bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Sex Chromosome Dosage Induces Coordinated Shifts in Cortical Anatomy and Anatomical Covariance
Authors: Xenophontos Anastasia , Seidlitz Jakob , Liu Siyuan , Clasen Liv S , Blumenthal Jonathan D , Giedd Jay N , Alexander-Bloch Aaron , Raznahan Armin
Published: September 2019

Sex chromosome dosage (SCD) variation increases risk for neuropsychiatric impairment, which may reflect direct SCD effects on brain organization. Here, we 1) map cumulative X- and Y-chromosome dosage effects on regional cortical thickness (CT) and investigate potential functional implications of these effects using Neurosynth, 2) test if this map is organized by patterns of CT covariance that are evident in health, and 3) characterize SCD effects on CT covariance itself. We modeled SCD effects on CT and CT covariance for 308 equally sized regions of the cortical sheet using structural neuroimaging data from 301 individuals with varying numbers of sex chromosomes (169 euploid, 132 aneuploid). Mounting SCD increased CT in the rostral frontal cortex and decreased CT in the lateral temporal cortex, bilaterally. Regions targeted by SCD were associated with social functioning, language processing, and comprehension. Cortical regions with a similar degree of SCD-sensitivity showed heightened CT covariance in health. Finally, greater SCD also increased covariance among regions similarly affected by SCD. Our study both 1) develops novel methods for comparing typical and disease-related structural covariance networks in the brain and 2) uses these techniques to resolve and identify organizing principles for SCD effects on regional cortical anatomy and anatomical covariance.
Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin
Authors: Sato Takafumi , Yamawaki Kenji
Published: September 2019

The emergence of antimicrobial resistance is a significant public health issue worldwide, particularly for healthcare-associated infections caused by carbapenem-resistant gram-negative pathogens. Cefiderocol is a novel siderophore cephalosporin targeting gram-negative bacteria, including strains with carbapenem resistance. The structural characteristics of cefiderocol show similarity to both ceftazidime and cefepime, which enable cefiderocol to withstand hydrolysis by β-lactamases. The unique chemical component is the addition of a catechol moiety on the C-3 side chain, which chelates iron and mimics naturally occurring siderophore molecules. Following the chelation of iron, cefiderocol is actively transported across the outer membrane of the bacterial cell to the periplasmic space via specialized iron transporter channels. Furthermore, cefiderocol has demonstrated structural stability against hydrolysis by both serine- and metallo-β-lactamases, including clinically relevant carbapenemases such as Klebsiella pneumoniae carbapenemase, oxacillin carbapenemase-48, and New Delhi metallo-β-lactamase. Cefiderocol has demonstrated promising in vitro antibacterial and bactericidal activity, which correlates with its in vivo efficacy in several animal models. This article reviews the discovery and chemistry of cefiderocol, as well as some of the key microbiological and in vivo findings on cefiderocol from recently conducted investigations.
Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin
Authors: Katsube Takayuki , Echols Roger , Wajima Toshihiro
Published: September 2019

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent in vitro activity and in vivo efficacy against most gram-negative bacteria, including carbapenem-resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In phase 1 studies, cefiderocol demonstrated linear pharmacokinetics, primarily urinary excretion, an elimination half-life of 2–3 hours, and a protein binding of 58% in human plasma. Cefiderocol is a time-dependent cephalosporin; the probability of a target attainment at ≥75% of the dosing interval during which the free drug concentration exceeds the minimum inhibitory concentration (ƒT/MIC) for bacterial strains with an MIC of ≤4 μg/mL is likely to be achieved at the therapeutic dose of 2 g over 3-hour infusion every 8 hours in most patients. As expected, renal function markers were the most influential covariates for the pharmacokinetics of cefiderocol for patients with renal impairment or augmented renal clearance (ARC). Dose adjustment is recommended for patients with impaired renal function, and additionally, in ARC patients with creatinine clearance >120 mL/minute, a more frequent dosing regimen (ie, 2 g every 6 hours) was predicted to achieve the target fT > MIC. The single and multiple doses of cefiderocol tested were well tolerated in both healthy subjects and those with renal impairment. Furthermore, neither QT interval prolongation nor drug–drug interaction via organic anion transporters was demonstrated in healthy subjects. Cefiderocol is being investigated in phase 3 clinical studies for the treatment of infections caused by carbapenem-resistant bacteria.
Pathogen-focused Clinical Development to Address Unmet Medical Need: Cefiderocol Targeting Carbapenem Resistance
Authors: Echols Roger , Ariyasu Mari , Nagata Tsutae Den
Published: September 2019

Historically, the regulatory requirements of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for developing new antibiotics have not addressed pathogen-focused indications for drug approval. The design of the necessary randomized controlled trials traditionally involves the enrollment of patients with site-specific infections caused by susceptible as well as resistant pathogens. Cefiderocol has undergone a streamlined clinical development program to address serious carbapenem-resistant infections. The regulatory approach, and the pivotal clinical trials, differed between the FDA and EMA. In the United States, the APEKS-cUTI (Acinetobacter, Pseudomonas, Escherichia coli, Klebsiella, Stenotrophomonas–complicated urinary tract infection) study was conducted to provide the basis for FDA approval of a site-specific cUTI indication. The EMA, however, preferred the CREDIBLE-CR (A MultiCenter, RandomizED, Open-label ClInical Study of S-649266 or Best AvailabLE Therapy for the Treatment of Severe Infections Caused by Carbapenem-Resistant Gram-negative Pathogens) study, in which patients with nosocomial pneumonia, bloodstream infections, or cUTIs were enrolled if they had a carbapenem-resistant pathogen. The resulting European label will be pathogen focused rather than infection site specific (ie, treatment of gram-negative infection in patients with limited treatment options). The implications and limitations of these different regulatory processes are discussed.
Consensus Report on Shigella Controlled Human Infection Model: Clinical Endpoints
Authors: MacLennan Calman A , Riddle Mark S , Chen Wilbur H , Talaat Kawsar R , Jain Varsha , Bourgeois A Louis , Frenck Robert , Kotloff Karen , Porter Chad K
Published: September 2019

The Shigella controlled human infection model (CHIM) is valuable for assessing candidate Shigella vaccine efficacy and potentially accelerating regulatory approval. The Shigella CHIM is currently being conducted at 3 sites in the United States using Shigella flexneri 2a strain 2457T and Shigella sonnei strain 53G. Shigellosis can present variably as watery diarrhea alone or with dysentery, and can be accompanied by manifestations including fever, abdominal cramps, tenesmus, and malaise. For comparability, it is important to harmonize the primary clinical endpoint. An expert working group was convened on 2 February 2018 to review clinical data from Shigella CHIM studies performed to date and to develop a consensus primary endpoint. The consensus endpoint enabled “shigellosis” to present as severe diarrhea or moderate diarrhea or dysentery. The latter 2 criteria are met when concurrent with fever of 38.0°C and/or vomiting, and/or a constitutional/enteric symptom graded at least as “moderate” severity. The use of a blinded independent committee to adjudicate the primary endpoint by subject was also regarded as important. As safety of volunteers in challenge studies is of paramount importance and treatment timing can affect primary outcomes, a standard for early antibiotic administration was established as follows: (1) when the primary endpoint is met; (2) if a fever of ≥39.0°C develops; or (3) if the study physician deems it appropriate. Otherwise, antibiotics are given at 120 hours postinfectious challenge. The working group agreed on objective and subjective symptoms to be solicited, and standardized methods for assessing subject-reported severity of symptoms.
Trial design and baseline characteristics of CaLIPSO: a randomized, double-blind placebo-controlled trial of SNF472 in patients receiving haemodialysis with cardiovascular calcification
Authors: Bellasi Antonio , Raggi Paolo , Bover Jordi , Bushinsky David A , Chertow Glenn M , Ketteler Markus , Rodriguez Mariano , Sinha Smeeta , Salcedo Carolina , Garg Rekha , Gold Alex , Perelló Joan
Published: September 2019

Background

The objective of CaLIPSO, a Phase 2b, randomized, double-blind, placebo-controlled clinical trial, is to test the hypothesis that myo-inositol hexaphosphate (SNF472) attenuates the progression of cardiovascular calcification in patients receiving maintenance haemodialysis. Here we report the trial design and baseline characteristics of trial participants.

Methods

Adult patients on maintenance haemodialysis (≥6 months) with an Agatston coronary artery calcium score, as measured by a multidetector computed tomography scanner, of 100–3500 U were enrolled. Patients were stratified by Agatston score (100–<400, 400–1000 or >1000 U) and randomized in a 1:1:1 ratio to receive placebo, SNF472 300 mg or SNF472 600 mg administered intravenously three times weekly during each haemodialysis session.

Results

Overall, 274 patients were randomized. The mean age of trial participants was 63.6 (standard deviation 8.9) years and 39% were women. The coronary artery, aorta and aortic valve median (25th-75th percentile) Agatston scores at baseline were 730 U (315–1435), 1728 U (625–4978) and 103 U (31–262), respectively, and the median (25th–75th percentile) calcium volume scores at baseline were 666 (310–1234), 1418 (536–4052) and 107 (38–278), respectively. Older age and diabetes mellitus were associated with higher calcium scores at baseline.

Conclusions

The CaLIPSO trial enrolled patients on haemodialysis with pre-existent cardiovascular calcification to test the hypothesis that SNF472 attenuates its progression in the coronary arteries, aorta and aortic valve.
An unyielding valve leading to venous spasm during pacemaker implantation: a case report
Authors: Krishnappa Darshan , Sakaguchi Scott , Kasinadhuni Ganesh , Tholakanahalli Venkatakrishna N
Published: September 2019

Background

Subclavian venous spasm is an uncommon complication during permanent pacemaker implantation. The exact aetiology of subclavian venous spasm is not clear but has been suggested to be due to either mechanical irritation of the vein during needle puncture or due to chemical irritation from contrast injection. Here, we report a case of an unyielding subclavian vein valve that impeded guidewire advancement and the repeated guidewire manipulation led to venous spasm.

Case summary

A 45-year-old woman with a history of surgical repair of Tetrology of Fallot in childhood presented with symptomatic bifascicular block and underwent a permanent pacemaker implantation. A subclavian venogram done prior to the procedure showed a prominent valve in the distal portion of the vein. Following venous puncture, guidewire advancement was impeded by the prominent valve. The resulting guidewire manipulation led to subclavian venous spasm necessitating a medial subclavian venous puncture and access.

Discussion

Prolonged mechanical irritation of the vein during pacemaker implantation may lead to venous spasm impeding pacemaker implantation. Early identification of an impeding valve and obtaining access medial to the valve may help prevent this uncommon complication.
Loperamide overdose causing torsades de pointes and requiring Impella temporary mechanical support: a case report
Authors: Cicci Jonathan D , Jagielski Sarah M , Clarke Megan M , Rayson Robert A , Cavender Matthew A
Published: September 2019

Background

Loperamide is a widely available oral μ-opioid receptor agonist, and loperamide abuse is increasing by those seeking intoxication. Loperamide has potent QTc-prolonging properties, placing patients at risk for ventricular arrhythmias and sudden cardiac death.

Case summary

A 23-year-old woman was found to be in pulseless ventricular fibrillation with a QTc of 554 ms and received multiple defibrillations and IV lidocaine. Her toxicology studies were negative. She subsequently experienced multiple episodes of torsades de pointes and was found to be in cardiogenic shock with a left ventricular ejection fraction of 5%. Following multiple defibrillations, an Impella® mechanical circulatory support device was placed, and she was given IV magnesium and IV lidocaine. After mechanical circulatory support was withdrawn, she experienced major bleeding and was found to have a deep vein thrombosis, bilateral radial artery thrombosis, and multiple pulmonary embolisms in the setting of heparin-induced thrombocytopenia. After stabilizing, she admitted to taking 80 tablets of loperamide 2 mg in pursuit of euphoria.

Discussion

Loperamide is an increasingly popular agent of abuse. Loperamide-associated ventricular arrhythmias are rare with normal doses but more common with high doses, chronic ingestion, or interacting medications. Loperamide cardiotoxicity may be prolonged due to a long half-life and accumulation. Loperamide abuse may be under-recognized, leading to delays in treatment. Intravenous fluids, magnesium supplementation, chronotropes, transcutaneous or transvenous pacing, and defibrillation may be helpful in mitigating loperamide-associated polymorphic ventricular tachycardia. Clinicians should monitor for drug interactions in patients taking loperamide and screen for electrocardiographic abnormalities in those taking chronic or high-dose loperamide.
Inherited and Sporadic Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degenerations arising from Pathological Condensates of Phase Separating Proteins
Authors: Fernandopulle Michael , Wang GuoZhen , Nixon-Abell Jonathon , Qamar Seema , Balaji Varun , Morihara Ryuta , St George-Hyslop Peter H
Published: September 2019

Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).
The Fissured Worker: Personal Service Companies and Employment Rights
Authors: Ford Michael
Published: September 2019

A personal service company (PSC) is a form of intermediary with separate legal personality used as a vehicle to provide the labour of the individual who controls the PSC. The rapid growth of PSCs in recent years, and their potential to disguise employment status for tax purposes, have been the subject of much policy and legislation. But their detrimental effect on the employment rights, both individual and collective, has almost been ignored. Evidence shows that PSCs continue to increase at a faster rate than employment, are colonising sectors of the labour market characterised by dependent labour and are often imposed to avoid the duties owed to workers or employees. In this article, I analyse how the existing law might provide a means of protecting the labour rights of individuals who are engaged via PSCs, examining the statutory provisions specific to some legal rights and more general doctrines based on shams, labels and piercing the corporate veil. Although the law provides some protection in some circumstances, PSCs retain their allure as a means of avoiding employment rights. I discuss potential legislative solutions to this problem, which highlights the interaction of tax and employment law and the difficulties caused by relying on the bilateral contract as the keystone of labour rights.
Serum Mac-2-Binding Protein Glycosylation Isomer at Virological Remission Predicts Hepatocellular Carcinoma and Death in Chronic Hepatitis B-Related Cirrhosis
Authors: Su Tung-Hung , Peng Cheng-Yuan , Tseng Tai-Chung , Yang Hung-Chih , Liu Chun-Jen , Liu Chen-Hua , Chen Pei-Jer , Chen Ding-Shinn , Kao Jia-Horng
Published: September 2019

Background

To investigate serum Mac-2-binding protein glycosylation isomer (M2BPGi) levels in predicting hepatocellular carcinoma (HCC) and mortality at virological remission (VR, HBV DNA <20 IU/mL) following antiviral therapy in chronic hepatitis B (CHB) patients with cirrhosis.

Methods

This retrospective cohort study included patients with CHB-related Child-Pugh A cirrhosis undergoing long-term antiviral therapy. Serum M2BPGi levels were quantified and multivariable Cox proportional hazards regression models were used to identify risk predictors for HCC and death.

Results

A total of 126 and 145 patients were included in the derivation and validation cohorts, respectively. The mean age was 56, and the mean M2BPGi level was 1.86 cut-off index (COI) in the derivation cohort. After adjustment for confounders, a higher M2BPGi level at VR significantly predicted HCC (hazard ratio [HR]: 1.58, 95% confidence interval [CI]: 1.19-2.10, P=0.002) and death (HR: 2.17, 95% CI: 1.02-4.62, P=0.044). The M2BPGi ³3 COI significantly increased the risk of HCC and death in the derivation and validation cohorts. Serial M2BPGi levels declined significantly (P=0.0001) in non-HCC patients only, and remained significantly lower than those who developed HCC afterwards (P=0.039).

Conclusions

Serum M2BPGi levels at antiviral therapy-induced VR predict HCC development and death in patients with CHB-related Child-Pugh A cirrhosis.
Formyl-Peptide Receptor Activation Enhances Phagocytosis of Community-Acquired Methicillin-Resistant Staphylococcus aureus
Authors: Weiß Elisabeth , Schlatterer Katja , Beck Christian , Peschel Andreas , Kretschmer Dorothee
Published: September 2019

Background

Formyl-peptide receptors (FPRs) are important pattern recognition receptors that sense specific bacterial peptides. Formyl-peptide receptors are highly expressed on neutrophils and monocytes, and their activation promotes the migration of phagocytes to sites of infection. It is currently unknown whether FPRs may also influence subsequent processes such as bacterial phagocytosis and killing. Staphylococcus aureus, especially highly pathogenic community-acquired methicillin-resistant S aureus strains, release high amounts of FPR2 ligands, the phenol-soluble modulins.

Methods

We demonstrate that FPR activation leads to upregulation of complement receptors 1 and 3 as well as FCγ receptor I on neutrophils and, consequently, increased opsonic phagocytosis of S aureus and other pathogens.

Results

Increased phagocytosis promotes killing of S aureus and interleukin-8 release by neutrophils.

Conclusions

We show here for the first time that FPRs govern opsonic phagocytosis. Manipulation of FPR2 activation could open new therapeutic opportunities against bacterial pathogens.
Nonoptimal Vaginal Microbiota After Azithromycin Treatment for Chlamydia trachomatis Infection
Authors: Tamarelle Jeanne , Ma Bing , Gajer Pawel , Humphrys Mike S , Terplan Mishka , Mark Katrina S , Thiébaut Anne C M , Forney Larry J , Brotman Rebecca M , Delarocque-Astagneau Elisabeth , Bavoil Patrik M , Ravel Jacques
Published: September 2019

We characterized the composition and structure of the vaginal microbiota in a cohort of 149 women with genital Chlamydia trachomatis infection at baseline who were followed quarterly for 9 months after antibiotic treatment. At time of diagnosis, the vaginal microbiota was dominated by Lactobacillus iners or a diverse array of bacterial vaginosis–associated bacteria including Gardnerella vaginalis. Interestingly, L. iners–dominated communities were most common after azithromycin treatment (1 g monodose), consistent with the observed relative resistance of L. iners to azithromycin. Lactobacillus iners–dominated communities have been associated with increased risk of C. trachomatis infection, suggesting that the impact of antibiotic treatment on the vaginal microbiota could favor reinfections. These results provide support for the dual need to account for the potential perturbing effect(s) of antibiotic treatment on the vaginal microbiota, and to develop strategies to protect and restore optimal vaginal microbiota.
Metacytofilin Is a Potent Therapeutic Drug Candidate for Toxoplasmosis
Authors: Leesombun Arpron , Iijima Masatomi , Umeda Kousuke , Kondoh Daisuke , Pagmadulam Baldorj , Abdou Ahmed M , Suzuki Yutaka , Ohba Shun-Ichi , Isshiki Kunio , Kimura Tomoyuki , Kubota Yumiko , Sawa Ryuichi , Nihei Coh-Ichi , Nishikawa Yoshifumi
Published: September 2019

Background

Toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, is an important cause of miscarriage or adverse fetal effects, including neurological and ocular manifestations in humans. Current anti-Toxoplasma drugs have limited efficacy against toxoplasmosis and also have severe side effects. Therefore, novel efficacious drugs are urgently needed. Here, we identified metacytofilin (MCF) from a fungal Metarhizium species as a potential anti-Toxoplasma compound.

Methods

Anti-Toxoplasma activities of MCF and its derivatives were evaluated in vitro and in vivo using nonpregnant and pregnant mice. To understand the mode of action of MCF, the RNA expression of host and parasite genes was investigated by RNAseq.

Results

In vitro, MCF inhibited the viability of intracellular and extracellular T. gondii. Administering MCF intraperitoneally or orally to mice after infection with T. gondii tachyzoites increased mouse survival compared with the untreated animals. Remarkably, oral administration of MCF to pregnant mice prevented vertical transmission of the parasite. Interestingly, RNA sequencing of T. gondii–infected cells treated with MCF showed that MCF inhibited DNA replication and enhanced RNA degradation in the parasites.

Conclusions

With its potent anti–T. gondii activity, MCF is a strong candidate for future drug development against toxoplasmosis.
Colonoscopy Trainers Experience Greater Stress During Insertion than Withdrawal: Implications for Endoscopic Curricula
Authors: Lemke Madeline , Banwell Alison , Rubinger Natalie , Wiepjes Michelle , Ropeleski Mark , Vanner Stephen , Hookey Lawrence
Published: September 2019

Background

Optimal colonoscopy training curricula should minimize stress and cognitive load. This study aimed to determine whether withdrawal or insertion colonoscopy skills training is associated with less stress or cognitive load for trainees or trainers.

Methods

In Phase I, participants were randomized to train on either insertion or withdrawal in a simulated environment. In Phase II, participants were randomized to begin with either insertion or withdrawal in patient encounters. Salivary cortisol levels, heart rate, and State-Trait Anxiety Inventory (STAI) surveys were used to assess stress in trainees and trainers. NASA Task Load Index (TLX) survey was used to assess cognitive workload in trainees.

Results

In Phase I, trainee stress increased during the simulation training during both withdrawal and insertion compared to baseline, while trainer stress changed minimally. Cognitive load was higher for trainees during withdrawal (P = 0.005). In Phase II, trainers’ STAI scores were greater during insertion training (P = 0.013). Trainees’ stress was highest prior to beginning patient training and decreased during training, while trainer’s stress increased during training. Trainees reported insertion training being of greater value (70.0%), while trainers reported withdrawal was preferred (77.8%).

Conclusion

Trainees and trainers exhibit important differences in stress during colonoscopy skills training. Trainees reported more stress during simulation training and greatest cognitive load during simulation withdrawal, whereas trainers reported greatest stress during patient encounters, particularly training of insertion techniques. Attention to the effect of stress on trainees and trainers and the drivers of stress is warranted and could be incorporated in competency based medical education.
“If He Has it, We Know What to Do”: Parent Perspectives on Familial Risk for Autism Spectrum Disorder
Authors: MacDuffie Katherine E , Turner-Brown Lauren , Estes Annette M , Wilfond Benjamin S , Dager Stephen R , Pandey Juhi , Zwaigenbaum Lonnie , Botteron Kelly N , Pruett John R , Piven Joseph , Peay Holly L ,   The IBIS Network, Piven J , Hazlett H C , Chappell C , Dager S , Estes A , Shaw D , Botteron K , McKinstry R , Constantino J , Pruett J , Schultz R , Pandey J , Paterson S , Zwaigenbaum L , Ellison J , Wolff J , Evans A C , Collins D L , Pike G B , Fonov V , Kostopoulos P , Das S , MacIntyre L , Gerig G , Styner M , Gu H
Published: September 2019

Objective

Predictive testing for familial disorders can guide healthcare and reproductive decisions. Familial disorders with onset in childhood (e.g., autism spectrum disorder [ASD]) are promising targets for presymptomatic prediction; however, little is known about parent perceptions of risk to their children in the presymptomatic period. The current study examined risk perceptions in parents of infants at high familial risk for ASD enrolled in a longitudinal study of brain and behavior development.

Methods

Semistructured interviews were conducted with 37 parents of high-risk infants during the presymptomatic window (3–15 months) that precedes an ASD diagnosis. Infants were identified as high familial risk due to having an older sibling with ASD. Parent interview responses were coded and interpreted to distill emerging themes.

Results

The majority of parents were aware of the increased risk of ASD for their infants, and risk perceptions were influenced by comparisons to their older child with ASD. Parents reported a variety of negative emotions in response to perceived risk, including worry, fear, and sadness, and described impacts of perceived risk on their behavior: increased vigilance to emerging symptoms, altered reproductive and healthcare decisions, and seeking ongoing assessment through research.

Conclusions

Parents of children at high familial risk for childhood-onset disorders like ASD face a period of challenging uncertainty during early development. In anticipation of a future in which presymptomatic testing for ASD is made available, it is important to understand how parents react to and cope with the elevated—but still highly uncertain—risk conveyed by family history.
Higher Rates of Sleep Disturbance Among Offspring of Parents With Recurrent Depression Compared to Offspring of Nondepressed Parents
Authors: Hamilton Jessica L , Ladouceur Cecile D , Silk Jennifer S , Franzen Peter L , Bylsma Lauren M
Published: September 2019

Objective

Youth who have a parent with recurrent depression are at high risk for mental health problems. There is a need to identify transdiagnostic and clinically actionable mechanisms that explain higher rates of psychopathology among high-risk youth. The present study sought to examine whether offspring of depressed parents exhibit greater parent- and self-reported sleep disturbance, shorter sleep duration, and later sleep midpoint compared to youth without any parental psychopathology.

Method

Participants included 82 youth, including 41 youth (ages 9–13; mean age = 11.07 years; 46% female) deemed to be at high-risk based on having a parent with a recurrent depression history, and 41 (mean age = 11.16 years; 49% female) at low-risk based on having parents without any history of psychopathology. Youth and their parents completed measures of youth sleep disturbance, and youth completed measures of sleep duration and midpoint using a daily sleep diary for 9 days.

Results

Offspring of parents with depression exhibited more sleep disturbance (e.g., problematic nighttime behaviors and daytime sleepiness) than low-risk youth as reported by both parents and youth. For parent-reported sleep disturbance, there were also sex differences. High-risk girls had more sleep disturbance than high-risk boys or low-risk girls. There were no group differences for daily sleep duration and midpoint.

Conclusion

Sleep disturbance may be an important area for assessment among offspring of parents with depression. Our findings highlight one potential transdiagnostic risk factor that may emerge among high-risk youth, and sex-specific differences in sleep disturbance, which have implications for prevention and intervention.
PROMIS® Pediatric Depressive Symptoms as a Harmonized Score Metric
Authors: Kaat Aaron J , Kallen Michael A , Nowinski Cindy J , Sterling Stacy A , Westbrook Sherrilyn R , Peters John T
Published: September 2019

Objective

To conduct an evidence-based review of adolescent self-report depression measures and to demonstrate how various measures can be rescored onto a harmonized metric.

Method

Six widely used person-reported outcome measures (PROMs) were reviewed. Psychometric properties were evaluated using previously published guidance for PROMs. Next, two secondary data sources (from an outpatient behavioral health clinic and from the general population) were evaluated to harmonize scores across three of the measures. Both item response theory and equipercentile linking methods were used and compared.

Results

All six PROMs demonstrated a high evidence base for widespread use depending on the purpose of the assessments. Adolescent involvement when developing the PROM for content validity and floor or ceiling effects were the least frequent available evidence. Three of the PROMs were linked to the PROMIS® Pediatric Depressive Symptoms v2.0 (PROMIS-PedDepSx) metric. The scales were highly correlated and essentially unidimensional when aggregated. All linking methods were broadly comparable. Group-level score conversions are recommended to minimize linking bias.

Conclusions

There are a number of strong, widely used PROMs for the evidence-based assessment (EBD) of adolescent depression. However, score comparability is a concern whenever there is a proliferation of measures. Harmonized score metrics support data aggregation and re-analysis. Using four PROMs, one of which served as the scoring metric, we demonstrated the possibility of harmonized depression scores. Future directions for EBD should evaluate whether harmonized PROMs for other pediatric health domains would be useful.
The Rudeness and Reverence of Geoffrey Hill’s Mariology
Authors: Russell Jesse
Published: September 2019

Due to his seemingly reactionary politics and theology, the recently deceased English lyricist Geoffrey Hill has courted controversy throughout his life. However, while Hill’s work is replete with qualified nostalgia for premodern British history, and he does treat a number of Christian themes in his work, the great British poet defies easy categorisation. Moreover, drawing from the theology of Simone Weil, Rowan Williams, and others, Hill’s work is saturated with a profound awareness of the fallen state of human nature. One of the most profound tropes Hill uses as a representative of what could be called Original Sin is the image of the Blessed Virgin Mary. As a tormented believer and a poet very aware of the fallenness of the world, Hill’s depiction of Mary reveals that Hill is a Christian poet who does not fall into ready categories.
DNMIVD: DNA methylation interactive visualization database
Authors: Ding Wubin , Chen Jiwei , Feng Guoshuang , Chen Geng , Wu Jun , Guo Yongli , Ni Xin , Shi Tieliu
Published: September 2019

Aberrant DNA methylation plays an important role in cancer progression. However, no resource has been available that comprehensively provides DNA methylation-based diagnostic and prognostic models, expression–methylation quantitative trait loci (emQTL), pathway activity-methylation quantitative trait loci (pathway-meQTL), differentially variable and differentially methylated CpGs, and survival analysis, as well as functional epigenetic modules for different cancers. These provide valuable information for researchers to explore DNA methylation profiles from different aspects in cancer. To this end, we constructed a user-friendly database named DNA Methylation Interactive Visualization Database (DNMIVD), which comprehensively provides the following important resources: (i) diagnostic and prognostic models based on DNA methylation for multiple cancer types of The Cancer Genome Atlas (TCGA); (ii) meQTL, emQTL and pathway-meQTL for diverse cancers; (iii) Functional Epigenetic Modules (FEM) constructed from Protein-Protein Interactions (PPI) and Co-Occurrence and Mutual Exclusive (COME) network by integrating DNA methylation and gene expression data of TCGA cancers; (iv) differentially variable and differentially methylated CpGs and differentially methylated genes as well as related enhancer information; (v) correlations between methylation of gene promoter and corresponding gene expression and (vi) patient survival-associated CpGs and genes with different endpoints. DNMIVD is freely available at http://www.unimd.org/dnmivd/. We believe that DNMIVD can facilitate research of diverse cancers.
New substituted quinoxalines inhibit triple-negative breast cancer by specifically downregulating the c-MYC transcription
Authors: Hu Ming-Hao , Wu Tian-Ying , Huang Qiong , Jin Guangyi
Published: September 2019

Conventional chemotherapy remains the primary treatment option for triple-negative breast cancer (TNBC). However, the current chemotherapeutic drugs have limited effects on TNBC, and often lead to serious side effects as well as drug resistance. Thus, more effective therapeutic options are sorely needed. As c-MYC oncogene is highly expressed during TNBC pathogenesis, inhibiting c-MYC expression would be an alternative anti-TNBC strategy. In this study, we designed and synthesized a serial of quinoxaline analogs that target c-MYC promoter G-quadruplex (G4), which is believed to be a repressor of c-MYC transcription. Among them, a difluoro-substituted quinoxaline QN-1 was identified as the most promising G4-stabilizing ligand with high selectivity to c-MYC G4 over other G4s, which is distinguished from many other reported ligands. Intracellular studies indicated that QN-1 induced cell cycle arrest and apoptosis, repressed metastasis and inhibited TNBC cell growth, primarily due to the downregulation of c-MYC transcription by a G4-dependent mechanism. Notably, inhibition by QN-1 was significantly greater for c-MYC than other G4-driven genes. Cancer cells with c-MYC overexpression were more sensitive to QN-1, relative to normal cells. Furthermore, QN-1 effectively suppressed tumor growth in a TNBC mouse model. Accordingly, this work provides an alternative strategy for treating TNBC.
The invasive proteome of glioblastoma revealed by laser-capture microdissection
Authors: Daubon Thomas , Guyon Joris , Raymond Anne-Aurélie , Dartigues Benjamin , Rudewicz Justine , Ezzoukhry Zakaria , Dupuy Jean-William , Herbert John M J , Saltel Frédéric , Bjerkvig Rolf , Nikolski Macha , Bikfalvi Andreas
Published: September 2019

Background

Glioblastomas are heterogeneous tumors composed of a necrotic and tumor core and an invasive periphery.

Methods

Here, we performed a proteomics analysis of laser-capture micro-dissected glioblastoma core and invasive areas of patient-derived xenografts.

Results

Bioinformatics analysis identified enriched proteins in central and invasive tumor areas. Novel markers of invasion were identified, the genes proteolipid protein 1 (PLP1) and Dynamin-1 (DNM1), which were subsequently validated in tumors and by functional assays.

Conclusions

In summary, our results identify new networks and molecules that may play an important role in glioblastoma development and may constitute potential novel therapeutic targets.
Association of Tobacco Use During Pregnancy, Perceived Stress, and Depression Among Alaska Native Women Participants in the Healthy Pregnancies Project
Authors: Patten Christi A , Lando Harry A , Desnoyers Chris A , Klejka Joseph , Decker Paul A , Bock Martha J , Hughes Christine A , Alexie Lucinda , Boyer Rahnia , Resnicow Kenneth , Burhansstipanov Linda
Published: September 2019

Introduction

In general population samples, higher levels of stress and depression have been associated with increased prevalence of smoking in pregnancy. Little is known about the association of prenatal tobacco use, stress, and depression among American Indian or Alaska Native (AI/AN) women.

Methods

The Healthy Pregnancies Project is a cluster-randomized controlled trial, evaluating a community-level intervention compared with usual care, for reducing tobacco use during pregnancy and postpartum among AN women in 16 villages in western Alaska. This cross-sectional study analyzed baseline data from enrolled pregnant women. Baseline measures included the self-reported, 7-day, point-prevalence current use of any tobacco, Perceived Stress Scale (PSS), and the Center for Epidemiological Studies-Depression (CES-D). Generalized estimating equations (GEE) analyses adjusted for village, participant age, and gestational age.

Results

Participants (N = 352) were on average (SD) 25.8 (5.0) years of age and at 26.8 (9.8) weeks gestation. 66.5% were current tobacco users, of which 77% used Iqmik, a homemade form of smokeless tobacco. Compared with nonusers, tobacco users reported lower PSS score (p = .020) and less clinical levels of depression (CES-D ≥ 16) (18.1% vs. 9.3%, p = .21). Findings were not accounted for by nicotine dependence severity or self-reported tobacco use before pregnancy.

Conclusions

In this sample of pregnant AN women, tobacco users report less stress and clinical levels of depression than nonusers. A potential challenge with tobacco treatment for pregnant AN women is to provide alternative ways of deescalating stress and affect management instead of using tobacco.

Implications

This study contributes novel information on the association of tobacco use, perceived stress, and depression among Alaska Native women enrolled in a clinical trial to promote healthy pregnancies. Most prior studies addressing this topic were conducted among general population samples of pregnant women who smoked cigarettes. Little is known about these associations with prenatal smokeless tobacco, or among American Indian or Alaska Native women. The results are contrary to findings reported previously, because current tobacco use was associated with less stress and depression than nonuse. The study findings have implications for cessation treatment for this tobacco-use disparity group.
Impact of Catheter Management on Clinical Outcome in Adult Cancer Patients With Gram-Negative Bacteremia
Authors: Fares Johny , Khalil Melissa , Chaftari Anne-Marie , Hachem Ray , Jiang Ying , Kantarjian Hagop M , Raad Issam I
Published: September 2019

Objective

Gram-negative organisms have become a major etiology of bloodstream infections. We evaluated the effect of central venous catheter management on cancer patients with gram-negative bloodstream infections.

Method

We retrospectively identified patients older than 14 years with central venous catheters who were diagnosed with gram-negative bloodstream infections to determine the effect of catheter management on outcome. Patients were divided into 3 groups: Group 1 included patients with central line-associated bloodstream infections (CLABSI) without mucosal barrier injury and those whose infection met the criteria for catheter-related bloodstream infection; group 2 included patients with CLABSI with mucosal barrier injury who did not meet the criteria for catheter-related bloodstream infection; and group 3 included patients with non-CLABSI.

Results

The study included 300 patients, with 100 patients in each group. Only in group 1 was central venous catheter removal within 2 days of bloodstream infection significantly associated with a higher rate of microbiologic resolution at 4 days compared to delayed central venous catheter removal (3–5 days) or retention (98% vs 82%, P = .006) and a lower overall mortality rate at 3-month follow-up (3% vs 19%, P = .01). Both associations persisted in multivariate analyses (P = .018 and P = .016, respectively).

Conclusions

Central venous catheter removal within 2 days of the onset of gram-negative bloodstream infections significantly improved the infectious outcome and overall mortality of adult cancer patients with catheter-related bloodstream infections and CLABSI without mucosal barrier injury.
Presentation of treatment effect in glioblastoma after dose-escalation radiation therapy
Authors: Cicka Danielle , Ford Charles Lester , Templin Erica , Pitts Zachary , Gurbani Saumya , Eaton Bree , Lowder Lindsey , Olson Jeffrey , Weinberg Brent D , Shim Hyunsuk , Sengupta Soma
Published: September 2019

Glioblastoma is the most aggressive primary brain tumor in adults. Limited treatment options and the intense nature of therapy make determining the appropriate treatment course for each patient difficult. The appearance of transient worsening of imaging findings, known as treatment effect, after chemoradiation further complicates clinical decision-making. Accurately differentiating treatment effects from true progression is critical as subsequent treatment decisions are based largely on radiographic evidence of tumor progression. As chemoradiation can cause worsening of imaging findings, it is possible that the use of new treatments and modified chemoradiation regimens may alter the presentation of treatment effect. Therefore, physicians should be aware that atypical presentations of treatment effects can occur, and may be more likely, when treatment regimens are modified. Here, we present the case of a patient with isocitrate dehydrogenase 1 wild type, O-6-methylguanine-DNA methyltransferase-methylated glioblastoma who underwent dose-escalation radiation therapy (to 75 Gy) and exhibited worsened imaging findings at 8 months post-radiation.
Listeriosis in an immunocompetent patient after diagnostic colonoscopy
Authors: Burch Jacob , Kandola Samanjit , Enofe Ikponmwosa
Published: September 2019

We present an 80-year-old female with type II diabetes (well controlled) who presented to the emergency department with a hemoglobin of 6.5 mg/d consistent with iron deficiency anemia (IDA). As part of the workup for IDA, she had an esophagogastroduodenoscopy (EGD) and colonoscopy. EGD was unremarkable. Colonoscopy revealed a mass occupying about 50% of the circumference of her descending colon suspicious for malignancy, which was biopsied. Thirty-six hours later, she developed fevers; blood cultures grew Listeria monocytogenes. Workup to identify the source of bacteremia was negative for other sources of infection. Due to the temporal relationship, the development of bacteremia was attributed to the disturbance of the gastrointestinal tract possibly from recent biopsy of the colonic mass. She was treated with penicillin for a total of about 4 weeks with complete resolution of symptoms and clearance of bacteremia. She had a transverse colectomy 6 weeks later with surgical pathology of the lesion showing intramucosal adenocarcinoma. This case represents a rare complication of colonoscopy and is novel because our patient was not immunocompromised as previously reported in other cases.
Recurrent auricular inflammation caused by Kimura’s disease: reminiscent of the early phase of relapsing polychondritis?
Authors: Ito Toshiki
Published: September 2019

Recurrent auricular inflammation with pain and swelling is due to the composition and environmental exposures experienced by the constituent parts of the ear. A painful, swollen ear may suggest acute perichondritis, subperichondrial hematoma or relapsing polychondritis (RP). Here, we report a case of a 51-year-old Asian man who had an approximately 2-year history of recurrent auricular swelling and was referred for suspected RP. Biopsy of the lesion revealed the formation of lymphoid follicles with a dense infiltrate of lymphocytes, histiocytes and eosinophils. His serum IgE level was 12 040 U/mL (normal range 0–358). These findings suggest that the patient had Kimura’s disease (KD). Physicians should be aware of KD as a potential cause of recurrent auricular inflammation.
On the Transnational Destruction of Cities: What Japan and the United States Learned from the Bombing of Britain and Germany in the Second World War*
Authors: Garon Sheldon
Published: September 2019

How did it become ‘normal’ to bomb civilians? Focusing on the aerial bombardment of China, Germany, Britain, and Japan in 1937-45, this essay spotlights the role of transnational learning in the construction and destruction of ‘home fronts’. Belligerents vigorously studied each other's strategies to destroy the enemy's cities and ‘morale’, while investigating efforts to defend one's own home front by means of ‘civilian defence’. The inclusion of Japan, as bomber and bombed, contributes to a more global, connected history of the Second World War. Japan's sustained bombardment of Chinese cities not only reflected emerging transnational ideas of strategic bombing and total war, but also imparted new ‘lessons’ to Western air forces. Moreover, the devastating US firebombing of Japanese cities in 1945 challenges widely accepted judgments that bombing was generally ineffective, serving only to stiffen civilian morale. Why Japanese cities were bombed, and how they were bombed, was not an exceptional story, but was intimately connected to what the Allies had learned from bombing European urban areas.
A note on viscous flow induced by half-line sources bounded by conical surfaces
Authors: Rajamanickam Prabakaran , Weiss Adam D
Published: September 2019

In this article, axisymmetric solutions of the Navier–Stokes equations governing the flow induced by a half-line source when the fluid domain is bounded by a conical wall are discussed. Two types of boundary conditions are identified; one in which the radial velocity along the axis is prescribed, and the other in which the radial velocity along the axis is obtained as an eigenvalue of the problem. The existence of these solutions is limited to a range of Reynolds numbers, and the transition from one case to the other is discussed in detail.