bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of endoscopic submucosal dissection for papillary adenocarcinoma-type early gastric cancer
Authors: Park Jae Ho , Kim Ju Seok , Kang Sun Hyung , Moon Hee Seok , Sung Jae Kyu , Jeong Hyun Yong
Published: June 2019

Endoscopic submucosal dissection (ESD) has increasingly been used to treat early gastric cancer (EGC); however, its efficacy in treating papillary adenocarcinoma-type EGC remains unknown.

We sought to identify risk factors for lymph node (LN) metastasis in papillary adenocarcinoma-type EGC and evaluate the clinical outcome after ESD.

This study retrospectively reviewed the medical records of patients who were diagnosed with EGC in our hospital from January 2009 to December 2016. In total, 85 patients had papillary adenocarcinoma-type EGC, of whom 52 and 33 underwent surgical treatment and ESD, respectively. This study analyzed the LN metastasis risk factors and clinical outcomes between these 2 groups and with those of an existing ESD indication group.

LN metastasis occurred in 13 (25.0%) of 52 patients who underwent surgery. Multivariate analysis indicated that lymphovascular invasion was an independent risk factor (odds ratio: 20.624; 95% confidence interval: 19.628–21.497; P = .001). Of 33 patients who underwent ESD, 21 (63.6%) had an absolute indication and 12 (36.4%) had an expanded indication. All 3 (9.1%) patients with non-curative resection underwent additional surgery. The clinical outcomes were compared to those of 926 patients who underwent ESD of non-papillary adenocarcinoma-type EGC. There were no significant differences in curative resection rate (P = .327), procedure-related complication (P = .853), local recurrence (P = 1.000), or overall survival (P = 1.000).

ESD of papillary adenocarcinoma-type EGC showed an acceptable outcome in comparison to an existing ESD indication group. However, these patients exhibit a relatively higher risk of LN metastasis.
Rhinoplasty outcomes and trends
Authors: Ho Osan Y.M. , Ku Peter K.M. , Tong Michael C.F.
Published: June 2019

Purpose of review

This article reviewed studies that support the use of implants for nasal valve surgery and augmentation rhinoplasty.

Recent findings

For nasal valve collapse, there is a trend for rhinoplasty surgeons to use Monarch nasal implant, absorbable valve implant and titanium butterfly implant rather than traditional cartilaginous grafts. For augmentation rhinoplasty, it is still a gold standard to use autologous cartilage. However, alloplastic implants are still very popular for Asian rhinoplasty. A combination of implant materials for augmentation rhinoplasty can improve outcomes while minimizing complications.

Application of implants and newer techniques in nasal valve surgery and augmentation rhinoplasty are important to enhance the outcome in rhinoplasty.
Telemedicine for Interfacility Nurse Handoffs*
Authors: Lieng Monica K. , Siefkes Heather M. , Rosenthal Jennifer L. , Sauers-Ford Hadley S. , Mouzoon Jamie L. , Sigal Ilana S. , Dayal Parul , Chen Shelby T. , McBeth Cheryl L. , Dial Sandie , Dizon Genevieve , Dannewitz Haley E. , Kozycz Kiersten , Jennings-Hill Torryn L. , Martinson Jennifer M. , Huerta Julia K. , Pons Emily A. , Vance Nicole , Warnock Breanna N. , Marcin James P.
Published: June 2019

Objective:

To compare nurse preparedness and quality of patient handoff during interfacility transfers from a pretransfer emergency department to a PICU when conducted over telemedicine versus telephone.

Design:

Cross-sectional nurse survey linked with patient electronic medical record data using multivariable, multilevel analysis.

Setting:

Tertiary PICU within an academic children’s hospital.

Participants:

PICU nurses who received a patient handoff between October 2017 and July 2018.

Interventions:

None.

Main Results and Measurements:

Among 239 eligible transfers, 106 surveys were completed by 55 nurses (44% survey response rate). Telemedicine was used for 30 handoffs (28%), and telephone was used for 76 handoffs (72%). Patients were comparable with respect to age, sex, race, primary spoken language, and insurance, but handoffs conducted over telemedicine involved patients with higher illness severity as measured by the Pediatric Risk of Mortality III score (4.4 vs 1.9; p = 0.05). After adjusting for Pediatric Risk of Mortality III score, survey recall time, and residual clustering by nurse, receiving nurses reported higher preparedness (measured on a five-point adjectival scale) following telemedicine handoffs compared with telephone handoffs (3.4 vs 3.1; p = 0.02). There were no statistically significant differences in both bivariable and multivariable analyses of handoff quality as measured by the Handoff Clinical Evaluation Exercise. Handoffs using telemedicine were associated with increased number of Illness severity, Patient summary, Action list, Situation awareness and contingency planning, Synthesis by receiver components (3.3 vs 2.8; p = 0.04), but this difference was not significant in the adjusted analysis (3.1 vs 2.9; p = 0.55).

Conclusions:

Telemedicine is feasible for nurse-to-nurse handoffs of critically ill patients between pretransfer and receiving facilities and may be associated with increased perceived and objective nurse preparedness upon patient arrival. Additional research is needed to demonstrate that telemedicine during nurse handoffs improves communication, decreases preventable adverse events, and impacts family and provider satisfaction.
Perioperative Assessment of Cerebral Oxygen Metabolism in Infants With Functionally Univentricular Hearts Undergoing the Bidirectional Cavopulmonary Connection
Authors: Neunhoeffer Felix , Michel Jörg , Nehls Wilma , Marx Milena , Mustafi Migdat , Magunia Harry , Schuhmann Martin , Schlensak Christian , Hofbeck Michael
Published: June 2019

Objectives:

The transition from single-ventricle lesions with surgically placed systemic-to-pulmonary artery shunt to the circulation following a bidirectional cavopulmonary connection results in higher pressure in the superior vena cava when compared with the preceding circulation. The aim of this study was to evaluate the impact of this transition on the perioperative cerebral oxygen metabolism.

Design:

Prospective observational cohort study.

Setting:

Pediatric critical care unit of a tertiary referral center.

Patients:

Sixteen infants after bidirectional cavopulmonary connection.

Intervention:

Cardiac surgery (bidirectional cavopulmonary connection).

Measurements and Main Results:

We measured regional cerebral oxygen saturation, amount of hemoglobin, blood flow velocity, and microperfusion immediately before, 12–24 hours, and 36–48 hours following bidirectional cavopulmonary connection. Based on these measurements, we calculated cerebral fractional tissue oxygen extraction and approximated cerebral metabolic rate of oxygen. Mean pressure in the superior vena cava increased significantly (8 vs 17 mm Hg; p < 0.001) following bidirectional cavopulmonary connection. Mean cerebral oxygen saturation increased from 49.0% (27.4–61.0) to 56.9% (39.5–64.0) (p = 0.008), whereas mean cerebral blood flow velocity decreased from 80.0 arbitrary units (61.9–93.0) to 67.3 arbitrary units (59.0–83.3) (p < 0.001). No change was found in the cerebral amount of hemoglobin and in the cerebral microperfusion. Mean cerebral fractional tissue oxygen extraction (0.48 [0.17–0.63] vs 0.30 [0.19–0.56]; p = 0.006) and approximated cerebral metabolic rate of oxygen (5.82 arbitrary units [2.70–8.78] vs 2.27 arbitrary units [1.19–7.35]; p < 0.001) decreased significantly.

Conclusions:

Establishment of bidirectional cavopulmonary connection is associated with postoperative improvement in cerebral oxygen metabolism. Cerebral amount of hemoglobin did not increase, although creation of the bidirectional cavopulmonary connection results in significant elevation in superior vena cava pressure. Improvement in cerebral oxygen metabolism was due to lower cerebral blood flow velocity and stable microperfusion, which may indicate intact cerebral autoregulation.
Short- and Long-Term Outcomes of Extremely Preterm Infants in Japan According to Outborn/Inborn Birth Status*
Authors: Sasaki Yoshihito , Ishikawa Kaoru , Yokoi Akira , Ikeda Tomoaki , Sengoku Kazuo , Kusuda Satoshi , Fujimura Masanori
Published: June 2019

Objectives:

Outborn (born outside tertiary centers) infants, especially extremely preterm infants, are at an increased risk of mortality and morbidity in comparison to inborn (born in tertiary centers) infants. Extremely preterm infants require not only skilled neonatal healthcare providers but also highly specialized equipment and environment surroundings. Maternal transport at an appropriate timing must be done to avoid the delivery of extremely preterm infants in a facility without the necessary capabilities. Cases of unexpected deliveries at birth centers or level I maternity hospitals need to be attended emergently. We compared the differences in short- and long-term outcomes between outborn and inborn infants to improve our regional perinatal system.

Design:

Retrospective cohort study.

Setting:

Neonatal Research Network of Japan database.

Patients:

Extremely preterm infants (gestational age between 22 + 0 and 27 + 6 wk) in the Neonatal Research Network of Japan database between 2003 and 2011.

Interventions:

None.

Measurements and Main Results:

A total of 12,164 extremely preterm infants, who were divided into outborn (n = 785, 6.5%) and inborn (n = 11,379, 93.5%) groups, were analyzed. Significant differences were observed in demographic and clinical factors between the two groups. Outborn infants had higher short-term odds of severe intraventricular hemorrhage (adjusted odds ratio, 1.49; 95% CI, 1.11–2.00; p < 0.01), necrotizing enterocolitis (adjusted odds ratio, 1.49; 95% CI, 1.11–2.00; p < 0.01), and focal intestinal perforation (adjusted odds ratio, 1.58; 95% CI, 1.09–2.30; p = 0.02). There were no significant differences in long-term outcomes between the two groups, except in the rate of cognitive impairment (adjusted odds ratio, 1.49; 95% CI, 1.01–2.20; p = 0.04).

Conclusions:

The frequency of severe intraventricular hemorrhage, necrotizing enterocolitis or focal intestinal perforation, and cognitive impairment was significantly higher in outborn infants. Thus, outborn/inborn birth status may play a role in short- and long-term outcomes of extremely preterm infants. However, more data and evaluation of improvement in the current perinatal environment are needed.
Borderline Personality Disorder in Patients With Medical Illness: A Review of Assessment, Prevalence, and Treatment Options
Authors: Doering Stephan
Published: June 2019

Objective

Borderline personality disorder (BPD) occurs in 0.7% to 3.5% of the general population. Patients with BPD experience excessive comorbidity of psychiatric and somatic diseases and are known to be high users of health care services. Because of a range of challenges related to adverse health behaviors and their interpersonal style, patients with BPD are often regarded as “difficult” to interact with and treat optimally.

Methods

This narrative review focuses on epidemiological studies on BPD and its comorbidity with a specific focus on somatic illness. Empirically validated treatments are summarized, and implementation of specific treatment models is discussed.

Results

The prevalence of BPD among psychiatric inpatients (9%–14%) and outpatients (12%–18%) is high; medical service use is very frequent, annual societal costs vary between €11,000 and €28,000. BPD is associated with cardiovascular diseases and stroke, metabolic disease including diabetes and obesity, gastrointestinal disease, arthritis and chronic pain, venereal diseases, and HIV infection as well as sleep disorders. Psychotherapy is the treatment of choice for BPD. Several manualized treatments for BPD have been empirically validated, including dialectical behavior therapy, transference-focused psychotherapy, mentalization-based therapy, and schema-focused therapy.

Conclusions

Health care could be substantially improved if all medical specialties would be familiar with BPD, its pathology, medical and psychiatric comorbidities, complications, and treatment. In mental health care, several empirically validated treatments that are applicable in a wide range of clinical settings are available.
Externalized Mesentery Monitoring of Vascularized Jejunum Transfers
Authors: Arata Jun , Suzuki Mayu , Marukawa Yudai , Kaito Shuko , Kumakiri Masanori
Published: June 2019

Purpose

The use of externalized jejunal monitoring flaps for jejunum transfers could be facilitative for the direct clinical assessment. Although this monitoring method would seem to be highly reliable, we modified this method and used mesentery only as a monitor to make it easy to manage the monitor more.

Methods

Between 2013 and 2018, 43 patients underwent vascularized jejunum transfer for reconstruction of laryngopharyngectomy using the externalized mesentery monitor. There were 39 men and 4 women, and patient ages ranged from 40 to 80 years (average, 66.6 years). The nursing staff monitored the externalized mesentery by using handheld Doppler ultrasonography every 2 hours for 7 days after surgery.

Results

Three patients had rather weak signal of handheld Doppler ultrasonography on the externalized mesentery monitors during operation, and handheld Doppler ultrasonography could not be applied. Of the remaining 40 patients using the externalized mesentery monitor with handheld Doppler ultrasonography, 39 had an uncomplicated postoperative period. In 1 patient, no signal of Doppler ultrasonography and lack of bleeding by pin prick from the monitor segment were noted in the immediate postoperative period, and revision of the vascular anastomosis was performed. Finally, the graft was salvaged. There was no case of infection in the monitoring flap or hypertrophic scar at the resected part of the flap.

Conclusions

Using the externalized mesentery monitoring flaps, clinical monitoring by examining the exteriorized monitoring flap is possible, and only mesentery monitors were managed easily compared with jejunum monitoring flaps.
Depression Rates After Facial Paralysis
Authors: Saadi Robert , Shokri Tom , Schaefer Eric , Hollenbeak Christopher , Lighthall Jessyka G.
Published: June 2019

Introduction

Facial paralysis (FP) has many functional consequences with a large impact on daily life. Although an association with FP and depression has been observed and described in the literature, there are currently no large-scale studies to further validate this correlation. Our goal was to determine whether patients with FP become depressed at a higher rate compared with matched controls.

Methods

We performed a retrospective cohort study using MarketScan Commercial Claims and Encounters Database by Truven Health. From the database, all inpatient and outpatient claims with International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for FP and depression between 2005 and 2013 were extracted. Patients younger than 18 years were categorized as children and those 18 years or older as adults. Patients were subcategorized as having a history of depression if a diagnosis of depression preceding a diagnosis of FP was noted. We matched each patient to a control in the MarketScan database based on age, sex, and state of residence. We compared rates of depression between these patients and matched controls using conditional logistic regression. The method of Kaplan and Meier was used to estimate cumulative incidence curves of depression by each group.

Results

Approximately 57,941 patients were identified with International Classification of Diseases, Ninth Revision, codes for FP. Among children and adult patients without a diagnosis of depression before the index date for FP, 6.4% (285) and 9.7% (4733), respectively, had a diagnosis of depression within 2 years of the diagnosis of FP. Matched controls showed depression rates within 2 years of 3.9% for children (P < 0.001) and 6.1% for adults (P < 0.001).

Conclusions

The present study adds to the current body of knowledge on FP and depression given its large sample size and analysis of adult and pediatric populations over 2 years. Indeed, we found that depression rates were significantly increased in both adults and children as compared with matched controls. Our results suggest a need for long-term depression screening in patients with FP.
Incidence of Secondary Lip Correction for Children With Unilateral Cleft Lip
Authors: Zhang Zhuo , Miyabe Mai , Morioka Daichi , Nomura Misako , Tosa Yasuyoshi , Ohkubo Fumio , Kadomatsu Koichi
Published: June 2019

Background

Numerous reports have described the incidence of secondary lip correction for patients with cleft lip (CL), and this incidence broadly varies among centers. The purpose of this study was to determine this revision rate for a reasonably large number of patients in our center and identify the clinical factors that contribute to the revision rate.

Methods

A retrospective chart review was conducted for all infants with unilateral CL with or without cleft palate who underwent primary cheiloplasty at our cleft center from 2006 to 2012. Four surgeons were in charge of almost all operations. We investigated how many children underwent lip revisions by the end of 2017.

Results

In total, 490 infants underwent primary lip repair, and 47 underwent revision surgery by the age of 8 years. Half of them (24 children) underwent revisions at the age of 5 or 6 years. There was no significant difference in the revision rate by sex or cleft side. The revision rate in children with CL only tended to be lower than that in children with alveolar cleft or cleft palate, but it was not significantly associated with the cleft type. The revision rate ranged from 2.8% to 15.2% among surgeons.

Conclusions

The overall revision rate was 9.6%, which is relatively lower than that in other cleft centers. However, the repair technique and cleft care program should not be evaluated using the revision rate only. Various factors, including surgeons' preference, contribute to the indications for revision, and these factors can change with age. We plan to follow up the patients until our completion of the cleft care program and report the final revision rate.
Preexpansion in Phalloplasty Patients
Authors: Elfering Lian , van der Sluis Wouter B. , Bouman Mark-Bram , Buncamper Marlon E. , van de Grift Tim C. , Lissenberg-Witte Birgit I. , Middelkoop Esther , Mullender Margriet G.
Published: June 2019

Background

Phalloplasty is performed as genital gender-affirming surgery in transmasculine persons. It requires the harvest of sizeable autologous fasciocutaneous flaps, which is associated with donor-site morbidity and extensive scarring. Flap preexpansion has been used to facilitate wound closure and reduce scarring, but the efficacy of flap preexpansion in phalloplasty is unclear. The objective of this study was to assess the safety and effectiveness of preexpansion before phalloplasty.

Methods

Transmasculine persons who underwent phalloplasty between December 2006 and July 2014 at our institution were identified and invited to participate. A chart review was performed to obtain patient demographics and expander-related complications. Outcomes regarding the donor-site scar (Patient Observer Scar Assessment Scale, scar size, patient satisfaction) were measured at the outpatient clinic and compared between transmasculine persons treated with and transmasculine persons treated without preexpansion.

Results

Of 33 transmasculine persons who underwent phalloplasty, 17 underwent preexpansion. Phalloplasty techniques included the use of the radial forearm free flap, the anterolateral thigh flap, or a combination of both. In total, 34 tissue expanders were placed in the forearm (n = 12) and/or thigh (n = 22). Complications occurred in 18 (52.9%) of 34 tissue expanders and in 13 (76.5%) of 17 transmasculine persons. Seven reoperations were performed because of extrusion (n = 2), infection (n = 2), port failure (n = 2), or leakage (n = 1). Sixteen transmasculine persons visited our clinic for scar assessment (8 with and 8 without preexpansion). Primary closure was achieved in 4 (31%) of 13 expanded donor sites. Relative scar size was reduced when the wound could be closed primarily, but overall scar size, quality, and satisfaction did not differ significantly between groups.

Conclusion

Donor-site expansion before phalloplasty was associated with high rates of expander-related complications and expander failure. Primary closure of the donor site was achieved in less than a third of the cases. Primary closure may potentially lead to smaller scars and greater satisfaction; however, we concluded that the potential advantages of preexpansion do not outweigh the high risk of complications and lack of success.
Cranial Suture Anchor Temporalis Resuspension: A New Technique to Reconstruct Temporal Hollowing After Craniotomy
Authors: Van Kouwenberg Emily , Kotamarti Vasanth , Reinhardt Myrna , Adetayo Oluwaseun A.
Published: June 2019

Introduction:

Proper temporalis resuspension following craniotomy or craniectomy is necessary to prevent significant temporofacial deformity. Several methods of temporalis reconstruction have been described with varying success; currently there are no reports of suture anchor utilization.

Methods:

A patient is presented displaying successful temporalis resuspension using suture anchor fixation. An incision was made in the temporal hair-bearing scalp to access and lengthen the retracted temporalis under direct visualization. Stab incisions were then made in the scalp to expose the superior temporal line, where suture anchors were placed for muscle fixation. After confirming appropriate vectors for muscle resuspension, 1 suture arm was passed through a subgaleal tunnel to capture the temporalis and the other was fixated to the temporoparietal skull. The suture anchors were secured and the incisions were closed in layers.

Results:

A 36-year-old female with history of decompressive craniectomy for hemorrhagic stroke presented with significant temporal hollowing. Her temporalis was retracted with a noticeable defect on frontal view and bulging over the zygomatic arch. The patient underwent temporalis resuspension as described with durable correction resembling her premorbid state. The buried suture anchors were nonpalpable.

Conclusion:

Temporal hollowing after craniotomy is a difficult contour deformity to correct. In the presented patient, reconstruction with temporalis elevation and suture anchor resuspension was found to be an effective technique with excellent cosmetic outcome. The efficiency of suture anchor placement, postoperative maintenance of muscle tension, and nonpalpable profile of the buried suture anchors suggest comparable efficacy to plate fixation and suture-only techniques.
Pterygoid Hamulus Bursitis: A Rare Intra-Oral Pain Syndrome
Authors: Thukral Himanshu , Nagori Shakil Ahmed , Rawat Aditi , Jose Anson
Published: June 2019

Pterygoid hamular bursitis is a rare craniofacial pain syndrome used to describe palatal and pharyngeal pain due to an enlarged pterygoid hamulus. The pterygoid hamulus is a hook-shaped bony process located bilaterally on each medial pterygoid plate of the sphenoid bone, posterior and medial to each maxillary tuberosity. These processes project downward and anterolaterally; serve as attachment for ligaments and a network of muscles. It can be palpated in patients with a finger palpating the posteromedial to maxillary tuberosity. The pathogenesis is elusive and varies from bursitis of tensor veli palatine, elongated pterygoid hamulus, persistent trauma to the mucosa overlying the pterygoid hamulus. The clinical features include strange chronic sensation, burning, swelling, and erythema of the pterygoid hamulus region. The pain often radiates to pharynx, ipsilateral face and sometimes radiating to temporal region making it difficult to diagnose from headache, temporomandibular disorders, and dental infections like pericoronitis. The anatomical neighboring structures in relation to oropharyngeal region may give a misleading diagnosis to dentist in case of pterygoid hamulus bursitis. The understanding of pterygoid hamulus anatomy and its relation to surrounding structures is necessary to get the correct diagnosis of the inflammatory or traumatic pain in oropharyngeal region.
Isolated Actinomycosis of the Hard Palate Incurred Subsequent to Local Anesthesia
Authors: Gurbanov Vugar , Torul Damla
Published: June 2019

Tissue necrosis associated with local anesthesia and actinomycosis is rare. Here, the authors present management of excessive palatal necrosis associated with local anesthesia and actinomycotic infection. In oral surgery a simple procedure can lead to severe complications. Thus, preformation of any surgical procedure with a rigorous manner preferably by a qualified clinician may prevent the occurrence of this type of complications.
Caring for the informal cancer caregiver
Authors: Sun Virginia , Raz Dan J. , Kim Jae Y.
Published: June 2019

Purpose of review

Informal cancer caregivers play a vital role in the physical, functional, and emotional well being of cancer patients. However, the majority of informal caregivers are not prepared for their caregiving role. We reviewed and synthesized the recent literature (last 18 months) and focused on research in the following understudied areas: technology-driven interventions for informal caregivers; informal caregivers of older adults with cancer; interrelationship between informal caregiver and dyadic outcomes; and research priorities and guidelines to improve informal caregiver support.

Recent findings

Studies focused on technology-driven informal caregiver interventions, with evidence of good feasibility and acceptability with benefits for burden and quality of life (QOL). Studies also focused on QOL for caregivers of older adults with cancer. Finally, research priorities and clinical guidelines were established through Delphi survey studies.

Despite the substantial evidence on informal cancer caregiving, more research is needed to further characterize caregivers at high risk for burden, explicate interrelationships between caregiver/patient outcomes, and test innovative and scalable interventions. Studies are also needed to understand the specific needs of informal caregivers in cancer surgery, an understudied treatment population.
Genetic correlates of evolutionary adaptations in cognitive functional brain networks and their relationship to human cognitive functioning and disease
Authors: Wei Yongbin , de Lange Siemon C. , Scholtens Lianne H. , Watanabe Kyoko , Ardesch Dirk Jan , Jansen Philip R. , Savage Jeanne E. , Li Longchuan , Preuss Todd M. , Rilling James K. , Posthuma Danielle , van den Heuvel Martijn P.
Published: June 2019

Cognitive functional networks such as the default-mode network (DMN), frontal-parietal network (FPN), and salience network (SN), are key networks of the human brain. Here, we show that the distinct rapid evolutionary cortical expansion of cognitive networks in the human brain, and most pronounced the DMN, runs parallel with high expression of genes important for human evolution (so-called HAR genes). Comparative gene expression examination then shows that HAR genes are more differentially expressed in cognitive networks in humans compared to the chimpanzee and macaque. Genes with distinct high expression in the DMN display broad involvement in the formation of synapses and dendrites. Next, we performed a genome-wide association analysis on functional MRI data, and show that HAR genes are associated with individual variations in DMN functional connectivity in today’s human population. Finally, gene-set analysis suggests associations of HAR genes with intelligence, social cognition, and mental conditions such as schizophrenia and autism. Taken together, our results indicate that the expansion of higher-order functional networks and their cognitive properties have been an important locus of change in recent human brain evolution.
Unexpectedly High Subclonal Mutational Diversity in Human Colorectal Cancer and Its Significance
Authors: Loeb Lawrence A. , Kohrn Brendan F. , Loubet-Senear Kaitlyn J. , Dunn Yasmin J. , Ahn Eun Hyun , O’Sullivan Jacintha N. , Salk Jesse J. , Bronner Mary P. , Beckman Robert A.
Published: June 2019

Human colorectal cancers (CRC) contain both clonal and subclonal mutations. Clonal mutations are positively selected, present in most cells and drive malignant progression. Subclonal mutations are randomly dispersed throughout the genome; they provide a vast reservoir of mutant cells that can expand, repopulate the tumor and result in the rapid emergence of resistance, as well as being a major contributor to tumor heterogeneity. Here, we apply Duplex Sequencing (DS) methodology to quantify subclonal mutations in CRC tumor with unprecedented depth (104) and accuracy (<10−7). We measured mutation frequencies in genes encoding replicative DNA polymerases and in genes frequently mutated in CRC, and found an unexpectedly high effective mutation rate, 7.1 × 10−7. The curve of subclonal mutation accumulation as a function of sequencing depth, using DNA obtained from five different tumors, is in accord with a neutral model of tumor evolution. We present a new theoretical approach to model neutral evolution independent of the infinite sites assumption (which states that a particular mutation arises only in one tumor cell at any given time). Our analysis indicates that the infinite sites assumption is not applicable once the number of tumor cells exceeds the reciprocal of the mutation rate, a circumstance relevant to even the smallest clinically diagnosable tumor. Our methods allow accurate estimation of the total mutation burden in clinical cancers. Our results indicate that no DNA locus is wild type in every malignant cell within a tumor at the time of diagnosis (probability of all cells wild type = 10−308).

Significance Statement

Cancers evolve many mutations. Clonal mutations are selected early. Subsequent evolution occurs in a branching fashion, possibly without selection (“neutral evolution”). Rarer mutations occur later on smaller branches of the evolutionary tree. Using a DNA sequencing method, duplex sequencing, with unprecedented accuracy and sensitivity, we quantified very rare unique subclonal mutations in diagnostic specimens from five human colorectal cancers. Rarer subclones probe later evolutionary timepoints than previously possible. We confirm neutral evolution at later times and find many more subclonal mutations than expected. A novel theoretical method allowed us to extrapolate further forward in time to diagnosis. At diagnosis, every base in DNA is mutated in at least one cancer cell. In particular any therapy resistance mutation would be present.
High-density lipoprotein characteristics and coronary heart disease: a Mendelian randomization study
Authors: Prats-Uribe Albert , Sayols-Baixeras Sergi , Fernández-Sanlés Alba , Subirana Isaac , Carreras-Torres Robert , Vilahur Gemma , Civeira Fernando , Marrugat Jaume , Fitó Montserrat , Hernáez Álvaro , Elosua Roberto
Published: June 2019

Background

The causal role of high-density lipoproteins (HDL) in coronary artery disease (CAD) has been questioned. Our aim was to analyze whether genetically determined quantitative and qualitative HDL characteristics were independently associated with CAD.

Methods

We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I quantity, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al study,N=24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D,N=184,305). We validated these results by defining our genetic variables in another database (METSIM,N=8,372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits (potential pleiotropy) we used the Multi-trait-based Conditional & Joint analysis.

Results

Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β=0.27 [95%CI=0.19; 0.35]), cholesterol levels in very large HDLs (β=0.29 [95%CI=0.17; 0.40]), and triglyceride content in very large HDLs (β=0.14 [95%CI=0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β=-0.076 [95%CI=-0.10; −0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data. Genetic variants linked to both HDL qualitative traits and CAD risk were located withinLIPC, theAPOE/C1/C4/C2cluster,APOB, PCIF1-PLTP, andTTC39B.

Conclusions

Some HDL characteristics related to size, particle distribution, and triglyceride content are related to CAD risk whilst HDL cholesterol levels are not. This relationship could be mediated by the hepatic lipase; the apolipoproteins E, C-I, and B; the phospholipid transfer protein; and the tetratricopeptide repeat domain protein 39B, which arise as potential therapeutic targets in cardiovascular disease.
A DNA Methylation Fingerprint of Cellular Senescence
Authors: Levine Morgan E. , Leung Diana , Minteer Christopher , Gonzalez John
Published: June 2019

Recent years have witnessed an influx of therapies aimed at targeting the biological aging process. While many hold promise for potentially delaying the simultaneous onset of multiple chronic conditions, a major hurdle in developing interventions to slow human aging is the lack of reliable and valid endpoints from which to evaluate potential candidates. The aim of this study was to develop a biomarker that could serve as a potential endophenotype in evaluation of one of the most promising and exciting aging therapeutics being developed—senolytics. Senolytics are compounds which selectively clear senescent cells by targeting anti-apoptotic pathways. Using DNAm data from fibroblasts and mesenchymal stromal cells (MSC) in culture, we developed a predictor of cellular senescence that related to three distinct senescence inducers (replicative, oncogene induced (OIS), and ionizing radiation (IR)). Our measure, termed DNAmSen, showed expected classification of validation data from embryonic stem cells (ESC), induced pluripotent stem cells (iPSC), and near senescent cells in culture. Further, using bulk data from whole blood, peripheral tissue samples, and postmortem tissue, we observed robust correlations between age and DNAmSen. We also observed age adjusted associations between DNAmSen and idiopathic pulmonary fibrosis (IPS), COPD, lung cancer, and Werner syndrome compared to controls. When characterizing the 88 CpGs in the DNAmSen measure, we observed a enrichment for those located in enhancer regions and regulatory regions marked by DNase I hypersensitive sites (DHSs). Interestingly most of the CpGs were observed to be moderately hypomethyled in early passage cells, yet exhibited further hypomethylation upon induction of cellular senescence, suggesting senescence is accompanied by programmatic alterations to the epigenome, rather than entropic drift.
Estimation of the force of infection and infectious period of skin sores in remote Australian communities using interval-censored data
Authors: Lydeamore Michael J. , Campbell Patricia T. , Price David J. , Wu Yue , Marcato Adrian J. , Cuningham Will , Carapetis Jonathan R. , Andrews Ross M. , McDonald Malcolm I. , McVernon Jodie , Tong Steven Y. C. , McCaw James M.
Published: June 2019

Prevalence of impetigo (skin sores) remains high in remote Australian Aboriginal communities, Fiji, and other areas of socio-economic disadvantage. Skin sore infections, driven primarily in these settings by Group AStreptococcus(GAS) contribute substantially to the disease burden in these areas. Despite this, estimates for the force of infection, infectious period and basic reproductive ratio — all necessary for the construction of dynamic transmission models — have not been obtained. By utilising three datasets each containing longitudinal infection information on individuals, we estimate each of these epidemiologically important parameters. With an eye to future study design, we also quantify the optimal sampling intervals for obtaining information about these parameters. We verify the estimation method through a simulation estimation study, and test each dataset to ensure suitability to the estimation method. We find that the force of infection differs by population prevalence, and the infectious period is estimated to be between 12 and 20 days. We also find that optimal sampling interval depends on setting, with an optimal sampling interval between 9 and 11 days in a high prevalence setting, and 21 and 27 days for a lower prevalence setting. These estimates unlock future model-based investigations on the transmission dynamics of GAS and skin sores.
Does Sex Modify an Association of Electrophysiological Substrate with Sudden Cardiac Death? The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Howell Stacey J. , German David , Bender Aron , Phan Francis , Mukundan Srini V. , Perez-Alday Erick A. , Rogovoy Nichole M. , Haq Kazi , Yang Katherine , Wirth Ashley , Jensen Kelly , Tereshchenko Larisa G.
Published: June 2019

Background

Sex is a well-recognized risk factor for sudden cardiac death (SCD). Sex differences in electrophysiological (EP) substrate of SCD are known. However, it remains unknown whether sex can modify an association of EP substrate with SCD.

Methods

Participants from the Atherosclerosis Risk in Communities study with analyzable ECGs (n=14,725; age, 54.2±5.8 yrs; 55% female, 74% white) were included. EP substrate was characterized by traditional 12-lead ECG (heart rate, QRS, QTc, Cornell voltage), spatial ventricular gradient (SVG) and sum absolute QRST integral (SAI QRST) metrics. Two competing outcomes were adjudicated SCD and nonSCD. Interaction of ECG metrics with sex was studied in Cox proportional hazards and Fine-Gray competing risk models. Relative hazard ratio (RHR) and relative sub-hazard ratio (RSHR) with a 95% confidence interval for SCD and nonSCD risk for women relative to men were calculated. Model 1 was adjusted for prevalent cardiovascular disease (CVD) and risk factors. Time-updated model 2 was additionally adjusted for incident non-fatal CVD.

Results

Over a median follow-up of 24.4 years, there were 530 SCDs (incidence 1.72 (1.58-1.88)/1000 person-years) and 2,178 nonSCDs (incidence 7.09; (6.80-7.39)/ 1000 person-years). Women experienced a greater than men risk of SCD associated with Cornell voltage (RHR 1.18(1.06-1.32); P=0.003), SAI QRST (RHR 1.16(1.04-1.30); P=0.007), area SVG magnitude (RHR 1.24(1.05-1.45); P=0.009), and peak SVG magnitude (RHR 1.22(1.04-1.44); P=0.018), independently from incident CVD. Greater risk of SCD for women than men associated with QRS duration (RHR 1.24(1.07-1.44); P=0.004) and QTc (RSHR 1.15(1.02-1.30); P=0.025) was explained by incident CVD. Furthermore, women had greater odds of SCD associated with heart rate (RSHR 1.19(1.01-1.40); P=0.036), independently of incident CVD.

Conclusions

Sex modifies an association of EP substrate with SCD. In women, global EP substrate is associated with up to 27% greater risk of SCD than in men. Development of sex-specific risk scores of SCD is necessary. Further studies of mechanisms behind sex differences in EP substrate of SCD are warranted.
Efficacy and safety of a novel vaginal medical device in recurrent bacterial vaginosis: an international multicentre clinical trial
Authors: Murina Filippo , Crişan Ciprian , Biriş Marius , Sîrbu Daniela , Barattini Dionisio Franco , Ardolino Luca Ivan , Casolati Elena
Published: June 2019

Several risk factors have been identified but the etiology and pathogenesis of Bacterial vaginosis (BV) are still not completely understood, and the recurrence rate of BV remains high despite adequate chemotherapy treatment.

The primary objective of the study was to assess the effectiveness of a new vaginal medical device, which contains polycarbophil, 0.04 % lauryl glucoside, and glycerides (Polybactum®– Effik Italia), in reducing BV recurrence rate.

This was a multicenter, open label, not comparative study performed in Italy and Romania. Female subjects over 18-years-old affected by recurrent BV were included. The latest episode was diagnosed by Amsel criteria 6-9 days before the start of the study and treated with vaginal metronidazole (gel 0.75% mg for 5 days or ovules 500 mg for 7 days). The recurrence was defined by at least 2 episodes in the previous 12 months. Polybactum®vaginal ovules, day 1-4-7, were started within the 12th and the 24th hr after the end of metronidazole therapy and repeated monthly for 3 cycles.

The first 41 patients enrolled were evaluated for an interim analysis 6 months after the study started; 2 patients interrupted the trial, leaving 39 evaluable subjects. The recurrence rate was significantly reduced compared to previous published data (10.26% vs 40% p<0.001). In 35 patients without recurrence, the assessment of Lactobacillus vaginal flora performed by phase contrast microscopy evidenced a significant improvement form baseline (p=0.022) The Investigator global assessment of tolerability was excellent in 38 out of 39 cases.

IMPORTANCE

Bacterial vaginosis (BV) is the most common vaginal disorder in women of childbearing age. In BV, Lactobacillus species, which are predominant in a healthy vaginal flora, are replaced by anaerobes, mainly Gardnerella vaginalis. BV is responsible for more than 60% of vulvovaginal infections and has been linked to serious, potentially life-threatening conditions, including: pelvic inflammatory disease, postoperative infections, acquisition and transmission of the human immunodeficiency virus, preterm birth, and several adverse pregnancy outcomes. Our research showed that 3 monthly cycles of Polybactum®ovules administered after one course of metronidazole vaginal therapy can reduce the rate of Bacterial vaginosis recurrence and improve the vaginal milieu, favouring the growth of vaginal lactobacillus species. Taken together our results confirm that Polibactum®is a safe and effective treatment to reduce BV recurrence rate after a first line therapy with metronidazole.
Serum level of High-density lipoprotein particles are independently associated with long-term prognosis in patients with coronary artery disease: The GENES study
Authors: Duparc Thibaut , Ruidavets Jean-Bernard , Genoux Annelise , Ingueneau Cécile , Najib Souad , Ferrieres Jean , Perret Bertrand , Martinez Laurent O.
Published: June 2019

BACKGROUND

HDL-Cholesterol (HDL-C) is not an accurate surrogate marker to measure the cardioprotective functions of HDL in coronary artery diseases (CAD) patients. Hence, measurement of other HDL-related parameters may have prognostic superiority over HDL-C.

OBJECTIVE

This work aimed to examine the predictive value of HDL particles profile for long-term mortality in CAD patients. Its informative value was compared to that of HDL-C and apoA-I.

METHODS

HDL particles profile were measured by nuclear magnetic resonance (NMR) spectroscopy in 214 male participants with stable CAD (45-74 years). Median follow up was 12.5 years with a 36.4% mortality rate. Cardiovascular mortality accounted for 64.5 %.

RESULTS

Mean concentrations of total HDL particles (HDL-P), small-sized HDL (SHDL-P) and apoA-I were lower in deceased than in surviving patients whereas no difference was observed according to HDL-C and large HDL particles. All NMR-HDL measures were correlated between themselves and with other HDL markers (HDL-C, apoA-I and LpA-I). In a multivariate model adjusted for 14 cardiovascular risk factors and bioclinical variables, HDL-P and SHDL-P displayed the strongest inverse association with all-cause and cardiovascular mortality. Weaker associations were recorded for apoA-I.

CONCLUSION

HDL particle profile measured by NMR spectroscopy should be considered to better stratify risk in population at high risk or in the setting of pharmacotherapy.
Using machine learning to predict quantitative phenotypes from protein and nucleic acid sequences
Authors: Sauer David B. , Wang Da-Neng
Published: June 2019

Background

The link between protein or nucleic acid sequence and biochemical or organismal phenotype is essential for understanding the molecular mechanisms of evolution, reverse ecology, and designing proteins and genes with specific properties. However, it is difficult to practically make use of the relationship between sequence and phenotype due to the complex relationship between sequence and folding or activity.

Results

Here, we predict the originating species’ optimal growth temperatures of individual protein sequences using trained machine learning models. Both multilayer perceptron and k Nearest Neighbor regression outperformed linear regression could predict the originating species’ optimal growth temperature from protein sequences, achieving a root mean squared error of 3.6 °C. Similar machine learning models could predict organismal optimal growth pH and oxygen tolerance, and the quantitative properties of individual proteins or nucleic acids.

Conclusions

Using multilayer perceptron and k Nearest Neighbor regressions, we were able to build models specific to individual protein or nucleic acid families that can predict a variety of quantitative phenotypes. This methodology will be useful thein silicoscreening of individual mutations for particular properties, and also effective in the predicting the phenotypes of uncharacterized biological sequences and organisms.
Regulation of community functional composition across taxonomic variation by resource-consumer dynamics
Authors: Worden Lee
Published: June 2019

High-throughput sequencing techniques such as metagenomic and metatranscriptomic technologies allow cataloging of functional characteristics of microbial community members as well as their taxonomic identity. Such studies have found that a community’s composition in terms of ecologically relevant functional traits or guilds can be conserved more strictly across varying settings than taxonomic composition is. I use a standard ecological resource-consumer model to examine the dynamics of traits relevant to resource consumption, and analyze determinants of functional composition. This model demonstrates that interaction with essential resources can regulate the community-wide abundance of ecologically relevant traits, keeping them at consistent levels despite large changes in the abundances of the species housing those traits in response to changes in the environment, and across variation between communities in species composition. Functional composition is shown to be able to track differences in environmental conditions faithfully across differences in community composition. Mathematical conditions on consumers’ vital rates and functional responses sufficient to produce conservation of functional community structure across taxonomic differences are presented.