bluuebunny/crossref_metadata_2025 huggingface dataset:
New Developments in Surgery for Endometriosis and Pelvic Pain
Authors: LUU THANH HA , UY-KROH M. JEAN
Published: March 2017

Endometriosis is a common disease affecting reproductive age women. Pain is one of the most common symptoms associated with endometriosis. When medical therapy has failed or in known deeply infiltrating endometriosis, surgical management is warranted. Laparoscopy is the gold standard for diagnosis and treatment of endometriosis. Recent developments in surgery have shown the feasibility of robotic surgery for endometriosis, although these methods have not been shown to be superior to conventional laparoscopy. Enhanced imaging techniques including fluorescence imaging and narrow band imaging have also been studied. However, long-term clinical benefits have yet to be demonstrated.
Cost-effectiveness of the 13-valent Pneumococcal Conjugate Vaccine in Children in Portugal
Authors: Gouveia Miguel , Fiorentino Francesca , Jesus Gonçalo , Costa João , Borges Margarida
Published: March 2017

Background:

Pneumococcal infections are the leading cause of vaccine-preventable death in children. In June 2015, the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in the Portuguese Immunization Program. We evaluated the cost-effectiveness of children vaccinated with PCV13 versus no vaccination for preventing pneumococcal diseases.

Methods:

A cohort simulation model for 2014 Portuguese newborns was used, considering a lifetime horizon and existence of herd effect on adults. Model outcomes measured life years gained, direct and indirect healthcare costs and net benefits considering €20,000 per life years gained. PCV13 clinical effectiveness rate by serotype covered was assumed similar to PCV7. Patients’ resource use was based on 2014 diagnostic-related group database and experts’ opinion, while national legislation and official drug cost database were the main sources for unitary costs. Univariate sensitivity analyses were conducted to assess results’ effectiveness.

Results:

In base case scenario, PCV13 was a dominant strategy, being associated with better health outcomes and lower costs. In a lifetime, a total of 6238 infections (excluding acute otitis media) and 130 deaths were averted, with a total saving of €397,217 ($432,966). Net benefits were estimated above €28 million ($30 million). Results were robust in all sensitivity analyses, with positive net benefits, except when herd effect was excluded.

Conclusions:

Vaccination of children with PCV13 starting in their first year of life is a cost-effective intervention with the potential to save costs to the Portuguese health system and to provide health gains by reducing the burden of pneumococcal disease in the vaccines and through the herd effect of this vaccine.
Impact of Multisystem Health Care on Readmission and Follow-up Among Veterans Hospitalized for Chronic Obstructive Pulmonary Disease
Authors: Rinne Seppo T. , Elwy Anashua R. , Bastian Lori A. , Wong Edwin S. , Wiener Renda S. , Liu Chuan-Fen
Published: March 2017

Background:

Chronic obstructive pulmonary disease (COPD) is one of the most common causes of readmission at Veterans Affairs (VA) hospitals. Previous studies demonstrate worse outcomes for veterans with multisystem health care, though the impact of non-VA care on COPD readmissions is unknown.

Objective:

To examine the association of use of non-VA outpatient care with 30-day readmission and 30-day follow-up among veterans admitted to the VA for COPD.

Design:

This is a retrospective cohort study using VA administrative data and Medicare claims.

Subjects:

In total, 20,472 Medicare-eligible veterans who were admitted to VA hospitals for COPD during October 1, 2008 and September 30, 2011.

Measures:

We identified the source of outpatient care during the year before the index hospitalization as VA-only, dual-care (VA and Medicare), and Medicare-only. Outcomes of interest included any-cause 30-day readmission, COPD-specific 30-day readmission and follow-up visit within 30 days of discharge. We used mixed-effects logistic regression, controlling for baseline severity of illness, to examine the association between non-VA care and postdischarge outcomes.

Results:

There was no association between non-VA care and any-cause readmission. We did identify an increased COPD-specific readmission risk with both dual-care [odds ratio (OR)=1.20; 95% confidence interval (CI), 1.02–1.40] and Medicare-only (OR=1.41; 95% CI, 1.15–1.75). Medicare-only outpatient care was also associated with significantly lower rates of follow-up (OR=0.81; 95% CI, 0.72–0.91).

Conclusions:

Differences in disease-specific readmission risk may reflect differences in disease management between VA and non-VA providers. Further research is needed to understand how multisystem care affects coordination and other measures of quality for veterans with COPD.
Association of the Affordable Care Act With Smoking and Tobacco Treatment Utilization Among Adults Newly Enrolled in Health Care
Authors: Young-Wolff Kelly C. , Klebaner Daniella , Campbell Cynthia I. , Weisner Constance , Satre Derek D. , Adams Alyce S.
Published: March 2017

Objectives:

To examine rates of smoking and tobacco treatment utilization by insurance coverage status (Medicaid, commercial, exchange) among newly enrolled patients in the post Affordable Care Act (ACA) era.

Methods:

We examined new members who enrolled in Kaiser Permanente Northern California through Medicaid, the California exchange, or nonexchange commercial plans (N=122,298) in the first 6 months of 2014 following ACA implementation. We compared these groups on smoking prevalence and tested whether smokers in each group differed on sociodemographic characteristics and in their utilization of tobacco treatment (pharmacotherapy and counseling) in 2014.

Results:

Smoking prevalence was higher among Medicaid (22%) than exchange (13%) or commercial (12%) patients (P<0.0001). Controlling for key sociodemographic and clinical characteristics, Medicaid (odds ratio, 1.49; 95% confidence interval, 1.29–1.73) smokers had greater odds of tobacco treatment use than commercial smokers. Other groups at risk for underuse included men, younger patients, Asians, and Latinos.

Conclusions:

In this cohort of newly enrolled patients after ACA implementation, Medicaid patients were more likely to be smokers compared with exchange and commercial patients, but they were also more likely to use tobacco treatment. Low tobacco treatment use among exchange and commercial plan smokers, as well as younger men, Asians and Latinos poses a significant obstacle to improving public health and additional targeted outreach strategies may be needed to engage these patients with available health services.
Dissecting Leapfrog
Authors: Smith Shawna N. , Reichert Heidi A. , Ameling Jessica M. , Meddings Jennifer
Published: March 2017

Background:

Voluntary Leapfrog Safe Practices Score (SPS) measures were among the first public reports of hospital performance. Recently, Medicare’s Hospital Compare website has reported compulsory measures. Leapfrog’s Hospital Safety Score (HSS) grades incorporate SPS and Medicare measures. We evaluate associations between Leapfrog SPS and Medicare measures, and the impact of SPS on HSS grades.

Methods:

Using 2013 hospital data, we linked Leapfrog HSS data with central line–associated bloodstream infection (CLABSI) and catheter-associated urinary tract infection (CAUTI) standardized infection ratios (SIRs), and Hospital Readmission and Hospital-Acquired Condition (HAC) Reduction Program penalties incorporating 2013 performance. For SPS-providing hospitals, we used linear and logistic regression models to predict CLABSI/CAUTI SIRs and penalties as a function of SPS. For hospitals not reporting SPS, we simulated change in HSS grades after imputing a range of SPS.

Results:

In total, 1089 hospitals reported SPS; >50% self-reported perfect scores for all but 1 measure. No SPS measures were associated with SIRs. One SPS (feedback) was associated with lower odds of HAC penalization (odds ratio, 0.86; 95% confidence interval, 0.76–0.97). Among hospitals not reporting SPS (N=1080), 98% and 54% saw grades decline by 1+ letters with first and 10th percentile SPS imputed, respectively; 49% and 54% saw grades improve by 1+ letter with median and highest SPS imputed.

Conclusions:

Voluntary Leapfrog SPS measures skew toward positive self-report and bear little association with compulsory Medicare outcomes and penalties. SPS significantly impacts HSS grades, particularly when lower SPS is reported. With increasing compulsory reporting, Leapfrog SPS seems limited for comparing hospital performance.
Variability in Objective Refraction for Persons with Down Syndrome
Authors: Marsack Jason D. , Ravikumar Ayeswarya , Benoit Julia S. , Anderson Heather A.
Published: March 2017

Purpose

Down syndrome (DS) is associated with ocular and cognitive sequelae, which both have the potential to influence clinical measures of refractive error. This study compares variability of autorefraction among subjects with and without DS.

Methods

Grand Seiko autorefraction was performed on 139 subjects with DS (age: 8–55, mean: 25 ± 9 yrs) and 138 controls (age: 7–59, mean: 25 ± 10 yrs). Subjects with three refraction measures per eye (DS: 113, control: 136) were included for analysis. Each refraction was converted to power vector notation (M,J0,J45) and a difference in each component (ΔM, ΔJ0, ΔJ45) was calculated for each refraction pairing. From these quantities, average dioptric strength ( JOURNAL/opvis/04.03/00006324-201705000-00005/inline-graphic1/v/2023-08-23T160455Z/r/image-tiff : square root of the sum of the squares ofM,J0, andJ45) and average dioptric difference ( JOURNAL/opvis/04.03/00006324-201705000-00005/inline-graphic2/v/2023-08-23T160455Z/r/image-tiff : square root of the sum of the squares of ΔM, ΔJ0, and ΔJ45) were calculated.

Results

The DS group exhibited a greater median JOURNAL/opvis/04.03/00006324-201705000-00005/inline-graphic3/v/2023-08-23T160455Z/r/image-tiff (1Q: 1.38D M: 2.38D 3Q: 3.41D) than control eyes (1Q: 0.47D M: 0.96D 3Q: 2.75D) (P< .001). Likewise, the DS group exhibited a greater median JOURNAL/opvis/04.03/00006324-201705000-00005/inline-graphic4/v/2023-08-23T160455Z/r/image-tiff in refraction (1Q: 0.27D M: 0.42D 3Q: 0.78D) than control eyes (1Q: 0.11D M: 0.15D 3Q: 0.23D) (P< .001) with 97.1% of control eyes exhibiting JOURNAL/opvis/04.03/00006324-201705000-00005/inline-graphic5/v/2023-08-23T160455Z/r/image-tiff ≤0.50D, compared to 59.3% of DS eyes. An effect of JOURNAL/opvis/04.03/00006324-201705000-00005/inline-graphic6/v/2023-08-23T160455Z/r/image-tiff on JOURNAL/opvis/04.03/00006324-201705000-00005/inline-graphic7/v/2023-08-23T160455Z/r/image-tiff was not detected (P= .3009) nor was a significant interaction between JOURNAL/opvis/04.03/00006324-201705000-00005/inline-graphic8/v/2023-08-23T160455Z/r/image-tiff and group detected (P= .49).

Conclusions

In the current study, comparing three autorefraction readings, median total dioptric difference with autorefraction in DS was 2.8 times the levels observed in controls, indicating greater potential uncertainty in objective measures of refraction for this population. The analysis demonstrates thatJ45is highly contributory to the observed variability.
Task-induced Changes in Idiopathic Infantile Nystagmus Vary with Gaze
Authors: Salehi Fadardi Marzieh , Bathke Arne C. , Harrar Solomon W. , Abel Larry Allen
Published: March 2017

Purpose

Investigations of infantile nystagmus syndrome (INS) at center or at the null position have reported that INS worsens when visual demand is combined with internal states, e.g. stress. Visual function and INS parameters such as foveation time, frequency, amplitude, and intensity can also be influenced by gaze position. We hypothesized that increases from baseline in visual demand and mental load would affect INS parameters at the null position differently than at other gaze positions.

Methods

Eleven participants with idiopathic INS were asked to determine the direction of Tumbling-E targets, whose visual demand was varied through changes in size and contrast, using a staircase procedure. Targets appeared between ±25° in 5° steps. The task was repeated with both mental arithmetic and time restriction to impose higher mental load, confirmed through subjective ratings and concurrent physiological measurements.

Results

Within-subject comparisons were limited to the null and 15° away from it. No significant main effects of task on any INS parameters were found. At both locations, high mental load worsened task performance metrics, i.e. lowest contrast (P = .001) and smallest optotype size reached (P = .012). There was a significant interaction between mental load and gaze position for foveation time (P = .02) and for the smallest optotype reached (P = .028). The increase in threshold optotype size from the low to high mental load was greater at the null than away from it. During high visual demand, foveation time significantly decreased from baseline at the null as compared to away from it (mean difference ± SE: 14.19 ± 0.7 msec; P = .010).

Conclusions

Under high visual demand, the effects of increased mental load on foveation time and visual task performance differed at the null as compared to 15° away from it. Assessment of these effects could be valuable when evaluating INS clinically and when considering its impact on patients’ daily activities.
GIST Manifesting as a Retroperitoneal Tumor
Authors: Miettinen Markku , Felisiak-Golabek Anna , Wang Zengfeng , Inaguma Shingo , Lasota Jerzy
Published: March 2017

Most gastrointestinal stromal tumors (GISTs) occur in the tubular gastrointestinal (GI) tract, but some present apparently outside the GI tract. In this study, we analyzed 112 GISTs located in the retroperitoneum. These tumors occurred in 55 women and 57 men with a median age of 65 years (range: 21 to 89 y). On the basis of clinically or histologically detected connections to GI tract, 15 tumors were considered likely of gastric, 9 duodenal, and 13 of small intestinal origin. The remaining cases were categorized by location as peripancreatic (n=25), pelvic (n=11), mesenteric (n=4), and of unspecified/miscellaneous sites (n=35). The tumors varied in size 3 to 35 cm (median, 15 cm) and by mitotic rate per 5 mm2, 0 to >100 (median, 10). Histologically the tumors apparently arising outside the GI tract had features of intestinal (n=41) and gastric GISTs (n=25); 9 cases had indeterminate histology. The histologic variants included spindled, epithelioid, vacuolated, nested, and myxoid potentially simulating other tumors such as liposarcoma and solitary fibrous tumor. Most GISTs were KIT-positive (106/112 cases), and the remaining 6 tumors were DOG1/Ano1-positive. Five cases showed focal nuclear positivity for MDM2. KIT mutations were detected in 42/59 cases, and PDGFRA mutations in 4/16 KIT wild-type and 3/5 of the KIT-negative tumors analyzed. One pelvic retroperitoneal GIST was succinate dehydrogenase deficient. All 79 patients were dead at last follow-up with a median survival of 14 months, with few survivals >5 years. Only operable versus inoperable tumor was a statistically favorable factor in univariate analysis (P<0.01). In multivariate analysis, mitotic rate >50/5 mm2 was significant for a shorter survival (hazard ratio, 5.25; 95% confidence interval, 1.65-16.8; P<0.01). Histologic and clinicopathologic similarity of extragastrointestinal retroperitoneal GISTs with GISTs of GI tract suggests their GI tract origin. Potentially overlapping features between GIST and other retroperitoneal tumors necessitate use of multiple diagnostic markers and molecular genetic studies.
Xp11 Translocation Renal Cell Carcinomas (RCCs) With RBM10-TFE3 Gene Fusion Demonstrating Melanotic Features and Overlapping Morphology With t(6;11) RCC
Authors: Xia Qiu-yuan , Wang Xiao-tong , Zhan Xue-mei , Tan Xiao , Chen Hao , Liu Yi , Shi Shan-shan , Wang Xuan , Wei Xue , Ye Sheng-bing , Li Rui , Ma Heng-hui , Lu Zhen-feng , Zhou Xiao-jun , Rao Qiu
Published: March 2017

Xp11 translocation renal cell carcinomas (RCC) are characterized by several different translocations involving the TFE3 gene. Tumors with different specific gene fusions may have different clinicopathologic manifestations. Only 3 RBM10-TFE3 RCCs have been reported to date. Here, we added 4 cases of this rare type of tumors with clinicopathologic, immunohistochemical, molecular, and ultrastructural analyses. Most tumors had similar patterns with mixed architectures as follows: acinar, tubular and papillary patterns of epithelioid cells combined with sheets of small cells with “pseudorosette-like” architectures, mimicking the typical morphology of t(6;11) RCC. Cytoplasmic vacuolization, nuclear groove, and psammoma bodies were observed in most cases. Immunohistochemically, all 4 cases demonstrated moderate to strong immunoreactivity for TFE3, Cathepsin K, CD10, Ksp-cadherin, E-cadherin, P504S, RCC marker, PAX8 and vimentin, whereas negativity for TFEB, HMB45, and CK7. CKpan and Melan-A were at least focally expressed. The antibody to Ki-67 showed labeling of 3% to 8% (mean, 5%) of tumor cell nuclei. ;Of interest, several immunostainings demonstrated expression discrepancy in different histology patterns. RBM10-TFE3 fusion transcripts were identified in all cases by reverse transcription-polymerase chain reaction. By fluorescence in situ hybridization, all 4 cases showed unusual split signals with a distance <1 signal diameter (co-localized or subtle split signals) and usually had false-negative results. We also observed ultrastructures, including melanin pigment, nuclear groove, numerous glycogens, mitochondrion with areas of high electron density material, basement membrane material, and cell junctions with poor development. All 4 patients were alive with no evidence of recurrent disease. Our report adds to the known data regarding RBM10-TFE3 RCC.
LMO2-negative Expression Predicts the Presence of MYC Translocations in Aggressive B-Cell Lymphomas
Authors: Colomo Luis , Vazquez Ivonne , Papaleo Natalia , Espinet Blanca , Ferrer Anna , Franco Catalina , Comerma Laura , Hernandez Silvia , Calvo Xavier , Salar Antonio , Climent Fina , Mate José Luis , Forcada Pilar , Mozos Anna , Nonell Lara , Martinez Antonio , Carrio Anna , Costa Dolors , Dlouhy Ivan , Salaverria Itziar , Martin-Subero Jose Ignacio , Lopez-Guillermo Armando , Valera Alexandra , Campo Elias
Published: March 2017

MYC translocation is a defining feature of Burkitt lymphoma (BL), and the new category of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 translocations, and occurs in 6% to 15% of diffuse large B-cell lymphomas (DLBCLs). The low incidence of MYC translocations in DLBCL makes the genetic study of all these lymphomas cumbersome. Strategies based on an initial immunophenotypic screening to select cases with a high probability of carrying the translocation may be useful. LMO2 is a germinal center marker expressed in most lymphomas originated in these cells. Mining gene expression profiling studies, we observed LMO2 downregulation in BL and large B-cell lymphoma (LBCL) with MYC translocations, and postulated that LMO2 protein expression could assist to identify such cases. We analyzed LMO2 protein expression in 46 BLs and 284 LBCL. LMO2 was expressed in 1/46 (2%) BL cases, 146/268 (54.5%) DLBCL cases, and 2/16 (12.5%) high-grade B-cell lymphoma cases with MYC and BCL2 and/or BCL6 translocations. All BLs carried MYC translocation (P<0.001), whereas LMO2 was only positive in 6/42 (14%) LBCL with MYC translocation (P<0.001). The relationship between LMO2 negativity and MYC translocation was further analyzed in different subsets of tumors according to CD10 expression and cell of origin. Lack of LMO2 expression was associated with the detection of MYC translocations with high sensitivity (87%), specificity (87%), positive predictive value and negative predictive value (74% and 94%, respectively), and accuracy (87%) in CD10+ LBCL. Comparing LMO2 and MYC protein expression, all statistic measures of performance of LMO2 surpassed MYC in CD10+ LBCL. These findings suggest that LMO2 loss may be a good predictor for the presence of MYC translocation in CD10+ LBCL.
Methodology for self-report of rest pain (or spontaneous pain) vs evoked pain in chronic neuropathic conditions: a prospective observational pilot study
Authors: He David , Grant Brian , Holden Ronald R. , Gilron Ian
Published: March 2017

Introduction:

The distinction between pain at rest and pain evoked by touch or movement has important clinical implications and may be associated with different mechanisms. However, current methods of clinical pain assessment pay little attention to directly distinguishing between these contrasting components of symptom burden.

Objectives:

We developed the 10-item “Functional Impact of Neuropathic Evoked and Spontaneous Symptom Evaluation” questionnaire designed to distinguish between rest and evoked pain.

Methods:

A prospective observational pilot study of this questionnaire was conducted in 78 participants with neuropathic pain diagnoses. Other study measures included the self-report version of the Leeds Assessment of Neuropathic Symptoms and Signs questionnaire and a modified Brief Pain Inventory. Exploratory analyses were conducted to evaluate the validity of the Functional Impact of Neuropathic Evoked and Spontaneous Symptom Evaluation questionnaire.

Results:

Pain symptoms often/very often/always (1) evoked by touch or movement, and (2) occurring at rest without tactile stimulation were reported by 81% and 65%, respectively. Evoked pain was associated with walking (64%) and standing (35%); and rest pain was associated with watching television (47%), reading (37%), and sitting (36%). Participants reporting both rest and evoked pain tended to report higher levels of pain interference compared to those reporting evoked pain only.

Discussion:

These results provide support for the feasibility and validity of new patient-report methods to distinguish between rest pain and evoked pain in chronic neuropathic conditions. Future studies are needed to confirm the reliability and validity of these methods, which may facilitate important improvements in the research and development of new treatments for chronic pain.
Brief Report: Hormonal Contraception Is Not Associated With Reduced ART Effectiveness Among Women Initiating ART: Evidence From Longitudinal Data
Authors: Patel Rena C. , Baeten Jared M. , Heffron Renee , Hong Ting , Davis Nicole L. , Nanda Kavita , Coombs Robert W. , Lingappa Jairam R. , Bukusi Elizabeth A. , Hurst Stacey , Thomas Katherine K. , Kourtis Athena P. , Mugo Nelly ,   for the Partners in Prevention HSV/HIV Transmission Study and Partners PrEP Study Teams
Published: March 2017

Background:

To explore the association between concomitant hormonal contraceptive and antiretroviral therapy (ART) use and (1) plasma viral suppression and (2) genital HIV shedding among HIV-positive women initiating ART.

Methods:

We analyzed plasma viral load and genital viral RNA shedding from 1079 HIV-positive women initiating ART who were followed prospectively in 3 sub-Saharan African HIV prevention studies. Plasma and endocervical swab samples were collected every 6 months. Self-reported contraceptive use was categorized into injectable, implant, oral, or nonhormonal/no contraception. We used multivariate Cox regression to assess time to plasma viral suppression and logistic regression with generalized estimating equations to assess genital viral shedding for each contraceptive method.

Results:

At the time of ART initiation, there were 211 (20%) injectable, 69 (6%) implant, 50 (5%) oral, and 749 (69%) nonhormonal or no method users. Plasma viral suppression was high (90% by 6 months) and hormonal contraceptives did not diminish time to plasma viral suppression as compared to nonhormonal/no methods [adjusted hazard ratios: injectables 0.89 (95% confidence interval: 0.75 to 1.07), implants 0.91 (0.68 to 1.23), and oral methods 1.33 (1.06 to 1.66)]. Genital viral shedding was uncommon any time after ART initiation (only 9% of samples had detectable viral shedding) and hormonal contraceptives were not associated with an increased detection of genital viral shedding [adjusted odds ratios: injectables 1.07 (0.69 to 1.65), implants 0.67 (0.31 to 1.49), and oral methods 0.56 (0.19 to 1.69)].

Conclusions:

The hormonal contraceptives assessed were not associated with reduced ART effectiveness among HIV-positive women initiating ART. HIV-positive women should continue to be offered contraceptive options, including hormonal ones that best meet their needs.
Novel Synthetic, Host-defense Peptide Protects Against Organ Injury/Dysfunction in a Rat Model of Severe Hemorrhagic Shock
Authors: Yamada Noriaki , Martin Lukas B. , Zechendorf Elisabeth , Purvis Gareth S. D. , Chiazza Fausto , Varrone Barbara , Collino Massimo , Shepherd Joanna , Heinbockel Lena , Gutsmann Thomas , Correa Wilmar , Brandenburg Klaus , Marx Gernot , Schuerholz Tobias , Brohi Karim , Thiemermann Christoph
Published: March 2017

Objective:

To evaluate (1) levels of the host-defense/antimicrobial peptide LL-37 in patients with trauma and hemorrhagic shock (HS) and (2) the effects of a synthetic host-defense peptide; Pep19-4LF on multiple organ failure (MOF) associated with HS.

Background:

HS is a common cause of death in severely injured patients. There is no specific therapy that reduces HS-associated MOF.

Methods:

(1) LL-37 was measured in 47 trauma/HS patients admitted to an urban major trauma center. (2) Male Wistar rats were submitted to HS (90 min, target mean arterial pressure: 27–32 mm Hg) or sham operation. Rats were treated with Pep19-4LF [66 (n = 8) or 333 μg/kg · h (n = 8)] or vehicle (n = 12) for 4 hours following resuscitation.

Results:

Plasma LL-37 was 12-fold higher in patients with trauma/HS compared to healthy volunteers. HS rats treated with Pep19-4LF (high dose) had a higher mean arterial pressure at the end of the 4-hour resuscitation period (79 ± 4 vs 54 ± 5 mm Hg) and less renal dysfunction, liver injury, and lung inflammation than HS rats treated with vehicle. Pep19-4LF enhanced (kidney/liver) the phosphorylation of (1) protein kinase B and (2) endothelial nitric oxide synthase. Pep19-4LF attenuated the HS-induced (1) translocation of p65 from cytosol to nucleus, (2) phosphorylation of IκB kinase on Ser176/180, and (3) phosphorylation of IκBα on Ser32/36 resulting in inhibition of nuclear factor kappa B and formation of proinflammatory cytokines. Pep19-4LF prevented the release of tumor necrosis factor alpha caused by heparan sulfate in human mononuclear cells by binding to this damage-associated molecular pattern.

Conclusions:

Trauma-associated HS results in release of LL-37. The synthetic host-defense/antimicrobial peptide Pep19-4LF attenuates the organ injury/dysfunction associated with HS.
Is It Time to Reconsider Postoperative Epidural Analgesia in Patients Undergoing Elective Ventral Hernia Repair?
Authors: Prabhu Ajita S. , Krpata David M. , Perez Arielle , Phillips Sharon , Huang Li-Ching , Haskins Ivy N. , Rosenblatt Steven , Poulose Benjamin K. , Rosen Michael J.
Published: March 2017

Objective:

We aimed to evaluate the association of epidural analgesia (EA) with hospital length of stay (LOS), wound morbidity, postoperative complications, and patient-reported outcomes in patients undergoing ventral hernia repair (VHR).

Background:

EA has been shown to reduce LOS in certain surgical populations. The LOS benefit in VHR is unclear.

Methods:

Patients having VHR performed in the Americas Hernia Society Quality Collaborative (AHSQC) were separated into 2 comparable groups matched on several confounding factors using a propensity score algorithm: one group received postoperative EA, and the other did not. The groups were then evaluated for hospital LOS, 30-day wound morbidity, other complications, and 30-day patient-reported outcomes using pain and hernia-specific quality-of-life instruments.

Results:

A 1:1 match was achieved and the final analysis included 763 patients receiving EA and 763 not receiving EA. The EA group had an increased LOS (5.49 vs 4.90 days; P < 0.05). The rate of wound events was similar between the groups. There was an increased risk of having any postoperative complication associated with having EA (26% vs 21%; P < 0.05). Pain intensity-scaled scores were significantly higher (worse) in the EA group versus the non-EA group (47.6 vs 44.0; P = 0.04).

Conclusions:

The LOS benefit of EA noted for other operations may not apply to patients undergoing VHR. Further study is necessary to determine the beneficial role of invasive pain management procedures in this group of patients with an extremely common disease state.
Effects of Intraoperative Fluid Management on Postoperative Outcomes
Authors: Shin Christina H. , Long Dustin R. , McLean Duncan , Grabitz Stephanie D. , Ladha Karim , Timm Fanny P. , Thevathasan Tharusan , Pieretti Alberto , Ferrone Cristina , Hoeft Andreas , Scheeren Thomas W. L. , Thompson Boyd Taylor , Kurth Tobias , Eikermann Matthias
Published: March 2017

Objective:

Evaluate the dose-response relationship between intraoperative fluid administration and postoperative outcomes in a large cohort of surgical patients.

Background:

Healthy humans may live in a state of fluid responsiveness without the need for fluid supplementation. Goal-directed protocols driven by such measures are limited in their ability to define the optimal fluid state during surgery.

Methods:

This analysis of data on file included 92,094 adult patients undergoing noncardiac surgery with endotracheal intubation between 2007 and 2014 at an academic tertiary care hospital and two affiliated community hospitals. The primary exposure variable was total intraoperative volume of crystalloid and colloid administered. The primary outcome was 30-day survival. Secondary outcomes were respiratory complications within three postoperative days (pulmonary edema, reintubation, pneumonia, or respiratory failure) and acute kidney injury. Exploratory outcomes were postoperative length of stay and total cost of care. Our models were adjusted for patient-, procedure-, and anesthesia-related factors.

Results:

A U-shaped association was observed between the volume of fluid administered intraoperatively and 30-day mortality, costs, and postoperative length of stay. Liberal fluid volumes (highest quintile of fluid administration practice) were significantly associated with respiratory complications whereas both liberal and restrictive (lowest quintile) volumes were significantly associated with acute kidney injury. Moderately restrictive volumes (second quintile) were consistently associated with optimal postoperative outcomes and were characterized by volumes approximately 40% less than traditional textbook estimates: infusion rates of approximately 6–7 mL/kg/hr or 1 L of fluid for a 3-hour case.

Conclusions:

Intraoperative fluid dosing at the liberal and restrictive margins of observed practice is associated with increased morbidity, mortality, cost, and length of stay.
The Most Informative Neural Code Accounts For Population Heterogeneity
Authors: Zavitz Elizabeth , Price Nicholas SC
Published: March 2017

Perception is produced by ‘reading out’ the representation of a sensory stimulus contained in the firing rates of a population of neurons. To examine experimentally how populations code information, a common approach is to decode a linearly-weighted sum of the neurons’ firing rates. This approach is popular because of its biological validity: weights in a computational decoder are analogous to synaptic strengths. For neurons recorded in vivo, weights are highly variable when derived through machine learning methods, but it is unclear what neuronal properties explain this variability, and how the variability affects decoding performance. To address this, we recorded from neurons in the middle temporal area (MT) of anesthetized marmosets (Callithrix jacchus) viewing stimuli comprising a sheet of dots that moved coherently in one of twelve different directions. We found that high gain and direction selectivity both predicted that a neuron would be weighted more highly in an optimised decoding model. Although learned weights differed markedly from weights chosen according to apriorirules based on a neuron’s tuning profile, decoding performance was only marginally better for the learned weights. In the models with apriorirules, selectivity is the best predictor of weighting, and defining weights according to a neuron’s preferred direction and selectivity improves decoding performance to very near the maximum level possible, as defined by the learned weights.

New & Noteworthy

We examined which aspects of a neuron’s tuning account for its contribution to sensory coding. Strongly direction-selective neurons were weighted most highly by machine learning algorithms trained to discriminate motion direction. Models witha prioridefined decoding weights demonstrate that the learned weighting scheme causally improved direction representation by a neuronal population. Optimising decoders (using machine learning) lead to only marginally better performance than decoders based purely on a neuron’s preferred direction and selectivity.
A Possible Link Between Pyriproxyfen and Microcephaly
Authors: Bar-Yam Yaneer , Frederik Nijhout H. , Parens Raphael , Costa Felipe , Morales Alfredo J.
Published: March 2017

The Zika virus has been the primary suspect in the large increase in incidence of microcephaly in 2015-6 in Brazil. However its role is not confirmed despite individual cases in which viral infections were found in neural tissue. Recently, the disparity between the incidences in different geographic locations has led to questions about the virus’s role. Here we consider the alternative possibility that the use of the insecticide pyriproxyfen for control of mosquito populations in Brazilian drinking water is the primary cause. Pyriproxifen is a juvenile hormone analog which has been shown to correspond in mammals to a number of fat soluble regulatory molecules including retinoic acid, a metabolite of vitamin A, with which it has cross-reactivity and whose application during development has been shown to cause microcephaly. Methoprene, another juvenile hormone analog that was approved as an insecticide based upon tests performed in the 1970s, has metabolites that bind to the mammalian retinoid X receptor, and has been shown to cause developmental disorders in mammals. Isotretinoin is another example of a retinoid causing microcephaly in human babies via maternal exposure and activation of the retinoid X receptor in developing fetuses. Moreover, tests of pyriproxyfen by the manufacturer, Sumitomo, widely quoted as giving no evidence for developmental toxicity, actually found some evidence for such an effect, including low brain mass and arhinencephaly—incomplete formation of the anterior cerebral hemispheres—in exposed rat pups. Finally, the pyriproxyfen use in Brazil is unprecedented— it has never before been applied to a water supply on such a scale. Claims that it is not being used in Recife, the epicenter of microcephaly cases, do not distinguish the metropolitan area of Recife, where it is widely used, and the municipality, and have not been adequately confirmed. Given this combination of information about molecular mechanisms and toxicological evidence, we strongly recommend that the use of pyriproxyfen in Brazil be suspended until the potential causal link to microcephaly is investigated further.
Dynamical networks: finding, measuring, and tracking neural population activity using network science
Authors: Humphries Mark D.
Published: March 2017

Systems neuroscience is in a head-long rush to record from as many neurons at the same time as possible. As the brain computes and codes using neuron populations, it is hoped these data will uncover the fundamentals of neural computation. But with hundreds, thousands, or more simultaneously recorded neurons comes the inescapable problems of visualising, describing, and quantifying their interactions. Here I argue that network science provides a set of scalable, analytical tools that already solve these problems. By treating neurons as nodes and their interactions as links, a single network can visualise and describe an arbitrarily large recording. I show that with this description we can quantify the effects of manipulating a neural circuit, track changes in population dynamics over time, and quantitatively define theoretical concepts of neural populations such as cell assemblies. Using network science as a core part of analysing population recordings will thus provide both qualitative and quantitative advances to our understanding of neural computation.
Psychiatric Genomics: An Update and an Agenda
Authors: Sullivan Patrick F , Agrawal Arpana , Bulik Cynthia M , Andreassen Ole A , Børglum Anders D , Breen Gerome , Cichon Sven , Edenberg Howard J , Faraone Stephen V , Gelernter Joel , Mathews Carol A , Nievergelt Caroline M , Smoller Jordan , O’Donovan Michael C ,   for the Psychiatric Genomics Consortium
Published: March 2017

The Psychiatric Genomics Consortium (PGC) is the largest consortium in the history of psychiatry. In the past decade, this global effort has delivered a rapidly increasing flow of new knowledge about the fundamental basis of common psychiatric disorders, particularly given its dedication to rapid progress and open science. The PGC has recently commenced a program of research designed to deliver “actionable” findings - genomic results that (a) reveal the fundamental biology, (b) inform clinical practice, and (c) deliver new therapeutic targets. This is the central idea of the PGC: to convert the family history risk factor into biologically, clinically, and therapeutically meaningful insights. The emerging findings suggest that we are entering into a phase of accelerated translation of genetic discoveries to impact psychiatric practice within a precision medicine framework.

Collaborators

PGC Coordinating Committee: Mark Daly, Michael Gill, John Kelsoe, Karestan Koenen, Douglas Levinson, Cathryn Lewis, Ben Neale, Danielle Posthuma, Jonathan Sebat, and Pamela Sklar.
Quantitative evaluation of two-photon calcium imaging modalities for high-speed volumetric calcium imaging in scattering brain tissue
Authors: Weisenburger Siegfried , Prevedel Robert , Vaziri Alipasha
Published: March 2017

Considerable efforts are currently being devoted to enhance the speed, spatial resolution and the size of the 3D sample volumes in which calcium imaging methods can capture neuronal network activity in different model systems. In the mammalian brain, tissue scattering severely limits the use of parallel acquisition techniques such as wide-field imaging and, as a consequence, methods based on two-photon point-scanning (2PM) have become the method of choice. However, 2PM faces severe restrictions due to technical limitations such as scan speed, laser power, and those related to the fluorescent probes, calling for conceptually new approaches to enhance the performance of two-photon calcium imaging schemes. Here we provide a detailed quantitative evaluation and comparison of different excitation/detection modalities from the perspective of detecting neuronal activity that are based on different point-spread functions (PSF), laser repetition rates and sampling strategies. We demonstrate the conditions for which imaging speed and signal-to-noise ratio are optimized for a given average power. Our results are based on numerical simulations which are informed by experimentally measured parameters and show that volumetric field of view and acquisition speed can be considerably improved compared to traditional 2PM schemes by a holistic optimization approach.
Synthetic analysis of natural variants yields insights into the evolution and function of auxin signaling F-box proteins inArabidopsis thaliana
Authors: Wright R. Clay , Zahler Mollye L. , Gerben Stacey R. , Nemhauser Jennifer L.
Published: March 2017

The evolution of complex body plans in land plants has been paralleled by gene duplication and divergence within nuclear auxin-signaling networks. A deep mechanistic understanding of auxin signaling proteins therefore may allow rational engineering of novel plant architectures. Towards that end, we analyzed natural variation in the auxin receptor F-box family of wild accessions of the reference plantArabidopsis thalianaand used this information to populate a structure/function map. We employed a synthetic assay to identify natural hypermorphic F-box variants, and then assayed auxin-associated phenotypes in accessions expressing these variants. To more directly measure the impact of the strongest variant in our synthetic assay on auxin sensitivity, we generated transgenic plants expressing this allele. Together, our findings link evolved sequence variation to altered molecular performance and auxin sensitivity. This approach demonstrates the potential for combining synthetic biology approaches with quantitative phenotypes to harness the wealth of available sequence information and guide future engineering efforts of diverse signaling pathways.
Modeling signaling-dependent pluripotent cell states with boolean logic can predict cell fate transitions
Authors: Yachie-Kinoshita Ayako , Onishi Kento , Ostblom Joel , Posfai Eszter , Rossant Janet , Zandstra Peter W.
Published: March 2017

Pluripotent stem cells (PSCs) exist in multiple stable states, each with specific cellular properties and molecular signatures. The process by which pluripotency is either maintained or destabilized to initiate specific developmental programs is poorly understood. We have developed a model to predict stabilized PSC gene regulatory network (GRN) states in response to combinations of input signals. While previous attempts to model PSC fate have been limited to static cell compositions, our approach enables simulations of dynamic heterogeneity by combining an Asynchronous Boolean Simulation (ABS) strategy with simulated single cell fate transitions using Strongly Connected Components (SCCs). This computational framework was applied to a reverse-engineered and curated core GRN for mouse embryonic stem cells (mESCs) to simulate responses to LIF, Wnt/β-catenin, FGF/ERK, BMP4, and Activin A/Nodal pathway activation. For these input signals, our simulations exhibit strong predictive power for gene expression patterns, cell population composition, and nodes controlling cell fate transitions. The model predictions extend into early PSC differentiation, demonstrating, for example, that a Cdx2-high/Oct4-low state can be efficiently and robustly generated from mESCs residing in a naïve and signal-receptive state sustained by combinations of signaling activators and inhibitors.

One Sentence Summary

Predictive control of pluripotent stem cell fate transitions
Gut microbiota analysis in rats with methamphetamine-induced conditioned place preference
Authors: Ning Tingting , Gong Xiaokang , Xie Lingling , Baomiao MA
Published: March 2017

Methamphetamine abuse is a major public health crisis. Because accumulating evidence supports the hypothesis that the gut microbiota plays an important role in central nervous system (CNS) function, and research on the roles of the microbiome in CNS disorders holds conceivable promise for developing novel therapeutic avenues for treating CNS disorders, we sought to determine whether administration of methamphetamine leads to alterations in the intestinal microbiota. In this study, the gut microbiota profiles of rats with methamphetamine-induced conditioned place preference (CPP) were analysed through 16S rRNA gene sequencing. The faecal microbial diversity was slightly higher in the METH CPP group. The propionate-producing genusPhascolarctobacteriumwas attenuated in the METH CPP group, and the familyRuminococcaceaewas elevated in the METH CPP group. Short chain fatty acid analysis revealed that the concentrations of propionate were decreased in the faecal matter of METH-administered rats. These findings provide direct evidence that administration of METH causes gut dysbiosis, enable a better understanding of the function of gut microbiota in the process of drug abuse, and provide a new paradigm for addiction treatment.
The Sentieon Genomics Tools - A fast and accurate solution to variant calling from next-generation sequence data
Authors: Freed Donald , Aldana Rafael , Weber Jessica A. , Edwards Jeremy S.
Published: March 2017

In the past six years worldwide capacity for human genome sequencing has grown by more than five orders of magnitude, with costs falling by nearly two orders of magnitude over the same period [1], [2]. The rapid expansion in the production of next-generation sequence data and the use of these data in a wide range of new applications has created a need for improved computational tools for data processing. The Sentieon Genomics tools provide an optimized reimplementation of the most accurate pipelines for calling variants from next-generation sequence data, resulting in more than a 10-fold increase in processing speed while providing identical results to best practices pipelines. Here we demonstrate the consistency and improved performance of Sentieon’s tools relative to BWA, GATK, MuTect, and MuTect2 through analysis of publicly available human exome, low-coverage genome, and high-depth genome sequence data.
Widespread paleopolyploidy, gene tree conflict, and recalcitrant relationships among the carnivorous Caryophyllales
Authors: Walker Joseph F. , Yang Ya , Moore Michael J. , Mikenas Jessica , Timoneda Alfonso , Brockington Samuel F. , Smith Stephen A.
Published: March 2017

The carnivorous members of the large, hyperdiverse Caryophyllales (e.g. Venus flytrap, sundews andNepenthespitcher plants) represent perhaps the oldest and most diverse lineage of carnivorous plants. However, despite numerous studies seeking to elucidate their evolutionary relationships, the early-diverging relationships remain unresolved.

To explore the utility of phylogenomic data sets for resolving relationships among the carnivorous Caryophyllales, we sequenced ten transcriptomes, including all the carnivorous genera except those in the rare West African liana family (Dioncophyllaceae). We used a variety of methods to infer the species tree, examine gene tree conflict and infer paleopolyploidy events.

Phylogenomic analyses support the monophyly of the carnivorous Caryophyllales, with an origin of 68-83 mya. In contrast to previous analyses recover the remaining non-core Caryophyllales as non-monophyletic, although there are multiple reasons this result may be spurious and node supporting this relationship contains a significant amount gene tree discordance. We present evidence that the clade contains at least seven independent paleopolyploidy events, previously debated nodes from the literature have high levels of gene tree conflict, and taxon sampling influences topology even in a phylogenomic data set.

Our data demonstrate the importance of carefully considering gene tree conflict and taxon sampling in phylogenomic analyses. Moreover, they provide a remarkable example of the propensity for paleopolyploidy in angiosperms, with at least seven such events in a clade of less than 2500 species.