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Background: Neonatal chest-Xray (CXR)s are commonly performed as a first line investigation for the evaluation of respiratory complications. Although lung area derived from CXRs correlates well with functional assessments of the neonatal lung, it is not currently utilised in clinical practice, partly due to the lack of reference ranges for CXR-derived lung area in healthy neonates. Advanced MR techniques now enable direct evaluation of both fetal pulmonary volume and area. This study therefore aims to generate reference ranges for pulmonary volume and area in uncomplicated pregnancies, evaluate the correlation between prenatal pulmonary volume and area, as well as to assess the agreement between antenatal MRI-derived and neonatal CXR-derived pulmonary area in a cohort of fetuses that delivered shortly after the antenatal MRI investigation., Methods: Fetal MRI datasets were retrospectively analysed from uncomplicated term pregnancies and a preterm cohort that delivered within 72 h of the fetal MRI. All examinations included T2 weighted single-shot turbo spin echo images in multiple planes. In-house pipelines were applied to correct for fetal motion using deformable slice-to-volume reconstruction. An MRI-derived lung area was manually segmented from the average intensity projection (AIP) images generated. Postnatal lung area in the preterm cohort was measured from neonatal CXRs within 24 h of delivery. Pearson correlation coefficient was used to correlate MRI-derived lung volume and area. A two-way absolute agreement was performed between the MRI-derived AIP lung area and CXR-derived lung area., Results: Datasets from 180 controls and 10 preterm fetuses were suitable for analysis. Mean gestational age at MRI was 28.6 ± 4.2 weeks for controls and 28.7 ± 2.7 weeks for preterm neonates. MRI-derived lung area correlated strongly with lung volumes (p < 0.001). MRI-derived lung area had good agreement with the neonatal CXR-derived lung area in the preterm cohort [both lungs = 0.982]., Conclusion: MRI-derived pulmonary area correlates well with absolute pulmonary volume and there is good correlation between MRI-derived pulmonary area and postnatal CXR-derived lung area when delivery occurs within a few days of the MRI examination. This may indicate that fetal MRI derived lung area may prove to be useful reference ranges for pulmonary areas derived from CXRs obtained in the perinatal period., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Climate change driven increases in permafrost thaw and terrestrial runoff are expected to facilitate the mobilization and transport of mercury (Hg) from catchment soils to coastal areas in the Arctic, potentially increasing Hg exposure of marine food webs. The main aim of this study was to determine the impacts of seasonal riverine inputs on land-ocean Hg transport, zooplankton diet and Hg bioaccumulation in an Arctic estuary (Adventfjorden, Svalbard). The Adventelva River was a source of dissolved and particulate Hg to Adventfjorden, especially in June and July during the river's main discharge period. Stable isotope and fatty acid analyses suggest that zooplankton diet varied seasonally with diatoms dominating during the spring phytoplankton bloom in May and with increasing contributions of dinoflagellates in the summer months. In addition, there was evidence of increased terrestrial carbon utilization by zooplankton in June and July, when terrestrial particles contributed substantially to the particulate organic matter pool. Total (TotHg) and methyl Hg (MeHg) concentrations in zooplankton increased from April to August related to increased exposure to riverine inputs, and to shifts in zooplankton diet and community structure. Longer and warmer summer seasons will probably increase riverine runoff and thus Hg exposure to Arctic zooplankton., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Epidemiologic studies have shown that low levels of high-density lipoprotein-cholesterol (HDL-C) and elevated triglycerides are independent predictors of cardiovascular (CV) events, though randomized trials of HDL-C-raising therapies to reduce clinical events have been largely disappointing. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial failed to show that extended release niacin (ERN) reduced CV events in patients with atherogenic dyslipidemia who were on statin-based therapy., Objective: We sought to determine whether extended follow-up of AIM-HIGH participants changed these null results., Methods: AIM-HIGH was a placebo-controlled trial of 3414 patients with established CV disease, low baseline HDL-C, and elevated triglycerides levels randomized to ERN 1500-2000 mg/d vs placebo. Participants also received simvastatin with or without ezetimibe to attain on-treatment low-density lipoprotein cholesterol levels of 40-80 mg/dL. The trial was halted after a mean 3-year follow-up because of futility., Results: Among 3236 participants alive at the end of blinded study, 2613 (81%; ERN = 1,312, placebo = 1301) were followed a mean 1.1 additional years. Ninety-five percent of subjects remained on statin, but only 4% on ERN. At a mean total follow-up of 4.1 years, there were 343 primary CV endpoints in the ERN arm and 305 CV endpoints in placebo participants (HR 1.11, 95% CI 0.96, 1.30). Ischemic stroke was also not significantly different after extended follow-up in the two groups (2.2% vs 1.5%, P = .13)., Conclusions: In patients with CV disease and atherogenic dyslipidemia on statin-based therapy, 3 years of ERN treatment did not lower CV event rates. An additional year of follow-up off assigned treatment did not alter these findings., (Copyright © 2018 National Lipid Association. All rights reserved.)

DSL ligands activate the Notch receptor in many cellular contexts across metazoa to specify cell fate. In addition, Notch receptor activity is implicated in post-mitotic morphogenesis and neuronal function. In C. elegans, the DSL family ligand APX-1 is expressed in a subset of cells of the proximal gonad lineage, where it can act as a latent proliferation-promoting signal to maintain proximal germline tumors. Here we examine apx-1 in the proximal gonad and uncover a role in the maintenance of normal ovulation. Depletion of apx-1 causes an endomitotic oocyte (Emo) phenotype and ovulation defects. We find that lag-2 can substitute for apx-1 in this role, that the ovulation defect is partially suppressed by loss of ipp-5, and that lin-12 depletion causes a similar phenotype. In addition, we find that the ovulation defects are often accompanied by a delay of spermathecal distal neck closure after oocyte entry. Although calcium oscillations occur in the spermatheca, calcium signals are abnormal when the distal neck does not close completely. Moreover, oocytes sometimes cannot properly transit through the spermatheca, leading to fragmentation of oocytes once the neck closes. Finally, abnormal oocytes and neck closure defects are seen occasionally when apx-1 or lin-12 activity is reduced in adult animals, suggesting a possible post-developmental role for APX-1 and LIN-12 signaling in ovulation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study examines the impact of ambient temperature on emotional well-being in the U.S. population aged 18+. The U.S. is an interesting test case because of its resources, technology and variation in climate across different areas, which also allows us to examine whether adaptation to different climates could weaken or even eliminate the impact of heat on well-being. Using survey responses from 1.9 million Americans over the period from 2008 to 2013, we estimate the effect of temperature on well-being from exogenous day-to-day temperature variation within respondents' area of residence and test whether this effect varies across areas with different climates. We find that increasing temperatures significantly reduce well-being. Compared to average daily temperatures in the 50-60°F (10-16°C) range, temperatures above 70°F (21°C) reduce positive emotions (e.g. joy, happiness), increase negative emotions (e.g. stress, anger), and increase fatigue (feeling tired, low energy). These effects are particularly strong among less educated and older Americans. However, there is no consistent evidence that heat effects on well-being differ across areas with mild and hot summers, suggesting limited variation in heat adaptation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials., Methods: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening., Results: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017., Conclusion: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis., Methods: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0.9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867., Findings: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3.7%, 95% CI 0.1-7.3; p=0.046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups., Interpretation: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials., Funding: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme., (Copyright © 2015 Alton et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: In retrospective swine and human investigations of ventricular fibrillation (VF) cardiac arrest, the amplitude-spectral area (AMSA), determined from the VF waveform, can predict defibrillation and a return of spontaneous circulation (ROSC)., Objectives: We hypothesized that an algorithm using AMSA in real time to direct postshock chest compression (CC) duration would shorten the time to ROSC and improve neurological outcome in a swine model of VF cardiac arrest with acute myocardial infarction (AMI) or nonischemic myocardium., Methods: AMI was induced by occlusion of the left anterior descending artery. VF was untreated for 10 min. Animals were randomized to either traditional resuscitation with 2 min of CC after each shock or to an AMSA-guided algorithm where postshock CCs were shortened to 1 min if the preshock AMSA exceeded 20 mV-Hz., Results: A total of 48 animals were studied, 12 in each group (AMI vs. normal, and traditional vs. AMSA-guided). There was a nonsignificant shorter time to ROSC with an AMSA-guided approach in AMI swine (17.2 ± 3.4 vs. 18.5 ± 4.7 min, p = NS), and in normal swine (13.5 ± 1.1 vs. 14.4 ± 1.2, p = NS). Neurological outcome was similar between traditional and AMSA-guided animals. AMSA predicted ROSC (p < 0.001), and a threshold of 20 mV-Hz gave a sensitivity of 89%, with specificity of 29%., Conclusion: Although AMSA predicts ROSC in a swine model of VF arrest in both AMI and normal swine, a waveform-guided approach that uses AMSA to direct postshock CC duration does not significantly shorten the time to ROSC or alter neurological outcome., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To summarize a conference convened to examine how cystic fibrosis screening might appropriately be introduced into routine prenatal practice., Methods: Participants included experts from various relevant disciplines. Systematic reviews and data from individual trials were presented; issues were identified and discussed., Results: Judged by published criteria, prenatal cystic fibrosis screening is suitable for introduction. Screening can be performed cost-effectively by identifying racial/ethnic groups at sufficient risk and then using either of two models for delivering laboratory services. Validated educational materials exist. Ethical issues are not unique., Conclusions: Once adequate facilities for patient and provider education, testing, counseling, quality control, and monitoring are in place, individual programs can begin prenatal screening for cystic fibrosis.

Epidemiologic evidence linking elevated cholesterol concentrations and coronary heart disease (CHD) through the eighth decade of life provides a rationale for lowering cholesterol concentrations to reduce morbidity and mortality from CHD. Pravastatin, a well tolerated HMG CoA reductase inhibitor with a convenient once-daily dosing regimen, has been shown to effectively lower total and low density lipoprotein (LDL) cholesterol. Individual data from more than 1800 hypercholesterolemic patients enrolled in six double-blind, randomized, multicenter studies were pooled and then analyzed to compare the safety and efficacy of pravastatin in the elderly (i.e., patients at least 65 years old) and the non-elderly. In short-term studies (8-16 weeks), response was dose-related and similar in elderly and non-elderly subjects. Pravastatin 20 or 40 mg daily lowered total cholesterol 19-25%, LDL-cholesterol 25-33%, and triglycerides 14-23%; high density lipoprotein (HDL) cholesterol increased 5-10%. During long-term studies, improvements were sustained for more than 24 months in both the non-elderly and elderly. The incidences of adverse drug events and laboratory abnormalities were similar in the elderly and non-elderly patients in all groups (active treatment control with resin, pravastatin alone, or combination therapy). In short-term studies, treatment was discontinued because of adverse events in < 1% of all patients treated with pravastatin (all doses) or placebo. The frequency and profile of adverse events were similar among patients treated with pravastatin or placebo. In long-term studies, treatment was discontinued in 0.4% of patients in the pravastatin group and in 0.3% of the patients in the bile-acid-binding resin group. If drug therapy is warranted, pravastatin appears to be safe and effective for long-term use in elderly patients with hypercholesterolemia.

The Pravastatin, Lipids, and Atherosclerosis in the Carotids trial (PLAC-II) was initiated in 1987 and is the first double-masked randomized clinical trial with progression of early extracranial carotid atherosclerosis as an outcome variable. The trial will compare a lipid-lowering agent (pravastatin, a hydroxymethylglutaryl CoA reductase inhibitor) with placebo for ability to retard the rate of progression of extracranial carotid atherosclerosis over 3 years. Inclusion criteria consisted of prevalent coronary artery disease, moderately elevated low-density lipoprotein (LDL) cholesterol (between the 60th and 90th percentiles), and the presence of at least one extracranial carotid artery atherosclerotic plaque that had an intimal-medial thickness (IMT) > or = 1.3 mm as visualized by B-mode ultrasound. Of approximately 650 patients who qualified on the basis of coronary disease and elevated LDL cholesterol, 55% were excluded because of B-mode criteria. One hundred and fifty-one males and females 50-75 years of age were recruited. Random allocation produced placebo-treated and test-treated groups that were similar for baseline historical data, physical findings, laboratory tests, lipid values, and B-mode characteristics. Baseline concentrations of plasma total cholesterol, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol were 234, 166, and 41 mg/dl, respectively. Baseline plasma concentration of triglyceride was 170 mg/dl. Despite selection of participants whose arteries, overall, were suitable for the trial, individual segments in some participants could not be visualized. Ninety-seven percent of the individual carotid artery segments were visualized in the common carotid, 88% in the bifurcation, and 63% in the internal carotid artery. Far walls were slightly more often visualized than near walls, and nonvisualization was most common for the near wall of the internal carotid. Nonvisualized segments were comparable between both treatment groups. The distribution of arterial walls with qualifying plaque of > or = 1.3 mm IMT was similar for the two groups, and the two groups were also comparable for the primary outcome determinant, mean maximum IMT (mean of maximum of all visualizable sites, 1.32 mm for each treatment group). There are special problems related to recruitment and evaluation of patients for a clinical trial such as this, but the atherosclerosis outcome measurement markedly enhances power and compensates for difficulty in recruitment.

Heart transplant recipients in whom high levels of lymphocytotoxic antibodies directed towards a spectrum of histocompatibility antigens develop frequently represent difficult management problems. Recipients of multiple transplants and multiparous females generally form higher levels of panel reactive antibodies, which have been associated with fatal rejection episodes and accelerated graft atherosclerosis. In this study, two multiple transplant patients with preexistent high levels of panel reactive antibodies and two multiparous women who were considered at risk of sensitization were treated with a new form of immunotherapy termed photochemotherapy in addition to conventional immunosuppression. High levels of panel reactive antibodies have been reduced, and patients have suffered few rejection episodes and no infectious complications. This preliminary experience shows that the addition of photochemotherapy to conventional regimens may improve the clinical course of hypersensitized transplant patients without additional immunosuppressive risk.

The factors that influence women in choosing between first-trimester chorionic villi sampling and second-trimester amniocentesis for prenatal diagnosis were investigated. Five hundred twenty women of advanced maternal age who had previously undergone prenatal diagnosis by amniocentesis and were delivered of a normal infant were requested to complete a questionnaire concerning their attitudes toward amniocentesis and chorionic villi sampling. The majority of respondents indicated that the time at which chorionic villi sampling is performed (76%), the rapid availability of diagnostic results (72%), and the type of abortion procedure available (68%) would make them choose this method. In contrast, the factors that influenced women to choose amniocentesis included the known low risk of spontaneous abortion (76%) and confidence in the skill of the obstetrician who would perform the procedure (56%). When all factors were considered together, 68% of the respondents chose amniocentesis based on the known low risk of spontaneous abortion, whereas for those who chose chorionic villi sampling (32%), the major criterion was the fact that the procedure is performed in the first trimester. However, 87% of women who preferred amniocentesis indicated that if the risk of spontaneous abortion associated with chorionic villi sampling. These results indicate that for many women of advanced maternal age, the acceptability and the use of chorionic villi sampling will be dependent on the demonstration that the risk of fetal loss is low, approaching that of amniocentesis.

A blind 19 yr old severely retarded man was referred for behavior therapy because of violent and disruptive tantrums. Previous behavioral strategies had failed for various reasons. A very mild, brief, vestibular oriented physical procedure was designed to provide a low level disruptive effect. Intervention consisted of loud teacher demands to stop and work appropriately as well as guiding him through one 360 degrees turn while standing. The data demonstrated rapid and long term success in eliminating the client's tantrums. The results were interpreted in terms of a behavioral interruptor of a chained sequence allowing refocusing of client attention and increased levels of reinforcement.

The concept of Case Mix in community mental health service program evaluation can be useful in mental health program evaluation if the definition of case mix is expanded beyond Diagnostic Related Groups (DRG), where DRG is solely based upon diagnosis and length of hospitalization stay. A case mix definition based upon two principal characteristics is offered. One characteristic is clinical status defined in terms of diagnostic signs and symptoms, level of functioning, and age. The other characteristic is typical treatment strategy for a given period of time (e.g., 13 weeks). Two cases mixes typical of services designed for the chronically mentally ill are discussed.