moreover, the work fairly judges the generated LFM signals realistic via a decent qualitative and quantitative analysis, unlike other studies which rely solely on qualitative evaluation by human observers. The proposed study outcome reveals the WGAN’s efficiency in synthesizing high-quality LFM signals while reducing the training time and resource requirements.
We describe a unique case of hyperphosphatemia associated with a very high bone turnover rate in a 51-year-old postmenopausal woman with undiagnosed anorexia nervosa (AN) who presented with a ...low-trauma hip fracture. In view of her severely malnourished state, she was not fit for surgery. She was treated according to a refeeding protocol that mandated bed rest. Contrary to expectation, she developed sustained hyperphosphatemia and borderline hypercalcemia. Bone remodelling markers, both resorption and formation, were markedly elevated. Parathyroid hormone (PTH) was low-normal at 1.7 pmol/L, C-terminal fibroblast growth factor 23 (FGF23) was high at 293 RU/ml, but tubular maximum reabsorption of phosphate (TmPO4/GFR) was elevated at 1.93 mmol/L. Denosumab 60 mg was administered that was followed by: rapid normalisation of serum phosphate; normalisation of resorption markers, transient hypocalcaemia with secondary hyperparathyroidism, and normalisation of both TmPO4/GFR and C-terminal FGF23. We speculate that prolonged immobilization as part of AN management led to a high remodelling state followed by hyperphosphatemia and high-normal calcium with appropriate suppression of PTH and that marked hyperphosphatemia and high TmP/GFR despite high FGF23 indicates the necessity of PTH adequacy for excess FGF23 to lower TmP/GFR.
One in 15 school age children have dyslexia, which is characterized by phoneme-processing problems and difficulty learning to read. Dyslexia is associated with mutations in the gene KIAA0319. It is ...not known whether reduced expression of KIAA0319 can degrade the brain's ability to process phonemes. In the current study, we used RNA interference (RNAi) to reduce expression of Kiaa0319 (the rat homolog of the human gene KIAA0319) and evaluate the effect in a rat model of phoneme discrimination. Speech discrimination thresholds in normal rats are nearly identical to human thresholds. We recorded multiunit neural responses to isolated speech sounds in primary auditory cortex (A1) of rats that received in utero RNAi of Kiaa0319. Reduced expression of Kiaa0319 increased the trial-by-trial variability of speech responses and reduced the neural discrimination ability of speech sounds. Intracellular recordings from affected neurons revealed that reduced expression of Kiaa0319 increased neural excitability and input resistance. These results provide the first evidence that decreased expression of the dyslexia-associated gene Kiaa0319 can alter cortical responses and impair phoneme processing in auditory cortex.
Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical ...and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.
IntroductionIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease. The majority of patients with IPF report cough which is associated with significant negative physical, social ...and psychological consequences. At present there are no approved treatments for IPF-related cough. We evaluated the effect of low dose controlled-release morphine sulfate (MST) as an antitussive therapy in individuals with IPF.DesignPulmonAry Fibrosis (PAciFy) Cough was a randomised, double-blind, placebo-controlled, two-way crossover trial of MST in subjects with IPF. Patients were randomised (1:1) to either placebo twice daily or MST 5 mg twice daily for 14 days. Patients then underwent crossover after a 7-day washout period. The primary endpoint was percent change in objective awake cough frequency at day 14 of treatment. The primary endpoint was percent change in objective awake cough frequency at day 14 of treatment in the intention-to-treat population. Secondary endpoints included change from baseline in patient reported outcomes (cough VAS, Leicester Cough Questionnaire LCQ, Dyspnoea 12, Living with IPF L-IPF questionnaires). This study was registered at ClinicalTrials.gov, NCT04429516.ResultsAmong the 44 patients who were randomized (mean age 71 years; 70% men), 43 completed the morphine arm and 41 completed the placebo arm. In the ITT analysis, MST reduced awake cough frequency by 39.4% compared to placebo (95% CI, -54.4 to -19.4; P < 0.001). The proportion of responders was greater in the MST arm (25/43) compared to placebo (odds ratio 2.48, 95% CI 1.01 to 5.9). Furthermore, MST treatment led to improvements in cough VAS (-16.1mm, P < 0.001), LCQ (1.8 points, P < 0.001), L-IPF impacts (-5.2, P = 0.033) and L-IPF cough domain (-10.8, P < 0.001). The main side effects reported were nausea (14%) and constipation (21%). One serious adverse event (death) occurred during the placebo arm, the cause of which was not related to trial drug.ConclusionMST is an effective antitussive in patients with IPF. Given the established safety profile of morphine in IPF these findings are rapidly translatable into clinical practice.
Encapsulation of Doxorubicin (Dox), a potent cytotoxic agent and immunogenic cell death inducer, in pegylated (Stealth) liposomes, is well known to have major pharmacologic advantages over treatment ...with free Dox. Reformulation of alendronate (Ald), a potent amino-bisphosphonate, by encapsulation in pegylated liposomes, results in significant immune modulatory effects through interaction with tumor-associated macrophages and activation of a subset of gamma-delta T lymphocytes. We present here recent findings of our research work with a formulation of Dox and Ald co-encapsulated in pegylated liposomes (PLAD) and discuss its pharmacological properties vis-à-vis free Dox and the current clinical formulation of pegylated liposomal Dox. PLAD is a robust formulation with high and reproducible remote loading of Dox and high stability in plasma. Results of biodistribution studies, imaging with radionuclide-labeled liposomes, and therapeutic studies as a single agent and in combination with immune checkpoint inhibitors or gamma-delta T lymphocytes suggest that PLAD is a unique product with distinct tumor microenvironmental interactions and distinct pharmacologic properties when compared with free Dox and the clinical formulation of pegylated liposomal Dox. These results underscore the potential added value of PLAD for chemo-immunotherapy of cancer and the relevance of the co-encapsulation approach in nanomedicine.
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