bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Previous Lower Abdominal Surgery on Outcomes Following Totally Extraperitoneal (TEP) Inguinal Hernia Repair
Authors: Prassas Dimitrios , Ntolia Argyro , Brosa Julia , Kounnamas Aristodemos , Rolfs Thomas-Marten , Schumacher Franz-Josef , Krieg Andreas
Published: February 2019

Background:

Previous lower abdominal surgery is generally considered as a relative contraindication for laparoscopic totally extraperitoneal (TEP) inguinal hernia repair. Our objective was to investigate the feasibility and safety of TEP repair in patients with a history of lower abdominal surgery.

Materials and Methods:

A retrospective analysis of 301 patients with inguinal hernia who underwent elective laparoscopic TEP repair between August 2010 and August 2014 was conducted. One-hundred five patients (34.9%) had previously undergone lower abdominal surgery. The main outcome measures included intraoperative and postoperative morbidity and mortality. Secondary outcomes were immediate postoperative pain, presence of chronic pain at follow-up, and hernia recurrence.

Results:

Patient demographics and clinical variables were balanced between the 2 groups, with the exception of age. Intraoperative morbidity was similar between cases without previous lower abdominal surgery (nPS) and cases with history of lower abdominal surgery (PS) [nPS vs. PS: 0.5% (n=1) vs. 2.8% (n=3), P=0.09]. Overall 30-day morbidity was found to be significantly higher in the PS patient group [nPS vs. PS: 1.5% (n=3) vs. 6.6% (n=7), P=0.018]. Mortality was nil. There were no differences noted between the 2 groups with respect to early postoperative pain and chronic inguinal pain. Complete follow-up information was available for 149 of 301 patients (follow-up rate of 49.5%, range: 3 to 48 mo) with a mean follow-up time of 20.38 months (SD=7.7). There was no statistically significant difference noted in the recurrence rate between the 2 patient groups at follow-up [nPS vs. PS: 3.2% (n=3) vs. 1.8% (n=1), P=0.6].

Conclusions:

The present work demonstrates higher incidence of postoperative scrotal hematoma after TEP repair in patients with history of previous lower abdominal surgery. All remaining outcomes of interest were found to be similar between the 2 patient groups. Further trials will be needed to verify our findings.
The Feasibility of Conventional Forward-viewing Endoscope for Endoscopic Retrograde Cholangiopancreatography in Patients With Altered Gastrointestinal Anatomy
Authors: Bayraktar Onur , Bayraktar Bariş
Published: February 2019

Background:

Endoscopic retrograde cholangiopancreatography (ERCP) has been commonly used for biliopancreatic diseases of patients with normal gastrointestinal (GI) anatomy with a success rate of >90%. However, this procedure may also be necessary in patients with altered GI anatomy such as Billroth II or Roux-en-Y reconstructions. Performing ERCP in these patients may pose extreme technical challenges, and increase the risk of complications. The aim of this study was to analyze the feasibility of ERCP using forward-viewing endoscopy in patients with altered GI anatomy.

Materials and Methods:

Twenty-three patients with previous gastric resections and GI anastomosis, who underwent ERCP between 2012 and 2017, were included in this retrospective study. The major indication for ERCP was choledocholithiasis in 19 patients, and the others were acute cholangitis, sphincter Oddi dysfunction, and biliary pancreatitis. The sedation was induced using a combination of midazolam and propofol, and all procedures were performed using a forward-viewing endoscope.

Results:

Among the 23 patients, 14 were male individuals and 9 were female individuals, with an average age of 62 (range: 58 to 73) years. The median procedure time was 24 (range: 19 to 43) minutes. The success rate of bile duct cannulation was 91.3% (21/23 patients) and that of stone extirpation was 89.4% (17/19 patients with choledocholithiasis). Plastic stents were placed in the 2 patients in whom stone extirpation was not successfully performed. ERCP was repeated in these patients 8 weeks after the initial approach, and stone extraction procedures were successfully completed. The only procedure-related complication was edematous pancreatitis, which was observed in 1 patient (4.7%). The mean length of hospitalization was 2 (range: 1 to 5) days.

Conclusions:

Forward-viewing endoscopes can be effectively used in patients with altered GI anatomy by facilitating the access to the papilla and bile duct cannulation without increasing the incidence of complications.
A Comparative Study of Double-Tract Reconstruction and Roux-en-Y After Gastrectomy for Gastric Cancer
Authors: Hong Jun , Wang Shu-Yan , Hao Han-Kun
Published: February 2019

Background:

The meta-analysis was performed to compare surgical and functional results of double-tract (DT) and Roux-en-Y (RY) reconstruction, applied in both partial and total gastrectomy.

Methods:

PubMed, Ovid, Web of Science, Wiley, EBSCO, and the Cochrane Library Central were searched for studies comparing DT and RY after partial or total gastrectomy. Surgical, nutritional, and long-term outcomes were collected and analyzed.

Results:

A total of 595 patients from 8 studies were included. Operative time, time to first flatus, length of hospital stays, complications, postoperative nutritional variables, and functional result were similar between 2 groups. Group DT had significantly less blood loss, shorter time to oral intake and less loss of body weight at 2 years after operation.

Conclusions:

DT reconstruction is comparable with RY after gastrectomy in safety, surgical outcomes including reflux symptom and postoperative recovery and shows better food intake and body weight maintenance.
Hand-assisted Laparoscopic Splenectomy Advantages Over Complete Laparoscopic Splenectomy For Splenomegaly
Authors: Sun Xiangyu , Liu Zhou , Selim M.H , Huang Yong
Published: February 2019

Background:

Laparoscopic splenectomy (LS) is generally applied for splenectomy, However, it also brings some technical challenges, especially for splenomegaly. Hand-assisted laparoscopic splenectomy (HALS) can help to overcome these drawbacks while maintaining the superiority of LS. This study was aimed to evaluate the efficacy and advantage of HALS for splenomegaly.

Materials and Methods:

Between January 2014 and November 2017, 91 patients with splenomegaly in 2 surgical centers were randomly assigned to either HALS (n=45) or LS (n=46). The patients’ characteristics, intraoperative details, and the postoperative outcomes in both groups were compared.

Results:

Baseline features (sex, age, main diameter, Child-Pugh grade) of both groups had no significant difference (P<0.05). Compared with LS group, the HALS group operation time (141±46 vs. 172±43 min; P=0.001) was shorter, intraoperative blood loss [215 (122.332) vs. 230 (130.740) mL; P=0.026], hospital expenses (5.5±1.5 vs. 6.4±2.4 WanRMB; P=0.022), and conversion rate (1/45 vs. 9/46; P=0.015) were lower. However, there was no significant difference for hospital stay (6.4±2.8 vs. 6.7±3.0 d; P=0.662) and complications (15/45 vs. 12/46; P=0.893) between the 2 groups. In addition, there were no significant differences in postoperative white blood cell (10.6±2.9 vs. 10.9±3.5; P=0.747), AST [61 (47.94) vs. 57 (37.86) U/L; P=0.513], and ALT [68 (54.120) vs. 55 (36.99) U/L; P=0.302] levels.

Conclusions:

HALS can maximize the benefits for patients, while maintaining the advantages of LS and open splenectomy. It is the ideal surgical treatment for splenomegaly.
Overactive Bladder Symptoms After Pelvic Organ Prolapse Repair
Authors: Johnson Justine R. , High Rachel A. , Dziadek Olivia , Ocon Adriana , Muir Tristi W. , Xu Jiaqiong , Antosh Danielle D.
Published: February 2019

Objectives

This study aimed to identify the characteristics associated with overactive bladder (OAB) symptoms perioperatively in patients undergoing pelvic organ prolapse (POP) surgery with and without slings and to determine the rate of OAB symptom resolution postoperatively.

Methods

This retrospective, single-institution study involved women undergoing prolapse surgery with and without concomitant midurethral sling from 2011 to 2016. A validated questionnaire was used to determine OAB symptoms preoperatively and postoperatively. The primary outcome was rate of resolution in OAB symptoms after POP surgery with and without midurethral sling. Baseline characteristics and surgery type were presented, and univariate and multivariate logistic regression models were applied to evaluate characteristics associated with OAB symptoms at the first postoperative visit.

Results

The analysis included 203 patients. Among those with baseline OAB symptoms, 103 (61%) had symptom resolution, whereas 66 (39.1%) reported persistent symptoms. Among 34 patients without baseline OAB symptoms, 6% developed de novo symptoms. Older age was found to be a significant risk factor for persistence of symptoms postoperatively both on univariate (odds ratio, 0.97; 95% confidence interval, 0.94–1; P = 0.038) and multivariate logistic regression (odds ratio, 0.96, 95% confidence interval, 0.92–1; P = 0.049). The rate of medication discontinuation postoperatively was 25%.

Conclusions

Approximately 61% of patients undergoing POP surgery had resolution of OAB symptoms postoperatively whether or not an incontinence procedure was performed. Older age was significantly related to persistent OAB symptoms in both univariate (P = 0.038) and multivariate (P = 0.049) models. The rate of de novo OAB symptoms was 6%.
Intraoperative Hemodynamic Parameters and Acute Kidney Injury After Living Donor Liver Transplantation
Authors: Kim Won Ho , Oh Hye-Won , Yang Seong-Mi , Yu Je Hyuk , Lee Hyung-Chul , Jung Chul-Woo , Suh Kyung-Suk , Lee Kook Hyun
Published: February 2019

Background.

Acute kidney injury (AKI) after living donor liver transplantation (LDLT) is associated with increased mortality. We sought to identify associations between intraoperative hemodynamic variables and postoperative AKI.

Methods.

We retrospectively reviewed 734 cases of LDLT. Intraoperative hemodynamic variables of systemic and pulmonary arterial pressure, central venous pressure (CVP), and pulmonary artery catheter–derived parameters including mixed venous oxygen saturation (Svo
2), right ventricular end-diastolic volume (RVEDV), stroke volume, systemic vascular resistance, right ventricular ejection fraction, and stroke work index were collected. Propensity score matching analysis was performed between patients with (n = 265) and without (n = 265) postoperative AKI. Hemodynamic variables were compared between patients with AKI, defined by Kidney Disease Improving Global Outcomes criteria, and those without AKI in the matched sample.

Results.

The incidence of AKI was 36.1% (265/734). Baseline CVP, baseline RVEDV, and Svo
2 at 5 minutes before reperfusion were significantly different between patients with and without AKI in the matched sample of 265 pairs. Multivariable logistic regression analysis revealed that baseline CVP, baseline RVEDV, and Svo
2 at 5 minutes before reperfusion were independent predictors of AKI (CVP per 5 cm H2O increase: odds ratio [OR], 1.20; 95% confidence interval [CI], 1.09-1.32; Svo
2: OR, 1.45; 95% CI, 1.27-1.71; RVEDV: OR, 1.48; 95% CI, 1.24-1.78).

Conclusions.

The elevated baseline CVP, elevated baseline RVEDV after anesthesia induction, and decreased Svo
2 during anhepatic phase were associated with postoperative AKI. Prospective trials are required to evaluate whether the optimization of these variables may decrease the risk of AKI after LDLT.
Conversion From Calcineurin Inhibitors to Belatacept in HLA-sensitized Kidney Transplant Recipients With Low-level Donor-specific Antibodies
Authors: Ulloa Camilo E. , Anglicheau Dany , Snanoudj Renaud , Scemla Anne , Martinez Frank , Timsit Marc-Olivier , Legendre Christophe , Sberro-Soussan Rebecca
Published: February 2019

Background.

Belatacept could be the treatment of choice in renal-transplant recipients with renal dysfunction attributed to calcineurin inhibitor (CNI) nephrotoxicity. Few studies have described its use in patients with donor-specific antibody (DSA).

Methods.

We retrospectively evaluated conversion from CNIs to belatacept in 29 human leukocyte antigen-immunized renal-transplant recipients. Data about acute rejection, DSA, and renal function were collected. These patients were compared with 42 nonimmunized patients treated with belatacept.

Results.

Patients were converted from CNIs to belatacept a median of 444 days (interquartile range, 85-1200) after transplantation and were followed up after belatacept conversion, for a median of 308 days (interquartile range, 125-511). At conversion, 16 patients had DSA. Nineteen DSA were observed in these 16 patients, of which 11/19 were <1000 mean fluorescence intensity (MFI), 7/19 were between 1000 and 3000 MFI, and one was >3000 MFI. At last follow-up, preexisting DSA had decreased or stabilized. Seven patients still had DSA with a mean MFI of 1298 ± 930 at the last follow-up. No patient developed a de novo DSA in the DSA-positive group. In the nonimmunized group, one patient developed de novo DSA (A24-MFI 970; biopsy for cause did not show biopsy-proven acute rejection or microinflammation score). After belatacept conversion, one antibody-mediated rejection was diagnosed. The mean estimated glomerular filtration rate improved from 31.7 ± 14.2 mL/min/1.73 m2 to 40.7 ± 12.3 mL/min/1.73 m2 (P < 0.0001) at 12 months after conversion. We did not find any significant difference between groups in terms of renal function, proteinuria, or biopsy-proven acute rejection.

Conclusions.

We report on a safe conversion to belatacept in human leukocyte antigen-immunized patients with low DSA levels.
Tandem Orthotopic Living Donor Liver Transplantation Followed by Same Donor Haploidentical Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency
Authors: Freeman Alexandra F. , Yazigi Nada , Shah Nirali N. , Kleiner David E. , Parta Mark , Atkinson Prescott , Heller Theo , Holland Steven M. , Kaufman Stuart S. , Khan Khalid M. , Hickstein Dennis D.
Published: February 2019

Background.

An 11-year-old girl with dedicator of cytokinesis 8 (DOCK8) deficiency was proposed for potentially curative hematopoietic stem cell transplantation (HSCT), the donor being her haploidentical mother. However, end-stage liver disease caused by chronicCryptosporidiuminfection required liver transplantation before HSCT.

Methods.

Consequently, a staged approach of a sequential liver transplant followed by a HSCT was planned with her mother as the donor for both liver and HSCT.

Results.

The patient successfully underwent a left-lobe orthotopic liver transplant; however, she developed a biliary leak delaying the HSCT. Notably, the recipient demonstrated 3% donor lymphocyte chimerism in her peripheral blood immediately before HSCT. Haploidentical-related donor HSCT performed 2 months after liver transplantation was complicated by the development of acyclovir-resistant herpes simplex virus viremia, primary graft failure, and sinusoidal obstruction syndrome. The patient died from sinusoidal obstruction syndrome–associated multiorgan failure withCandidasepsis on day +40 following HSCT.

Conclusions.

We discuss the many considerations inherent to planning for HSCT preceded by liver transplant in patients with primary immunodeficiencies, including the role of prolonged immunosuppression and the risk of infection before immune reconstitution. We also discuss the implications of potential recipient sensitization against donor stem cells precipitated by exposure of the recipient to the donor lymphocytes from the transplanted organ.
Dementia Reported Missing
Authors: Lissemore Frances M. , Shatzman Stephanie , Clark Nicholas , Nash Jessica , Miller Rachel , Lerner Alan J.
Published: February 2019

Background:

Persons with dementia (PWD) reported missing are known to be at high risk for mortality. Analysis of online search engines’ reports of missing PWD may show patterns in the data of this relatively common event and the broad patterns relevant to mortality risk factors.

Methods:

We searched Google news for PWD reported missing for 2015. Demographics, personal details, and outcomes were recorded.

Results:

Of 673 cases, 67 were found deceased, 525 alive, and the remainder had unknown outcomes. Mortality did not differ significantly by race/ethnicity for cases with known outcomes, but cases with unknown outcomes were significantly overrepresented among non-Caucasians (P<0.001; analysis of variance). Duration missing predicted mortality (P<0.001; χ2), and mortality was lower if a photograph was provided (P<0.05; χ2). Five states had no reports and some appeared to have fewer reports that would be expected based on estimates of dementia prevalence.

Conclusions:

Duration missing was the strongest predictor of mortality. Likelihood of mortality was not predicted by use of missing person alerts, and this may be a consequence of inconsistent reporting and follow-up of cases across states. Prevalence and mortality may likewise be underestimated because of the variability in usage and reporting of relevant search terms and definitions. Online resources and social media can provide information about trends and outcomes related to missing persons with dementia, but greater consistency is needed in definitions, searching, and reporting.
Therapeutic noninvasive brain stimulation in Alzheimer's disease and related dementias
Authors: Buss Stephanie S. , Fried Peter J. , Pascual-Leone Alvaro
Published: February 2019

Purpose of review

Alzheimer's disease is a progressive neurodegenerative disease without effective pharmacological treatment. Noninvasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), are increasingly being investigated for their potential to ameliorate the symptoms of Alzheimer's disease and related dementias (ADRD).

Recent findings

A comprehensive literature review for primary research reports that investigated the ability of TMS/tES to improve cognition in ADRD patients yielded a total of 20 reports since 2016. Eight studies used repetitive TMS and 12 used transcranial direct current stimulation, the most common form of tES. Eight of the studies combined NIBS with cognitive training. Promising results should encourage continued investigation, however there is currently insufficient evidence to support widespread adoption of NIBS-based clinical treatments for ADRD.

NIBS remains an active area of investigation for treatment of ADRD, though the predominance of small, heterogeneous, proof-of-principle studies precludes definitive conclusions. We propose the establishment of a consortium to achieve the benefits of large-scale, controlled studies using biomarker-based diagnostic characterization of participants, development of neurophysiological markers to verify target engagement, and standardization of parameters.
A curated transcriptome dataset collection to investigate inborn errors of immunity
Authors: Bougarn Salim , Boughorbel Sabri , Chaussabel Damien , Marr Nico
Published: February 2019

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders, frequently caused by loss-of-function and less commonly by gain-of-function mutations, which can result in susceptibility to a broad or a very narrow range of infections but also in inflammatory, allergic or malignant diseases. Owing to the wide range in clinical manifestations and variability in penetrance and expressivity, there is an urgent need to better understand the underlying molecular, cellular and immunological phenotypes in PID patients in order to improve clinical diagnosis and management. Here we have compiled a manually curated collection of public transcriptome datasets mainly obtained from human whole blood, peripheral blood mononuclear cells (PBMCs) or fibroblasts of patients with PIDs and of control subjects for subsequent meta-analysis, query and interpretation. A total of nineteen (19) datasets derived from studies of PID patients were identified and retrieved from the NCBI Gene Expression Omnibus (GEO) database and loaded in GXB, a custom web application designed for interactive query and visualization of integrated large-scale data. The dataset collection includes samples from well characterized PID patients that were stimulated ex vivo under a variety of conditions to assess the molecular consequences of the underlying, naturally occurring gene defects on a genome-wide scale. Multiple sample groupings and rank lists were generated to facilitate comparisons of the transcriptional responses between different PID patients and control subjects. The GXB tool enables browsing of a single transcript across studies, thereby providing new perspectives on the role of a given molecule across biological systems and PID patients. This dataset collection is available at: http://pid.gxbsidra.org/dm3/geneBrowser/list.
Lifelong genetically lowered sclerostin and risk of cardiovascular disease
Authors: Bovijn Jonas , Krebs Kristi , Chen Chia-Yen , Boxall Ruth , Censin Jenny C. , Ferreira Teresa , Pulit Sara L. , Glastonbury Craig A. , Laber Samantha , Millwood Iona Y. , Lin Kuang , Li Liming , Chen Zhengming , Milani Lili , Walters Robin G. , Mägi Reedik , Neale Benjamin M. , Lindgren Cecilia M. , Holmes Michael V.
Published: February 2019

Background

Inhibition of sclerostin is a novel therapeutic approach to lowering fracture risk. However, phase III randomised controlled trials (RCTs) of romosozumab, a monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events.

Methods

We used two independent genetic variants (rs7209826 and rs188810925) in SOST (encoding sclerostin) associated with bone mineral density (BMD) as proxies for therapeutic inhibition of sclerostin. We estimated the effects on risk of osteoporosis, fracture, coronary heart disease (CHD) and a further 22 cardiometabolic risk factors and diseases, by combining data from up to 478,967 participants of European ancestry from three prospective cohorts and up to 1,030,836 participants from nine GWAS consortia. In addition, we performed meta-analyses of cardiovascular outcome data from phase III RCTs of romosozumab.

Results

Meta-analysis of RCTs identified a higher risk of cardiac ischemic events in patients randomised to romosozumab (25 events among 4,298 individuals; odds ratio [OR] 2·98; 95% confidence interval [CI], 1·18 to 7·55; P=0·017). Scaled to the equivalent dose of romosozumab (210mg/month; 0·09 g/cm2 higher BMD), the SOST variants associated with lower risk of fracture (OR, 0·59; 95% CI, 0·54-0·66; P= 1·4×10−24), and osteoporosis (OR, 0·43; 95% CI, 0·36-0·52; P=2·4×10−18). The SOST variants associated with higher risk of myocardial infarction and/or coronary revascularisation (69,649 cases; OR, 1·18; 95% CI, 1·06-1·32; P=0·003) and type 2 diabetes (OR 1·15; 95% CI, 1·05-1·27; P=0·003), higher systolic blood pressure (1·3mmHg; 95% CI 0·8-1·9; P=5·9×10−6) and waist-to-hip-ratio adjusted for BMI (0·05 SDs; 95% CI, 0·02 to 0·08; P=8·5×10−4).

Conclusions

Genetically and therapeutically lowered sclerostin leads to higher risk of cardiovascular events. Rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors is warranted.
National HIV testing and diagnosis coverage in sub-Saharan Africa: a new modeling tool for estimating the “first 90” from program and survey data
Authors: Maheu-Giroux M , Marsh K , Doyle C , Godin A , Lanièce Delaunay C , Johnson LF , Jahn A , Abo K , Mbofana F , Boily MC , Buckeridge DL , Hankins C , Eaton JW
Published: February 2019

Abstract

Objective

HIV testing services (HTS) are a crucial component of national HIV responses. Learning one’s HIV diagnosis is the entry point to accessing life-saving antiretroviral treatment and care. Recognizing the critical role of HTS, theJoint United Nations Programme on HIV/AIDS(UNAIDS) launched the 90-90-90 targets stipulating that by 2020, 90% of people living with HIV know their status, 90% of those who know their status receive antiretroviral therapy, and 90% of those on treatment have a suppressed viral load. Countries will need to regularly monitor progress on these three indicators. Estimating the proportion of people living with HIV who know their status (i.e., the “first 90”), however, is difficult.

Methods

We developed a mathematical model (henceforth referred to as “F90”) that formally synthesizes population-based survey and HTS program data to estimate HIV status awareness over time. The proposed model uses country-specific HIV epidemic parameters from the standard UNAIDS Spectrum model to produce outputs that are consistent with other national HIV estimates. The F90 model provides estimates of HIV testing history, diagnosis rates, and knowledge of HIV status by age and sex. We validate the F90 model using both in-sample comparisons and out-of-sample predictions using data from three countries: Côte d’Ivoire, Malawi, and Mozambique.

Results

In-sample comparisons suggest that the F90 model can accurately reproduce longitudinal sex-specific trends in HIV testing. Out-of-sample predictions of the fraction of PLHIV ever tested over a 4-to-6-year time horizon are also in good agreement with empirical survey estimates. Importantly, out-of-sample predictions of HIV knowledge are consistent (i.e., within 4% points) with those of the fully calibrated model in the three countries, when HTS program data are included. The F90 model’s predictions of knowledge of status are higher than available self-reported HIV awareness estimates, however, suggesting –in line with previous studies– that these self-reports are affected by non-disclosure of HIV status awareness.

Conclusion

Knowledge of HIV status is a key indicator to monitor progress, identify bottlenecks, and target HIV responses. The F90 model can help countries track progress towards their “first 90” by leveraging surveys of HIV testing behaviors and annual HTS program data.
Testing models of mRNA localization reveals robustness regulated by reducing transport between cells
Authors: Harrison J. U. , Parton R. M. , Davis I. , Baker R. E.
Published: February 2019

Robust control of gene expression in both space and time is of central importance in the regulation of cellular processes, and for multicellular development. However, the mechanisms by which robustness is achieved are generally not identified or well understood. For example, mRNA localization by molecular-motor-driven transport is crucial for cell polarization in numerous contexts, but the regulatory mechanisms that enable this process to take place in the face of noise or significant perturbations are not fully understood. Here we use a combined experimental-theoretical approach to characterize the robustness ofgurken/TGF-alphamRNA localization inDrosophilaegg chambers, where the oocyte and 15 surrounding nurse cells are connected in a stereotypic network via intracellular bridges known as ring canals. We construct a mathematical model that encodes simplified descriptions of the range of steps involved in mRNA localization, including production and transport between and within cells until the final destination in the oocyte. Using Bayesian inference, we calibrate this model using quantitative single molecule fluorescence in situ hybridization data. By analyzing both the steady state and dynamic behaviours of the model, we provide estimates for the rates of different steps of the localization process, as well as the extent of directional bias in transport through the ring canals. The model predicts that mRNA synthesis and transport must be tightly balanced to maintain robustness, a prediction which we tested experimentally using an over-expression mutant. Surprisingly, the over-expression mutant fails to display the anticipated degree of overaccumulation of mRNA in the oocyte predicted by the model. Through careful model-based analysis of quantitative data from the over-expression mutant we show evidence of saturation of transport of mRNA through ring canals. We conclude that this saturation engenders robustness of the localization process, in the face of significant variation in the levels of mRNA synthesis.

Statement of significance

For development to function correctly and reliably across a population, gene expression must be controlled robustly in a repeatable manner. How this robustness is achieved is not well understood. We use modelling to better study the localization of polarity determining transcripts (RNA) in fruit fly development. By calibrating our model with quantitative imaging data we are able to make experimentally testable predictions, comparison of which with data from a genetic mutant, reveals evidence that saturation of RNA transport contributes to the robustness of RNA localization.
Multiscale analysis of a non-periodic epidemic time series using wavelet transform
Authors: Gaudart Jean , Rebaudet Stanislas , Texier Gaetan , Barrais Robert , Piarroux Renaud , Giorgi Roch
Published: February 2019

The aim of the present study was to develop a method for multiscale analysis of non-stationary and non-periodic epidemic time series. Indeed, the epidemiologists may need to know the features, at different resolutions, of short duration outbreaks that did not exhibit periodic cycles. Among of the large number of wavelets, we have developed a continuous wavelet that shows an analogous shape to the Haar wavelet, and leads to precise time localization. We applied the wavelet transform to the cholera epidemic, which began in October 2010 in Haiti. We determined the wavelet spectra of both the cholera case toll and rainfall time series, from September 01, 2010, to November 20, 2012 (812 days). The relationship between case toll and rainfall was analyzed using cross-wavelet spectra at different lags. Cholera case toll scalogram highlighted four epidemic bursts. Cross-wavelet analysis highlighted an absence of relationship between the first epidemic burst and rainfall, but a clear relationship between the following epidemic bursts and rainfall after a 3 to 8 day lag.
The role of “spillover” in antibiotic resistance
Authors: Olesen Scott W. , Lipsitch Marc , Grad Yonatan H.
Published: February 2019

Antibiotic use is a key driver of antibiotic resistance. Understanding the quantitative association between antibiotic use and resulting resistance is important for predicting future rates of antibiotic resistance and for designing antibiotic stewardship policy. However, the use-resistance association is complicated by “spillover”, in which one population’s level of antibiotic use affects another population’s level of resistance via the transmission of bacteria between those populations. Spillover is known to have effects at the level of families and hospitals, but it is unclear if spillover is relevant at larger scales. We used mathematical modeling and analysis of observational data to address this question. First, we used dynamical models of antibiotic resistance to predict the effects of spillover. Whereas populations completely isolated from one another do not experience any spillover, we found that if even 1% of interactions are between populations, then spillover may have large consequences: the effect of a change in antibiotic use in one population on antibiotic resistance in that population could be reduced by as much as 50%. Then, we quantified spillover in observational antibiotic use and resistance data from US states and European countries for 3 pathogen-antibiotic combinations, finding that increased interactions between populations were associated with smaller differences in antibiotic resistance between those populations. Thus, spillover may have an important impact at the level of states and countries, which has ramifications for predicting the future of antibiotic resistance, designing antibiotic resistance stewardship policy, and interpreting stewardship interventions.
More accuracy estimation of the worm burden in the ascariasis of children in Kinshasa
Authors: Tshima Guyguy Kabundi , Mulumba Paul Madishala
Published: February 2019

The present study aims to give a better estimate of the worm burden (ascariasis) to address accurately the impact of intestinal parasitosis on the children growth in Africa.

The study was conducted on 20 subjects aged 10 months to 10 years (Mean ± SD: 5.6 ± 2.3 years). They were treated with 10 mg/kg of Pyrantel pamoate. The next day, the stools were collected, washed and filtered to harvest all adult ascaris. In total, 141 ascaris (71 males and 70 females) were extracted for 879.9 g of stool. The geometric mean of eggs counted was 29 by 2 mg of stool. The daily eggs laying per female was estimated to 202,500 eggs/days (CI95%: 128,800 – 276,200).

Statistical analysis shows that the parasitic worm burden was proportional both to the number eggs counted per unit of stool volume, and to age of infested subject. A regression model based on these two parameters, with a coefficient of determination equal to 59 %, was retained. Thus, for an old subject respectively of 1, 5 and 10 years, at which 1 egg of ascaris in approximately 2 mg of a preparation would lodge a respective parasitic mass of 1, 3 and 9 g. The results are in the form of confidence interval. For example, for a 5 years old subject with an average of 10 eggs (CI95% = 5.6 - 14.4) after reading of 2 separated preparations coming from the same specimen, the estimated parasitic load is laying between 7 and 11 g.
The ‘hidden side’ of spin labeled oligonucleotides: Molecular Dynamics study focusing on the EPR-silent components of base pairing
Authors: Chandra Dantu Sarath , Sicoli Giuseppe
Published: February 2019

Nitroxide labels are combined with nucleic acid structures and studied using electron paramagnetic resonance experiments (EPR). As X-ray/NMR structures are unavailable with the nitroxide labels, detailed residue level information, down to atomic resolution, about the effect of these nitroxide labels on local RNA structures is currently lacking. This information is critical to evaluate the choice of spin label. In this study, we compare and contrast the effect of TEMPO-based (NT) and rigid spin (Ç) labels (in both 2’-O methylated and not-methylated forms) on RNA duplexes. We also investigate sequence-dependent effects of NT label on RNA duplex along with the more complex G-quadruplex RNA. Distances measured from molecular dynamics simulations between the two spin labels are in agreement with the EPR experimental data. To understand the effect of labeled oligonucleotides on the structure, we studied the local base pair geometries and global structure in comparison with the unlabeled structures. Based on the structural analysis, we can conclude that TEMPO-based and Ç labels do not significantly perturb the base pair arrangements of the native oligonucleotide. When experimental structures for the spin labelled DNA/RNA molecules are not available, general framework offered by the current study can be used to provide information critical to the choice of spin labels to facilitate future EPR studies.

Graphical abstract
Islands of retroelements are the major components ofDrosophilacentromeres
Authors: Chang Ching-Ho , Chavan Ankita , Palladino Jason , Wei Xiaolu , Martins Nuno M. C. , Santinello Bryce , Chen Chin-Chi , Erceg Jelena , Beliveau Brian J. , Wu Chao-Ting , Larracuente Amanda M. , Mellone Barbara G.
Published: February 2019

Centromeres are essential chromosomal regions that mediate kinetochore assembly and spindle attachments during cell division. Despite their functional conservation, centromeres are amongst the most rapidly evolving genomic regions and can shape karyotype evolution and speciation across taxa. Although significant progress has been made in identifying centromere-associated proteins, the highly repetitive centromeres of metazoans have been refractory to DNA sequencing and assembly, leaving large gaps in our understanding of their functional organization and evolution. Here, we identify the sequence composition and organization of the centromeres ofDrosophila melanogasterby combining long-read sequencing, chromatin immunoprecipitation for the centromeric histone CENP-A, and high-resolution chromatin fiber imaging. Contrary to previous models that heralded satellite repeats as the major functional components, we demonstrate that functional centromeres form on islands of complex DNA sequences enriched in retroelements that are flanked by large arrays of satellite repeats. Each centromere displays distinct size and arrangement of its DNA elements but is similar in composition overall. We discover that a specific retroelement,G2/Jockey-3, is the most highly enriched sequence in CENP-A chromatin and is the only element shared among all centromeres.G2/Jockey-3is also associated with CENP-A in the sister speciesDrosophila simulans, revealing an unexpected conservation despite the reported turnover of centromeric satellite DNA. Our work reveals the DNA sequence identity of the active centromeres of a premier model organism and implicates retroelements as conserved features of centromeric DNA.
An olfactory receptor gene underlies reproductive isolation in perfume-collecting orchid bees
Authors: Brand P. , Hinojosa-Díaz I. A. , Ayala R. , Daigle M. , Yurrita Obiols C. L. , Eltz T. , Ramírez S. R.
Published: February 2019

Speciation is facilitated by the evolution of reproductive barriers that prevent or reduce hybridization among diverging lineages. However, the genetic mechanisms that control the evolution of reproductive barriers remain elusive, particularly in natural populations. We identify a gene associated with divergence in chemical courtship signaling in a pair of nascent orchid bee lineages. Male orchid bees collect perfume compounds from flowers and other sources to subsequently expose during courtship display, thereby conveying information on species identity. We show that these two lineages exhibit differentiated perfume blends and that this change is associated with the rapid evolution of a single odorant receptor gene. Our study suggests that reproductive isolation evolved through divergence of a major barrier gene involved in chemically mediated pre-mating isolation via genetic coupling.
Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine
Authors: Belo Yael , Mielko Zack , Nudelman Hila , Afek Ariel , Ben-David Oshrit , Shahar Anat , Zarivach Raz , Gordan Raluca , Arbely Eyal
Published: February 2019

The signal transducer and activator of transcription 3 (STAT3) protein is activated by phosphorylation of a specific tyrosine residue (Tyr705) in response to various extracellular signals. STAT3 activity was also found to be regulated by acetylation of Lys685. However, the molecular mechanism by which Lys685 acetylation affects the transcriptional activity of STAT3 remains elusive. By genetically encoding the co-translational incorporation of acetyl-lysine into position Lys685 and co-expression with the Elk receptor tyrosine kinase, we were able to biochemically characterize site-specifically acetylated, and simultaneously acetylated and phosphorylated STAT3. We measured the effect of acetylation on the crystal structure, and DNA binding affinity and specificity of Tyr705-phosphorylated and non-phosphorylated STAT3. In addition, we monitored the deacetylation of acetylated Lys685 by reconstituting the mammalian enzymatic deacetylation reaction in live bacteria. Surprisingly, we found that acetylation, per se, had no effect on the crystal structure, and DNA binding affinity or specificity of STAT3, implying that the previously observed acetylation-dependent transcriptional activity of STAT3 involves an additional cellular component. In addition, we discovered that Tyr705-phosphorylation protects Lys685 from deacetylation in bacteria, providing a new possible explanation for the observed correlation between STAT3 activity and Lys685 acetylation.
Extracellular spike waveform dissociates four functionally distinct cell classes in primate cortex
Authors: Trainito Caterina , von Nicolai Constantin , Miller Earl K. , Siegel Markus
Published: February 2019

Understanding the function of different neuronal cell types is key to understanding brain function. However, cell type diversity is typically overlooked in electrophysiological studies in awake behaving animals. Here, we show that four functionally distinct cell classes can be robustly identified from extracellular recordings in several cortical regions of awake behaving monkeys. We recorded extracellular spiking activity from dorsolateral prefrontal cortex (dlPFC), the frontal eye field (FEF), and the lateral intraparietal area of macaque monkeys during a visuomotor decision-making task. We employed unsupervised clustering of spike waveforms, which robustly dissociated four distinct cell classes across all three brain regions. The four cell classes were functionally distinct. They showed different baseline firing statistics, visual response dynamics, and coding of visual information. While cell class-specific baseline statistics were consistent across brain regions, response dynamics and information coding were regionally specific. Our results identify four waveform-based cell classes in primate cortex. This opens a new window to dissect and study the cell-type specific function of cortical circuits.
Cxcr4 desensitization is an essential regulatory mechanism controlling the extra-follicular B cell response
Authors: Alouche Nagham , Bonaud Amélie , Rondeau Vincent , Nguyen Julie , Cricks Etienne , Setterblad Niclas , Mahevas Matthieu , Balabanian Karl , Espéli Marion
Published: February 2019

The signaling axis formed by the chemokine CXCL12 and its receptor CXCR4 plays an important role in B cell development and activation and is finely regulated by a process termed desensitization. Mutations leading to a truncation of the C-terminus tail of CXCR4 and thus to a defective desensitization have been reported in two diseases, a rare immunodeficiency called the WHIM syndrome and a B cell plasmacytoma called Waldenstrom’s Macroglobulinemia (WM). How CXCR4 desensitization may impact B cell activation in the context of a T-independent extra-follicular response is still unknown. Here using a unique mouse model bearing an orthologous gain of function mutation ofCxcr4we report that Cxcr4 desensitization is an essential gatekeeper controlling B lymphocyte entry into cycle, plasma cell differentiation, migration and maturation upon Myd88-dependent signaling. Altogether, our results support an essential role for Cxcr4 desensitization in limiting the depth and width of the B cell extra-follicular response and PC development.
Modeling microbial communities using biochemical resource allocation analysis
Authors: Sharma Suraj , Steuer Ralf
Published: February 2019

To understand the functioning and dynamics of microbial communities remains a fundamental challenge at the forefront of current biology. To tackle this challenge, the construction of computational models of interacting microbes is an indispensable tool. Currently, however, there is a large chasm between ecologically-motivated descriptions of microbial growth used in ecosystems simulations, and detailed metabolic pathway and genome-based descriptions developed within systems and synthetic biology. Here, we seek to demonstrate how current biochemical resource allocation models of microbial growth offer the potential to advance ecosystem simulations and their parameterization. In particular, recent work on quantitative microbial growth and cellular resource allocation allow us to formulate mechanistic models of microbial growth that are physiologically meaningful while remaining computationally tractable. Biochemical resource allocation models go beyond Michaelis-Menten and Monod-type growth models, and allow to account for emergent properties that underlie the remarkable plasticity of microbial growth. We exemplify our approach using a coarse-grained model of cyanobacterial phototrophic growth, and demonstrate how the model allows us to represent physiological acclimation to different environments, co-limitation of growth by several nutrients, as well as emergent switches between alternative nutrient sources. Our approach has implications for building models of microbial communities to understand their interactions, dynamics and response to environmental changes.
GeNet: Deep Representations for Metagenomics
Authors: Rojas-Carulla Mateo , Tolstikhin Ilya , Luque Guillermo , Youngblut Nicholas , Ley Ruth , Schölkopf Bernhard
Published: February 2019

We introduce GeNet, a method for shotgun metagenomic classification from raw DNA sequences that exploits the known hierarchical structure between labels for training. We provide a comparison with state-of-the-art methods Kraken and Centrifuge on datasets obtained from several sequencing technologies, in which dataset shift occurs. We show that GeNet obtains competitive precision and good recall, with orders of magnitude less memory requirements. Moreover, we show that a linear model trained on top of representations learned by GeNet achieves recall comparable to state-of-the-art methods on the aforementioned datasets, and achieves over 90% accuracy in a challenging pathogen detection problem. This provides evidence of the usefulness of the representations learned by GeNet for downstream biological tasks.
A practive faeces collection protocol for multidisciplinary research in wildlife science
Authors: Biswas Suvankar , Bhatt Supriya , Paul Shrutarshi , Modi Shrushti , Ghosh Tista , Habib Bilal , Nigam Parag , Talukdar Gautam , Pandav Bivash , Mondol Samrat
Published: February 2019

Faecal samples have become important non-invasive source of information in wildlife biology and ecological research. Despite regular use of faeces, there is no universal protocol available for faeces collection and storage to answer various questions in wildlife biology. We collected 1408 faeces from ten different species using a dry sampling approach, and achieved 94.87% and 86.02% success rate in mitochondrial and nuclear marker amplifications. We also suggest a universal framework to use the same samples for different use. This protocol provides an easy, quick and cheap option to collect non-invasive samples from species living at different environmental conditions to answer multidisciplinary questions in wildlife biology.
Fracking and Ostwald ripening position the lumen of the mouse blastocyst
Authors: Dumortier Julien G. , Le Verge-Serandour Mathieu , Tortorelli Anna-Francesca , Mielke Annette , de Plater Ludmilla , Turlier Hervé , Maître Jean-Léon
Published: February 2019

During mouse preimplantation development, the formation of the blastocoel, a fluid-filled lumen, breaks the radial symmetry of the blastocyst. What controls the formation and positioning of this basolateral lumen remains obscure. We find that accumulation of pressurized fluid fractures cell-cell contacts into hundreds of micron-size lumens. Microlumens eventually discharge their volumes into a single dominant lumen, which we model as a process akin to Ostwald ripening, underlying the coarsening of foams. Using chimeric mutant embryos, we tune the tracking of cell-cell contacts and steer the coarsening of microlumens, allowing us to successfully manipulate the final position of the lumen. We conclude that hydraulic fracture of cell-cell contacts followed by directed coarsening of microlumens sets the first axis of symmetry of the mouse embryo.