bluuebunny/crossref_metadata_2025 huggingface dataset:
Nivolumab-associated Nephrotic Syndrome in a Patient With Renal Cell Carcinoma: A Case Report
Authors: Daanen Robin A. , Maas Rutger J.H. , Koornstra Rutger H.T. , Steenbergen Eric. J. , van Herpen Carla M.L. , Willemsen Annelieke E.C.A.B.
Published: September 2017

Introduction:

Immune checkpoint inhibitors have taken an important place in the treatment of different types of malignancies. These drugs are known to have specific immune-mediated adverse events. We describe a case of severe nephrotic syndrome secondary to treatment with nivolumab in a patient with renal cell carcinoma.

Case Presentation:

A 62-year-old man was treated with nivolumab for papillary renal cell carcinoma type 2 for 8 weeks when he was admitted to the hospital with a severe nephrotic syndrome and acute kidney injury. Renal biopsy showed focal segmental glomerulosclerosis. Treatment with high-dose corticosteroids had insufficient effect, but the addition of mycophenolate mofetil resulted in remission of the nephrotic syndrome and recovery of renal function. Proteinuria subsequently relapsed during corticosteroid tapering.

Conclusions:

The time course in this patient strongly suggests that the nephrotic syndrome occurred as an adverse drug reaction to nivolumab treatment. If during nivolumab treatment renal insufficiency, hypoalbuminemia, or proteinuria develops, further analysis for a possible nephrotic syndrome is warranted for early detection and treatment of this life-threatening complication.
Does mindfulness meditation improve chronic pain? A systematic review
Authors: Ball Elizabeth F. , Nur Shafina Muhammad Sharizan Emira , Franklin Genny , Rogozińska Ewelina
Published: September 2017

Purpose of review

Psychological factors are associated with chronic pain. Mindfulness meditation may ameliorate symptoms. The objective was to evaluate the effects of mindfulness meditation in chronic pain.

Recent findings

A systematic search of four databases identified 534 citations; 13 Randomised controlled trials satisfied the inclusion criteria. Mindfulness meditation significantly reduced depression [Standardised mean difference (SMD) −0.28; 95% confidence interval (CI) −0.53, −0.03; P = 0.03; I
2 = 0%]. For affective pain (SMD −0.13; 95% CI −0.42, 0.16; I
2 = 0%), sensory pain (SMD −0.02; 95% CI −0.31, 0.27; I
2 = 0%) and anxiety (SMD −0.16; 95% CI −0.47, 0.15; I
2 = 0%) there was a trend towards benefit with intervention. Quality of life items on mental health (SMD 0.65; 95% CI −0.27, 1.58; I
2 = 69%), physical health (SMD 0.08; 95% CI −0.40, 0.56; I
2 = 32%) and overall score (SMD 0.86, 95% CI −0.06, 1.78; I
2 = 88%) improved with mindfulness meditation.

Mindfulness meditation has most prominent effect on psychological aspects on living with chronic pain, improving associated depression and quality of life.
Cost-effectiveness of Ovarian Cancer Prevention Strategies
Authors: KWON JANICE S.
Published: September 2017

Ovarian cancer remains to be the most lethal of all gynecologic malignancies. There is no effective screening test proven to reduce the mortality associated with this disease. Costs of treating ovarian cancer are substantial and among the highest of all cancer types. Therefore, it is essential to pursue strategies to prevent ovarian cancer that are cost-effective in the context of our health care system. There are 2 subgroups of women for whom ovarian cancer prevention strategies have been evaluated for effectiveness and costs: (1) general population at risk, and (2) BRCA mutation carriers with a high lifetime risk.
MECHANISM OF “FLAP CLOSURE” AFTER THE INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE
Authors: Bonińska Karolina , Nawrocki Jerzy , Michalewska Zofia
Published: September 2017

Purpose:

Recent studies described that in approximately 14% to 16% of cases of macular holes treated with the inverted internal limiting membrane flap technique, the hole was closed only by a thin layer of inverted internal limiting membrane—“flap closure.” The aim of this article was to describe the functional and anatomical results in flap closure macular holes and also the mechanism of flap closure.

Methods:

A retrospective observational study of 149 eyes of 139 patients treated with vitrectomy using the inverted internal limiting membrane flap technique was reviewed to aggregate eyes with flap closure. Complete ophthalmic examination was performed preoperatively and at 7 days, 1, 3, 6, and 12 months after surgery.

Results:

Flap closure (Group 1) was noted in 24 eyes and other closure types in 125 eyes (Group 2). The mean minimal and base diameters of the macular holes in the flap closure group were greater than those in Group 2 (P < 0.001). The mean postoperative best-corrected visual acuity in the flap closure group (20/100) was lower than that in Group 2 (20/50) (P < 0.001).

Conclusion:

Flap closure probably enables closure of large macular holes with a higher probability of remaining open without the use of the inverted internal limiting membrane flap technique. Foveal architecture continuously improved.
RESULTS OF RETINAL DETACHMENT SURGERY IN EYES WITH OSTEO-KERATOPROSTHESIS
Authors: Vilaplana Ferran , Nadal Jeroni , Temprano José , Julio Gemma , Barraquer Rafael I.
Published: September 2017

Purpose:

To evaluate the anatomical and functional results of pars plana vitrectomy in eyes with osteo-keratoprosthesis, who have suffered retinal detachment.

Methods:

An observational, retrospective study of 18 eyes which underwent pars plana vitrectomy for retinal detachment after an implantation of an osteo-keratoprosthesis, with a minimum of 1-year follow-up. A descriptive study and a Kaplan–Meier survival analysis for anatomical and functional success were performed. Anatomical success was defined as an attached retina at the end of vitreoretinal surgery with no redetachment during the follow-up. Functional success was defined as a postoperative visual acuity of more than or equal to 20/400.

Results:

The overall rate of anatomical success was 56%, and the anatomical survival rates were 67% and 53% at 6 months and 12 months, respectively, maintaining this last value at 24 months after pars plana vitrectomy. The overall rate of functional success was 17%, and the functional survival rates were 83%, 39%, and 14% at 6 months, 12 months, and 24 months after pars plana vitrectomy, respectively. The most frequent complication after retinal surgery was retroprosthetic membrane (33%).

Conclusion:

Despite the reserved prognosis and the severe complications, vitrectomy represents a valid method for treating retinal detachment in patients with osteo-keratoprosthesis, with good anatomical results but poor visual acuity.
Multicenter Study of 6-Month Clinical Outcomes After Descemet Membrane Endothelial Keratoplasty
Authors: Oellerich Silke , Baydoun Lamis , Peraza-Nieves Jorge , Ilyas Abbas , Frank Laurence , Binder Perry S. , Melles Gerrit R. J. ,   on behalf of the International DMEK Study Group
Published: September 2017

Purpose:

To report the 6-month clinical outcomes of a large cohort of Descemet membrane endothelial keratoplasty (DMEK) eyes operated by 55 starting or experienced surgeons.

Methods:

This is a retrospective, multicenter, interventional, cohort study with a total of 2485 eyes. Best-corrected visual acuity (BCVA), endothelial cell density (ECD) decrease, and intra- and post-operative complications were evaluated. Three groups based on case order were compared: group I (cases 1–24), group II (cases 25–99), and group III (cases ≥100). Forty-nine percent of the surgeons were in their learning curve (<25 cases), representing 10.4% of the surgeries.

Results:

Six months after DMEK, BCVA improved in 90.5% of eyes, remained unchanged in 4.6%, and deteriorated in 4.9% (n = 1936); 75.4% of eyes reached a BCVA of ≥20/40 (≥0.5), 45.4% ≥20/25 (≥0.8), and 25.8% ≥20/20 (≥1.0) (n = 1959) and ECD decreased by 40% (±19) (n = 1272,P< 0.05). BCVA and ECD outcomes did not differ between groups I and III (P> 0.05). Intraoperative complications were reported for 9.4% of eyes, whereas graft detachment was the main postoperative complication (27.4%), with lower intra- and post-operative complication rates in group III than group I (P< 0.05). Rebubbling was performed in 20.1% of eyes; 13.8% required secondary keratoplasty within 6 months.

Conclusions:

DMEK is applicable for surgeons in various settings with good clinical outcomes. After an arbitrary learning curve (<25 cases), virtually all transplant-related complications declined with experience. Notably, surgeons with a higher annual caseload may pass faster through their learning curve than surgeons performing their first surgeries over an extended period.
Risk Factors of Gastrointestinal Bleeding After Continuous Flow Left Ventricular Assist Device
Authors: Balcioglu Ozlem , Kemal Hatice S. , Ertugay Serkan , Ozturk Pelin , Engin Yaprak , Nalbantgil Sanem , Engin Cagatay , Yagdi Tahir , Ozbaran Mustafa
Published: September 2017

This study aimed to compare von Willebrand factor (vWF) levels, ristocetin cofactor levels, platelet counts, aortic valve movements, and right heart failure (RHF) as risk factors of gastrointestinal (GI) bleeding in patients with continuous flow left ventricular assist device (cf-LVAD). In a single centre, 90 patients (mean age 52.0 ± 10.5 years), of which 59 were male and 31 were female, had cf-LVAD implantation from October 2010 to November 2012. Seventy-six (84.4%) patients had HeartWare (Medtronic, Mounds View, MN) and 14 (15.5%) had Heartmate II (Thoratec, Pleasanton, CA) implanted. vWF level, ristocetin cofactor level, and platelet count were measured before and after implantation to determine the presence of acquired von Willebrand Syndrome; aortic valve movement and postoperative RHF were evaluated to compare the difference in bleeding and nonbleeding patient groups. Fifteen patients (16.6%) suffered GI bleeding after cf-LVAD implantation. A statistically significant decrease was found in vWF and ristocetin cofactor levels from preoperative period to postoperative period in both bleeding and nonbleeding patient groups (p < 0.05). There was no significant difference in bleeding and nonbleeding groups regarding aortic valve movements (p ≥ 0.05). Postoperative RHF incidence was significantly high in the bleeding patient group compared with the nonbleeding group (p < 0.05). Therefore, depending on the findings of this study, acquired von Willebrand Syndrome was seen in all cf-LVAD patients, and postoperative RHF was an important risk factor for GI bleeding.
Risk Factors and Nomogram for Common Bile Duct Stricture in Chronic Pancreatitis
Authors: Hao Lu , Bi Ya-Wei , Zhang Di , Zeng Xiang-Peng , Xin Lei , Pan Jun , Wang Dan , Ji Jun-Tao , Du Ting-Ting , Lin Jin-Huan , Ye Bo , Zou Wen-Bin , Chen Hui , Xie Ting , Li Bai-Rong , Zheng Zhao-Hong , Wang Teng , Guo Hong-Lei , Liao Zhuan , Li Zhao-Shen , Hu Liang-Hao
Published: September 2017

Goals:

To identify the risk factors and develop nomograms for common bile duct (CBD) stricture in chronic pancreatitis (CP) patients.

Background:

CBD stricture is a common complication in CP and has a variable clinical presentation ranging from asymptomatic to overt jaundice and cholangitis.

Study:

Patients with CP admitted to Changhai Hospital (Shanghai, China) from January 2000 to December 2013 were enrolled. Cumulative rates of CBD stricture after onset and diagnosis of CP were calculated. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. On the basis of the training cohort, risk factors for CBD stricture and symptomatic CBD stricture were identified through Cox proportional hazards regression model, and nomograms was developed, respectively. Internal and external validations were performed based on the training and validation cohort, respectively.

Results:

With a total of 2153 patients, the median duration of follow-up was 7.0 years. CBD strictures were detected in 340 (15.8%) patients, whereas 159 of them were symptomatic. Male gender, age at onset of CP, smoking, body mass index, and morphology of main pancreatic duct were identified risk factors for CBD stricture development. Age at onset of CP, body mass index, and type of pain were identified risk factors for symptomatic CBD stricture development. Both nomograms achieved good concordance indexes with well-fitted calibration curves.

Conclusions:

The nomogram achieved an individualized prediction of symptomatic CBD stricture development in CP patients. It may help the early diagnosis and intervention of symptomatic CBD stricture and reduce the rates of severe adverse events.
Food Therapy in Sinosphere Asia
Authors: Chu Natural Hoi Sing , Yao Chu Kion , Tan Victoria Ping Yi
Published: September 2017

Traditional Chinese Food Therapy has long been an integral part of dietary practices in Sinosphere Asia. This therapy is defined by the classification of foods into cooling (Yin) and heaty (Yang) and the manipulation of dietary intake of these foods as a therapeutic strategy for chronic diseases. Both functional dyspepsia (FD) and irritable bowel syndrome (IBS) are chronic, functional gut disorders widely prevalent in Sinosphere Asia. Diet is increasingly recognized as a symptom trigger in FD and IBS, and the evidence suggesting the utility of diet therapies as front-line management is growing, particularly in the West. Specifically, a diet low in Fermentable, Oligosaccharides, Disaccharides, Monosaccharides, and Polyols is an efficacious therapy for patients with IBS. In contrast, a proportion of patients with IBS in Sinosphere Asia utilize Chinese Food Therapy for symptom management. Chinese Food Therapy provides an attractive target for integration with evidence-based Western dietary therapies as a management strategy in FD and IBS. However, significant gaps in research exist with the utility of Chinese Food Therapy that first need to be addressed. This includes a lack of standardization for heaty and cooling classification, limited mechanistic rationale or clinical studies supporting its efficacy in FD and IBS, and the lack of an ideal practitioner for implementation of Chinese Food Therapy. Hence, the review provides a summary of the role of diet and nutrition in Sinosphere Asia with an emphasis on FD and IBS, and an examination of how modern dietary practices may be able to be integrated into practices in this region.
The Role of Gastroesophageal Reflux in Provoking High Blood Pressure Episodes in Patients With Hypertension
Authors: Li Zhi-tong , Ji Feng , Han Xin-wei , Wang Li , Yue Yong-qiang , Wang Zhong-gao
Published: September 2017

Goals:

We assessed the relationship between gastroesophageal reflux disease (GERD) and hypertension and whether antiacid therapy could be used to control blood pressure (BP) on hypertension in patients with GERD.

Background:

Gastroesophageal reflux disease (GERD) may provoke cardiovascular disease. Many factors are involved in the development of essential hypertension, but whether GERD has a role needs further study.

Study:

Patients with essential hypertension (n=86) were studied by 24-hour continuous BP monitoring and esophageal impedance and pH monitoring. Patients fulfilling the GERD criteria received 14-day therapy with omeprazole (20 mg twice a day), and the effect on BP was studied.

Results:

Of the 86 essential hypertension patients, 38 (44.2%) had GERD. Among these 38 patients, 494 episodes of pathologic reflux (PR), and 684 episodes of high BP were recorded. PR was significantly more common at nighttime especially when supine. Of the 684 episodes of hypertension, 102 (14.9%) were synchronous with PR. GERD patients had significantly higher nocturnal BP than non-GERD patients. Antiacid therapy brought about significant reduction in all esophageal monitoring parameters as well as in BP parameters in GERD patients.

Conclusions:

This study demonstrated that there is significant correlation between hypertension and GERD. Antiacid therapy can restore normal esophageal pH and help maintain normal BP.
Health‐related Quality of Life in Adolescent Patients With Hepatitis C Genotype 1 Treated With Sofosbuvir and Ledipasvir
Authors: Younossi Zobair M. , Stepanova Maria , Balistreri William , Schwarz Kathleen , Murray Karen F. , Rosenthal Philip , Bansal Sanjay , Hunt Sharon
Published: September 2017

Objective:

The aim of the study was to assess the effect of treatment with ledipasvir/sofosbuvir (LDV/SOF) on the health‐related quality of life (HRQL) of pediatric patients with chronic hepatitis C virus (HCV) infection.

Methods:

Adolescents (12–17 years) with HCV were treated with LDV/SOF (90/400 mg daily) for 12 weeks. HRQL was assessed using the PedsQLv4.0‐SF15 completed by the children and caregivers before, during, and after treatment.

Results:

We included 100 adolescents with HCV genotype 1 infection (14.7 ± 2.0 years, 1% known cirrhosis, 80% treatment‐naïve, 97% sustained virologic response‐12). At baseline, HRQL the caregiver‐ perceived HRQL scores were lower than adolescents’ self‐reported scores (by 6.7–7.9 points, all P < 0.01). At the end of 12 weeks of treatment, however, the caregiver‐reported HRQL scores showed a significant improvement (+all P < 0.04), whereas the adolescents’ self‐reported scores did not change from the baseline. HRQL scores reported by caregivers remained higher than baseline (by +4.7–+7.5, P < 0.01) through 12 weeks after treatment, as did the adolescents’ self‐reported Emotional Functioning scores (+4.3 from baseline, P = 0.0009); observed improvements were sustained after 24 weeks of follow‐up (all P < 0.04). Multivariate analysis showed that, after adjustment for location, age, and sex, having a history of anxiety and panic disorders were consistent predictors of impaired HRQL in adolescents with HCV infection (P < 0.05).

Conclusions:

Treatment of HCV in adolescents with LDV/SOF is associated with some improvement in HRQL. Caregivers’ reports of HRQL in adolescents with HCV significantly increased with treatment and were similar to the adolescent self‐reported HRQL after sustained virologic response‐12.
Political Affiliation, Probable PTSD, and Symptoms of Depression in Iraq and Afghanistan Combat Veterans
Authors: Lating Jeffrey M. , Moore Rich A. , Sherman Martin F. , Kirkhart Matthew W. , Everly George S. , Chen Justin K.
Published: September 2017

Ideological commitment of military personnel has been associated with mitigating trauma and protecting mental health. This pilot study assessed whether Democratic and Republican political affiliation differentially predicted probable posttraumatic stress disorder (PTSD) and symptoms of depression in 62 male Iraq and Afghanistan combat veterans. The Liberalism-Conservatism Scale, the PTSD Checklist-Military Version (PCL-M), and the Patient Health Questionnaire–9 (PHQ-9) were assessment measures. Results revealed that Democratic combat veterans had stronger liberal attitudes than Republican combat veterans (r = 0.95). Moreover, of the 50% of the entire sample higher than the cutoff score of 50 on the PCL-M, 84.8% were Democrats compared with 10.3% of Republicans. On the PHQ-9, 46.9% of Democrats compared with 3.7% of Republicans were higher than the cutoff score of 20. These initial results suggest possible mechanisms of action, including differences in shattered world view assumptions, willingness to disclose emotional concerns, and physiological reactions between Democratic and Republican combat veterans.
Case Report: Use of Self-retained Cryopreserved Amniotic Membrane in the Treatment of Acute Chemical Ocular Burn
Authors: Shupe Adam T. , Cheng Anny M. S.
Published: September 2017

SIGNIFICANCE

Ocular chemical injury is a medical emergency in which immediate treatment is critical to prevent visual morbidity. We report a severe ocular burn case that illustrates in-office management to promote rapid re-epithelialization and reduce inflammation to restore ocular surface integrity.

PURPOSE

To report a case of severe acid burn that was managed successfully with self-retained cryopreserved amniotic membrane (AM).

METHODS

A 43-year-old man presented with complaints of pain, light sensitivity, and blurred vision in both eyes 1 day after ocular exposure to acid. Symptoms and signs were more severe in the left eye. Examination revealed diffuse conjunctival inflammation and extensive corneal, conjunctival, and limbal epithelial defects in the left eye; hence, application of cryopreserved AM was performed.

RESULTS

Placement of three self-retained AMs over a 10-day period resulted in resolution of symptoms, reduction in inflammation, complete re-epithelialization of corneal and limbal defects, and improvement of visual acuity from 20/50 to 20/20. Intriguingly, areas of conjunctival inflammation not covered by the AM remained inflamed.

CONCLUSIONS

In this case of acute chemical burn, application of self-retained AM 24 hours after injury was effective in promoting ocular surface healing, reducing inflammation, and restoring visual acuity.
Patient-reported Outcomes in Practice: Clinicians’ Perspectives From an Inpatient Psychiatric Setting
Authors: BURR SEAN K. , FOWLER JAMES C. , ALLEN JON G. , WILTGEN ANIKA , MADAN ALOK
Published: September 2017

The use of patient-reported outcomes (PROs) has become increasingly common. They have been used to assess quality of care and to support policy decisions, but the evidence concerning their utility to improve patient outcomes is inconsistent. A better understanding of clinicians’ experience with PROs has the potential to improve their effectiveness. This exploratory, quantitative, and qualitative study investigated the perspectives of clinicians (N=70) from multiple disciplines (psychiatrists, psychologists, social workers, and psychiatric nurses) on the utility of PROs in an inpatient psychiatric setting. During scheduled, monthly, discipline-specific administrative meetings, clinicians in attendance completed a 1-time, 5-item survey. The highest rated item related to the frequency of reviewing outcomes reports; this item was rated higher than all other items (mean±SD, 4.5±1.5), which 37.5% of the participants in the overall sample stated they “always” did. The lowest rated item related to the frequency of conveying the results of the outcomes reports to patients (3.3±1.9), which 20% of participants reported “always” doing; this item was rated lower than all other items (P<0.03). Qualitative analyses were based on 30 comments from 22 clinicians, which resulted in the emergence of 6 themes. The 2 themes that received the highest number of comments related to: (1) the sensitivity and specificity of measures across the PROs platform and (2) the value of the reports in directly influencing treatment decisions. Clinicians’ relatively favorable perspective of PROs in practice in this study may be related to the assessment-oriented culture at the study institution. Nonetheless, many barriers to the routine use of PROs exist. Addressing clinician concerns has the potential to improve utilization of this facet of good clinical care.
Introduction of the Nurse Endoscopist Role in One Australian Health Service
Authors: Duncan Nerissa , Bonney Deanne , Au Catherine , Chalmers Cheyne , Bennett Paul N.
Published: September 2017

In Australia, nurses performing endoscopic procedures is a recent phenomenon and is uncommon. Challenges include gastroenterologist and patient acceptance of the nurse endoscopist role. This article aims to explore Monash Health's experience with the introduction of a nurse endoscopist. A nurse endoscopist trainee undertook a comprehensive training program under the supervision of a gastroenterologist. All procedural data were collected, organizational policy and procedures were developed, and patients (n= 40) completed a telephone interview postprocedure. The nurse endoscopist trainee completed all training requirements during the 12-month program and was deemed competent for independent practice. The trainee performed 255 colonoscopies, with no complications reported. The organization successfully implemented the expanded scope of practice, established a new model of care for patients, and initiated a governance framework for this advanced practice role. Eighty percent of patients (n= 32) reported that overall, they had a very good experience with the nurse endoscopist trainee. A nurse endoscopist initiative can facilitate the expansion of endoscopy services to meet the growing need for gastroenterological procedures within the community. This pilot program has demonstrated that it is possible to integrate an advanced practice nurse role into an established endoscopy unit.
Impact of advance care planning on end-of-life management
Authors: Lunder Urška , Červ Branka , Kodba-Čeh Hana
Published: September 2017

Purpose of review

The aim of this review is to critically appraise the recent evidence on different aspects of impact of advance care planning (ACP) in palliative care and to reflect on further implications on practice and research in the future.

Recent findings

Evidence about various ACP impacts is rapidly growing and most common outcome measures are still advance directive completion, change in hospital admission rate and patients’ and families’ views and experiences with ACP. Mainly descriptive studies bring new information of ACP impact for specific groups of patients, their families, settings, countries, contexts, staff and healthcare system as such. It is not yet clear who and when would best conduct ACP, from general practitioners (GPs) to specialists in the hospitals and even lay-navigators for cancer patients; from early ACP conversations to critical ACP in acute events at the end-of-life. The need for ACP impacts high-quality evidence is becoming more urgent because latest future projections are showing higher palliative care needs than previously expected.

Recent studies on various ACP impacts reveal variety of outcomes for different patient groups and settings, and are contributing to a wider picture of ACP situation around the world. However, high-quality evidence on ACP impact is still urgently expected in times of growing need for system-level changes for effective ACP implementation.
A manganese photosensitive tricarbonyl molecule [Mn(CO)3(tpa-κ3
N)]Br enhances antibiotic efficacy in a multi-drug-resistant Escherichia coli
Authors: Rana Namrata , Jesse Helen E. , Tinajero-Trejo Mariana , Butler Jonathan A. , Tarlit John D. , von und zur Muhlen Milena L. , Nagel Christoph , Schatzschneider Ulrich , Poole Robert K.
Published: September 2017

Carbon monoxide-releasing molecules (CORMs) are a promising class of new antimicrobials, with multiple modes of action that are distinct from those of standard antibiotics. The relentless increase in antimicrobial resistance, exacerbated by a lack of new antibiotics, necessitates a better understanding of how such novel agents act and might be used synergistically with established antibiotics. This work aimed to understand the mechanism(s) underlying synergy between a manganese-based photoactivated carbon monoxide-releasing molecule (PhotoCORM), [Mn(CO)3(tpa-κ3
N)]Br [tpa=tris(2-pyridylmethyl)amine], and various classes of antibiotics in their activities towards Escherichia coli EC958, a multi-drug-resistant uropathogen. The title compound acts synergistically with polymyxins [polymyxin B and colistin (polymyxin E)] by damaging the bacterial cytoplasmic membrane. [Mn(CO)3(tpa-κ3
N)]Br also potentiates the action of doxycycline, resulting in reduced expression of tetA, which encodes a tetracycline efflux pump. We show that, like tetracyclines, the breakdown products of [Mn(CO)3(tpa-κ3
N)]Br activation chelate iron and trigger an iron starvation response, which we propose to be a further basis for the synergies observed. Conversely, media supplemented with excess iron abrogated the inhibition of growth by doxycycline and the title compound. In conclusion, multiple factors contribute to the ability of this PhotoCORM to increase the efficacy of antibiotics in the polymyxin and tetracycline families. We propose that light-activated carbon monoxide release is not the sole basis of the antimicrobial activities of [Mn(CO)3(tpa-κ3
N)]Br.
High-resolution genome-wide functional dissection of transcriptional regulatory regions in human
Authors: Wang Xinchen , He Liang , Goggin Sarah , Saadat Alham , Wang Li , Claussnitzer Melina , Kellis Manolis
Published: September 2017

Genome-wide epigenomic maps revealed millions of regions showing signatures of enhancers, promoters, and other gene-regulatory elements1. However, high-throughput experimental validation of their function and high-resolution dissection of their driver nucleotides remain limited in their scale and length of regions tested. Here, we present a new method, HiDRA (High-Definition Reporter Assay), that overcomes these limitations by combining components of Sharpr-MPRA2and STARR-Seq3with genome-wide selection of accessible regions from ATAC-Seq4. We used HiDRA to test ~7 million DNA fragments preferentially selected from accessible chromatin in the GM12878 lymphoblastoid cell line. By design, accessibility-selected fragments were highly overlapping (up to 370 per region), enabling us to pinpoint driver regulatory nucleotides by exploiting subtle differences in reporter activity between partially-overlapping fragments, using a new machine learning model SHARPR2. Our resulting maps include ~65,000 regions showing significant enhancer function and enriched for endogenous active histone marks (including H3K9ac, H3K27ac), regulatory sequence motifs, and regions bound by immune regulators. Within them, we discover ~13,000 high-resolution driver elements enriched for regulatory motifs and evolutionarily-conservednucleotides, and help predict causal genetic variants underlying disease from genome-wide association studies. Overall, HiDRA provides a general, scalable, high-throughput, and high-resolution approach for experimental dissection of regulatory regions and driver nucleotides in the context of human biology and disease.
Non-Elastic Remodeling of the 3D Extracellular Matrix by Cell-Generated Forces
Authors: Malandrino Andrea , Mak Michael , Trepat Xavier , Kamm Roger D.
Published: September 2017

The mechanical properties of the extracellular matrix (ECM) – a complex, 3D, fibrillar scaffold of cells in physiological environments – modulate cell behavior and can drive tissue morphogenesis, regeneration, and disease progression. For simplicity, it is often convenient to assume these properties to be time-invariant. In living systems, however, cells dynamically remodel the ECM and create time-dependent local environments. Here, we demonstrate that cell generated contractile forces are capable of producing substantial irreversible changes to the density and architecture of physiologically relevant ECMs – collagen I and fibrin – in a matter of minutes. We measure the 3D mechanical deformation profiles of the ECM surrounding cancer and endothelial cells during stages when force generation is active or inactive. We further correlate these measurements to both discrete fiber simulations that incorporate fiber crosslink unbinding kinetics and continuum-scale modeling. Our findings reveal that plasticity, as a mechanical law in these networks, is fundamentally related to the force-driven unbinding of fiber crosslinks. These results illustrate the dynamic nature of the mechanical environment of physiologically mimicking cell-in-gel systems.
Gene transfers, like fossils, can date the Tree of Life
Authors: Davín Adrián A. , Tannier Eric , Williams Tom A. , Boussau Bastien , Daubin Vincent , Szöllősi Gergely J.
Published: September 2017

Biodiversity has always been predominantly microbial and the scarcity of fossils from bacteria, archaea and microbial eukaryotes has prevented a comprehensive dating of the tree of life. Here we show that patterns of lateral gene transfer deduced from the analysis of modern genomes encode a novel and abundant source of information about the temporal coexistence of lineages throughout the history of life. We use new phylogenetic methods to reconstruct the history of thousands of gene families and demonstrate that dates implied by gene transfers are consistent with estimates from relaxed molecular clocks in Bacteria, Archaea and Eukaryotes. An inspection of discrepancies between transfers and clocks and a comparison with mammal fossils show that gene transfer in microbes is potentially as informative for dating the tree of life as the geological record in macroorganisms.
Using Temporal ICA to Selectively Remove Global Noise While Preserving Global Signal in Functional MRI Data
Authors: Glasser Matthew F. , Coalson Timothy S. , Bijsterbosch Janine D. , Harrison Samuel J. , Harms Michael P. , Anticevic Alan , Van Essen David C. , Smith Stephen M.
Published: September 2017

Temporal fluctuations in functional Magnetic Resonance Imaging (fMRI) have been profitably used to study brain activity and connectivity for over two decades. Unfortunately, fMRI data also contain structured temporal “noise” from a variety of sources, including subject motion, subject physiology, and the MRI equipment. Recently, methods have been developed to automatically and selectively remove spatially specific structured noise from fMRI data using spatial Independent Components Analysis (ICA) and machine learning classifiers. Spatial ICA is particularly effective at removing spatially specific structured noise from high temporal and spatial resolution fMRI data of the type acquired by the Human Connectome Project and similar studies. However, spatial ICA is mathematically, by design, unable to separate spatially widespread “global” structured noise from fMRI data (e.g., blood flow modulations from subject respiration). No methods currently exist to selectively and completely remove global structured noise while retaining the global signal from neural activity. This has left the field in a quandary—to do or not to do global signal regression—given that both choices have substantial downsides. Here we show that temporal ICA can selectively segregate and remove global structured noise while retaining global neural signal in both task-based and resting state fMRI data. We compare the results before and after temporal ICA cleanup to those from global signal regression and show that temporal ICA cleanup removes the global positive biases caused by global physiological noise without inducing the network-specific negative biases of global signal regression. We believe that temporal ICA cleanup provides a “best of both worlds” solution to the global signal and global noise dilemma and that temporal ICA itself unlocks interesting neurobiological insights from fMRI data.
Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation
Authors: Larragoite Erin T. , Nell Racheal A. , Martins Laura J. , Barrows Louis R. , Planelles Vicente , Spivak Adam M.
Published: September 2017

Introduction

Latency reversal agents (LRAs), such as protein kinase C (PKC) agonists, constitute a promising strategy for exposing and eliminating the HIV-1 latent reservoir. PKC agonists activate NF-κB and, in turn, induce deleterious pro-inflammatory cytokine production. Adjuvant pharmacological agents, such as ruxolitinib, a JAK inhibitor, and rapamycin, an mTOR inhibitor, have previously been combined with LRAs to reduce deleterious pro-inflammatory cytokine secretion without inhibiting HIV-1 viral reactivation in vitro. Histone deacetylase inhibitors (HDACi) are known to dampen pro-inflammatory cytokine secretion in the context of other diseases and can synergize with other LRAs to bring dormant proviruses out of latency. In this study we investigated whether a broad panel of epigenetic modifiers, including HDACi, could effectively dampen PKC-induced pro-inflammatory cytokine secretion during latency reversal.

Methods

We screened an epigenetic modifier library to identify compounds that reduced intracellular IL-6 production induced by the PKC agonist Ingenol-3,20-dibenzoate. We further tested the most promising epigenetic inhibitor class, HDACi, for their ability to reduce a broad panel of pro-inflammatory cytokines and reactivate latent HIV-1ex vivo.

Results

We identified nine epigenetic modulators that reduced PKC-induced intracellular IL-6. In cells from aviremic individuals living with HIV-1, the HDAC1-3 inhibitor, suberohydroxamic acid (SBHA), reduced secretion of pro-inflammatory cytokines TNF-α, IL-5, IL-2r, and IL-17 but did not significantly reactivate latent HIV-1 when used in combination with Ingenol-3,20-dibenzoate.

Conclusion

The addition of SBHA to Ingenol-3,20-dibenzoate reduces deleterious cytokine production during latency reversal but does not induce significant viral reactivation in aviremic donor PBMCs. The ability of SBHA to reduce PKC-induced pro-inflammatory cytokines when used in combination with Ingenol-3,20-dibenzoate suggests that SBHA can be used to reduced PKC induced pro-inflammatory cytokines but not to achieve latency reversal in the context of HIV-1.
A universal, genome-wide guide finder for CRISPR/Cas9 targeting in microbial genomes
Authors: Spoto Michelle , Fleming Elizabeth , Oh Julia
Published: September 2017

Background

The CRISPR/Cas system has significant potential to facilitate gene editing in a variety of bacterial species. CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) represent modifications of the CRISPR/Cas9 system utilizing a catalytically inactive Cas9 protein for transcription repression or activation, respectively. While CRISPRi and CRISPRa have tremendous potential to systematically investigate gene function in bacteria, no pan-bacterial, genome-wide tools exist for guide discovery. We have created Guide Finder: a customizable, user-friendly program that can design guides for any annotated bacterial genome.

Results

Guide Finder designs guides from NGG PAM sites for any number of genes using an annotated genome and fasta file input by the user. Guides are filtered according to user-defined design parameters and removed if they contain any off-target matches. Iteration with lowered parameter thresholds allows the program to design guides for genes that did not produce guides with the more stringent parameters, a feature unique to Guide Finder. Guide Finder has been tested on a variety of diverse bacterial genomes, on average finding guides for 95% of genes. Moreover, guides designed by the program are functionally useful—focusing on CRISPRi as a potential application—as demonstrated by essential gene knockdown in two staphylococcal species.

Conclusions

Through the large-scale generation of guides, this open-access software will improve accessibility to CRISPR/Cas studies for a variety of bacterial species.
Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder
Authors: Arnau-Soler Aleix , Adams Mark J. ,   Generation Scotland,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Hayward Caroline , Thomson Pippa A.
Published: September 2017

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene,ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p= 1.48×10-7; Bonferroni-corrected significance thresholdp< 2.79×10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.
Fennec - Functional Exploration of Natural Networks and Ecological Communities
Authors: Ankenbrand Markus J. , Hohlfeld Sonja , Weber Lorenz , Förster Frank , Keller Alexander
Published: September 2017

Species composition assessment of ecological communities and networks is an important aspect of biodiversity research. Yet often ecological traits of organisms in a community are more informative than scientific names only. Furthermore, other properties like threat status, invasiveness, or human usage are relevant for many studies, but cannot be evaluated from taxonomy alone. Despite public databases collecting such information, it is still a tedious manual task to enrich community analyses with such, especially for large-scaled data.

Thus we aimed to develop a public and free tool that eases bulk trait mapping of community data in a web browser, implemented with current standard web and database technologies.

Here we present the Fennec, a workbench that eases the process of mapping publicly available trait data to the user’s communities in an automated process. Usage is either by a local self-hosted or a public instance (https://fennec.molecular.eco) covering exemplary traits. Alongside the software we also provide usage and hosting documentation as well as online tutorials.

The Fennecaims to motivate public trait data submission and its reuse in meta-analyses. Further, it is an open-source development project with the code freely available to use and open for community contributions (https://github.com/molbiodiv/fennec).
The Complex Simplicity of the Brittle Star Nervous System
Authors: Zueva Olga , Khoury Maleana , Heinzeller Thomas , Mashanova Daria , Mashanov Vladimir
Published: September 2017

Brittle stars (Ophiuroidea, Echinodermata) have been increasingly used in studies of animal behavior, locomotion, regeneration, physiology, and bioluminescence. The success of these studies directly depends on good working knowledge of ophiuroid nervous system. Here, we describe the arm nervous system at different levels of organization: microanatomy of the radial nerve cord and peripheral nerves, neural ultrastructure, and localization of different cell types using specific antibody markers. We standardize the nomenclature of nerves and ganglia and provide an anatomically accurate digital 3D model of the arm nervous system as a reference for future studies. Our results helped identify several general features characteristic to the adult echinoderm nervous system, including the extensive anatomical interconnections between the ectoneural and hyponeural components and neuroepithelial organization of the central nervous system with its supporting scaffold formed by radial glial cells. In addition, we provide further support to the notion that the echinoderm radial glia is a complex and diverse cell population. We also tested the suitability of a range of specific cell-type markers for studies of the brittle star nervous system and established that the radial glial cells are reliably labeled by the ERG1 antibodies, whereas the best neuronal markers are acetylated tubulin, ELAV and synaptotagmin B. The transcription factor Brn1/2/4, a marker of neuronal progenitors, is expressed not only in neurons, but also in a subpopulation of radial glia. For the first time, we describe putative ophiuroid proprioceptors associated with the hyponeural part of the central nervous system.
Quaddles: A multidimensional 3D object set with parametrically-controlled and customizable features
Authors: Watson Marcus. R. , Voloh Benjamin , Naghizadeh Milad , Womelsdorf Thilo
Published: September 2017

Many studies of vision and cognition require novel three-dimensional object sets defined by a parametric feature space. Creating such sets and verifying that they are suitable for a given task, however, can be extremely time-consuming and effortful. Here we present a new set of multidimensional objects,Quaddles, designed for a study of feature-based learning and attention, but adaptable for many research purposes. Quaddles have features that are all equally-visible from any angle around the vertical axis, and which all have similar response biases on a feature detection task, thus removing one potential source of bias in object selection. They are available as two-dimensional images, rotating videos, and FBX object files suitable for use with any modern video game engine. We also provide examples and tutorials for modifying Quaddles or creating completely new object sets from scratch, hopefully greatly speeding up the development time of future novel object studies.

Author’s note

This work was supported by grant MOP 102482 from the Canadian Institutes of Health Research (TW) and by the Natural Sciences and Engineering Research Council of Canada Brain in Action CREATE-IRTG program (MRW, TW). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of this manuscript. Authors would like to thank Hongying Wang for technical support, and Isabel Gauthier for comments on a draft version of the manuscript.

The study described herein was approved by the York University Office of Research Ethics (Certificate # 2016-214).

A draft version of this manuscript is available online at BioRχiv:
Smart switching in feedforward control of grip force during manipulation of elastic objects
Authors: White Olivier , Karniel Amir , Leib Raz , Papaxanthis Charalambos , Barbiero Marie , Nisky ilana
Published: September 2017

Switching systems are common in artificial control systems. Here, we suggest that the brain adopts a switched feedforward control of grip forces during manipulation of objects. We measured how participants modulated grip force when interacting with soft and rigid virtual springs when stiffness varied nearly continuously between trials. We identified a sudden phase transition between two forms of feedforward control that differed in the timing of the synchronization between the anticipated load force and the applied grip force. The switch occurred several trials after a threshold stiffness level. These results suggest that in the control of grip force, the brain acts as a switching control system. This opens new research questions as to the nature of the discrete state variables that drive the switching.
Olfactory fear conditioning non-specifically enhances glomerular odor responses and increases representational overlap of learned and neutral odors
Authors: Ross Jordan M. , Fletcher Max L.
Published: September 2017

Associative fear learning produces fear toward the conditioned stimulus (CS) and often generalization, the expansion of fear from the CS to similar, unlearned stimuli. However, how fear learning affects early sensory processing of learned and unlearned stimuli in relation to behavioral fear responses to these stimuli remains unclear. We subjected mice to a classical olfactory fear conditioning paradigm and used awake,in vivocalcium imaging to quantify learning-induced changes in glomerular odor responses, which constitutes the first site of olfactory processing in the brain. The results demonstrate that olfactory fear learning non-specifically enhances glomerular odor representations in a learning-dependent manner and increases representational similarity between the CS and non-conditioned odors. This mechanism may prime the system towards generalization of learned fear. Additionally, CS-specific enhancements remain even when associative learning is blocked; suggesting two separate mechanisms lead to enhanced glomerular responses following odor-shock pairings.