bluuebunny/crossref_metadata_2025 huggingface dataset:
The first photometric investigation and orbital period variation analysis of the W UMa type binary IK Bootis
Authors: Kriwattanawong Wichean , Sanguansak Nuanwan , Maungkorn Sakdawoot
Published: April 2017

With new CCD observations of the W UMa type binary IK Boo, we present the first investigation of photometric parameters and orbital period change. The BVRc light curve fit shows that IK Boo is a W-type contact system with a mass ratio of q = 1.146 and a shallow contact with a fill-out factor of f = 2.22%. The orbital period decrease was found to be a rate of −3.28 × 10−7 d yr−1, corresponding to a mass transfer from the more massive to the less massive component with a rate of −2.83 × 10−6 M⊙ yr−1. The inner and outer critical Roche lobes will contract and cause the contact degree to increase. Therefore, IK Boo may evolve into a deeper contact system. Furthermore, a possible cyclic variation was found with a period of 9.74 yr, which could be explained by the light-travel time effect due to the existence of a third companion in the system.
Credit-Market Sentiment and the Business Cycle*
Authors: López-Salido David , Stein Jeremy C. , Zakrajšek Egon
Published: April 2017

Using U.S. data from 1929 to 2015, we show that elevated credit-market sentiment in year t − 2 is associated with a decline in economic activity in years t and t + 1. Underlying this result is the existence of predictable mean reversion in credit-market conditions. When credit risk is aggressively priced, spreads subsequently widen. The timing of this widening is, in turn, closely tied to the onset of a contraction in economic activity. Exploring the mechanism, we find that buoyant credit-market sentiment in year t − 2 also forecasts a change in the composition of external finance: net debt issuance falls in year t, while net equity issuance increases, consistent with the reversal in credit-market conditions leading to an inward shift in credit supply. Unlike much of the current literature on the role of financial frictions in macroeconomics, this article suggests that investor sentiment in credit markets can be an important driver of economic fluctuations.
A Systematic Review and Meta-analysis Examining the Impact of Incident Postoperative Delirium on Mortality
Authors: Hamilton Gavin M. , Wheeler Kathleen , Di Michele Joseph , Lalu Manoj M. , McIsaac Daniel I.
Published: April 2017

Background

Delirium is an acute and reversible geriatric syndrome that represents a decompensation of cerebral function. Delirium is associated with adverse postoperative outcomes, but controversy exists regarding whether delirium is an independent predictor of mortality. Thus, we assessed the association between incident postoperative delirium and mortality in adult noncardiac surgery patients.

Methods

A systematic search was conducted using Cochrane, MEDLINE/PubMed, Cumulative Index to Nursing and Allied Health Literature, and Embase. Screening and data extraction were conducted by two independent reviewers. Pooled-effect estimates calculated with a random-effects model were expressed as odds ratios with 95% CIs. Risk of bias was assessed using the Cochrane Risk of Bias Tool for Non-Randomized Studies.

Results

A total of 34 of 4,968 screened citations met inclusion criteria. Risk of bias ranged from moderate to critical. Pooled analysis of unadjusted event rates (5,545 patients) suggested that delirium was associated with a four-fold increase in the odds of death (odds ratio = 4.12 [95% CI, 3.29 to 5.17]; I2 = 24.9%). A formal pooled analysis of adjusted outcomes was not possible due to heterogeneity of effect measures reported. However, in studies that controlled for prespecified confounders, none found a statistically significant association between incident postoperative delirium and mortality (two studies in hip fractures; n = 729) after an average follow-up of 21 months. Overall, as study risk of bias decreased, the association between delirium and mortality decreased.

Conclusions

Few high-quality studies are available to estimate the impact of incident postoperative delirium on mortality. Studies that controlled for prespecified confounders did not demonstrate significant independent associations of delirium with mortality.
A Phase 1, Single-center, Double-blind, Placebo-controlled Study in Healthy Subjects to Assess the Safety, Tolerability, Clinical Effects, and Pharmacokinetics–Pharmacodynamics of Intravenous Cyclopropyl-methoxycarbonylmetomidate (ABP-700) after a Single Ascending Bolus Dose
Authors: Struys Michel M. R. F. , Valk Beatrijs I. , Eleveld Douglas J. , Absalom Anthony R. , Meyer Peter , Meier Sascha , den Daas Izaak , Chou Thomas , van Amsterdam Kai , Campagna Jason A. , Sweeney Steven P.
Published: April 2017

Background

Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new “soft” etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose–response and pharmacokinetic/pharmacodynamic relationships.

Methods

Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer’s assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated.

Results

Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration–effect relationship was described for the modified observer’s assessment of alertness/sedation and Bispectral Index.

Conclusions

This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile.
Goal-directed Fluid Therapy Does Not Reduce Primary Postoperative Ileus after Elective Laparoscopic Colorectal Surgery
Authors: Gómez-Izquierdo Juan C. , Trainito Alessandro , Mirzakandov David , Stein Barry L. , Liberman Sender , Charlebois Patrick , Pecorelli Nicolò , Feldman Liane S. , Carli Franco , Baldini Gabriele
Published: April 2017

Background

Inadequate perioperative fluid therapy impairs gastrointestinal function. Studies primarily evaluating the impact of goal-directed fluid therapy on primary postoperative ileus are missing. The objective of this study was to determine whether goal-directed fluid therapy reduces the incidence of primary postoperative ileus after laparoscopic colorectal surgery within an Enhanced Recovery After Surgery program.

Methods

Randomized patient and assessor-blind controlled trial conducted in adult patients undergoing laparoscopic colorectal surgery within an Enhanced Recovery After Surgery program. Patients were assigned randomly to receive intraoperative goal-directed fluid therapy (goal-directed fluid therapy group) or fluid therapy based on traditional principles (control group). Primary postoperative ileus was the primary outcome.

Results

One hundred twenty-eight patients were included and analyzed (goal-directed fluid therapy group: n = 64; control group: n = 64). The incidence of primary postoperative ileus was 22% in the goal-directed fluid therapy and 22% in the control group (relative risk, 1; 95% CI, 0.5 to 1.9; P = 1.00). Intraoperatively, patients in the goal-directed fluid therapy group received less intravenous fluids (mainly less crystalloids) but a greater volume of colloids. The increase of stroke volume and cardiac output was more pronounced and sustained in the goal-directed fluid therapy group. Length of hospital stay, 30-day postoperative morbidity, and mortality were not different.

Conclusions

Intraoperative goal-directed fluid therapy compared with fluid therapy based on traditional principles does not reduce primary postoperative ileus in patients undergoing laparoscopic colorectal surgery in the context of an Enhanced Recovery After Surgery program. Its previously demonstrated benefits might have been offset by advancements in perioperative care.
Vitamin D and rheumatoid arthritis: an ongoing mystery
Authors: Bragazzi Nicola L. , Watad Abdulla , Neumann Shana G. , Simon Michael , Brown Stav B. , Abu Much Arsalan , Harari Adam , Tiosano Shmuel , Amital Howard , Shoenfeld Yehuda
Published: April 2017

Purpose of review

In recent years, there has been a growing interest in the value of vitamin D and its effects on autoimmunity. The aim of this review is to summarize the current knowledge on the association between vitamin D and rheumatoid arthritis (RA) in terms of prevalence, disease activity, clinical expression, serology and gene polymorphisms of vitamin D receptors.

Recent findings

Studies have shown contrasting findings concerning the association between vitamin D levels and RA. Vitamin D seems to have immunomodulatory properties. Therefore, low vitamin D levels could contribute to increased immune activation. However, the potential role of vitamin D supplementation in preventing RA manifestation and its beneficial role as a component of RA treatment remain controversial. The relationship between RA susceptibility and vitamin D polymorphisms is also unclear.

Despite advancements synthesized by some recent meta-analyses, the relationship between vitamin D and RA requires further evaluation. Further research is needed to confirm the relationship between RA susceptibility and vitamin D polymorphisms and to determine whether vitamin D plays a role in preventing the manifestation of RA. Finally, additional studies are required to determine the impact and optimal amount of vitamin D supplementation in the treatment of RA patients.
Withholding Pantoprazole for Stress Ulcer Prophylaxis in Critically Ill Patients: A Pilot Randomized Clinical Trial and Meta-Analysis*
Authors: Alhazzani Waleed , Guyatt Gordon , Alshahrani Mohammed , Deane Adam M. , Marshall John C. , Hall Richard , Muscedere John , English Shane W. , Lauzier François , Thabane Lehana , Arabi Yaseen M. , Karachi Tim , Rochwerg Bram , Finfer Simon , Daneman Nick , Alshamsi Fayez , Zytaruk Nicole , Heel-Ansdell Diane , Cook Deborah
Published: April 2017

Introduction:

A decreased frequency of upper gastrointestinal bleeding and a possible association of proton pump inhibitor use with Clostridium difficile and ventilator-associated pneumonia have raised concerns recently. The Reevaluating the Inhibition of Stress Erosions Pilot Trial determined the feasibility of undertaking a larger trial investigating the efficacy and safety of withholding proton pump inhibitors in critically ill patients.

Methods:

In 10 ICUs, we randomized adult ICU patients anticipated to be mechanically ventilated for greater than or equal to 48 hours to receive 40 mg of IV pantoprazole daily or placebo. We excluded patients who had acute or recent gastrointestinal bleed, used dual antiplatelet agents, had a medical condition requiring proton pump inhibitor treatment, or had already received more than one dose of acid suppression daily. Patients, families, clinicians, and research staff were blinded. We conducted a systematic review and meta-analysis of similar trials.

Main Results:

Ninety-one patients (49 pantoprazole and 42 placebo) from 10 centers in Canada, Saudi Arabia, and Australia were enrolled. All feasibility goals were met: 1) recruitment rate was 2.6 patients per month; 2) consent rate was 77.8%; and 3) protocol adherence was 97.7%. Upper gastrointestinal bleeding developed in 6.1% of patients in the pantoprazole group and 4.8% in the placebo group (p = 1.0). Ventilator-associated pneumonia developed in 20.4% of patients in the pantoprazole group and 14.3% in the placebo group (p = 0.58). C. difficile was identified in 4.1% pantoprazole patients and in 2.4% placebo patients (p = 1.0). We meta-analyzed five trials (604 patients) of proton pump inhibitors versus placebo; there was no statistically significant difference in the risk of upper gastrointestinal bleeding, infections, or mortality.

Conclusions:

Our results support the feasibility of a larger trial to evaluate the safety of withholding stress ulcer prophylaxis. Although the results are imprecise, there was no alarming increase in the risk of upper gastrointestinal bleeding; the effect of proton pump inhibitors on ventilator-associated pneumonia and C. difficile remain unclear.
Patients' Perceived Treatment Effectiveness in Dry Eye Disease
Authors: Kheirkhah Ahmad , Crnej Alja , Ren Ai , Mullins Andrew , Satitpitakul Vannarut , Hamrah Pedram , Schaumberg Debra , Dana Reza
Published: April 2017

Purpose:

Patients' perceptions of the effectiveness of a treatment, or perceived treatment effectiveness (PTE), play an important role in medicine. This study aimed to evaluate patients' PTE in dry eye disease (DED) and investigate factors contributing to these patients' perceptions.

Methods:

This cross-sectional study included 66 patients with DED. At enrollment, all patients had comprehensive ophthalmic assessment. In addition, to evaluate the patient's PTE, they were asked to use a 10-point scale ranging from “strongly disagree (score 1)” to “strongly agree (score 10)” to score their views on whether their DED treatments had been effective. Changes in clinical parameters of DED over time during their care were also evaluated retrospectively and correlated with the patients' PTE.

Results:

The mean age of patients was 55.7 years; 79% were women. Regarding patients' PTE, 36.4% strongly (score 10) and 53.0% moderately (scores 6–9) believed that their DED treatment had been effective. However, 10.6% thought that their treatment had not been effective (scores 1–5). Less favorable PTE for the DED treatment was significantly associated with a younger age (P < 0.001), current use of antidepressant medications (P = 0.01), and a higher Ocular Surface Disease Index score (P = 0.01) at enrollment.

Conclusions:

A majority of patients with DED have positive perceptions regarding the effectiveness of their treatments. Less favorable perceptions are associated with more severe ocular symptoms and nonocular parameters such as younger age and current antidepressant use. In DED management, assessing patients' PTE should be considered as an important part of clinical practice.
Short-Term Effects of Y-27632, a Rho-Associated Protein Kinase Inhibitor, on Chromatin Supraorganization and DNA Amount in Epithelial Cells of the Rat Cornea and Limbus
Authors: Aldrovani Marcela , Barros Sobrinho Alexandre A. F. , Mairos Fernanda Santos , Laus José Luiz
Published: April 2017

Purpose:

To assess the short-term effects of instilling Y-27632, an inhibitor of Rho/Rho-associated protein kinases, on the chromatin supraorganization and DNA amount of corneal and limbal epithelial cells of healthy rats.

Methods:

Longitudinal sections (7 μm) of enucleated eyes of healthy rats that received, by instillation, balanced salt solution with or without 10 mM of Y-27632 daily for 7 or 15 days, were subjected to the Feulgen reaction. Feulgen-stained nuclei of corneal and limbal epithelial cells were studied by microscopy and video image analysis to establish the nuclear size (area and perimeter), supraorganization of chromatin (texture and degrees of condensation), and the Feulgen-DNA amount.

Results:

Instillation of Y-27632 for up to 15 days did not change the size of the nucleus or the chromatin texture of corneal and limbal epithelial cells. Samples treated with Y-27632 for 7 days showed condensed chromatin and a high Feulgen-DNA amount. Both corneal and limbal epithelium showed the presence of near-tetraploid nuclei corresponding to cells in the S and G2 phases of the cell cycle. The degrees of condensation and Feulgen-DNA amount of the nuclei of epithelial cells of the cornea and limbus of eyes from rats receiving Y-27632 for 15 days did not differ from control (no drug).

Conclusions:

Changes in chromatin supraorganization and DNA amount, such as seen in this study, are indicative of cell proliferation and do not seem to be associated with disturbances in gene activity and transcription of DNA.
HDL and the menopause
Authors: El Khoudary Samar R.
Published: April 2017

Purpose of review

To summarize recent provocative findings on conventional and novel metrics of HDL including HDL-C, HDL subclasses and HDL cholesterol efflux capacity as related to menopause.

Recent findings

Pattern of menopause-related changes in HDL-C are not consistent, suggesting a complex relationship between HDL and menopause. Growing body of literature indicates that higher levels of HDL-C may not be consistently cardio-protective in midlife women, suggesting a potential change in other metrics of HDL that could not be captured by the static metric HDL-C. It is also possible that higher HDL-C at certain conditions could be a marker of HDL metabolism dysfunctionality. Significant alterations in other metrics of HDL have been reported after menopause and found to be related to estradiol.

The impact of changes in novel metrics of HDL over the menopausal transition on cardiovascular disease (CVD) risk later in life is not clear in women. Much of our understanding of how the menopausal transition may impact HDL metrics comes from cross-sectional studies. Future longitudinal studies are needed to evaluate other metrics of HDL shown to better reflect the cardio-protective capacities of HDL, so that the complex association of menopause, HDL and CVD risk could be characterized.
Speech and swallowing outcomes following oral cavity reconstruction
Authors: Dawson Camilla , Al-Qamachi Laith , Martin Timothy
Published: April 2017

Purpose of review

This review explores speech and swallowing outcomes following oral cavity reconstruction for treatment of head and neck cancer, with focus on articles published within 2015–2016.

Recent findings

There is limited recent evidence that explores functional outcomes following oral cavity surgery in the literature; therefore, an overview of the literature describing surgical interventions and their associated functional outcomes is timely.

We discuss the challenges associated with achieving adequate surgical margins, alongside optimal functional outcomes. The correlation between the size, site and type of reconstruction with speech and swallowing function are described, along with novel surgical and therapeutic interventions that may reduce treatment morbidity and have the potential to impact positively on quality of life.
Intensive Short-Term Dynamic Psychotherapy Trial Therapy
Authors: Abbass Allan , Town Joel , Ogrodniczuk John , Joffres Michel , Lilliengren Peter
Published: April 2017

This study examined the effects of trial therapy interviews using intensive short-term dynamic psychotherapy with 500 mixed sample, tertiary center patients. Furthermore, we investigated whether the effect of trial therapy was larger for patients who had a major unlocking of the unconscious during the interview compared with those who did not. Outcome measures were the Brief Symptom Inventory (BSI) and the Inventory of Interpersonal Problems (IIP), measured at baseline and at 1-month follow-up. Significant outcome effects were observed for both the BSI and the IIP with small to moderate preeffect/posteffect sizes, Cohen's d = 0.52 and 0.23, respectively. Treatment effects were greater in patients who had a major unlocking of the unconscious compared with those who did not. The trial therapy interview appears to be beneficial, and its effects may relate to certain therapeutic processes. Further controlled research is warranted.
The Immunopathogenesis of Mycoplasma genitalium Infections in Women: A Narrative Review
Authors: Dehon Patricia M. , McGowin Chris L.
Published: April 2017

Mycoplasma genitalium is a common, predominately asymptomatic, and often undiagnosed sexually transmitted infection that is associated with inflammatory urogenital and reproductive tract disease syndromes of men and women. Without programmatic screening in the United States, and with increasing resistance to antibiotics used in empiric sexually transmitted infection management, undiagnosed M. genitalium infections put many women at risk for cervicitis and pelvic inflammatory disease. Chronic infection may also lead to tubal-factor infertility, adverse pregnancy outcomes in expectant mothers, and is a risk factor for acquisition and transmission of human immunodeficiency virus. This review details the dynamics of M. genitalium infection, and then examines the potentially deleterious role of host immunity in reproductive tract disease pathogenesis and enhanced human immunodeficiency virus acquisition/transmission.
Increases in the Rate of Neisseria gonorrhoeae Among Gay, Bisexual and Other Men Who Have Sex With Men—Findings From the Sexually Transmitted Disease Surveillance Network 2010–2015
Authors: Stenger Mark R. , Pathela Preeti , Anschuetz Greta , Bauer Heidi , Simon Julieann , Kohn Robert , Schumacher Christina , Torrone Elizabeth
Published: April 2017

Background

Inequalities in Neisseria gonorrhoeae (gonorrhea) burden by sexual minority status in the United States are difficult to quantify. Sex of sex partner is not routinely collected for reported cases. Population estimates of men who have sex with men (MSM) necessary to calculate case rates have not been available until recently. For these reasons, trends in reported gonorrhea rates among MSM have not been described across multiple jurisdictions.

Methods

We estimated of the number of MSM cases reported in 6 jurisdictions continuously participating in the STD Surveillance Network 2010–2015 based on interviews with a random sample of cases. Data were obtained for Baltimore, Philadelphia, New York City, San Francisco, California (excluding San Francisco), and Washington State. Estimates of the MSM, heterosexual male (MSW) and female populations were obtained from recently published estimates and census data. Case rates and rate-ratios were calculated comparing trends in reported cases among MSM, heterosexual males and women.

Results

The proportion of male gonorrhea cases among MSM varied by jurisdiction (range: 20% to 98%). Estimated MSM rate increased from 1369 cases per 100,000 in 2010 to 3435 cases per 100,000 in 2015. Between 2010 and 2015, the MSM-to-Women gonorrhea rate ratio increased from 13:1 to 24:1, and the MSM-to-MSW gonorrhea rate ratio increased from 16:1 to 31:1.

Conclusions

Estimated gonorrhea rate among MSM increased in a network of 6 geographically diverse US jurisdictions. Estimating the size of this population, determining MSM among reported cases and estimating rates are essential first steps for better understanding the changing epidemiology of gonorrhea.
The Natural History of Oral Human Papillomavirus in Young Costa Rican Women
Authors: Beachler Daniel C. , Lang Kuhs Krystle A. , Struijk Linda , Schussler John , Herrero Rolando , Porras Carolina , Hildesheim Allan , Cortes Bernal , Sampson Joshua , Quint Wim , Gonzalez Paula , Kreimer Aimée R.
Published: April 2017

Background

Oral human papillomavirus (HPV) infection and related oropharyngeal cancer are uncommon in lower-income countries, particularly compared to HPV-associated cervical cancer. However, little is known about the natural history of oral HPV in less-developed settings and how it compares to the natural history of cervical HPV.

Methods

Three hundred fifty women aged 22 to 33 years from the Costa Rica Vaccine Trial provided exfoliated cells from the cervical and oral regions at 2 visits 2 years apart. Samples from both visits were tested for 25 characterized α HPV types by the SPF10 PCR-DNA enzyme immunoassay-LiPA25 version 1 system. Risk factors for oral HPV persistence were calculated utilizing generalized estimating equations with a logistic link.

Results

Among the 82 women with characterized α oral HPV DNA detected at baseline, 14 persisted and were detected 2 years later (17.6%; 95% confidence interval [CI], 10.9–28.5%) and was similar to the persistence of α cervical HPV (40/223; 17.7%; 95% CI, 13.1–23.9%; P = 0.86). Acquisition of new α oral HPV type was low; incident infection (1.7%; 95% CI, 0.6–3.7%).

Conclusions

Oral HPV DNA is uncommon in young women in Latin America, and often appears to clear within a few years at similar rates to cervical HPV.
US Public Sexually Transmitted Disease Clinical Services in an Era of Declining Public Health Funding: 2013–14
Authors: Leichliter Jami S. , Heyer Kate , Peterman Thomas A. , Habel Melissa A. , Brookmeyer Kathryn A. , Arnold Pang Stephanie S. , Stenger Mark R. , Weiss Gretchen , Gift Thomas L.
Published: April 2017

Background

We examined the infrastructure for US public sexually transmitted disease (STD) clinical services.

Methods

In 2013 to 2014, we surveyed 331 of 1225 local health departments (LHDs) who either reported providing STD testing/treatment in the 2010 National Profile of Local Health Departments survey or were the 50 local areas with the highest STD cases or rates. The sample was stratified by jurisdiction population size. We examined the primary referral clinics for STDs, the services offered and the impact of budget cuts (limited to government funding only). Data were analyzed using SAS, and analyses were weighted for nonresponse.

Results

Twenty-two percent of LHDs cited a specialty STD clinic as their primary referral for STD services; this increased to 53.5% of LHDs when combination STD-family planning clinics were included. The majority of LHDs (62.8%) referred to clinics providing same-day services. Sexually transmitted disease clinics more frequently offered extragenital testing for chlamydia and/or gonorrhea (74.7%) and gonorrhea culture (68.5%) than other clinics (52.9%, 46.2%, respectively; P < 0.05). The majority of LHDs (61.5%) reported recent budget cuts. Of those with decreased budgets, the most common impacts were fewer clinic hours (42.8%; 95% confidence interval [CI], 24.4–61.2), reduced routine screening (40.2%; 95% CI, 21.7–58.8) and reductions in partner services (42.1%; 95% CI, 23.6–60.7). One quarter of those with reduced STD budgets increased fees or copays for clients.

Conclusions

Findings demonstrate gaps and reductions in US public STD services including clinical services that play an important role in reducing disease transmission. Furthermore, STD clinics tended to offer more specialized STD services than other public clinics.
Female Adnexal Tumors of Probable Wolffian Origin (FATWO): A Case Series With Next-Generation Sequencing Mutation Analysis
Authors: Cossu Antonio , Casula Milena , Paliogiannis Panagiotis , Tanda Francesco , Palomba Grazia , Sini Maria C. , Pisano Marina , Doneddu Valentina , Palmieri Giuseppe
Published: April 2017

Female adnexal tumors of probable Wolffian origin are rare gynecologic tumors with <90 cases reported in the current scientific literature. Their clinical features have been described extensively; less is known about the pathophysiological mechanisms and the molecular alterations underlying their development and growth. We performed a complete histopathologic examination and a systematic mutation analysis using a next-generation sequencing approach on 3 female adnexal tumors of probable Wolffian origin from the archives of our institution to detect possible genetic alterations and to explore their role in the development of these rare tumors. The 3 cases contained missense mutations in different genes belonging to distinct molecular pathways: CTNNB1 and MET mutations for the first case, PIK3CA for the second one, and BRAF and CDKN2A for the third one. Two variants with an unknown functional effect on the protein were found in KDR and TP53 genes. In conclusion, genetic heterogeneity was found in our series. No constant involvement of the most common pathways involved in tumorigenesis was found; nevertheless, further studies are necessary to confirm the results of this pilot study.
DNA Genotyping of Nonmolar Donor Egg Pregnancies With Abnormal Villous Morphology: Allele Zygosity Patterns Prevent Misinterpretation as Complete Hydatidiform Mole
Authors: Joseph Nancy M. , Pineda Caryll , Rabban Joseph T.
Published: April 2017

DNA genotyping is the gold standard diagnostic test to distinguish hydatidiform moles from nonmolar but morphologically abnormal products of conception (POC). The test is based on comparison of alleles at 15 short tandem repeat loci in the chorionic villi of the POC to those in the maternal decidual tissue. If alleles in the POC are not present in the decidua, then the most concerning interpretation is that the POC has a paternal uniparental genome diagnostic of a complete hydatidiform mole (CHM). However, a nonmolar pregnancy from a donated egg would also appear the same because the maternal genome of the POC would match that of the maternal donor, not that of the decidua of the individual carrying the pregnancy. Not surprisingly, 2 cases of potential misclassification of the genotype of a donor egg POC as CHM have been reported in the literature. We hypothesize that the ratio of heterozygous loci to homozygous loci (so-called allele zygosity ratio) distinguishes the genotype of a donor egg POC from CHM. We compared the allele zygosity ratio in 11 nonmolar donor egg POC, 5 dispermic (heterozygous) CHM and 31 monospermic (homozygous) CHM, without knowledge of the use of a donor egg, the histologic findings, or results of p57 immunohistochemical staining. In all 47 cases, the alleles from the chorionic villi did not match those in the decidua. The average ratio of heterozygous to homozygous loci was 4:1 in donor egg POC and 1:3 in dispermic CHM (P<0.0001). Monospermic CHM contained 100% homozygous loci. p57 staining was intact in all donor egg POC. We conclude that the allele zygosity ratio is important to evaluate when interpreting the genotype of morphologically abnormal POC that does not match the genotype of the decidua. A high heterozygous:homozygous ratio should raise concern for a nonmolar donor egg pregnancy. Correlation of this variable along with review of the histologic findings and p57 immunohistochemistry may prevent misclassification of the genotype of a donor egg POC with abnormal villous morphology as a dispermic (heterozygous) CHM.
Primary Ovarian Solid Pseudopapillary Neoplasm With CTNNB1 c.98C>G (p.S33C) Point Mutation
Authors: Singh Kamaljeet , Patel Nimesh , Patil Pallavi , Paquette Cherie , Mathews Cara A. , Lawrence W. Dwayne
Published: April 2017

Ovary is one of the extrapancreatic sites of origin of solid pseudopapillary neoplasm (SPN). Only 9 cases of primary ovarian SPN, 1 with CTNNB1 mutation similar to pancreatic SPN, have been reported in the English literature. We describe the second case of ovarian SPN with confirmed CTNNB1 mutation. A 49-year-old postmenopausal woman presented with a 4.5 cm right ovarian mass. Ovarian mass showed histologic and immunohistochemical features of pancreatic SPN. The ovarian surface was intact and uninvolved. Ki-67 index was low (1%–5%). DNA sequencing of CTNNB1 exon 3 revealed c.98C>G (p.S33C), a well-characterized activating mutation. Our case adds to the growing body of evidence that primary ovarian SPN are phenotypically and genotypically similar to pancreatic SPN.
Placenta Previa Increta in an Unscarred Uterus With Marked Thinning of Myometrium in the Entire Uterus in a Patient With Systemic Lupus Erythematosus
Authors: Mittal Namita , Pineda Maylene , Lim Boon , Carey Elizabeth
Published: April 2017

A 36-yr-old woman, G5P2, who had a background history of systemic lupus erythematosus (SLE) was found to have placenta previa and placenta accreta on second trimester ultrasound scan. She had previous 3 spontaneous miscarriages but there was no history of gynecologic interventions. Apart from SLE, there was no other explanation for her recurrent miscarriage. The patient had ongoing thrombocytopenia in this pregnancy. The patient was taken for elective lower uterine segment cesarean section at 36 wk+5 d gestation. Balloon catheters were placed in the anterior branches of the internal iliac arteries before the operation. Despite this and aggressive medical management, she experienced significant bleeding requiring peripartum hysterectomy. Histologic examination showed placenta increta with marked thinning of the myometrium. The myometrium was <1 mm thick in most of the uterus except for lower uterine segment without any evidence of uterine rupture or perforation. This paper presents this unusual case of diffuse marked thinning of myometrium in the uterus as well as presence of placenta previa increta, without any prior history of gynecologic intervention in a patient with SLE.
Changes in Fertility at the Population Level in the Era of ART in Rural Malawi
Authors: McLean Estelle , Price Alison , Chihana Menard , Kayuni Ndoliwe , Marston Milly , Koole Olivier , Zaba Basia , Crampin Amelia ,   the ALPHA Network
Published: April 2017

Introduction:

HIV reduces fertility through biological and social pathways, and antiretroviral treatment (ART) can ameliorate these effects. In northern Malawi, ART has been available since 2007 and lifelong ART is offered to all pregnant or breastfeeding HIV-positive women.

Methods:

Using data from the Karonga Health and Demographic Surveillance Site in Malawi from 2005 to 2014, we used total and age-specific fertility rates and Cox regression to assess associations between HIV and ART use and fertility. We also assessed temporal trends in in utero and breastfeeding HIV and ART exposure among live births.

Results:

From 2005 to 2014, there were 13,583 live births during approximately 78,000 person years of follow-up of women aged 15–49 years. The total fertility rate in HIV-negative women decreased from 6.1 [95% confidence interval (CI): 5.5 to 6.8] in 2005–2006 to 5.1 (4.8–5.5) in 2011–2014. In HIV-positive women, the total fertility rate was more stable, although lower, at 4.4 (3.2–6.1) in 2011–2014. In 2011–2014, compared with HIV-negative women, the adjusted (age, marital status, and education) hazard ratio was 0.7 (95% CI: 0.6 to 0.9) and 0.8 (95% CI: 0.6 to 1.0) for women on ART for at least 9 months and not (yet) on ART, respectively. The crude fertility rate increased with duration on ART up to 3 years before declining. The proportion of HIV-exposed infants decreased, but the proportion of ART-exposed infants increased from 2.4% in 2007–2010 to 3.5% in 2011–2014.

Conclusions:

Fertility rates in HIV-positive women are stable in the context of generally decreasing fertility. Despite a decrease in HIV-exposed infants, there has been an increase in ART-exposed infants.
Mapping an Extended Neurochemical Profile at 3 and 7 T Using Accelerated High-Resolution Proton Magnetic Resonance Spectroscopic Imaging
Authors: Gruber Stephan , Heckova Eva , Strasser Bernhard , Považan Michal , Hangel Gilbert J. , Minarikova Lenka , Trattnig Siegfried , Bogner Wolfgang
Published: April 2017

Objectives

The aim of this study was to compare high-resolution free induction decay magnetic resonance spectroscopic imaging (FID-MRSI) at 3 T and 7 T in the brain of healthy subjects and to showcase the clinical potential of accelerated FID-MRSI at 7 T in 2 brain tumor cases.

Materials and Methods

In this institutional review board–approved study, 10 healthy volunteers (8 men/2 women; age: 31 ± 6 years) were measured at 3 T and 7 T (Trio and 7T-Magnetom; Siemens Healthcare, Germany) and 2 patients (a 38-year-old man and a 37-year-old man), 1 with an anaplastic oligoastrocytoma (grade III) and 1 with a low-grade glioma (oligodendroglioma), were measured at 7 T.

Free induction decay MR spectroscopic imaging with 3.4 × 3.4 mm2 in-plane resolution was acquired in 30 minutes/6 minutes (nonaccelerated/accelerated) at both field strengths. In addition, single-slice or multi-slice FID-MRSI at 7 T was measured in the 2 tumor patients at 7 T within 6 minutes/13.3 minutes. Signal-to-noise ratio, Cramer-Rao lower bounds, and parallel imaging efficiency were assessed. High-resolution maps were created for 9 different brain metabolites.

Results

At 7 T, 7 of 9 metabolites were reliably mapped over the whole slice but only 3 at 3 T. Parallel imaging efficiency was significantly improved at 7 T. Signal-to-noise ratios were +75%/+66% (P < 0.05) for N-acetylaspartate and +97%/+74%(P < 0.05) for glutamine + glutamate [Glx], and full-widths at half maximum were +112%/+109%(P < 0.05) higher at 7 T than at 3 T (nonaccelerated/accelerated) for N-acetylaspartate. Cramer-Rao lower bounds were more than double at 3 T (P < 0.05).

Conclusions

At 7 T, FID-MRSI allowed the assessment of an extended neurochemical profile and yielded better metabolic maps in only approximately 6 minutes at 7 T than in approximately 30 minutes at 3 T. We found several potentially therapy-relevant neurochemical alterations in brain tumors that highlighted the potential of fast clinical FID-MRSI at 7 T.
T2-Weighted 4D Magnetic Resonance Imaging for Application in Magnetic Resonance–Guided Radiotherapy Treatment Planning
Authors: Freedman Joshua N. , Collins David J. , Bainbridge Hannah , Rank Christopher M. , Nill Simeon , Kachelrieß Marc , Oelfke Uwe , Leach Martin O. , Wetscherek Andreas
Published: April 2017

Objectives

The aim of this study was to develop and verify a method to obtain good temporal resolution T2-weighted 4-dimensional (4D-T2w) magnetic resonance imaging (MRI) by using motion information from T1-weighted 4D (4D-T1w) MRI, to support treatment planning in MR-guided radiotherapy.

Materials and Methods

Ten patients with primary non–small cell lung cancer were scanned at 1.5 T axially with a volumetric T2-weighted turbo spin echo sequence gated to exhalation and a volumetric T1-weighted stack-of-stars spoiled gradient echo sequence with golden angle spacing acquired in free breathing. From the latter, 20 respiratory phases were reconstructed using the recently developed 4D joint MoCo-HDTV algorithm based on the self-gating signal obtained from the k-space center. Motion vector fields describing the respiratory cycle were obtained by deformable image registration between the respiratory phases and projected onto the T2-weighted image volume. The resulting 4D-T2w volumes were verified against the 4D-T1w volumes: an edge-detection method was used to measure the diaphragm positions; the locations of anatomical landmarks delineated by a radiation oncologist were compared and normalized mutual information was calculated to evaluate volumetric image similarity.

Results

High-resolution 4D-T2w MRI was obtained. Respiratory motion was preserved on calculated 4D-T2w MRI, with median diaphragm positions being consistent with less than 6.6 mm (2 voxels) for all patients and less than 3.3 mm (1 voxel) for 9 of 10 patients. Geometrical positions were coherent between 4D-T1w and 4D-T2w MRI as Euclidean distances between all corresponding anatomical landmarks agreed to within 7.6 mm (Euclidean distance of 2 voxels) and were below 3.8 mm (Euclidean distance of 1 voxel) for 355 of 470 pairs of anatomical landmarks. Volumetric image similarity was commensurate between 4D-T1w and 4D-T2w MRI, as mean percentage differences in normalized mutual information (calculated over all respiratory phases and patients), between corresponding respiratory phases of 4D-T1w and 4D-T2w MRI and the tie-phase of 4D-T1w and 3-dimensional T2w MRI, were consistent to 0.41% ± 0.37%. Four-dimensional T2w MRI displayed tumor extent, structure, and position more clearly than corresponding 4D-T1w MRI, especially when mobile tumor sites were adjacent to organs at risk.

Conclusions

A methodology to obtain 4D-T2w MRI that retrospectively applies the motion information from 4D-T1w MRI to 3-dimensional T2w MRI was developed and verified. Four-dimensional T2w MRI can assist clinicians in delineating mobile lesions that are difficult to define on 4D-T1w MRI, because of poor tumor-tissue contrast.
Shortwave Infrared Fluorescence Imaging with the Clinically Approved Near-Infrared Dye Indocyanine Green
Authors: Carr Jessica A. , Franke Daniel , Caram Justin R. , Perkinson Collin F. , Askoxylakis Vasileios , Datta Meenal , Fukumura Dai , Jain Rakesh K. , Bawendi Moungi G. , Bruns Oliver T.
Published: April 2017

Fluorescence imaging is a method of real-time molecular trackingin vivothat has enabled many clinical technologies. Imaging in the shortwave infrared region (SWIR, 1-2 μm) promises higher contrast, sensitivity, and penetration depths compared to conventional visible and near-infrared (NIR) fluorescence imaging. However, adoption of SWIR imaging in clinical settings has been limited, due in part to the absence of FDA-approved fluorophores with peak emission in the SWIR. Here, we show that commercially available NIR dyes, including the FDA-approved contrast agent indocyanine green (ICG), exhibit optical properties suitable forin vivoSWIR fluorescence imaging. Despite the fact that their emission reaches a maximum in the NIR, these dyes can be imaged non-invasivelyin vivoin the SWIR spectral region, even beyond 1500 nm. We demonstrate real-time fluorescence angiography at wavelengths beyond 1300 nm using ICG at clinically relevant doses. Furthermore, we show tumortargeted SWIR imaging with trastuzumab labeled with IRDye 800CW, a NIR dye currently being tested in multiple phase II clinical trials. Our findings suggest that high-contrast SWIR fluorescence imaging can be implemented alongside existing imaging modalities by switching the detection of conventional NIR fluorescence systems from silicon-based NIR cameras to emerging indium gallium arsenide (InGaAs) SWIR cameras. Using ICG in particular opens the possibility of translating SWIR fluorescence imaging to human clinical applications.
A biological source of marine sedimentary iron oxides
Authors: Beam Jacob P. , Scott Jarrod J. , McAllister Sean M. , Chan Clara S. , McManus James , Meysman Filip J. R. , Emerson David
Published: April 2017

The biogeochemical cycle of iron is intricately linked to numerous element cycles. Although reductive biological processes that bridge the iron cycle to other element cycles are established, little is known about microbial oxidative processes on iron cycling in sedimentary environments—resulting in the formation of iron oxides. Here, we show that a major source of sedimentary iron oxides originates from the metabolic activity of iron-oxidizing bacteria from the class Zetaproteobacteria, stimulated by burrowing animals in coastal sediments. Zetaproteobacteria were estimated to be a global total of 1026cells in coastal, bioturbated sediments and would equate to an annual production of approximately 7.9 x 1015grams of sedimentary iron oxides—twenty-five times larger than the annual flux of iron oxides by rivers. These data suggest that iron-oxidizing Zetaproteobacteria are keystone organisms in marine sedimentary environments given their low numerical abundance; yet exert a profound impact via the production of iron oxides.
Meffil: efficient normalisation and analysis of very large DNA methylation samples
Authors: Min Josine , Hemani Gibran , Smith George Davey , Relton Caroline , Suderman Matthew
Published: April 2017

Abstract

Background

Technological advances in high throughput DNA methylation microarrays have allowed dramatic growth of a new branch of epigenetic epidemiology. DNA methylation datasets are growing ever larger in terms of the number of samples profiled, the extent of genome coverage, and the number of studies being meta-analysed. Novel computational solutions are required to efficiently handle these data.

Methods

We have developedmeffil, an R package designed to quality control, normalize and perform epigenome-wide association studies (EWAS) efficiently on large samples of Illumina Infinium HumanMethylation450 and MethylationEPIC BeadChip microarrays. We testedmeffilby applying it to 6000 450k microarrays generated from blood collected for two different datasets, Accessible Resource for Integrative Epigenomic Studies (ARIES) and The Genetics of Overweight Young Adults (GOYA) study.

Results

A complete reimplementation of functional normalization minimizes computational memory requirements to 5% of that required by other R packages, without increasing running time. Incorporating fixed and random effects alongside functional normalization, and automated estimation of functional normalisation parameters reduces technical variation in DNA methylation levels, thus reducing false positive associations and improving power. We also demonstrate that the ability to normalize datasets distributed across physically different locations without sharing any biologically-based individual-level data may reduce heterogeneity in meta-analyses of epigenome-wide association studies. However, we show that when batch is perfectly confounded with cases and controls functional normalization is unable to prevent spurious associations.

Conclusions

meffilis available online (https://github.com/perishky/meffil/) along with tutorials covering typical use cases.
Single-cell analysis of clonal dynamics in direct lineage reprogramming: a combinatorial indexing method for lineage tracing
Authors: Biddy Brent A. , Waye Sarah E. , Sun Tao , Morris Samantha A.
Published: April 2017

Single-cell technologies are offering unprecedented insight into complex biology, revealing the behavior of rare cell populations that are typically masked in bulk population analyses. The application of these methodologies to cell fate reprogramming holds particular promise as the manipulation of cell identity is typically inefficient, generating heterogeneous cell populations. One current limitation of single-cell approaches is that lineage relationships are lost as a result of cell processing, restricting interpretations of the data collected. Here, we present a single-cell resolution lineage-tracing approach based on the combinatorial indexing of cells, ‘CellTagging’. Application of this method, in concert with high-throughput single-cell RNA-sequencing, reveals the transcriptional dynamics of direct reprogramming from fibroblasts to induced endoderm progenitors. These analyses demonstrate that while many cells initiate reprogramming, complete silencing of fibroblast identity and transition to a progenitor-like state represents a rare event. Clonal analyses uncover a remarkable degree of heterogeneity arising from individual cells. Overall, very few cells fully reprogram to generate expanded populations with a low degree of clonal diversity. Extended culture of these engineered cells reveals an instability of the reprogrammed state and reversion to a fibroblast-like phenotype. Together, these results demonstrate the utility of our lineage-tracing approach to reveal dynamics of lineage reprogramming, and will be of broad utility in many cell biological applications.