bluuebunny/crossref_metadata_2025 huggingface dataset:
Photometric Evaluation of Long-term Changes in Breast Shape after Breast Augmentation and Vertical Mammaplasty
Authors: Swanson Eric
Published: June 2018

Background:

Little information is presently available regarding the long-term effects of breast augmentation and mammaplasties on breast shape. Existing studies typically use 1-dimensional measurements and mean follow-up times seldom exceed 1 year.

Methods:

Twenty women were studied: breast augmentation (n = 5), mastopexy (n = 5), augmentation/mastopexy (n = 5), and breast reduction (n = 5). For mammaplasties, a vertical method using a medial pedicle and intraoperative nipple siting was used in all cases. A 2-dimensional measurement system was used, with computer-assisted matching of lateral photographs of the right and left breasts. Measurements were evaluated at 3 times: before surgery, 1 year after surgery, and 10 years after surgery.

Results:

Breast implants significantly increased breast projection and upper pole projection. The nipple level was unchanged. The lower pole level dropped. These changes were preserved at 10 years. Vertical mastopexy provided a modest increment in breast projection and upper pole projection. The nipple level and lower pole level were raised significantly. Augmentation/mastopexy boosted breast projection and upper pole projection, and also elevated the nipple and lower pole level. Breast reduction changes were similar to mastopexy, but with greater elevation of nipple level and lower pole level, which were usually lower to start with. Implants increased upper pole convexity. Nipple overelevation was avoided by intraoperative nipple siting just below the breast apex.

Conclusions:

These measurements provide new information regarding the long-term effects of breast augmentation and vertical mammaplasties. This information may be used by plastic surgeons in procedure selection and patient counseling.
Improved Outcomes for Transscleral Cyclophotocoagulation Through Optimized Treatment Parameters
Authors: Quigley Harry A.
Published: June 2018

Purpose:

To compare outcomes of transscleral diode cyclophotocoagulation with the treatment parameters used.

Patients and Methods:

This was a retrospective chart review of a random, 50% sample of diode procedures using the G-probe over 10 years for uncontrolled glaucoma. The main outcome measure was intraocular pressure (IOP) reduction by 20% and final IOP≤21 mm Hg.

Results:

In 236 eyes (persons) treated by 5 glaucoma specialists, most eyes had severe glaucoma, with 75% having <20/200 acuity. Median follow-up was 2.7 years. In eyes receiving only 1 treatment, IOP success criterion was met in 72% (129/180). Success was significantly related to power per delivery and median total joules per treatment (successes=135 J, failures=98 J; P=0.0009), but not to number of deliveries, nor to extent of circumference treated. Greater success was associated with 3 or 4 second duration per delivery, power level based on audible cues, and firm pressure on the sclera. Using a standard 2000 mW, 2 seconds, 20 deliveries in each eye had the lowest success (49%). Of those with no preoperative pain, 40 persons (57%) had no postoperative pain, whereas 20 reported pain of 1-3/10 (29%). Phthisis occurred in 7 eyes (3%), 5 of which had severe secondary eye disease. Nine eyes had no light perception preoperatively, whereas 50 eyes were no light perception at last follow-up, many after additional surgeries for other conditions.

Conclusions:

Diode cyclophotocoagulation achieved reasonable IOP lowering, often without severe postoperative pain or complication. Greater success was achieved when audible effects were used to tailor the power settings to individual responses. Diode treatments with no intraoperative effect adjustment or using standardized protocols may not achieve optimal success.
Four Questions for Every Clinician Diagnosing and Monitoring Glaucoma
Authors: Hood Donald C. , De Moraes Carlos G.
Published: June 2018

We pose 4 questions for the clinician diagnosing and monitoring glaucoma, and supply evidence-based answers. The first question is: “When do you perform a 10-2 (2-degree grid) visual field (VF) test?” We argue the best answer is: anyone you would do, or have done, a 24-2 (6-degree grid) VF on should have both a 24-2 and a 10-2 VF within the first 2 visits. Second, “When do you perform an optical coherence tomography (OCT) scan of the macula?” We argue that, if you are performing an OCT test, then it should include both the macula and disc, either as a single scan or as 2 scans, one centered on the macula and the other on the disc. Third, “How do you know if the VF and OCT tests agree?” The poor answer is, “I use summary statistics such as 24-2 mean deviation and global or quadrant average of retinal nerve fiber layer (RNFL) thickness.” It is much better to topographically compare abnormal regions on the OCT to abnormal regions on the VF. Finally, the fourth question is: “When do you look at OCT images?” We argue that, at a minimum, the clinician should be directly examining an image of the circumpapillary RNFL, and this image should be sufficiently large and with sufficient resolution so that local damage can be seen, and the segmentation evaluated.
Building a Framework for Community Health Worker Skills Proficiency Assessment to Support Ongoing Professional Development
Authors: Allen Caitlin G. , Brownstein J. Nell , Cole Maria , Hirsch Gail , Williamson Susie , Rosenthal E. Lee
Published: June 2018

Although community health workers (CHWs) continue to gain credibility and recognition in the health care and public health sectors, there is still a need to expand workforce identity and development efforts, including identifying best practices for assessing CHW skill proficiencies. During this qualitative study, we interviewed 32 CHWs, trainers, and supervisors to understand current practice, perspectives, and perceived importance in assessing CHW skills and guiding principles for CHW skill assessment. Results from these interviews can be used to inform CHW workforce development to enhance efforts among those who are actively building CHW programs or who are considering improvements in strategies to assess CHW skill proficiencies.
Lessons Learned From Safety Engineering Case Studies Applied to Medical Devices
Authors: Block Frank E. , Kuo Jonathan Y.
Published: June 2018

Lessons learned from evaluating previous failures are crucial when engineering future products. As engineered products increase in complexity, their failure modes also increase. In this article, we examine several safety engineering case studies as they relate to medical devices and discuss how these lessons learned could be applied to future medical device design. Ultimately, through detailed reporting and thorough discussions of engineering mishaps, product safety can be improved.
Investigating Repeat Service Calls
Authors: Hyman William A.
Published: June 2018

Service on demand (repair) is a regular part of medical equipment maintenance. Repair can be approached as a 1-time situation of finding the problem and fixing it, or it can be approached as an integral part of keeping the medical device environment in full functioning condition at managed cost. The latter requires an organized commitment to not only repair but also determine why repair was needed and what if anything could be done to reduce subsequent failures. This is particularly the case for repeat service calls over an unexpectedly short period.
Pancreas transplantation in type 2 diabetes: expanding the criteria
Authors: Al-Qaoud Talal M. , Odorico Jon S. , Redfield Robert R.
Published: June 2018

Purpose of review

Pancreas transplantation in type 2 diabetes mellitus (T2DM) candidates remains disproportionately lower than in type 1 diabetes mellitus (T1DM); however, outcomes in carefully selected patients mirrors that of T1DM. Despite the 2014 United Network for Organ Sharing (UNOS) eligibility criteria for simultaneous pancreas/kidney transplant (SPK) transplantation in T2DM patients, an expected increase in the number of transplants was not observed.

Recent findings

In an updated International Pancreas and Transplant Registry (IPTR) analysis, 1514 primary deceased donor pancreas transplants were performed in T2DM recipients [1995–2015, SPK 88%, pancreas after kidney (PAK) 9%, pancreas transplant alone (PTA) 3%]. In contrast to the declining number of SPK transplants for T1DM, the number of primary SPK transplants in T2DM patients is increasing over time in the USA. Improvement over time was noted for T2DM SPK patient and graft survival, and the rate of technical failures decreased, paralleling similar overall trends for pancreas transplants in general. Long-term follow-up data of pancreas outcomes in C-peptide positive vs. negative demonstrate noninferior outcomes. BMI does not appear to impact outcomes in carefully selected T2DM candidates.

The current UNOS regulations that currently limit access of T2DM to pancreas transplantation based on strict BMI criteria and C-peptide levels need to be liberated.
Bioimpedance Spectroscopy Imprecisely Assesses Lean Body Mass in Pediatric Dialysis Patients
Authors: Milani Gregorio P. , Groothoff Jaap W. , Vianello Federica A. , Fossali Emilio F. , Paglialonga Fabio , Consolo Sivia , Edefonti Alberto , Consonni Dario , van Harskamp Dewi , van Goudoever Johannes B. , Schierbeek Henk , Agostoni Carlo , Oosterveld Michiel J.S.
Published: June 2018

Objectives:

Alterations in body compositions are strongly associated with poor outcomes in end‐stage renal disease patients. Hence, assessment of lean body mass is crucial for clinically monitoring these patients. The use of multifrequency bioimpedance spectroscopy measurements has also been advocated, but their usefulness in children is questioned. We investigated whether their application is appropriate for lean body mass measurement in pediatric patients receiving chronic dialysis.

Methods:

Lean body mass estimates as assessed by multifrequency bioimpedance spectroscopy and by deuterium dilution were obtained for 15 patients (mean age 10.9 ± 3.6 years).

Results:

Lean body mass (mean ± standard deviation) determined by bioimpedance was 24.2 ± 10.7 and 24.4 ± 10.3 kg by deuterium technique. Bland‐Altman analysis showed a mean (±standard deviation) difference between the 2 methods of −0.25 ± 2.30 kg with 95% limits of agreement of −4.80 to 4.25 kg. In a multiple linear regression model, the hydration status was associated with measurement bias after adjusting for age, sex, weight, and body surface area.

Conclusions:

Our results show a high level of agreement between measurements by bioimpedance and deuterium technique, but the limits of agreement were wide. These findings do not support the use of bioimpedance to individually assess lean body mass in pediatric dialysis patients with and without overhydration.
Obesity Does Not Affect Early Outcomes in Children With Newly Diagnosed Crohn Disease
Authors: Jain Animesh , Bricker Josh , Kappelman Michael D. , Dotson Jennifer L.
Published: June 2018

The impact of obesity on pediatric Crohn disease (CD) remains poorly characterized. We aimed to evaluate disease‐related outcomes in overweight and obese children with CD, compared to normal‐weight children. We conducted a retrospective cohort study of children with newly diagnosed CD enrolled in the ImproveCareNow Network. Patients were stratified into normal weight, overweight, and obese groups using standardized weight percentiles. A total of 898 children were included, with 87 children (10%) being overweight and 43 children (5%) being obese; baseline characteristics were similar between groups. There was no significant difference in number of visits in remission during 1 year between normal weight, overweight, and obese children. At 1‐year follow‐up, nutritional status, growth status, or medication use also did not differ between groups. Hence, obesity does not appear to adversely affect CD outcomes in children with newly diagnosed CD in the first year after diagnosis.
Hemodynamic Tolerance to IV Clonidine Infusion in the PICU*
Authors: Kleiber Niina , van Rosmalen Joost , Tibboel Dick , de Wildt Saskia N.
Published: June 2018

Objectives:

Clonidine is an antihypertensive drug used for analgosedation in the PICU. Lack of reliable data on its hemodynamic tolerance limits its use. This study explores the hemodynamic tolerance of IV clonidine infusion in a broad population of children with high severity of disease.

Design:

Retrospective analysis of prospectively collected data.

Setting:

A tertiary and quaternary referral PICU.

Patients:

Critically ill children age 0–18 years old who received an IV clonidine infusion for analgosedation of at least 1 hour.

Interventions:

None.

Measurements and Main Results:

The primary endpoints were the prevalences of bradycardia and hypotension. Secondary endpoints were changes in heart rate, blood pressure, Vasoactive-Inotropic Score, COMFORT Behavior score (a sedation scoring scale), and body temperature during the infusion. The association of bradycardia with other hemodynamic variables was explored, as well as potential risk factors for severe bradycardia. One-hundred eighty-six children (median age, 12.9 mo [interquartile range, 3.5–60.6 mo]) receiving a maximum median clonidine infusion of 0.7 µg/kg/hr (interquartile range, 0.3–1.5) were included. Severe bradycardia and systolic hypotension occurred in 72 patients (40.2%) and 105 patients (58%), respectively. Clonidine-associated bradycardia was hemodynamically well tolerated, as it was not related with hypotension and the need for vasoactive drugs decreased in parallel with a sedation score guided clonidine infusion rate increase. Younger age was the only identified risk factor for clonidine-associated bradycardia.

Conclusions:

Although administration of clonidine is often associated with bradycardia and hypotension, these complications do not seem clinically significant in a mixed PICU population with a high degree of disease severity. Clonidine may have a vasoactive-inotropic sparing effect.
Ruptured Thoracic and Abdominal Gastrointestinal Duplication Cysts Presenting With Failure to Thrive
Authors: Shinnick Julia K. , Jain Shabnam , Alazraki Adina L. , Durham Megan M.
Published: June 2018

Gastrointestinal duplication cysts are rare congenital malformations, with esophageal and gastric duplication cysts being among the rarest. We report an 8-week-old female who presented to the emergency department with failure to thrive and was subsequently found to have multiple gastric and esophageal duplication cysts that had ruptured intrathoracically and intra-abdominally. We describe the diagnosis and management of this patient who underwent successful resection of 4 gastrointestinal duplication cysts. This report emphasizes the unexpected, and sometimes relatively benign, presentations of gastrointestinal duplication cysts. To our knowledge, this is the first reported occurrence of multiple duplication cysts that independently ruptured thoracically and abdominally.
Perceived Partner Responsiveness, Daily Negative Affect Reactivity, and All-Cause Mortality: A 20-Year Longitudinal Study
Authors: Stanton Sarah C.E. , Selcuk Emre , Farrell Allison K. , Slatcher Richard B. , Ong Anthony D.
Published: June 2018

Objective

This study tested longitudinal associations between absolute levels of perceived partner responsiveness (PPR; how much people perceive that their romantic partners understand, care for, and appreciate them), daily negative affect reactivity and positive affect reactivity, and all-cause mortality in a sample of 1,208 adults for three waves of data collection spanning 20 years. We also tested whether longitudinal changes in PPR predicted mortality via affect reactivity.

Methods

Data were taken from the National Survey of Midlife Development in the United States. PPR was assessed at waves 1 and 2, affect reactivity to stressors was assessed by daily diary reports at wave 2, and mortality status was obtained at wave 3.

Results

Mediation analyses revealed absolute levels of PPR at wave 1 predicted wave 3 mortality via wave 2 affective reactivity in the predicted direction, but this did not remain robust when statistically accounting for covariates (e.g., marital risk, neuroticism), β = .004, 95% confidence interval = −.03 to .04. However, wave 1–2 PPR change predicted negative affect (but not positive affect) reactivity to daily stressors at wave 2, which then predicted mortality risk a decade later (wave 3); these results held when adjusting for relevant demographic, health, and psychosocial covariates, β = −.04, 95% confidence interval = −.09 to −.002.

Conclusions

These findings are among the first to provide direct evidence of psychological mechanisms underlying the links between intimate relationships and mortality and have implications for research aiming to develop interventions that increase or maintain responsiveness in relationships over time.
Attrition Across the HIV Cascade of Care Among a Diverse Cohort of Women Living With HIV in Canada
Authors: Kerkerian Geneviève , Kestler Mary , Carter Allison , Wang Lu , Kronfli Nadine , Sereda Paul , Roth Eric , Milloy M-J , Pick Neora , Money Deborah , Webster Kath , Hogg Robert S. , de Pokomandy Alexandra , Loutfy Mona , Kaida Angela ,   on behalf of the CHIWOS Research Team
Published: June 2018

Background:

In North America, women have lower engagement across the HIV cascade of care compared with men. Among women living with HIV (WLWH) in Canada, we measured the prevalence and correlates of attrition across cascade stages overall, and by key subpopulations.

Methods:

We analyzed baseline survey data regarding 6 nested stages of the HIV cascade among 1424 WLWH enrolled in the Canadian HIV Sexual and Reproductive Health Cohort Study (CHIWOS), including: linked to care, retained in care, initiated antiretroviral therapy (ART), current ART use, ART adherence (≥90%), and viral suppression (<50 copies/mL). Logistic regression identified factors associated with attrition at each stage.

Results:

Overall, 98% of WLWH were linked to care; 96% retained; 88% initiated ART; 83% were currently on ART; and, among those on ART, 68% were adherent and 72% were virally suppressed, with substantial variability by subpopulation (49%–84%).

The largest attrition occurred between current ART use and adherence (−17%), with the greatest losses among indigenous women (−25%), women who use illicit drugs (−32%), and women incarcerated in the past year (−45%). Substantial attrition also occurred between linkage to care and ART initiation (−11%), with the greatest losses among women 16–29 years (−20%) and with unstable housing (−27%). Factors independently associated with attrition at viral suppression included household annual income, racial discrimination, incarceration history, age, and resilience.

Conclusions:

Overall, 28% of WLWH were lost across the HIV care cascade, with significant differences by stage, subpopulation, and social inequities. Targeted interventions are needed to improve women's retention across the cascade.
Somatostatin Receptor PET/CT Features of Carcinoid Heart Disease
Authors: Arora Saurabh , Passah Averilicia , Damle Nishikant A. , Narang Rajiv , Sharma Atul , Yadav Madhav P. , Ballal Sanjana , Bhasin Dinkar , Bal Chandrasekhar
Published: June 2018

We present the case of a 35-year-old woman with metastatic neuroendocrine tumor undergoing treatment with long-acting octreotide and 177Lu-DOTATATE therapy. We present features of carcinoid heart disease on 68Ga-DOTANOC PET/CT, which revealed dilated right atrium, pericardial effusion, ascites, and congestive hepatopathy apart from the metastatic lesions in the liver. The scan cardiac findings were confirmed by echocardiography. This highlights the significance of identifying such patients early because additional management is required for carcinoid heart disease per se and a cautious approach is needed in administering amino acid infusion during PRRT that can result in fluid overload.
Imaging of Chemokine Receptor CXCR4 in Mycosis Fungoides Using 68Ga-Pentixafor PET/CT
Authors: Kuyumcu Serkan , Yilmaz Ebru , Büyükkaya Fikret , Özkan Zeynep Gözde , Ünal Seher Nilgün
Published: June 2018

A 52-year-old woman diagnosed with mycosis fungoides was referred for 18F-FDG PET/CT before treatment for the evaluation of disease severity. The patient also underwent 68Ga-pentixafor PET/CT for further evaluation. FDG uptake was observed in cervical, axillary, and pelvic lymph nodes and multiple widespread skin lesions throughout the body, suggestive of extensive involvement of mycosis fungoides. All lesions were visually identifiable with high target-to-background ratio on 68Ga-pentixafor PET/CT which demonstrated marked CXCR4 expression in all lesions that were detected using 18F-FDG PET/CT.
Modified Lefort Distraction Osteogenesis for the Treatment of Nager Syndrome-Associated Midface Hypoplasia: Technique and Review
Authors: Simpson Andrew M. , Mehta Sagar T. , Siddiqi Faizi , Yamashiro Duane , Gociman Barbu
Published: June 2018

The surgical management of midface hypoplasia in the setting of Nager syndrome remains a significant challenge for craniofacial surgeons. This study describes a novel technique using distraction osteogenesis and modified osteotomies for the treatment of midface bony defects in an 11-year-old child with Nager syndrome.

Presurgical 3-dimensional planning was performed to design the osteotomies and placement of distractors. The surgical approach required upper buccal sulcus and extended transconjunctival incisions only. Osteotomies were performed from the pyriform aperture through the orbit to include the lateral orbital wall, with bilateral osteotomy of the zygomas through the anterior arch via the transconjunctival incision. Distraction of the en bloc midface segment was successfully performed using external distractors. Bone grafting was not required. There were no complications.

External distraction was well tolerated and there were no intraoperative or postoperative complications. The distractors were removed uneventfully after consolidation. The midface was successfully advanced without the need for bone grafting or bicoronal incision. The occlusal plane was leveled and the aesthetic appearance of the child was improved.

Symmetrical midface hypoplasia in the context of Nager syndrome can be successfully corrected with en bloc distraction osteogenesis of the maxilla and bilateral zygomas through modified osteotomies that exclude the upper nasal pyramid. The approach is simplified and the need for bicoronal incision and bone grafting is mitigated in this technique, which the authors have named Lefort 2.5.
Positive airway pressure devices for the management of breathlessness
Authors: D’Cruz Rebecca F. , Kaltsakas Georgios , Suh Eui-Sik , Murphy Patrick B. , Hart Nicholas
Published: June 2018

Purpose of review

Breathlessness is a common symptom in many chronic diseases and may be refractory to pharmacotherapy. In this review, we discuss the pathophysiology of breathlessness and the role of positive airway pressure (PAP) devices to ameliorate it.

Recent findings

Breathlessness is directly related to neural respiratory drive, which can be modified by addressing the imbalance between respiratory muscle load and capacity. Noninvasive PAP devices have been applied to patients limited by exertional breathless and, as the disease progresses, breathlessness at rest. The application of PAP is focussed on addressing the imbalance in load and capacity, aiming to reduce neural respiratory drive and breathlessness. Indeed, noninvasive bi-level PAP devices have been employed to enhance exercise capacity by enhancing pulmonary mechanics and reduce neural drive in chronic obstructive pulmonary disease (COPD) patients, and reduce breathlessness for patients with progressive neuromuscular disease (NMD) by enhancing respiratory muscle capacity. Novel continuous PAP devices have been used to maintain central airways patency in patients with excessive dynamic airway collapse (EDAC) and target expiratory flow limitation in severe COPD.

PAP devices can reduce exertional and resting breathlessness by reducing the load on the system and enhancing capacity to reduce neural respiratory drive.
ClermonTyping: an easy-to-use and accurate in silico method for Escherichia genus strain phylotyping
Authors: Beghain Johann , Bridier-Nahmias Antoine , Le Nagard Hervé , Denamur Erick , Clermont Olivier
Published: June 2018

The genus Escherichia is composed of Escherichia albertii, E. fergusonii, five cryptic Escherichia clades and E. coli sensu stricto. Furthermore, the E. coli species can be divided into seven main phylogroups termed A, B1, B2, C, D, E and F. As specific lifestyles and/or hosts can be attributed to these species/phylogroups, their identification is meaningful for epidemiological studies. Classical phenotypic tests fail to identify non-sensu stricto E. coli as well as phylogroups. Clermont and colleagues have developed PCR assays that allow the identification of most of these species/phylogroups, the triplex/quadruplex PCR for E. coli phylogroup determination being the most popular. With the growing availability of whole genome sequences, we have developed the ClermonTyping method and its associated web-interface, the ClermonTyper, that allows a given strain sequence to be assigned to E. albertii, E. fergusonii, Escherichia clades I–V, E. coli sensu stricto as well as to the seven main E. coli phylogroups. The ClermonTyping is based on the concept of in vitro PCR assays and maintains the principles of ease of use and speed that prevailed during the development of the in vitro assays. This in silico approach shows 99.4 % concordance with the in vitro PCR assays and 98.8 % with the Mash genome-clustering tool. The very few discrepancies result from various errors occurring mainly from horizontal gene transfers or SNPs in the primers. We propose the ClermonTyper as a freely available resource to the scientific community at: http://clermontyping.iame-research.center/.
Size control of the inner ear via hydraulic feedback
Authors: Mosaliganti Kishore R. , Swinburne Ian A. , Chan Chon U , Obholzer Nikolaus D. , Green Amelia A. , Tanksale Shreyas , Mahadevan L. , Megason Sean G.
Published: June 2018

Animals make organs of precise size, shape, and symmetry despite noise in underlying molecular and cellular processes. How developing organs manage this noise is largely unknown. Here, we combine quantitative imaging, physical theory, and physiological measurement of hydrostatic pressure and fluid transport in zebrafish to study size control of the developing inner ear. We find that fluid accumulation creates hydrostatic pressure in the lumen leading to stress in the epithelium and expansion of the otic vesicle. Pressure, in turn, inhibits fluid transport into the lumen. This negative feedback loop between pressure and transport allows the otic vesicle to change growth rate to control natural or experimentally-induced size variation. Spatiotemporal patterning of contractility modulates pressure-driven strain for regional tissue thinning. Our work connects moleculardriven mechanisms, such as osmotic pressure driven strain and actomyosin tension, to the regulation of tissue morphogenesis via hydraulic feedback to ensure robust control of organ size.
Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals
Authors: Adhya Dwaipayan , Swarup Vivek , Nagy Roland , Dutan Lucia , Shum Carole , Valencia-Alarcón Eva P. , Jozwik Kamila Maria , Mendez Maria Andreina , Horder Jamie , Loth Eva , Nowosiad Paulina , Lee Irene , Skuse David , Flinter Frances A. , Murphy Declan , McAlonan Grainne , Geschwind Daniel H. , Price Jack , Carroll Jason , Srivastava Deepak P. , Baron-Cohen Simon
Published: June 2018

Background

Autism is a heterogenous collection of disorders with a complex molecular underpinning. Evidence from post-mortem brain studies using adult brains have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from autistic individuals with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism.

Methods

IPSCs were generated from 9 unrelated autistic individuals without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing, control, individuals. IPSCs were differentiated towards either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterise iPSCs at different stage of differentiation.

Results

A subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to post-mortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated towards a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors, and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs.

Conclusions

Taken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.
Objective Classification of Neocortical Pyramidal Cells
Authors: Kanari Lida , Ramaswamy Srikanth , Shi Ying , Morand Sebastien , Meystre Julie , Perin Rodrigo , Abdellah Marwan , Wang Yun , Hess Kathryn , Markram Henry
Published: June 2018

A consensus on the number of morphologically different types of pyramidal cells (PCs) in the neocortex has not yet been reached, despite over a century of anatomical studies. This is because of a lack of agreement on the subjective classifications of neuron types, which is based on expert analyses of neuronal morphologies: the shapes of somata, dendrites, and axons. Even for neurons that are visually different to non-experts, there is no common ground to consistently distinguish morphological types. We found that objective classification is possible with methods from algebraic topology, and that the dendritic arbor is sufficient for reliable identification of distinct types of PCs. We also provide a solution for the more challenging problem of whether two similar neurons belong to different types or to a continuum of the same type. Using this scheme, we objectively identify seventeen types of PCs in the rat somatosensory cortex. Our topological classification does not require expert input, is stable, and helps settle the long-standing debate on whether cell-types are discrete or continuous morphological variations of each other.
Spatiotemporal Gene Coexpression and Regulation in Mouse Cardiomyocytes of Early Cardiac Morphogenesis
Authors: Liu Yang , Lu Pengfei , Wang Yidong , Morrow Bernice E. , Zhou Bin , Zheng Deyou
Published: June 2018

Cardiac looping is an early morphogenic process critical for the formation of four-chambered mammalian hearts. To study the roles of signaling pathways, transcription factors (TFs) and genetic networks in the process, we constructed gene co-expression networks and identified gene modules highly activated in individual cardiomyocytes (CMs) at multiple anatomical regions and developmental stages. Function analyses of the module genes uncovered major pathways important for spatiotemporal CM differentiation. Interestingly, about half of the pathways were highly active in cardiomyocytes at outflow tract (OFT) and atrioventricular canal (AVC), including many well-known signaling pathways for cardiac development and several newly identified ones. Most of the OFT-AVC pathways were predicted to be regulated by 6 6 transcription factors (TFs) actively expressed at the OFT-AVC locations, with the prediction supported by motif enrichment analysis of the TF targets, including 10 TFs that have not been previously associated with cardiac development, e.g.,Etv5,Rbpms,andBaz2b. Finally, our study showed that the OFT-AVC TF targets were significantly enriched with genes associated with mouse heart developmental abnormalities and human congenital heart defects.
Transcriptome Profiling Reveals Inhibitory Effect of Down-regulated ZBTB38 gene on the Transcriptional Regulation of Tumor Cells Proliferation
Authors: Chen Jie , Xing Chaofeng , Wang Haosen , Zhang Zengmeng , Yu Daolun , Li Jie , Li Honglin , Li Jun , Cai Yafei
Published: June 2018

Transcription factor ZBTB38 belongs to the zinc finger protein family and contains the typical BTB domains. Only several predicted BTB domain-containing proteins encoded in the human genome have been functionally characterized. No relevant studies have been reported concerning the effect of down-regulated ZBTB38 gene expression on tumor cells through transcriptome analysis. In the present study, 2,438 differentially expressed genes in ZBTB38−/− SH-SY5Y cells were obtained via high-throughput transcriptome sequencing analysis, 83.5% of which was down-regulated. Furthermore, GO functional clustering and KEGG pathway enrichment analysis of these differentially expressed genes (DEGs) revealed that the knocked-down transcription factor ZBTB38 interacted with p53 and arrested cell cycles to inhibit the proliferation of the tumor cells. Besides, it also significantly down-regulated the expressions of PTEN, a “molecular switch” of the PI3K/Akt signaling pathway, and RB1CC1, the key gene for autophagy initiation, and blocked autophagy to accelerate the apoptosis of tumor cells. ZBTB38−/− SH-SY5Y cells were investigated at the whole transcriptome level and key DEGs were screened in the present study for the first time, providing a theoretical foundation for exploring the molecular mechanism of inhibition of tumor cell proliferation and targeted anti-tumor therapies.
Diffusion-weighted magnetic resonance spectroscopy enables cell-specific monitoring of astrocyte reactivity in vivo
Authors: Ligneul Clémence , Hernández-Garzón Edwin , Palombo Marco , Carrillo-de Sauvage María-Angeles , Flament Julien , Hantraye Philippe , Brouillet Emmanuel , Bonvento Gilles , Escartin Carole , Valette Julien
Published: June 2018

The diffusion of brain intracellular metabolites, as measured using diffusion-weighted magnetic resonance spectroscopy in vivo, is thought to specifically depend on the cellular structure constraining them. However, it has never been established that variations of metabolite diffusion, e.g. as observed in some diseases, could indeed be linked to alterations of cellular morphology. Here we demonstrate, in a mouse model of reactive astrocytes, that advanced diffusion-weighted magnetic resonance spectroscopy acquisition and modeling techniques enable non-invasive detection of reactive astrocyte hypertrophy (increased soma radius, increased fiber radius and length), as inferred from variations of myo-inositol diffusion, and as confirmed by confocal microscopy ex vivo. This establishes that specific alterations of intracellular metabolite diffusion can be measured and related to cell-specific morphological alterations. Furthermore, as reactive astrocytes are a hallmark of many brain pathologies, this work opens exciting perspectives for neuroscience and clinical research.
Genetic architecture of collective behaviors in zebrafish
Authors: Tang Wenlong , Zhang Guoqiang , Serluca Fabrizio , Li Jingyao , Xiong Xiaorui , Coble Matthew , Tsai Tingwei , Li Zhuyun , Molind Gregory , Zhu Peixin , Fishman Mark C.
Published: June 2018

Collective behaviors of groups of animals, such as schooling and shoaling of fish, are central to species survival, but genes that regulate these activities are not known. Here we parsed collective behavior of groups of adult zebrafish using computer vision and unsupervised machine learning into a set of highly reproducible, unitary, several hundred millisecond states and transitions, which together can account for the entirety of relative positions and postures of groups of fish. Using CRISPR-Cas9 we then targeted for knockout 35 genes associated with autism and schizophrenia. We found mutations in three genes had distinctive effects on the amount of time spent in the specific states or transitions between states. Mutation inimmp2l(inner mitochondrial membrane peptidase 2-like gene) enhances states of cohesion, so increases shoaling; mutation in in the Nav1.1 sodium channel,scn1lab+/− causes the fish to remain scattered without evident social interaction; and mutation in the adrenergic receptor,adra1aa−/−, keeps fish close together and retards transitions between states, leaving fish motionless for long periods. Motor and visual functions seemed relatively well-preserved. This work shows that the behaviors of fish engaged in collective activities are built from a set of stereotypical states. Single gene mutations can alter propensities to collective actions by changing the proportion of time spent in these states or the tendency to transition between states. This provides an approach to begin dissection of the molecular pathways used to generate and guide collective actions of groups of animals.
Coordinated host-pathogen transcriptional dynamics revealed using sorted subpopulations and single,Candida albicansinfected macrophages
Authors: Muñoz José F. , Delorey Toni , Ford Christopher B. , Li Bi Yu , Thompson Dawn A. , Rao Reeta P. , Cuomo Christina A.
Published: June 2018

The outcome of fungal infections depends on interactions with innate immune cells. Within a population of macrophages encounteringC. albicans, there are distinct host-pathogen trajectories; however, little is known about the molecular heterogeneity that governs these fates. We developed an experimental system to separate interaction stages and single macrophage cells infected withC. albicansfrom uninfected cells and assessed transcriptional variability in the host and fungus. Macrophages displayed an initial up-regulation of pathways involved in phagocytosis and proinflammatory response afterC. albicansexposure that declined during later time points. PhagocytosedC. albicansshifted expression programs to survive the nutrient poor phagosome and remodeled the cell wall. The transcriptomes of single infected macrophages and phagocytosedC. albicansrevealed a tightly coordinated shift in gene expression co-stages and revealed expression bimodality and differential splicing that may drive infection outcome. This work establishes an approach for studying host-pathogen trajectories to resolve heterogeneity in dynamic populations.
Speed-Selectivity in Retinal Ganglion Cells is Modulated by the Complexity of the Visual Stimulus
Authors: Ravello César R , Perrinet Laurent U , Escobar María-José , Palacios Adrián G
Published: June 2018

Motion detection represents one of the critical tasks of the visual system and has motivated a large body of research. However, is remain unclear precisely why the response of retinal ganglion cells (RGCs) to simple artificial stimuli does not predict their response to complex naturalistic stimuli. To explore this topic, we use Motion Clouds (MC), which are synthetic textures that preserve properties of natural images and are merely parameterized, in particular by modulating the spatiotemporal spectrum complexity of the stimulus by adjusting the frequency bandwidths. By stimulating the retina of the diurnal rodent,Octodon deguswith MC we show that the RGCs respond to increasingly complex stimuli by narrowing their adjustment curves in response to movement. At the level of the population, complex stimuli produce a sparser code while preserving movement information; therefore, the stimuli are encoded more efficiently. Interestingly, these properties were observed throughout different populations of RGCs. Thus, our results reveal that the response at the level of RGCs is modulated by the naturalness of the stimulus - in particular for motion - which suggests that the tuning to the statistics of natural images already emerges at the level of the retina.
Determining the Hierarchical Architecture of the Human Brain Using Subject-Level Clustering of Functional Networks
Authors: Akiki Teddy J. , Abdallah Chadi G.
Published: June 2018

Optimal integration and segregation of neuronal connections are necessary for efficient large-scale network communication between distributed cortical regions while allowing for modular specialization. This dynamic in the cortex is enabled at the network mesoscale—the organization of nodes into communities. Previous in vivo efforts to map the mesoscale architecture in humans had several limitations. Here we characterize a consensus multiscale community organization of the functional cortical network. We derive this consensus from the clustering of subject-level networks. We show that this subject-derived consensus framework yields clusters that better map to the individual, compared to the widely-used group-derived consensus approach. We applied this analysis to magnetic resonance imaging data from 1003 healthy individuals part of the Human Connectome Project. The hierarchical atlas and code will be made publicly available for future investigators.
Bayesian tip dating reveals heterogeneous morphological clocks in Mesozoic birds
Authors: Zhang Chi , Wang Min
Published: June 2018

Recently, comprehensive morphological datasets including nearly all the well-recognized Mesozoic birds become available, making it feasible for statistically rigorous methods to unveil finer evolutionary patterns during early avian evolution. However, few quantitative and statistical studies have yet been performed. Here, we exploited the advantage of Bayesian tip dating under relaxed morphological clocks to infer both the divergence times and evolutionary rates while accounting for their uncertainties. We further subdivided the characters into six body regions (i.e., skull, axial skeleton, pectoral girdle and sternum, forelimb, pelvic girdle, and hindlimb) to assess evolutionary rate heterogeneity both along the lineages and across partitions. We observed extremely high rates of morphological character changes during early avian evolution and the clock rates are quite heterogeneous among the six regions. The branch subtending Pygostylia shows extremely high rate in the axial skeleton, while the branches subtending Ornithothoraces and Enantiornithes show very high rates in the pectoral girdle and sternum, and moderately high rates in the forelimb. The extensive modifications in these body regions largely correspond to refinement of the flight capability. The rest of the relatively slow and even rates suggest that there is no dominant selective pressure in favoring of modifications in the skull and pelvis. This study reveals the power and flexibility of Bayesian tip dating implemented in MrBayes to investigate evolutionary dynamics in deep time.
Two new plasmid post-segregational killing mechanisms for the implementation of synthetic gene networks inE. coli
Authors: Fedorec Alex J H , Ozdemir Tanel , Doshi Anjali , Rosa Luca , Velazquez Oscar , Danino Tal , Barnes Chris P
Published: June 2018

Plasmids are the workhorse of both industrial biotechnology and synthetic biology, but ensuring they remain in bacterial cells is a challenge. Antibiotic selection, commonly used in the laboratory, cannot be used to stabilise plasmids in most real-world applications, and inserting dynamical gene networks into the genome is difficult. Plasmids have evolved several mechanisms for stability, one of which, post-segregational killing (PSK), ensures that plasmid-free cells do not grow or survive. Here we demonstrate the plasmid-stabilising capabilities of the axe/txe two component system and the microcin-V system in the probiotic bacteriaEscherichia coliNissle 1917 and show they can outperform the hok/sok system commonly used in biotechnological applications. Using plasmid stability assays, automated flow cytometry analysis, mathematical models and Bayesian statistics we quantified plasmid stabilityin vitro. Further, we used anin vivomouse cancer model to demonstrate plasmid stability in a real-world therapeutic setting. These new PSK systems, plus the developed Bayesian methodology, will have wide applicability in clinical and industrial biotechnology.
Representations of evidence for a perceptual decision in the human brain
Authors: Bitzer Sebastian , Park Hame , Maess Burkhard , von Kriegstein Katharina , Kiebel Stefan
Published: June 2018

In perceptual decision making the brain extracts and accumulates decision evidence from a stimulus over time and eventually makes a decision based on the accumulated evidence. Several characteristics of this process have been observed in human electrophysiological experiments, especially an average build-up of motor-related signals supposedly reflecting accumulated evidence, when averaged across trials. Another recently established approach to investigate the representation of decision evidence in brain signals is to correlate the within-trial fluctuations of decision evidence with the measured signals. We here report results for a two-alternative forced choice reaction time experiment in which we applied this approach to human magnetoencephalographic (MEG) recordings. These results consolidate a range of previous findings. In addition, they show: 1) that decision evidence is most strongly represented in the MEG signals in three consecutive phases, 2) that motor areas contribute longer to these representations than parietal areas and 3) that posterior cingulate cortex is involved most consistently, among all brain areas, in all three of the identified phases. As most previous work on perceptual decision making in the brain has focused on parietal and motor areas, our findings therefore suggest that the role of the posterior cingulate cortex in perceptual decision making may be currently underestimated.
Crystal structure and Hirshfeld surface analysis of 4-[4-(1H-benzo[d]imidazol-2-yl)phenoxy]phthalonitrile monohydrate
Authors: Sen Pinar , Kansiz Sevgi , Dege Necmi , Iskenderov Turganbay S. , Yildiz S. Zeki
Published: June 2018

In the title compound, C21H12N4O·H2O, the five-membered ring is essentially planar with a maximum deviation of 0.004 (2) Å. An N—H...O hydrogen bond connects the organic and water molecules. In the crystal, O—H...N hydrogen bonds link molecules into a two-dimensional network parallel to (100). Hirshfeld surface analyses and two-dimensional fingerprint plots were used to quantify the intermolecular interactions present in the crystal, indicating that the most important contributions for the crystal packing are from H...H (28.7%), C...H/H...C (27.1%), N...H/H...N (26.4%), C...N/N...C (6.1%), O...H/H...O (3.7%) and C...C (6.0%) interactions.
Hexacyclo[6.5.1.01,5.05,12.07,11.09,13]tetradecane-4,6,14-trione
Authors: Kotha Sambasivarao , Cheekatla Subba Rao , Gunta Rama
Published: June 2018

The structure of the title cage compound, C14H12O3, encompasses seven fused rings, viz. one four-membered, five five-membered and one six-membered. The four-membered ring is essentially planar, all five-membered rings adopt an envelope conformation and the six-membered ring adopts a boat conformation.