Adverse Birth Outcomes of adolescent and Young adult Women Diagnosed With Cancer During Pregnancy

BACKGROUND: We examined adverse birth outcomes among adolescent and young adult women diagnosed with cancer (AYA women, ages 15-39 years) during pregnancy. METHODS: We linked data from the Texas Cancer Registry, vital records, and Texas Birth Defects Registry to identify all singleton births to AYA women diagnosed during pregnancy from January 1999 to December 2016. We compared prevalence of adverse live birth outcomes between AYA women and women without cancer (matched 1:4 on age, race and ethnicity, and year). Among AYA women, we used log-binomial regression to identify factors associated with these outcomes. Statistical tests were 2-sided. RESULTS: AYA women had 1271 singleton live births and 20 stillbirths. AYA women (n = 1291) were 33.3% Hispanic and 9.8% non-Hispanic Black and most commonly had breast (22.5%), thyroid (19.8%), and gynecologic (13.3%) cancers. Among live births, AYA women had a higher prevalence of low birth weight offspring (30.1% vs 9.0%), very preterm (5.7% vs 1.2%), and preterm birth (25.1% vs 7.2%); cesarean delivery (44.3% vs 35.2%); and low Apgar score (2.7% vs 1.5%), compared with women without cancer (n = 5084) (all P \u3c .05). Prevalence of any birth defect by age 12 months did not statistically differ (5.2% vs 4.7%; P = .48), but live births to AYA women more often had heart and circulatory system defects (2.2% vs 1.3%; P = .01). In adjusted models, cancer type and chemotherapy were associated with adverse live birth outcomes. CONCLUSIONS: AYA women diagnosed during pregnancy have higher prevalence of adverse birth outcomes and face difficult decisions in balancing treatment risks and benefits

DSM-5 insomnia disorder in pregnancy: associations with depression, suicidal ideation, and cognitive and somatic arousal, and identifying clinical cutoffs for detection

STUDY OBJECTIVES: The study had three primary goals. First, we estimated survey-assessed DSM-5 insomnia disorder rates in pregnancy, and described associated sociodemographics, and sleep-wake and mental health symptoms. Second, we derived cutoffs for detecting DSM-5 insomnia disorder using common self-report measures of sleep symptoms. Third, we identified clinically relevant cut-points on measures of nocturnal cognitive and somatic arousal. METHODS: Ninety-nine women (85.9% in the 2nd trimester) completed online surveys including DSM-5 insomnia disorder criteria, the Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Presleep Arousal Scale’s Cognitive (PSASC) and Somatic (PSASS) factors, and Edinburgh Postnatal Depression Scale. RESULTS: DSM-5 insomnia disorder rate was 19.2%. Insomnia was associated with depression, suicidality, nocturnal cognitive and somatic arousal, and daytime sleepiness. An ISI scoring method that aligns with DSM-5 criteria yielded excellent metrics for detecting insomnia disorder and good sleep. Regarding quantitative cutoffs, ISI ≥ 10 and ISI ≥ 11 (but not ISI ≥ 15) were supported for detecting DSM-5 insomnia, whereas ISI ≤ 7 and ISI ≤ 9 performed well for detecting good sleep. PSQI cutoff of 5 was supported for detecting insomnia and good sleep. The optimal cutoff for nocturnal cognitive arousal was PSASC ≥ 18, whereas the optimal cutoff for somatic arousal was PSASS ≥ 13. CONCLUSIONS: Insomnia disorder affects a large segment of pregnant women. Empirically derived cutoffs for insomnia, good sleep, cognitive arousal, and somatic arousal may inform case identification and future perinatal sleep research methodology

Rapid disease progression on immune checkpoint inhibitors in young patients with stage IV melanoma

BackgroundImmune checkpoint inhibitors (ICIs) are the standard of care for metastatic cutaneous melanoma (mCM) patients, but their efficacy in young adults aged less than 40 years remains unclear.Materials and methodsWe retrospectively analyzed 303 stage IV melanoma patients of different ages treated with nivolumab, pembrolizumab, or ipilimumab plus nivolumab combination therapy. Clinical data and blood values such as LDH, CRP, and absolute immune cell counts were retrieved from the medical records. Pre-treatment serum concentrations of soluble immune checkpoint proteins were measured using ELISA. In addition, information on frequencies of various T cell subsets in the peripheral blood was collected from a previously reported study (ELEKTRA). Patient characteristics and clinical information was correlated with PFS and OS using univariate and multivariate cox regression analysis.ResultsOf 303 patients, 33 (11%) were ≤ 40 years old. The older patients had a median age of 64 (95% CI: 61–66). Concerning prognostic parameters, there was no difference between the age groups, e.g., in gender, LDH, or the existence of brain or liver metastases. Patients aged ≤ 40 years [p = 0.014; HR: 1.6 (95% CI: 1.1–2.4)], presence of liver metastases [p = 0.016; HR: 1.4 (95% CI: 1.0–1.9)], line of ICI treatment [p = 0.009; HR: 1.4 (1.0–1.9)], elevated LDH [p = 0.076; HR: 1.3 (95% CI: 0.97–1.8)], and brain metastasis [p = 0.080; HR: 1.3 (95% CI: 0.97–1.7)], were associated with shorter PFS in univariate analysis. Multivariate analysis revealed that the patient’s age (≤ 40 years) remains a high-risk factor upon adjusting for all potential confounders [p = 0.067; HR: 1.5 (95% CI: 0.97–2.3)]. Blood parameters revealed that patients ≤ 40 years have relatively higher frequencies of activated CD4 T cells (CD4 + Ki67 + CD4 + ICOS +) in the blood, and significantly lower number of basophils and CD45RA- memory T cells, compared to patients above 40 years (p < 0.05). In addition, patients ≤ 40 years experiencing disease progression within 6 months of ICI treatment had increased concentrations of sPDL1 (p = 0.05) and sTIM3 (p = 0.054) at baseline.ConclusionYoung patients with stage IV melanoma may experience shorter progression-free survival upon ICI treatment compared to patients above 40 years and are characterized by fewer basophils and memory T cells in the blood

Local Dynamics and Strong Correlation Physics I: 1D and 2D Half-filled Hubbard Models

We report on a non-perturbative approach to the 1D and 2D Hubbard models that is capable of recovering both strong and weak-coupling limits. We first show that even when the on-site Coulomb repulsion, U, is much smaller than the bandwith, the Mott-Hubbard gap never closes at half-filling in both 1D and 2D. Consequently, the Hubbard model at half-filling is always in the strong-coupling non-perturbative regime. For both large and small U, we find that the population of nearest-neighbour singlet states approaches a value of order unity as $T\to 0$ as would be expected for antiferromagnetic order. We also find that the double occupancy is a smooth monotonic function of U and approaches the anticipated non-interacting limit and large U limits. Finally, in our results for the heat capacity in 1D differ by no more than 1% from the Bethe ansatz predictions. In addition, we find that in 2D, the heat capacity vs T for different values of U exhibits a universal crossing point at two characteristic temperatures as is seen experimentally in a wide range of strongly-correlated systems such as $^3He$, $UBe_3$, and $CeCu_{6-x}Al_x$. The success of this method in recovering well-established results that stem fundamentally from the Coulomb interaction suggests that local dynamics are at the heart of the physics of strongly correlated systems.Comment: 10 pages, 16 figures included in text, Final version for publication with a reference added and minor corrections. Phys. Rev. B, in pres

Cation distribution in manganese cobaltite spinels Co3−xMnxO4 (0 ≤ x ≤ 1) determined by thermal analysis

Thermogravimetric analysis was used in order to study the reduction in air of submicronic powders of Co3−x Mn x O4 spinels, with 0 ≤ x ≤ 1. For x = 0 (i.e. Co3O4), cation reduction occurred in a single step. It involved the CoIII ions at the octahedral sites, which were reduced to Co2+ on producing CoO. For 0 < x ≤ 1, the reduction occurred in two stages at increasing temperature with increasing amounts of manganese. The first step corresponded to the reduction of octahedral CoIII ions and the second was attributed to the reduction of octahedral Mn4+ ions to Mn3+. From the individual weight losses and the electrical neutrality of the lattice, the CoIII and Mn4+ ion concentrations were calculated. The distribution of cobalt and manganese ions present on each crystallographic site of the spinel was determined. In contrast to most previous studies that took into account either CoIII and Mn3+ or Co2+, CoIII and Mn4+ only, our thermal analysis study showed that Co2+/CoIII and Mn3+/Mn4+ pairs occupy the octahedral sites. These results were used to explain the resistivity measurements carried out on dense ceramics prepared from our powders sintered at low temperature (700–750 °C) in a Spark Plasma Sintering apparatus

Intramuscular Olanzapine and Intramuscular Haloperidol in Acute Schizophrenia: Antipsychotic Efficacy and Extrapyramidal Safety During the First 24 Hours of Treatment

To determine the antipsychotic efficacy and extrapyramidal safety of intramuscular (IM) olanzapine and IM haloperidol during the first 24 hours of treatment of acute schizophrenia. Method: Patients (n = 311) with acute schizophrenia were randomly allocated (2:2: 1) to receive IM olanzapine (10.0 mg, n = 131), IM haloperidol (7.5 mg, n = 126), or IM placebo (n = 54). Results: After the first injection, IM olanzapine was comparable to IM haloperidol and superior to IM placebo for reducing mean change scores from baseline on the Brief Psychiatric Rating Scale (BRPS) Positive at 2 hours (-2.9 olanzapine, -2.7 haloperidol, and -1.5 placebo) and 24 hours (-2.8 olanzapine, -3.2 haloperidol, and -1.3 placebo); the BPRS Total at 2 hours (-14.2 olanzapine,-13.1 haloperidol, and -7.1 placebo) and 24 hours (-12.8 olanzapine, -12.9 haloperidol, and -6.2 placebo); and the Clinical Global Impressions (CGI) scale at 24 hours (-0.5 olanzapine, -0.5 haloperidol, and -0.1 placebo). Patients treated with IM olanzapine had significantly fewer incidences of treatment-emergent parkinsonism (4.3% olanzapine vs 13.3% haloperidol, P = 0.036), but not akathisia (1.1% olanzapine vs 6.5% haloperidol, P = 0.065), than did patients treated with IM haloperidol; they also required significantly less anticholinergic treatment (4.6% olanzapine vs 20.6% haloperidol, P < 0.001). Mean extrapyramidal symptoms (EPS) safety scores improved significantly from baseline during IM olanzapine treatment, compared with a general worsening during IM haloperidol treatment (Simpson-Angus Scale total score mean change: -0.61 olanzapine vs 0.70 haloperidol; P < 0.001; Barnes Akathisia Scale global score mean change: -0.27 olanzapine vs 0.01 haloperidol; P < 0.05). Conclusion: IM olanzapine was comparable to IM haloperidol for reducing the symptoms of acute schizophrenia during the first 24 hours of treatment, the efficacy of both being evident within 2 hours after the first injection. In general, more EPS were observed during treatment with IM haloperidol than with IM olanzapine

Reducing cognitive arousal and sleep effort alleviates insomnia and depression in pregnant women with DSM-5 insomnia disorder treated with a mindfulness sleep program

OBJECTIVES: Combining mindfulness with behavioral sleep strategies has been found to alleviate symptoms of insomnia and depression during pregnancy, but mechanisms for this treatment approach remain unclear. The present study examined nocturnal cognitive arousal and sleep effort as potential treatment mechanisms for alleviating insomnia and depression via a mindfulness sleep program for pregnant women. METHODS: Secondary analysis from a proof-of-concept trial of 12 pregnant women with DSM-5 insomnia disorder who were treated with Perinatal Understanding of Mindful Awareness for Sleep (PUMAS), which places behavioral sleep strategies within a mindfulness framework. Data were collected across eight weekly assessments: pretreatment, six sessions, and posttreatment. Measures included the insomnia severity index (ISI), Edinburgh postnatal depression scale (EPDS), pre-sleep arousal scale\u27s cognitive factor (PSASC), and the Glasgow sleep effort scale (GSES). We used linear mixed modeling to test cognitive arousal and sleep effort as concurrent and prospective predictors of insomnia and depression. RESULTS: Most patients reported high cognitive arousal before PUMAS (75.0%), which decreased to 8.3% after treatment. All insomnia remitters reported low cognitive arousal after treatment, whereas half of nonremitters continued reporting high cognitive arousal. Both nocturnal cognitive arousal and sleep effort were associated with same-week changes in insomnia throughout treatment, and sleep effort yielded a prospective effect on insomnia. Lower levels of nocturnal cognitive arousal and sleep effort prospectively predicted reductions in depression. CONCLUSIONS: The present study offers preliminary evidence that reducing sleep effort and nocturnal cognitive arousal may serve as key mechanisms for alleviating insomnia and depression via mindfulness-based insomnia therapy. ClinicalTrials.gov ID: NCT04443959

Higher urine 1-hydroxy pyrene glucuronide (1-OHPG) is associated with tobacco smoke exposure and drinking maté in healthy subjects from Rio Grande do Sul, Brazil

BACKGROUND: The highest rates of esophageal squamous cell carcinoma (ESCC) in Brazil occur in Rio Grande do Sul, the most southern state, which has incidence rates of 20.4/100,000/year for men and 6.5/100,000/year for women. Exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs) through tobacco smoke and other sources may increase the risk of ESCC. The aims of the current study were to investigate the degree and sources of PAH exposure of the inhabitants of this region of southern Brazil. METHODS: Two hundred healthy adults (half smokers, half non smokers, half male and half female) were recruited, given a standardized questionnaire, and asked to provide a urine sample for measurement of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite). Urine 1-OHPG concentrations were measured using immunoaffinity chromatography and synchronous fluorescence spectroscopy and urine cotinine was measured using a dipstick test. We examined factors associated with 1-OHPG concentration using Wilcoxon tests and multiple linear regression. RESULTS: Urine 1-hydroxypyrene glucuronide (1-OHPG) was successfully measured on 199 subjects. The median (interquartile range) of urine 1-OHPG in the 199 participants was 2.09 pmol/mL (0.51, 5.84). Tobacco smoke exposure and maté drinking were statistically significantly associated with higher urine 1-OHPG concentrations in the multivariate linear regression model. CONCLUSION: Tobacco smoke and maté both contribute to high levels of benzo[a]pyrene exposure in the people of southern Brazil. This high PAH exposure may contribute to the high rates of ESCC observed in this population. The increased urine 1-OHPG concentrations associated with maté suggest that contaminants, not just thermal injury, may help explain the increased risk of ESCC previously reported for maté consumption

Chemotype-selective Modes of Action of κ-Opioid Receptor Agonists

The crystal structures of opioid receptors provide a novel platform for inquiry into opioid receptor function. The molecular determinants for activation of the κ-opioid receptor (KOR) were studied using a combination of agonist docking, functional assays, and site-directed mutagenesis. Eighteen positions in the putative agonist binding site of KOR were selected and evaluated for their effects on receptor binding and activation by ligands representing four distinct chemotypes: the peptide dynorphin A(1–17), the arylacetamide U-69593, and the non-charged ligands salvinorin A and the octahydroisoquinolinone carboxamide 1xx. Minimally biased docking of the tested ligands into the antagonist-bound KOR structure generated distinct binding modes, which were then evaluated biochemically and pharmacologically. Our analysis identified two types of mutations: those that affect receptor function primarily via ligand binding and those that primarily affect function. The shared and differential mechanisms of agonist binding and activation in KOR are further discussed. Usually, mutations affecting function more than binding were located at the periphery of the binding site and did not interact strongly with the various ligands. Analysis of the crystal structure along with the present results provide fundamental insights into the activation mechanism of the KOR and suggest that “functional” residues, along with water molecules detected in the crystal structure, may be directly involved in transduction of the agonist binding event into structural changes at the conserved rotamer switches, thus leading to receptor activation

Cassini RADAR Sequence Planning and Instrument Performance

The Cassini RADAR is a multimode instrument used to map the surface of Titan, the atmosphere of Saturn, the Saturn ring system, and to explore the properties of the icy satellites. Four different active mode bandwidths and a passive radiometer mode provide a wide range of flexibility in taking measurements. The scatterometer mode is used for real aperture imaging of Titan, high-altitude (around 20 000 km) synthetic aperture imaging of Titan and Iapetus, and long range (up to 700 000 km) detection of disk integrated albedos for satellites in the Saturn system. Two SAR modes are used for high- and medium-resolution (300-1000 m) imaging of Titan's surface during close flybys. A high-bandwidth altimeter mode is used for topographic profiling in selected areas with a range resolution of about 35 m. The passive radiometer mode is used to map emission from Titan, from Saturn's atmosphere, from the rings, and from the icy satellites. Repeated scans with differing polarizations using both active and passive data provide data that can usefully constrain models of surface composition and structure. The radar and radiometer receivers show very good stability, and calibration observations have provided an absolute calibration good to about 1.3 dB. Relative uncertainties within a pass and between passes can be even smaller. Data are currently being processed and delivered to the planetary data system at quarterly intervals one year after being acquired