bluuebunny/crossref_metadata_2025 huggingface dataset:
A Clinical Nomogram for Predicting Node-positive Disease in Esophageal Cancer
Authors: Semenkovich Tara R. , Yan Yan , Subramanian Melanie , Meyers Bryan F. , Kozower Benjamin D. , Nava Ruben , Patterson G. Alexander , Kreisel Daniel , Puri Varun
Published: July 2019

Objective:

We developed and validated a nomogram predicting the likelihood of occult lymph node metastases in surgically resectable esophageal cancers.

Background:

Patients with esophageal cancer with positive lymph nodes benefit from neoadjuvant therapy, but limitations in current clinical staging techniques mean nodal metastases often go undetected preoperatively.

Methods:

The National Cancer Database was queried for patients with clinical T1-3N0M0 cancer undergoing upfront esophagectomy from 2004 to 2014. Multivariable logistic regression was used to develop the risk model using both statistical significance and clinical importance criteria for variable selection. Predictive accuracy was assessed and bootstrapping was used for validation. A nomogram was constructed for presentation of the final model.

Results:

Of 3186 patients, 688 (22%) had pathologic lymph node involvement (pN+) and 2498 (78%) had pN0 status. Variables associated with pN+ status included histology [adenocarcinoma vs squamous: odds ratio (OR) 1.75], tumor stage (T1: reference, T2: OR 1.90, T3: OR 2.17), tumor size (<1 cm: reference, 1–2 cm: OR 2.25, 2–3 cm: OR 3.82, 3–4 cm: OR 5.40, 4–5 cm: OR 5.66, ≥5 cm: OR 6.02), grade (1: reference, 2: OR 2.62, 3: OR 4.39, 4: OR 4.15, X: OR 1.87), and presence of lymphovascular invasion (absent: reference, present: OR 4.70, missing: OR 1.87), all P < 0.001. A nomogram with these variables had good predictive accuracy (Brier score: 0.14, calibration slope: 0.97, c-index: 0.77).

Conclusions:

We created a nomogram predicting the likelihood of pathologic lymph node involvement in patients with esophageal cancer who are clinically node negative using a generalizable dataset. Risk stratification with this nomogram could improve delivery of appropriate perioperative care.
Clinical Evaluation of Intraoperative Near Misses in Laparoscopic Rectal Cancer Surgery
Authors: Curtis Nathan J. , Dennison Godwin , Brown Chris S. B. , Hewett Peter J. , Hanna George B. , Stevenson Andrew R. L. , Francis Nader K.
Published: July 2019

Objective:

To investigate the frequency, nature, and severity of intraoperative adverse near miss events within advanced laparoscopic surgery and report any associated clinical impact.

Background:

Despite implementation of surgical safety initiatives, the intraoperative period is poorly documented with evidence of underreporting. Near miss analyses are undertaken in high-risk industries but not in surgical practice.

Methods:

Case video and data from 2 laparoscopic total mesorectal excision randomized controlled trials were analyzed (ALaCaRT ACTRN12609000663257, 2D3D ISRCTN59485808). Intraoperative adverse events were identified and categorized using the observational clinical human reliability analysis technique. The EAES classification was applied by 2 blinded assessors. EAES grade 1 events (nonconsequential error, no damage, or need for correction) were considered near misses. Associated clinical impact was assessed with early morbidity and histopathology outcomes.

Results:

One hundred seventy-five cases contained 1113 error events. Six hundred ninety-eight (62.7%) were near misses (median 3, IQR 2–5, range 0–15) with excellent inter-rater and test–retest reliability (κ=0.86, 95% CI 0.83–0.89, P < 0.001 and κ=0.88, 95% CI 0.85–0.9, P < 0.001 respectively). Significantly more near misses were seen in patients who developed early complications (4 (3–6) vs. 3 (2–4), P < 0.001). Higher numbers of near misses were seen in patients with more numerous (P = 0.002) and more serious early complications (P = 0.003). Cases containing major intraoperative adverse events contained significantly more near misses (5 (3–7) vs. 3 (2–5), P < 0.001) with a major event observed for every 19.4 near misses.

Conclusion:

Intraoperative adverse events and near misses can be reliably and objectively captured in advanced laparoscopic surgery. Near misses are commonplace and closely associated with morbidity outcomes.
Immunity to Vaccine-preventable Viral Infections in Australians Being Evaluated for Liver Transplantation
Authors: Gardiner Astrid , Liu Ken , Bonnichsen Mark , Joshi Vikram , Davis Rebecca J. , Strasser Simone I.
Published: July 2019

Background.

Vaccine-preventable viral infections are associated with increased risk of morbidity and mortality in immunocompromised patients. Current guidelines recommend routine screening and vaccination of all patients before solid organ transplantation. We studied rates of immunity against vaccine-preventable viruses in liver transplantation (LT) recipients.

Methods.

We retrospectively studied consecutive adult patients who underwent first deceased donor LT at a single center between August 2008 and October 2017. Viruses studied were hepatitis A (HAV), hepatitis B (HBV), varicella zoster virus (VZV), measles, and mumps. Hepatitis B surface antibody (anti-HBs) <10 IU/mL in HBV surface antigen-negative patients and negative IgG to other viruses was regarded as absent immunity.

Results.

Five hundred and fifty-five patients underwent LT (72.4% male; median age, 55.0 y). Percentages of patients who lacked immunity to vaccine-preventable infections were HAV (31.8%), HBV (63.8%), measles (1.4%), mumps (6.6%), and VZV (3.8%). Age was positively associated with immunity (from either past exposure or vaccination) against most viruses, including HAV, measles, mumps, and VZV (P < 0.05 for all). In contrast, older age was marginally associated with anti-HBs <10 IU/mL (P = 0.046). No significant changes in immunity rates were observed during the study period.

Conclusions.

A substantial number of patients undergoing LT are not immune to vaccine-preventable viruses at the time of assessment. This presents an opportunity for pre-LT vaccination and in particular younger patients may need to be targeted.
Comparing Pretransplant and Posttransplant Outcomes When Choosing a Transplant Center: Focus Groups and a Randomized Survey
Authors: Schaffhausen Cory R. , Bruin Marilyn J. , Chu Sauman , Wey Andrew , McKinney Warren T. , Snyder Jon J. , Lake Jack R. , Matas Arthur J. , Kasiske Bertram L. , Israni Ajay K.
Published: July 2019

Background.

In response to calls for an increased focus on pretransplant outcomes and other patient-centered metrics in public reports of center outcomes, a mixed methods study evaluated how the content and presentation style of new information influences decision-making. The mixed methods design utilized qualitative and quantitative phases where the strengths of one method help address limitations of the other, and multiple methods facilitate comparing results.

Methods.

First, a series of organ-specific focus groups of kidney, liver, heart, and lung patients helped to develop and refine potential displays of center outcomes and understand patient perceptions. A subsequent randomized survey included adult internet users who viewed a single, randomly-selected variation of 6 potential online information displays. Multinomial regression evaluated the effects of graphical presentations of information on decision-making.

Results.

One hundred twenty-seven candidates and recipients joined 23 focus groups. Survey responses were analyzed from 975 adults. Qualitative feedback identified patient perceptions of uncertainty in outcome metrics, in particular pretransplant metrics, and suggested a need for clear guidance to interpret the most important metric for organ-specific patient mortality. In the randomized survey, only respondents who viewed a note indicating that transplant rate had the largest impact on survival chose the hospital with the best transplant rate over the hospital with the best posttransplant outcomes (marginal relative risk and 95% confidence interval, 1.161.501.95).

Conclusions.

The presentation of public reports influenced decision-making behavior. The combination of qualitative and quantitative research helped to guide and enhance understanding of the impacts of proposed changes in reported metrics.
Safety and Risk Factors of Pure Laparoscopic Living Donor Right Hepatectomy: Comparison to Open Technique in Propensity Score–matched Analysis
Authors: Park Jungchan , Kwon David Choon Hyuck , Choi Gyu-Seong , Kim Sung Joo , Lee Suk-Koo , Kim Jong Man , Lee Kyo Won , Chung Young Jae , Kim Kyeong Sik , Lee Ji Soo , Rhu Jinsoo , Kim Gaab Soo , Gwak Mi Sook , Ko Justin Sangwook , Lee Ja Eun , Lee SeungHwan , Joh Jae-Won
Published: July 2019

Background.

The innovative pure laparoscopic living donor right hepatectomy (LLDRH) procedure for liver transplantation has never been fully compared to open living donor right hepatectomy (OLDRH). We aimed to compare the donor safety and graft results of pure LLDRH to those of OLDRH.

Methods.

From May 2013 to July 2017, 288 consecutive donors underwent either OLDRH (n = 197) or pure LLDRH (n = 91). After propensity score matching, 72 donors were included in each group. The primary outcome was postoperative complications during a 90-day follow-up period. Comprehensive complication index, duration of hospital stay, need for additional pain control, readmission, and donor outcomes were also compared.

Results.

The incidence of major complication during the 90-day follow-up was higher in the LLDRH group than the OLDRH group (6.6% vs 15.4%, P = 0.017) but was not statistically significant in propensity-matched analysis (11.1% vs 13.9%, odds ratio [OR], 1.29; 95% confidence interval [CI], 0.47-3.51; P = 0.62). A right hepatic duct <1 cm was independently associated with complication in the pure LLDRH group (odds ratio, 4.01; 95% confidence interval, 1.08-14.99; P = 0.04).

Conclusions.

In the initial 91 pure LLDRH cases, incidence of major complication was higher than in the OLDRH group, but the difference was not significant in propensity-matched analysis. A right hepatic duct verified as <1 cm may be related to increased frequency of complications in pure LLDRH donors. Further analysis is needed.
Safe Use of Right Lobe Live Donor Livers With up to 20% Macrovesicular Steatosis Without Compromising Donor Safety and Recipient Outcome
Authors: Bhangui Prashant , Sah Jayant , Choudhary Narendra , Gautam Dheeraj , Gupta Vikas , Srinivasan Thiagrajan , Rastogi Amit , Piplani Tarun , Saraf Neeraj , Saigal Sanjiv , Soin Avi
Published: July 2019

Background.

The principle in right lobe living donor liver transplantation is to use “near-perfect” grafts to maximize recipient benefit with minimal donor risk. Whether and what degree of graft macrovesicular steatosis is safe for both recipient and donor is debatable.

Methods.

We compared donor and recipient outcomes in 623 primary right lobe living donor liver transplantations, using grafts with (Group A; 10%–20% steatosis, n = 92) and without (Group B; <10%, n = 531) significant macrovesicular steatosis, on pre- or intraoperative biopsy.

Results.

Group A donors had higher body mass index, transaminases, fasting blood sugar, triglyceride, low density lipoprotein level, and lower high density lipoprotein, and liver attenuation index on CT scan, and similar future liver remnant. Mean postoperative day (POD) 7, aspartate aminotransferase (61.13 + 24.77 vs 73.17 + 53.71 IU/L;P= 0.04), and prothrombin time-international normalized ratio (1.16 + 0.36 vs 1.28 + 0.24;P= 0.0001) were lower in Group A donors. POD3 of 7 total bilirubin and alanine aminotransferase; POD3 aspartate aminotransferase and prothrombin time-international normalized ratio; postoperative morbidity (Dindo-Clavien >3b), hospital stay were similar in both groups. Recipients in both groups had similar age, model for end-stage liver disease score. Right lobe graft weight (764.8 + 145.46 vs 703.24 + 125.53 grams;P< 0.0001) and GRWR (1.09 + 0.29 vs 1.00 + 0.21;P= 0.0004) were higher in Group A. All biochemical parameters at POD 3 of 7, as well as hospital stay, 30-day mortality were similar in recipients of both groups, even after matching both groups for age, model for end-stage liver disease, and GRWR.

Conclusions.

Use of well-selected right lobe grafts (adequate future liver remnant in donor, GRWR in recipient), with up to 20% macrovesicular steatosis, does not compromise graft function and outcomes and is safe for the donor.
Stoma Bridge Types and Their Impact on Patient Outcomes
Authors: McTigue Toni , Lei Jason , Kowalski Mildred Ortu , Prestera Susan , Chiu Stephanie , Shehebar Josef A.
Published: July 2019

PURPOSE:

The purpose of this study was to describe the effect of rigid or flexible stoma bridges used for loop ostomy diversions on peristomal skin integrity. Additional aims were to describe surgeon practices related to stoma bridges, and determine the availability of an ostomy nurse specialist.

DESIGN:

Retrospective chart review and cross-sectional survey.

SAMPLE AND SETTING:

The sample used to address the first aim (effect of stoma bridges) comprised 93 adult patients cared for at Morristown Medical Center, Atlantic Health System, Morristown, New Jersey, an acute care facility. Data provided by 355 colorectal surgeons from 30 countries were used to describe surgeon practice in this area and determine the availability of an ostomy nurse specialist. Respondents were invited from an international roster of colorectal surgeons obtained with permission from the American Society of Colon and Rectal Surgeons (ASCRS).

METHODS:

In order to accomplish the initial aim, we retrospectively reviewed medical records of patients who underwent ostomy surgery from 2008 to 2015 and met inclusion criteria. In order to meet our additional aims, analyzed data were obtained from a survey of colorectal surgeons that queried practices related to stoma bridges, and availability of an ostomy nurse specialist.

RESULTS:

Patients managed with a rigid bridge were significantly more likely to experience leakage beneath the pouching system faceplate than were patients managed by a flexible bridge (42% vs 11%, P < .001). Slightly less than one quarter of patients who developed leakage (n = 22, 24%) experienced pressure and moisture-related peristomal skin complications. Peristomal wounds, inflammation, and infection were significantly higher when a rigid bridge was used (χ2 test, P < .003). The surgeon's survey (N = 355) showed variability in the use of bridges. Ninety-three percent of all surgeons indicated an ostomy nurse specialist was part of their health care team.

CONCLUSIONS:

Rigid ostomy bridges were associated with a higher likelihood of leakage from underneath the faceplate of the pouching system and impaired peristomal skin integrity. Analysis of colorectal surgeon responses to a survey indicated no clear consensus related to bridge use in patients undergoing loop ostomies.
Examining Prevalence and Risk Factors of Incontinence-Associated Dermatitis Using the International Pressure Ulcer Prevalence Survey
Authors: Kayser Susan A. , Phipps LeeAnn , VanGilder Catherine A. , Lachenbruch Charlie
Published: July 2019

PURPOSE:

To evaluate prevalence and risk factors of incontinence-associated dermatitis (IAD).

DESIGN:

Retrospective analysis of 2016 International Pressure Ulcer Prevalence survey data.

SUBJECTS AND SETTING:

Adult patients who were in acute care, long-term acute care, long-term care, and rehabilitation facilities in the United States and Canada.

METHODS:

IAD prevalence was calculated among all patients surveyed, among the incontinent patients only, across multiple care settings, and by incontinence type. A logistic regression examined risk factors for IAD in the incontinent population.

RESULTS:

Nearly 1 in 5 incontinent patients had IAD documented. Incontinence-associated dermatitis prevalence in the entire patient population was 4.3% while incontinence prevalence was 18%. Of incontinent patients, prevalence of IAD ranged from 8.4% in long-term care facilities to 19% in acute care facilities. Facilities with higher rates of incontinence did not necessarily have higher prevalence of IAD. Incontinence-associated dermatitis prevalence by incontinence type ranged from 12% for patients with urinary incontinence to 26% for patients with fecal management systems. Regression results support the association of the following factors with an increased likelihood of IAD documented: all types of incontinence, fecal management systems, higher body weight, diminished mobility, additional linen layers, longer length of stay, and lower Braden Scale scores.

CONCLUSIONS:

Incontinence-associated dermatitis remains a concern in acute care settings. Risk factors associated with IAD were similar to risk factors previously reported for hospital-acquired pressure injuries, such as limited mobility, longer lengths of stay, and additional linen layers. By consistently documenting IAD as well as pressure injury prevalence, facilities may benchmark overall skin prevention models.
Plasma Itaconate elevation following successful cDMARD treatment in early rheumatoid arthritis patients elucidates disease activity associated macrophage activation
Authors: Daly Rónán , Blackburn Gavin , Mudaliar Manikhandan , Burgess Karl , Stirling Anne , Porter Duncan , McInnes Iain , Barrett Michael P. , Dale James
Published: July 2019

Objective

To characterize changes in the plasma metabolic profile in newly diagnosed rheumatoid arthritis (RA) patients upon commencement of conventional disease modifying anti-rheumatic drug (cDMARD) therapy.

Methods

Plasma samples collected in an early RA randomized strategy study (NCT00920478) that compared clinical (DAS) disease activity assessment with musculoskeletal ultrasound assessment (MSUS) to drive treatment decisions were subjected to untargeted metabolomic analysis. Metabolic profiles were collected at pre- and 3 months post commencement of non-biologic cDMARD. Metabolites that changed in association with changes in the DAS44 score were identified at the 3 month timepoint.

Results

A total of ten metabolites exhibited a clear correlation with reduction in DAS44 score following cDMARD commencement, particularly itaconate, its derived anhydride and a derivative of itaconate coA. Increasing itaconate correlated with improved DAS44 score and decreasing levels of CRP.

Conclusion

cDMARD treatment effects invoke consistent changes in plasma detectable metabolites, that in turn implicate clinical disease activity with macrophages. Such changes inform RA pathogenesis and reveal for the first time a link between itaconate production and resolution of an inflammatory disease in humans. Quantitative metabolic biomarker based tests of clinical change in state are feasible and should be developed around the itaconate pathway.

Key Messages

What is already known about this subject?

Rheumatoid arthritis is associated with perturbations in metabolic activity, which have also been associated with response to certain treatments. In vitro work on immunometabolism has recently revealed itaconate as a key metabolite controlling macrophage activation.

What does this study add?

In newly diagnosed RA, commencement of csDMARD therapy is associated with changes in the levels of ten metabolites (especially itaconate and its derivatives) that correlate to a corresponding fall in disease activity Pathway analyses suggest these metabolites are associated with macrophage activation.

How might this impact on clinical practice?

Changes in metabolite levels in response to treatment provide additional new insights into RA pathogenesis that suggest a focus on macrophage activation state. The association of increased itaconate with decreased inflammation point to possible routes of intervention in RA.
Automated interpretation of the coronary angioscopy with deep convolutional neural networks
Authors: Miyoshi Toru , Higaki Akinori , Kawakami Hideo , Yamaguchi Osamu
Published: July 2019

Background

Coronary angioscopy (CAS) is a useful modality to assess atherosclerotic changes, but interpretation of the images requires expert knowledge. Deep convolutional neural networks (DCNN) can be used for diagnostic prediction and image synthesis.

Methods

107 images from 47 patients, who underwent coronary angioscopy in our hospital between 2014 and 2017, and 864 images, selected from 142 MEDLINE-indexed articles published between 2000 and 2019, were analyzed. First, we developed a prediction model for the angioscopic findings. Next, we made a generative adversarial networks (GAN) model to simulate the CAS images. Finally, we tried to control the output images according to the angioscopic findings with conditional GAN architecture.

Results

For both yellow color (YC) grade and neointimal coverage (NC) grade, we could observe strong correlations between the true grades and the predicted values (YC grade, average r value = 0.80 ± 0.02, p-value <0.001; NC grade, average r value = 0.73 ± 0.02, p < 0.001). The binary classification model for the red thrombus yielded 0.71 ± 0.03 F1-score and the area under the ROC curve (AUC) was 0.91 ± 0.02. The standard GAN model could generate realistic CAS images (average Inception score = 3.57 ± 0.06). GAN-based data augmentation improved the performance of the prediction models. In the conditional GAN model, there were significant correlations between given values and the expert’s diagnosis in YC grade and NC grade.

Conclusion

DCNN is useful in both predictive and generative modeling that can help develop the diagnostic support system for CAS.
The relationship between antihypertensive medications and mood disorders: analysis of linked healthcare data for 1.8 million patients
Authors: Shaw Richard J , Mackay Daniel , Pell Jill P. , Padmanabhan Sandosh , Bailey David S. , Smith Daniel J.
Published: July 2019

Background

Recent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists and calcium channel blockers, were associated with reduced risk of new-onset Major Depressive Disorder (MDD) or bipolar disorder.

Method

Two cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n=538,730) included patients with no previous history of mood disorder, whereas the other (n=262,278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression.

Results

For patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For angiotensin antagonist monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95%CI 1.04-1.31). Beta blockers’ association was stronger (HR 2.68; 95%CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against bipolar disorder, particularly angiotensin antagonists (HR 0.46; 95%CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD.

Conclusions

There was no evidence that antihypertensive medications prevented new episodes of MDD but angiotensin antagonists may represent a novel treatment avenue for bipolar disorder.
First detection of Infectious Spleen and kidney Necrosis Virus (ISKNV) associated with massive mortalities in farmed tilapia in Africa
Authors: Ramírez-Paredez José Gustavo , Paley Richard K. , Hunt William , Feist Stephen W. , Stone David M. , Field Terence R. , Haydon David J. , Ziddah Peter A. , Nkansa Mary , Pecku Emanuel K. , Awuni Joseph A. , Guilder James , Gray Joshua , Duodu Samuel , Wallis Timothy S. , Verner-Jeffreys David W.
Published: July 2019

In late 2018, unusual patterns of very high mortality (>50% production) were reported in intensive tilapia cage culture systems across Lake Volta in Ghana. Samples of fish and fry were collected and analysed from two affected farms between October 2018 and February 2019. Affected fish showed darkening, erratic swimming and abdominal distension with associated ascites. Histopathological observations of tissues taken from moribund fish at different farms revealed lesions indicative of viral infection. These included haematopoietic cell nuclear and cytoplasmic pleomorphism with marginalisation of chromatin and fine granulation. Transmission electron microscopy showed cells contained conspicuous virions with typical Iridovirus morphology i.e. enveloped, with icosahedral and or polyhedral geometries and with a diameter c.160 nm. PCR confirmation and DNA sequencing identified the virions as Infectious Spleen and Kidney Necrosis Virus (ISKNV). Samples of fry and older animals were all strongly positive for the presence of the virus by qPCR. All samples tested negative for TiLV and Nodavirus by qPCR. All samples collected from farms prior to the mortality event were negative for ISKNV. Follow up testing of fish and fry sampled from 5 additional sites in July 2019 showed all farms had fish that were PCR positive for ISKNV, whether there was active disease on the farm or not, demonstrating the disease was endemic to farms all over Lake Volta by that point. The results suggest that ISKNV was the cause of disease on the investigated farms and likely had a primary role in the mortality events. A common observation of coinfections with Streptococcus agalactiae and other tilapia bacterial pathogens further suggests that these may interact to cause severe pathology, particularly in larger fish. Results demonstrate that there are a range of potential threats to the sustainability of tilapia aquaculture that need to be guarded against.
Independent origin of MIRNA genes controlling homologous target genes by partial inverted duplication of antisense-transcribed sequences
Authors: Gramzow Lydia , Lobbes Dajana , Walter Sophia , Innard Nathan , Theißen Günter
Published: July 2019

Some microRNAs (miRNAs) are key regulators of developmental processes, mainly by controlling the accumulation of transcripts encoding transcription factors that are important for morphogenesis. MADS-box genes encode a family of transcription factors which control diverse developmental processes in flowering plants. Here we study the convergent evolution of two MIRNA (MIR) gene families, named MIR444 and MIR824, targeting members of the same clade of MIKCC-group MADS-box genes. We show that these two MIR genes most likely originated independently in monocots (MIR444) and in Brassicales (eudicots, MIR824). We provide evidence that in both cases the future target gene was transcribed in antisense prior to the evolution of the MIR genes. Both MIR genes then likely originated by a partial inverted duplication of their target genes, resulting in natural antisense organization of the newly evolved MIR gene and its target gene at birth. We thus propose a new model for the origin of MIR genes, MEPIDAS (MicroRNA Evolution by Partial Inverted Duplication of Antisense-transcribed Sequences). MEPIDAS is a refinement of the inverted duplication hypothesis. According to MEPIDAS, a MIR gene evolves at a genomic locus at which the future target gene is also transcribed in the antisense direction. A partial inverted duplication at this locus causes the antisense transcript to fold into a stem-loop structure that is recognized by the miRNA biogenesis machinery to produce a miRNA that regulates the gene at this locus. Our analyses exemplify how to elucidate the origin of conserved miRNAs by comparative genomics and will guide future studies.
Spatial variation in black-headed night monkey (Aotus nigriceps) vocalizations
Authors: Helenbrook W. D. , Linck N. A. , Pardo M. A. , Suarez J. A.
Published: July 2019

Quantitative acoustic analysis has been used to decipher individual differences, population structure, and taxonomic diversity in numerous primate species. We previously described three distinct call types in wildAotus nigriceps, and now assess acoustic differences in two of these call types between social groups and spatially distinct populations. Acoustic parameters for both analyzed call types exhibited significant variability between groups. Similarly, geographically distant field sites were acoustically distinct from one another. Several groups also used a variation of a common call: a triplet Ch Ch instead of a duplicate. Other groups made use of ultrasonic frequencies which have not previously been reported inAotus. Our results suggest thatAotus nigricepsexhibits substantial acoustic variability across sites that could potentially be useful for taxonomic classification, although additional geographically distant populations still need to be sampled. The possibility of individual signatures also exists and will require recording vocalizations from known individuals.
Female rats consume and prefer oxycodone more than males in a chronic two-bottle oral voluntary choice paradigm
Authors: Zanni Giulia , DeSalle Matthew J. , Deutsch Hannah M. , Barr Gordon A. , Eisch Amelia J.
Published: July 2019

The increased abuse of opioids - such as oxycodone - poses major challenges for health and socioeconomic systems. Human prescription opioid abuse is marked by continuous, voluntary, oral intake, and sex differences. Therefore the field would benefit from a preclinical in-depth characterization of sex differences in a chronic oral voluntary, free choice, and continuous access paradigm. Here we show in an oral oxycodone continuous access two-bottle choice paradigm sex-dependent voluntary drug intake, dependence, and motivation to take the drug. Adult female and male Long-Evans rats were given unlimited, continuous home cage access to two bottles containing water (Control) or one bottle of water and one bottle of oxycodone dissolved in water (Experimental). Most experimental rats voluntarily drank oxycodone (∼10 mg/kg/day) and escalated their intake over 22 weeks. Females self-administered twice as much oxycodone as males, leading to greater blood levels of oxycodone, and engaged in more gnawing behavior. Precipitated withdrawal revealed high levels of dependence in both sexes. Reflecting motivation to drink oxycodone, ascending concentration of citric acid suppressed the intake of oxycodone (Experimental) and the intake of water (Control); however Experimental rats returned to pre-citric acid preference levels whereas Controls rats did not. Thus, female rats consumed and preferred oxycodone more than males in this chronic two-bottle oral choice paradigm. Both sexes displayed many features of human oxycodone abuse, and behavioral pre-screening predicted parameters of intake and withdrawal. This model provides an additional paradigm for understanding mechanisms that mediate long-term voluntary drug use and for exploring potential treatment options.

HIGHLIGHTS

Adult rats offered continuous choice of oral oxycodone vs. water preferred oxycodone

Rats self-titrated oxycodone, yet females preferred and escalated more than males

Both sexes were motivated to drink oxycodone, as shown by a citric acid aversion test

Both sexes became dependent on oxycodone, as shown by precipitated withdrawal

Behavioral prescreening predicted later aspects of oxycodone intake and dependence
Sensitivity and specificity of a Bayesian single trial analysis for time varying neural signals
Authors: Mohl Jeff T. , Caruso Valeria C. , Tokdar Surya T. , Groh J. M.
Published: July 2019

We recently reported the existence of fluctuations in neural signals that may permit neurons to code multiple simultaneous stimuli sequentially across time1. This required deploying a novel statistical approach to permit investigation of neural activity at the scale of individual trials. Here we present tests using synthetic data to assess the sensitivity and specificity of this analysis. We fabricated datasets to match each of several potential response patterns derived from single-stimulus response distributions. In particular, we simulated dual stimulus trial spike counts that reflected fluctuating mixtures of the single stimulus spike counts, stable intermediate averages, single stimulus winner-take-all, or response distributions that were outside the range defined by the single stimulus responses (such as summation or suppression). We then assessed how well the analysis recovered the correct response pattern as a function of the number of simulated trials and the difference between the simulated responses to each “stimulus” alone. We found excellent recovery of the mixture, intermediate, and outside categories (>97% correct), and good recovery of the single/winner-take-all category (>90% correct) when the number of trials was >20 and the single-stimulus response rates were 50Hz and 20Hz respectively. Both larger numbers of trials and greater separation between the single stimulus firing rates improved categorization accuracy. These results provide a benchmark, and guidelines for data collection, for use of this method to investigate coding of multiple items at the individual-trial time scale.
A Systems Immunology Approach Identifies Cytokine-Induced STAT Signaling Pathways Critical to Rheumatoid Arthritis Disease Activity and Treatment Response
Authors: Ptacek Jason , Hawtin Rachael E. , Sun Dongmei , Louie Brent , Evensen Erik , Mittleman Barbara , Cesano Alessandra , Cavet Guy , Bingham Clifton O. , Cofield Stacey S. , Curtis Jeffrey R. , Danila Maria I. , Raman Chander , Furie Richard , Genovese Mark C. , Robinson William H. , Levesque Marc C. , Moreland Larry W. , Nigrovic Peter A. , Shadick Nancy A. , O’Dell James R. , Thiele Geoffrey M. , Clair E. William St , Striebich Christopher C. , Hale Matthew B. , Khalili Houman , Batliwalla Franak , Aranow Cynthia , Mackay Meggan , Diamond Betty , Nolan Garry P. , Gregersen Peter K. , Bridges S. Louis
Published: July 2019

Rheumatoid arthritis (RA), a chronic autoimmune disease characterized by circulating autoantibodies, involves many cytokine-mediated signaling pathways in multiple immune cell subsets. Most studies of immune cells in RA have limitations, such as analysis of a small number of cell subsets or pathways, and limited longitudinal data on patient phenotypes. In this study, we used an innovative systems immunology approach to simultaneously quantify up to 882 signaling nodes (Jak/STAT signaling readouts modulated by cytokines and other stimuli) in 21 immune cell subsets. We studied 194 RA patients and 41 controls, including 146 well-characterized RA patients prior to, and 6 months after, initiation of methotrexate or biologic agents from the Treatment Efficacy and Toxicity in RA Database and Repository (TETRAD). There was strikingly attenuated signaling capacity in RA patients in IFNα stimulation followed by measurement of phosphorylated STAT1 [IFNα→p-STAT1] in six immune cell subsets. Multiple nodes showed negative association with disease activity, including IFNα→STAT5 signaling in naive and memory B cells. In contrast, IL-6-induced STAT1 and STAT3 activation in central memory CD4-negative T cells showed a positive association with disease activity. Multiple nodes were associated with treatment response, including IFNα→STAT1 in monocytes and IL-6→STAT3 in CD4+ naive T cells. Decision tree analysis identified a model combining these two nodes as a high-performing classifier of treatment response to TNF inhibitors. Our study provides novel information on RA disease mechanisms and serves as a framework for the discovery and validation of biomarkers of treatment response in RA.
Drug screening to identify compounds to act as co-therapies for the treatment of pathogenic Burkholderia
Authors: Barker Sam , Harding Sarah V. , Gray David , Richards Mark I. , Atkins Helen S. , Harmer Nicholas
Published: July 2019

Burkholderia pseudomallei is a soil-dwelling organism present throughout the tropics, and is the causative agent of melioidosis, a disease that is believed to kill 89,000 people per year. It is naturally resistant to most currently available antibiotics. The most efficacious treatment for melioidosis requires at least two weeks of intravenous treatment with ceftazidime or meropenem. This places a large treatment burden on the predominantly middle income nations where the majority of disease occurs. We have established a high-throughput assay for compounds that could be used as a co-therapy to potentiate the effect of ceftazidime, using the related non-pathogenic bacterium Burkholderia thailandensis as a surrogate. Optimization of the assay gave a Z’ factor of 0.68. We screened a library of 61,250 compounds, and identified 29 compounds with a pIC50 (-log10(IC50)) greater than five. Detailed investigation allowed us to down select to six “best in class” compounds, which included the licensed drug chloroxine. Co-treatment of B. thailandensis with ceftazidime and chloroxine reduced culturable cell numbers by two orders of magnitude over 48 hours compared to treatment with ceftazidime alone. Hit expansion around chloroxine was performed using commercially available compounds. Minor modifications to the structure abolished activity, suggesting that chloroxine likely acts against a specific target. Finally, preliminary data also demonstrates the utility of chloroxine to act as a co-therapy to potentiate the effect of ceftazidime against B. pseudomallei. This approach successfully identified potential co-therapies for a recalcitrant Gram-negative bacterial species. Our assay could be used more widely to aid in chemotherapy against these bacteria.
Understanding behavior in a captive Lion-tailed macaques (Macaca silenus) group
Authors: Mazumder Jayashree
Published: July 2019

A captive lion-tailed macaque group, consisting of two adult males and one adult female, was observed over a period of three months. We collected the data from 8.30hrs to 17.30hrs, using both focal and scan animal sampling methods. In the study, we divided the behaviors into abnormal and normal behavioral traits which were further divided into self-directed and social interchange behaviors. When compared with the past records on the wild and captive group, most of the behaviors were similar which included behaviors like forage, grooming, aggressive display and reproductive behavior. Animals who were born in a zoo or confiscated from another zoo showed higher levels of abnormal behaviors. The results of this study discuss the range of behavioral patterns displayed by the captive animals, discuss the causal factors for the behavioral pathogens, and further suggests feasible solutions to increase the welfare of these macaques. In the study, the early life history of the animal and the lack of social and environmental stimulus could be very critical for the development of behavioral pathogens. However, to establish this would require more research.
The P300 as marker of inhibitory control – fact or fiction?
Authors: Huster René J. , Messel Mari S. , Thunberg Christina , Raud Liisa
Published: July 2019

Inhibitory control, i.e., the ability to stop or suppress actions, thoughts, or memories, represents a prevalent and popular concept in basic and clinical neuroscience as well as psychology. At the same time, it is notoriously difficult to study as successful inhibition is characterized by the absence of a continuously quantifiable direct behavioral marker. It has been suggested that the P3 latency, and here especially its onset latency, may serve as neurophysiological marker of inhibitory control as it correlates with the stop signal reaction time (SSRT). The SSRT estimates the average stopping latency, which itself is unobservable since no overt response is elicited in successful stop trials, based on differences in the distribution of go reaction times and the delay of the stop- relative to the go-signal in stop trials.

In a meta-analysis and an independent EEG experiment, we found that correlations between the P3-latency and the SSRT are indeed replicable, but also unspecific. Not only does the SSRT also correlate with the N2-latency, but both P3- and N2-latency measures show similar or even higher correlations with other behavioral parameters such as the go reaction time or stopping accuracy. The missing specificity of P3-SSRT correlations, together with the general pattern of associations, suggests that these manifest effects are driven by underlying latent processes other than inhibition, such as those associated with the speed-accuracy trade-off.
Maintenance of cell type-specific connectivity and circuit function requires Tao kinase
Authors: Tenedini Federico Marcello , González Maria Sáez , Hu Chun , Pedersen Lisa Hedegaard , Petruzzi Mabel Matamala , Spitzweck Bettina , Wang Denan , Richter Melanie , Petersen Meike , Szpotowicz Emanuela , Schweizer Michaela , Sigrist Stephan , de Anda Froylan Calderon , Soba Peter
Published: July 2019

Sensory circuits are typically established during early development, yet how circuit specificity and function are maintained during organismal growth has not been elucidated. To gain insight we quantitatively investigated synaptic growth and connectivity in theDrosophilanociceptive network during larval development. We show that connectivity between primary nociceptors and their downstream neurons scales with animal size. We further identified the conserved Ste20-like kinase Tao as a negative regulator of synaptic growth required for maintenance of circuit specificity and connectivity. Loss of Tao kinase resulted in exuberant postsynaptic specializations and aberrant connectivity during larval growth. Using functional imaging and behavioral analysis we show that loss of Tao-induced ectopic synapses with inappropriate partner neurons are functional and alter behavioral responses in a connection-specific manner. Our data show that fine-tuning of synaptic growth by Tao kinase is required for maintaining specificity and behavioral output of the neuronal network during animal growth.
Auditory brainstem models: adapting cochlear nuclei improve spatial encoding by the medial superior olive in reverberation
Authors: Brughera Andrew , Mikiel-Hunter Jason , Dietz Mathias , McAlpine David
Published: July 2019

Listeners perceive sound-energy as originating from the direction of its source, even as direct sound is followed milliseconds later by reflected sound from multiple different directions. Early-arriving sound is emphasised in the ascending auditory pathway, including the medial superior olive (MSO) where binaural neurons encode the interaural time difference (ITD) cue for spatial location. Behaviourally, weighting of ITD conveyed during rising sound-energy is stronger at 600 Hz, a frequency with higher reverberant energy, than at 200 Hz where reverberant energy is lower. Here we computationally explore the combined effectiveness of adaptation before ITD-encoding, and excitatory binaural coincidence detection within MSO neurons, in emphasising ITD conveyed in early-arriving sound. With excitatory inputs from adapting model spherical bushy cells (SBCs) of the bilateral cochlear nuclei, a Hodgkin-Huxley-type model MSO neuron reproduces the frequency-dependent emphasis of rising vs. peak sound-energy in ITD-encoding. Maintaining the adaptation in model SBCs, and adjusting membrane speed in model MSO neurons, hemispheric populations of model SBCs and MSO neurons, with simplified membranes for computational efficiency, also reproduce the stronger weighting of ITD information conveyed during rising sound-energy at 600 Hz compared to 200 Hz. This hemispheric model further demonstrates a link between strong weighting of spatial information during rising sound-energy, and correct unambiguous lateralisation of reverberant speech.
Establishment of primary transgenic human airway epithelial cell cultures to study respiratory virus – host interactions
Authors: Jonsdottir Hulda R. , Marti Sabrina , Geerts Dirk , Rodriguez Regulo , Thiel Volker , Dijkman Ronald
Published: July 2019

Primary human airway epithelial cell (hAEC) cultures represent a universal platform to propagate respiratory viruses and characterize their host interactions in authentic target cells. To further elucidate specific interactions between human respiratory viruses and important host factors in airway epithelium, it is important to make hAEC cultures amenable to genetic modification. However, the short and finite lifespan of primary cells in cell culture creates a bottleneck for the genetic modification of these cultures. In the current study, we show that the incorporation of the Rho-associated protein kinase (ROCK) inhibitor (Y-27632) during cell propagation extends the life span of primary human cells in vitro and thereby facilitates the incorporation of lentivirus-based expression systems. Using fluorescent reporters for FACS-based sorting, we generated homogenously fluorescent hAEC cultures that differentiate normally after lentiviral transduction. As proof-of-principle, we demonstrate that host gene expression can be modulated post-differentiation via inducible short hairpin (sh)RNA-mediated knockdown. Importantly, functional characterization of these transgenic hAEC cultures with exogenous poly(I:C), as a proxy for virus infection, demonstrates that such modifications do not influence the host innate immune response. Moreover, the propagation kinetics of both human coronavirus 229E (HCoV-229E) and human respiratory syncytial virus (RSV) were not affected. Combined, these results validate our newly established protocol for the genetic modification of hAEC cultures thereby unlocking a unique potential for detailed molecular characterization of virus – host interactions in human respiratory epithelium.
A genetic pathway encoding double-stranded RNA transporters and interactors regulates growth and plasticity inCaenorhabditis elegans
Authors: Braukmann Fabian , Jordan David , Miska Eric Alexander
Published: July 2019

The environment and genes shape the development, physiology and behaviour of organisms. Many animal species can take-up double-stranded RNA (dsRNA) from the environment. Environmental dsRNA changes gene expression through RNA interference (RNAi). While environmental RNAi is used as a laboratory tool, e.g. in nematodes, planaria and insects, its biological role remains enigmatic. Here we characterise the environmental dsRNA receptor SID-2 to understand the biological function of dsRNA uptake inCaenorhabditis elegans. First we determine that SID-2 localises to the apical membrane and the trans-Golgi-network (TGN) in the intestine, implicating the TGN as a central cellular compartment for environmental dsRNA uptake. We demonstrate that SID-2 is irrelevant for nucleotide uptake from the environment as a nutritional (nitrogen) source. Instead RNA profiling and high-resolution live imaging revealed a new biological function forsid-2in growth and phenotypic plasticity. Surprisingly, lack of the ability to uptake environmental RNA reduces plasticity of gene expression. Furthermore, using genetic analyses we show that the dsRNA pathway genessid-2, sid-1andrde-4together regulate growth. This work suggest that environmental RNA affects morphology and plasticity through gene regulation.
Activity of epigenetic inhibitors against Plasmodium falciparum asexual and sexual blood stages
Authors: Vanheer Leen , Kafsack Björn F.C.
Published: July 2019

Regulation of gene expression by epigenetic processes is critical for malaria parasite survival in multiple life stages. To evaluate the suitability of targeting these pathways we screened 350 epigenetic inhibitors against asexual blood stages and gametocytes of P. falciparum. We observed ≥90% inhibition at 10 µM for 28% of compounds, of which a third retained ≥90% inhibition at 1 µM. These results suggest epigenetic regulation as a promising target for the development of new multi-stage anti-malarials.