bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of polymorphisms in grainyhead-like-2 gene with the susceptibility to age-related hearing loss
Authors: Han Baoai , Yang Xiuping , Li Yongqin , Hosseini Davood K. , Tu Yaqin , Dong Yaodong , He Zuhong , Yuan Jie , Cai Hua , Zhang Kai , Zhang Xiujuan , Zhou Tao , Sun Haiying
Published: June 2019

Objective:

The grainyhead-like-2 (GRHL2) genetic variants were reported in age-related hearing impairment (ARHI) susceptibility in several case–control studies. However, their conclusions are conflicting; it is difficult to precisely assess the disease risk associated with the variants. Therefore we conduct the meta-analysis to discover the association of GRHL2 polymorphisms and the risk of ARHI.

Methods:

A related literature search was conducted in on-line databases, such as Wanfang database, China National Knowledge Infrastructure (CNKI), EMBASE, Web of Science, and PubMed (updated to August 30, 2018). We use Review Manager 5.0 and Stata SE 12.0 software to reckon the odds radio (OR), 95% confidence interval (CI) and P value in random- or fixed-effects model according to the I2 value in the heterogeneity test.

Results:

2762 cases and 2321 controls in 5 articles were provided data to the meta-analysis. The pooled ORs (95% CI) of the rs10955255 polymorphism were 1.26 (1.05–1.50, P = .01), 1.33 (1.07–1.65, P = .01), and 1.32 (1.12–1.55, P = .0007) in the allele, homozygote and recessive model separately. Besides, a significant association was detected between rs1981361 in mixed population and the ARHI risk in the allele, heterozygote, and dominant genetic model respectively. Then subgroup analyses was performed by ethnicity, for rs10955255 meaningful associations were detected for the allele model, homozygote model, dominant model and recessive model in the Caucasian population but no relations in any of the 5 genetic models in Asian population.

Conclusion:

The meta-analysis indicated that the rs10955255 polymorphism could be an important risk factor for ARHI, especially in the Caucasians. The rs1981361 polymorphism may be a risk factor for ARHI in Asians. Larger scale researches are needed to further bring the consequences up to date.
Association between TP53 gene codon72 polymorphism and prostate cancer risk
Authors: Han Pei-Zhen , Cao De-Hong , Zhang Xue-Ling , Ren Zheng-Ju , Wei Qiang
Published: June 2019

Background:

TP53 gene polymorphism could increase risks of several kinds of cancer. But it remained controversial whether TP53 gene codon72 polymorphism was associated with the susceptibility to prostate cancer. Thus, we conducted a meta-analysis that evaluated the association between TP53 gene codon72 polymorphism and prostate cancer risk.

Method:

A comprehensive research was performed from PubMed, Embase, Web of Science and China National Knowledge Infrastructure (CNKI) up to December 31, 2018. A random effect model was used to evaluate the effect of the outcome. The statistical analyses were performed with Review Manager 5.3.0 and Stata 14.0. The sensitivity analysis and publication bias tests were also performed to confirm the reliability of this meta-analysis.

Results:

22 studies included 3146 cases and 4010 controls were involved in this meta-analysis. Overall, no association was observed between TP53 gene codon72 polymorphism and prostate cancer risk (Arg vs Pro: odds ratio [OR] = 1.12, 95% confidence interval [CI] = 0.98–1.30; ArgArg vs ProPro: OR = 1.26, 95% CI = 0.90–1.75; ProPro vs ArgArg+ ArgPro: OR = 1.17, 95% CI = 0.86–1.57; ArgPro+ ProPro vs ArgArg: OR = 1.21, 95% CI = 0.97–1.51). Subgroup analyses, based on ethnicity, source of control and Hardy–Weinberg equilibrium (HWE) status, showed consistent results.

Conclusion:

The meta-analysis we performed showed that there was no association of TP53 gene codon72 polymorphism with prostate cancer risk.
Factors associated with postoperative outcomes in patients with intramedullary Grade II ependymomas
Authors: Sun Xiang-Yao , Wang Wei , Zhang Tong-Tong , Kong Chao , Sun Si-Yuan , Guo Ma-Chao , Ding Jun-Zhe , Lu Shi-Bao
Published: June 2019

Background:

Most of the previous studies combined all types of intramedullary ependymomas without providing accurate pathological subtypes. In addition, it was very difficult to evaluate the factors associated with postoperative outcomes of patients with different pathological subtypes of intramedullary Grade II ependymomas by traditional meta-analysis. This study evaluated the factors related with postoperative outcomes of patients with intramedullary Grade II ependymomas.

Methods:

Individual patient data analysis was performed using PubMed, Embase, and the Cochrane Central Register of Controlled Trials. The search included articles published up to April 2018 with no lower date limit on the search results. The topics were intramedullary Grade II ependymomas. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan–Meier survival analysis (log-rank test). The level of significance was set at P < .05.

Results:

A total of 21 studies with 70 patients were included in this article. PFS of patients who underwent total resection was much longer than the PFS of those who received subtotal resection (P < .001). Patients who received adjuvant therapy (P = .005) or radiotherapy and chemotherapy (P < .001) seemed to have shorter PFS than others; PFS of patients who had cerebrospinal fluid disease dissemination (P = .022) or scoliosis (P = .001) were significantly shorter than others. OS of cellular ependymoma patients was less than giant cell ependymoma patients (P < .001).

Conclusions:

PFS of patients who received total resection was much longer than those who received subtotal resection. Patients treated with adjuvant therapy or radiotherapy and chemotherapy appeared to have shorter PFS than others; PFS of patients with cerebrospinal fluid disease dissemination or scoliosis were significantly shorter than others. Cellular ependymomas would have better OS than giant cell ependymoma. However, giant cell ependymoma patients might have the worst OS.
Impact of Age of Packed RBC Transfusion on Oxygenation in Patients Receiving Extracorporeal Membrane Oxygenation
Authors: Datta Sumit , Chang Shelley , Jackson Nicholas J. , Ziman Alyssa , Federman Myke
Published: June 2019

Objective:

To determine the effect of age of packed RBCs on tissue oxygenation in children receiving extracorporeal membrane oxygenation support.

Design:

A retrospective study was done between March 2013 and August 2015. The following biomarkers were examined 6 hours before and 6 hours after the conclusion of a transfusion: serum and circuit hematocrits, serum and circuit venous saturations, serum lactate levels (mg/dL), and cerebral saturation via near-infrared spectroscopy. Biomarkers were examined with respect to time relative to transfusion using four discrete categories (< 3, –3 to 0, 0–3, and > 3 hr). The association between age of blood transfusion and change in biomarkers was accessed analyzing time relative to transfusion as described above. In addition, the age of blood transfusion was analyzed similarly, using four discrete categories (0–7, 7–14, 14–21, and > 21 d).

Setting:

Twenty-four bed mixed pediatric medical and cardiac ICU at a tertiary care center.

Subjects:

Zero- to 18-year-old patients of required extracorporeal membrane oxygenation support.

Interventions:

None.

Measurements and Main Results:

Circuit venous saturation demonstrated an increase of 2.5% (p < 0.001) in first 3 hours posttransfusion. This was followed by a 1.4% decrease after the initial 3 hours posttransfusion. Serum venous saturation showed no statistically significant change with relation to transfusions. Neither lactate levels nor near-infrared spectroscopy demonstrated any observed statistical change with relation to transfusion. With regards to the relationship between the age of RBC transfusion and tissue oxygenation biomarkers, none of the biomarkers exhibited a consistent interaction.

Conclusions:

Our study demonstrates that the age of packed RBC transfusion does not affect the degree tissue oxygenation in children receiving extracorporeal membrane oxygenation support, as measured by mixed venous oxygen saturation, lactate, and near-infrared spectroscopy. In addition, packed RBC transfusion, in general, did not produce any meaningful change in these markers of tissue oxygenation.
Rezoning Free Muscle-Sparing Transverse Rectus Abdominis Myocutaneous Flaps Based on Perforasome Groupings and a New Understanding of the Vascular Architecture of the Deep Inferior Epigastric Artery–Based Flaps
Authors: Tan Jialiang , Ohjimi Hiroyuki , Takagi Satoshi , Kawakami Yoshihisa , Eto Akiko
Published: June 2019

Background

We compare the vascular territory of free muscle-sparing transverse rectus abdominis myocutaneous (MS-TRAM) flaps, deep inferior epigastric perforator (DIEP) flaps, and crossover anastomosis (CA) flaps using intraoperative ex vivo angiography. We also use ex vivo angiography to analyze the vascular architecture of the MS-TRAM flap.

Methods

Our study includes 84 lower abdominal free flaps: MS-TRAM, DIEP-1 (1 perforator), DIEP-2 (2 perforators), and CA. We compare the arterial perfusion area and vascular territory pattern in each group. We also analyze the vascular architecture in MS-TRAM flaps and determine the number and location of their dominant perforators and the direction of the axial arteries connecting them.

Results

The CA's arterial perfusion area is the largest, and the DIEP-1's, the smallest of our groups; there is no statistically significant difference between MS-TRAM and DIEP-2. In all groups, average arterial perfusion area in the vascular pedicle's ipsilateral side is larger than in its contralateral side. The MS-TRAM and DIEP-2 flaps have homologous perfusion patterns and the same arterial perfusion areas. The DIEP-1 perfusion pattern varies with perforator location. Ex vivo angiograms show the MS-TRAM flap's axial arteries heading laterally to be larger and longer than those heading medially.

Conclusions

Two dominant perforators are preferable in DIEP flap breast reconstruction. Lateral perforators play a more important role in flap perfusion than do medial ones. Crossover anastomosis is an effective technology for increasing arterial perfusion areas. Our rezoning shows which areas are better for surgery and which have a high risk of complications—valuable information for a surgeon designing a flap for breast reconstruction.
End-to-Side Venous Anastomosis to a Ligated Vein Stump for Free Flap Transfer in Head and Neck Reconstruction
Authors: Akazawa Toshifumi , Sekido Mitsuru , Adachi Koji , Sasaki Kaoru , Aihara Yukiko , Shibuya Yoichiro , Makino Syujiro
Published: June 2019

Introduction

In head and neck reconstruction, use of a free flap paired with end-to-side anastomosis to a preserved vein is generally performed. However, it is frequently difficult to select the recipient vein after a neck dissection in which there is only a ligated internal jugular vein/external jugular vein (IJV/EJV). Here, a new anastomosis technique using a ligated IJV/EJV stump is described.

Patients and Methods

End-to-side anastomoses to ligated vein stump surgeries for free flap transfer in head and neck reconstruction were performed at the Department of Plastic and Reconstructive Surgery, University of Tsukuba, from 2009 to 2016.

Results

The subject pool comprised 6 patients. All patients received a free flap transfer after head and neck tumor excision. The free flaps used were 1 free radial forearm flap, 1 free tensor fascia lata muscle perforator flap, and 4 free rectus abdominis musculocutaneous flaps. The cervical vessels used were 3 IJVs and 3 EJVs. All veins of the free flaps could be anastomosed end-to-side to ligated vein stumps without vein grafting. All flaps survived completely without complications.

Conclusions

The end-to-side venous anastomosis to a ligated vein stump procedures were easy to perform and not dependent on the vessel diameters of the free flaps. No complications were observed in any patient owing to differences in vessel diameter, ease of anastomosis, and safety. Results suggest that this new technique is a simple and very useful option in head and neck reconstruction where the IJV/EJV cannot be preserved.
The Flower Petal Training System in Microsurgery
Authors: Volovici Victor , Dammers Ruben , Lawton Michael T. , Dirven Clemens M. F. , Ketelaar Tijs , Lanzino Giuseppe , Zamfirescu Dragos G.
Published: June 2019

Introduction

Despite hundreds of training models for microsurgery being available in the literature, very few of them are scientifically validated. We chose to validate our low-fidelity training model on flower petals by comparing it head-to-head with a moderate fidelity training model, the anastomosis on chicken leg femoral artery.

Materials and methods

A total of 16 participants of different levels of expertise were randomized into 2 groups, 1 training on flower petals and 1 on chicken leg femoral arteries. The groups were evaluated on performing a rat femoral artery anastomosis using the validated Stanford Microsurgical Assessment (SMaRT) Scale. The Mann-Whitney U test was used to check for statistically significant differences between the groups. The flower petal sutures were also evaluated and Pearson correlation was used to check for associations between better petal anastomosis scores and better final SMaRT results.

Results

After 6 weeks of flower petal training, microsurgical trainees had significantly better overall SMaRT scores than trainees using chicken leg training, better fine tissue feeling, and better scores in knot tying. The anastomosis times for the rat femoral arteries did not differ between the 2 groups. Good scores for flower petals strongly correlated with a better SMaRT score for the anastomosis. The number of rats used in training reduced after the implementation of this model in continuous training.

Conclusions

The flower petal technique, despite being a low-fidelity model, shows superiority in developing fine tissue feeling and improved knot tying in microsurgery beginners and intermediate level practitioners adding this training model to their program. Further research needs to establish if the improvements also apply to already seasoned microsurgeons and whether the petal score has predictive value for future clinical application.
Chimeric Lateral Arm Free Flap to Treat Pharyngocutaneous Fistula After Total Laryngectomy
Authors: Fodor Lucian , Chirila Magdalena , Sobec Raluca , Sita Laura , Fodor Marius
Published: June 2019

Pharyngocutaneous fistula is a major complication after total laryngectomy, leading to a severe adverse impact for the patient and social activity. The reported incidence ranges from 9% to 25% in the last decade. In this paper, the authors present our experience using chimeric lateral arm free flap for reconstruction of the pharyngo-esophageal segment. Eight patients with pharyngocutaneous fistula were treated with this technique. The flap has 2 skin islands, each one supplied by a perforator coming from the main pedicle. One skin island is used as a patch for pharynx closure and the other is used for anterior soft tissue coverage. The follow-up period ranged from 8 months to 3 years. All flaps survived. There was 1 small fistula that was sutured. External skin wound dehiscence was present in 1 case and it was secondary closed by itself. All patients were able to eat by mouth and there were no signs of stricture. The authors preferred this type of flap because both defects are simultaneously closed and each skin paddle is supplied by a perforator coming from the main pedicle. It has a better color match than other free flaps. The skin island is thin and remains thin even after the patients gain weight.
Short Nose Correction: Septal Cartilage Combined With Ethmoid Bone Graft
Authors: An Yang , Xie Lifeng , Chen Lujia , Yang Xin , Yang Xiao , Xue Hongyu , Li Dong
Published: June 2019

Background:

Multiple methods are employed to correct short nose deformities, with septal extension graft representing the first choice for Asians. However, the volume of the septal cartilage in many Asian patients is not sufficient to be used alone for such operation. The present work developed a new method combining the septal cartilage with ethmoid bone graft to overcome this issue in Asian patients with short noses.

Methods:

Thirty-five women with short noses underwent septal extension graft from February 2015 to March 2017. The endoscopic technique was utilized to harvest the ethmoid bone to enhance the L-strut structure. An L-strut, comprising 0.8 cm segments of the caudal and dorsal cartilaginous septa, is left altered in order to harvest more cartilage for septal extension. The harvested the septal cartilage, approximately 1.0 mm thick and 16 to 20 mm long, underwent grafting on one side of the caudal septum. This was followed by alar cartilage fixation at the septal cartilage graft end. Finally, nose length, nasal tip projection and nasolabial angle were assessed before and after the surgery.

Results:

Septal cartilage combined with ethmoid bone graft yielded an adequate nose lengthening and reduced nostril show, also in individuals showing extremely little septal cartilage.

Conclusions:

This new method is effective for short nose deformity correction in Asian patients. Combining the septal cartilage with ethmoid bone graft yields ideal outcome without overt complications, achieving commendable patient satisfaction.
Evaluation of the Effects of Low-Level Laser Therapy on Diabetic Bone Healing
Authors: Diker Nurettin , Aytac Duygu , Helvacioglu Fatma , Dagdelen Cansu , Oguz Yener
Published: June 2019

The aim of the present study was to evaluate the effects of low-level laser therapy (LLLT) and biphasic alloplastic bone graft material on diabetic bone healing. Induction of diabetes was performed in 14 male Sprague-Dawley rats by intraperitoneal injection of a 50 mg/kg dose of streptozotocin. Two bilaterally symmetrical non-critical-sized bone defects were created in the parietal bones in each rat. Right defects were filled with biphasic alloplastic bone graft. Rats were randomly divided into 2 groups, with 1 group receiving 10 sessions of LLLT (GaAlAs, 78.5 J/cm2, 100mW, 0.028 cm2beam). The LLLT was started immediately after surgery and once every 3 days during postoperative period. At the end of treatment period, new bone formation and osteoblast density were determined using histomorphometry. Empty (control), graft-filled, LLLT-treated and both graft-filled and LLLT-treated bone defects were compared. New bone formation was higher in the graft treatment samples compared with the control (P = 0.009) and laser samples (P = 0.029). In addition, graft–laser combination treatment samples revealed higher bone formation than control (P = 0.008) and laser (P = 0.026) samples. Osteoblast density was significantly higher in the laser treatment (P <0.001), graft treatment (P = 0.001) and graft–laser combination treatment (P <0.001) samples than control samples. In addition, significantly higher osteoblast density was observed in the graft-laser combination treatment samples compared to the graft treatment samples (P = 0.005). The LLLT was effective to stimulate osteoblastogenesis but failed to increase bone formation. Graft augmentation for treatment of bone defects seems essential for proper bone healing in diabetes, regeneration may be supported by the LLLT to enhance osteoblastogenesis.
A Novel Technique Using W-Shaped Steel Wire Suspension System to Improve the Stability of Rigid External Distraction Devise in a Child With Apert Syndrome
Authors: Yang Fan , Song Tao , Jin Xiaolei
Published: June 2019

Rigid external distraction device (RED) is an efficient and reliable technique for syndromic craniosynostosis patient's postoperative midface distraction. But the instability of the RED is still a major complication. In this case, the authors reported a novel and simple method to solve the RED movement after Le Fort III osteotomy by using W-shaped steel wire suspension system in a child with Apert syndrome whose bilateral temporal bone is extremely thin. The system resisted the rotational force produced by traction force and effectively restricted the RED rotation down, improving the stability of the RED. The authors think this technique has the advantages of being cheap, easy to accomplish and comfortable to wear. Although may cause extra trauma, it is an available technique to improve the postoperative stability of RED especially for patients with thin temporal bones.
Harvest of Costal Cartilage Through Periareolar Incision for Rhinoplasty in Mastopexy
Authors: Zhou Yiqun , Wang Wancheng , Liu Tianyi
Published: June 2019

At our department, the authors performed a periareolar mastopexy and harvested costal cartilage for use in a rhinoplasty through the same periareolar incision. This technique has several advantages compared to the traditional method, including less invasion, minimal chance of a hypertrophic scar and easier postoperative care. However, the location of the incision determines that the fifth costal cartilage is the lowest one accessible. Thus, calcification of the implant material poses a challenge to surgeons.

In this case report, the authors present a 25-year-old female with a low-profile nose and mild breast ptosis who received a periareolar mastopexy and a dorsal and nasal tip augmentation simultaneously. The operation method, outcomes, advantages and potential risks are included.
Superficial Orbital Rim Osteoma
Authors: Bagheri Abbas , Feizi Mohaddese , Rezai Kanavi Mojgan
Published: June 2019

A 29-year old woman presented with 2 small and firm subcutaneous nodules on the anterior aspect of the left inferonasal orbital rim. Orbital computed tomography scan showed small well-circumscribed exophytic masses of bone density on frontal process of maxillary bone. The patient refused any surgical intervention in this stage. After 5 years masses demonstrated a significant growth and she requested to do surgery. Complete surgical excision was performed and histopathological diagnosis was consistent with an ivory-typed osteoma. The patient was tumor-free in a 2-year follow up. Orbital osteoma may present as subcutaneous nodules on orbital rim, which can be eradicated by surgical excision of the tumor.
Catecholamines Induce Endoplasmic Reticulum Stress Via Both Alpha and Beta Receptors
Authors: Abdullahi Abdikarim , Wang Vivian , Auger Christopher , Patsouris David , Amini-Nik Saeid , Jeschke Marc G.
Published: June 2019

Severely burned patients suffer from a hypermetabolic syndrome that can last for years after the injury has resolved. The underlying cause of these metabolic alterations most likely involves the persistent elevated catecholamine levels that follow the surge induced by thermal injury. At the cellular level, endoplasmic reticulum (ER) stress in metabolic tissues is a hallmark observed in patients following burn injury and is associated with several detrimental effects. Therefore, ER stress could be the underlying cellular mechanism of persistent hypermetabolism in burned patients. Here, we show that catecholamines induce ER stress and that adreno-receptor blockers reduce stress responses in the HepG2 hepatocyte cell line. Our results also indicate that norepinephrine (NE) significantly induces ER stress in HepG2 cells and 3T3L1 mouse adipocytes. Furthermore, we demonstrate that the alpha-1 blocker, prazosin, and beta blocker, propranolol, block ER stress induced by NE. We also show that the effects of catecholamines in inducing ER stress are cell type-specific, as NE treatment failed to evoke ER stress in human fibroblasts. Thus, these findings reveal the mechanisms used by catecholamines to alter metabolism and suggest inhibition of the receptors utilized by these agents should be further explored as a potential target for the treatment of ER stress-mediated disease.
First-Days Reduction of Plasma and Skin Advanced Glycation End Products is Related to Outcome in Septic Patients
Authors: Rodriguez-Ruiz Emilio , Lopez-Lago Ana , Hernandez-Vaquero Rebeca , Granja-Gomez Isabel , Estany-Gestal Ana , Alvarez Ezequiel , Garcia-Gonzalez Miguel , Garcia-Allut Jose L.
Published: June 2019

Background:

Advanced glycation end products (AGEs) are a result of nonenzymatic glycation of proteins and lipids, which can attach to either their cell surface receptor (RAGE) or its soluble form (sRAGE). Evidence exists for the implication of AGE-RAGE axis in sepsis, but data are still insufficient and conflicting. We aimed to analyze the kinetics of plasma and skin AGEs and sRAGE during sepsis, and their association with outcome in septic patients.

Methods:

We performed a prospective observational study. We enrolled 90 consecutive patients with severe sepsis or septic shock, within the first 24 h of Intensive Care Unit admission. During the first 5 days of sepsis, we measured plasma autofluorescence (PAF) and skin autofluorescence (SAF) as surrogates of circulating and skin AGEs, respectively. sRAGE was measured on days 1, 3, and 5. Delta values were defined as the difference between the PAF, SAF, or sRAGE on a specific day and the value on day 1.

Results:

28-day mortality was 18%. Bivariate analysis found that ΔPAF3-1, ΔPAF4-1, ΔPAF5-1, and ΔSAF5-1 were significantly associated with 28-day mortality. Additionally, sRAGE1 was inversely correlated to ΔPAF4-1 (r = −0.250, P = 0.019) and ΔPAF5-1 (r = −0.246, P = 0.024), and significantly associated with 28-day mortality. In an adjusted multivariate logistic regression analysis, ΔPAF2-1, ΔPAF3-1, ΔPAF4-1, ΔPAF5-1, and ΔSAF5-1 were associated with 28-day mortality.

Conclusions:

Kinetics of plasma and skin AGEs during the first days of sepsis are independently associated with mortality, where a decrease of plasma and skin AGEs are related to higher mortality.
Outcomes of an Overnight-Stay Unit for Urogynecologic Surgery: Feasibility and Risk Factors for Failure of Next-Day Discharge
Authors: Clancy Aisling A. , Ilin Julius , Pascali Dante , Shehata Fady , Hickling Duane R.
Published: June 2019

Objective

To evaluate outcomes of patients undergoing urogynecologic procedures with postoperative care in an overnight-stay unit at a tertiary care center.

Methods

A retrospective cohort study of 1644 women admitted to an overnight-stay unit at a Canadian tertiary care center after urogynecologic surgery between 2014 and 2018 was completed. A multivariable logistic regression model was fit to identify risk factors for failed next-day discharge, defined as a delayed discharge of more than 24 hours, readmission within 30 days of surgery, or emergency room assessment within 7 days of surgery.

Results

One thousand five hundred seventy-eight patients (96%) were discharged within 24 hours of surgery. Mean patient age was 53.7 ± 15.1 years, with 21.2% 70 years or older. Surgical approaches included laparotomies (8.9%), major vaginal surgery (70.9%), and open retropubic procedures (2.1%). Hysterectomies were performed in 1120 patients (68.1%). One hundred one patients (6.1%) were assessed in the emergency department within 7 days of surgery, and 57 (3.5%) were readmitted to hospital within 30 days of their procedure. Multivariable regression identified the following as risk factors for failed next-day discharge: pulmonary disease (odds ratio [OR], 3.26; 95% confidence interval [CI], 1.32–8.06; P = 0.010), longer operating time (OR, 1.40; 95% CI, 1.10–1.79; P = 0.006, per 60 minutes), and intraoperative hemorrhagic complications (OR, 22.64; 95% CI, 5.83–88.00, P < 0.001).

Conclusions

Admission to an overnight-stay unit with next-day discharge is feasible for most patients undergoing urogynecologic surgery. Factors associated with requiring a longer hospital stay, presentation to an emergency department, or readmission to hospital within 7 days include pulmonary disease, longer operating times, and intraoperative hemorrhagic complications.
Climate drivers of malaria at its southern fringe in the Americas
Authors: Laneri Karina , Cabella Brenno , Prado Paulo Inácio , Coutinho Renato Mendes , Kraenkel Roberto André
Published: June 2019

In this work we analyze potential environmental drivers of malaria cases in Northwestern Argentina. We inspect causal links between malaria and climatic variables by means of the convergent cross mapping technique, which provides a causality criterion from the theory of dynamic systems. Analysis is based on 12 years of weekly malaria P. vivax cases in Tartagal, Salta, Argentina—at the southern fringe of malaria incidence in the Americas—together with humidity and temperature time-series spanning the same period. Our results show that there are causal links between malaria cases and both maximum temperature, with a delay of five weeks, and minimum temperature, with delays of zero and twenty two weeks. Humidity is also a driver of malaria cases, with thirteen weeks delay between cause and effect. Furthermore we also determined the sign and strength of the effects. Temperature has always a positive non-linear effect on cases, with maximum temperature effects more pronounced above 25° C and minimum above 17° C, while effects of humidity are more intricate: maximum humidity above 85% has a negative effect, whereas minimum humidity has a positive effect on cases. These results might be signaling processes operating at short (below 5 weeks) and long (over 12 weeks) time delays, corresponding to effects related to parasite cycle and mosquito population dynamics respectively. The non-linearities found for the strength of the effect of temperature on malaria cases make warmer areas more prone to higher increases in the disease incidence. Moreover, our results indicate that an increase of extreme weather events could enhance the risks of malaria spreading and re-emergence beyond the current distribution. Both situations, warmer climate and increase of extreme events, will be remarkably increased by the end of the century in this hot spot of climate change.
The “creatures” of the human cortical somatosensory system
Authors: Saadon-Grosman N. , Loewenstein Y. , Arzy S.
Published: June 2019

Penfield’s description of the “homunculus”, a “grotesque creature” with large lips and hands and small trunk and legs depicting the representation of body-parts within the primary somatosensory cortex (S1), is one of the most prominent contributions to the neurosciences. Since then, numerous studies have identified additional body-parts representations outside of S1. Nevertheless, it has been implicitly assumed that S1’s homunculus is representative of the entire somatosensory cortex. Therefore, the distribution of body-parts representations in other brain regions, the property that gave Penfield’s homunculus its famous “grotesque” appearance, has been overlooked. We used whole-body somatosensory stimulation, functional MRI and a new cortical parcellation to quantify the organization of the cortical somatosensory representation. Our analysis showed first, an extensive somatosensory response over the cortex; and second, that the proportional representation of body-parts differs substantially between major neuroanatomical regions and from S1, with, for instance, much larger trunk representation at higher brain regions, potentially in relation to the regions’ functional specialization. These results extend Penfield’s initial findings to the higher level of somatosensory processing and suggest a major role for somatosensation in human cognition.
Reliable confidence intervals for RelTime estimates of evolutionary divergence times
Authors: Tao Qiqing , Tamura Koichiro , Mello Beatriz , Kumar Sudhir
Published: June 2019

Confidence intervals (CIs) depict the statistical uncertainty surrounding evolutionary divergence time estimates. They capture variance contributed by the finite number of sequences and sites used in the alignment, deviations of evolutionary rates from a strict molecular clock in a phylogeny, and uncertainty associated with clock calibrations. Reliable tests of biological hypotheses demand reliable CIs. However, current non-Bayesian methods may produce unreliable CIs because they do not incorporate rate variation among lineages and interactions among clock calibrations properly. Here, we present a new analytical method to calculate CIs of divergence times estimated using the RelTime method, along with an approach to utilize multiple calibration uncertainty densities in these analyses. Empirical data analyses showed that the new methods produce CIs that overlap with Bayesian highest posterior density (HPD) intervals. In the analysis of computer-simulated data, we found that RelTime CIs show excellent average coverage probabilities, i.e., the true time is contained within the CIs with a 95% probability. These developments will encourage broader use of computationally-efficient RelTime approach in molecular dating analyses and biological hypothesis testing.
Simple and complex interactions between sleep-wake driven and circadian processes shape daily genome regulatory dynamics in the mouse
Authors: Hor Charlotte N. , Yeung Jake , Jan Maxime , Emmenegger Yann , Hubbard Jeffrey , Xenarios Ioannis , Naef Felix , Franken Paul
Published: June 2019

The timing and duration of sleep results from the interaction between a sleep-wake driven, or homeostatic, process (S) and a circadian process (C), and involves changes in gene expression and genomic regulation. Unraveling the respective contributions of S and C, and their interaction, to transcriptional and epigenomic regulatory dynamics requires sampling over time under unperturbed conditions and conditions of perturbed sleep. Here, we profiled mRNA expression and chromatin accessibility in the cerebral cortex of mice over a three-day period, including a 6-hour sleep deprivation (SD) on day two. Mathematical modeling established that a large proportion of rhythmic genes are actually governed by Process S with varying degrees of interaction with Process C, sometimes working in opposition. Remarkably, SD causes long-term effects on gene expression dynamics, outlasting phenotypic recovery, most strikingly illustrated by a dampening of the oscillation of most core clock genes, includingBmal1, suggesting that enforced wakefulness directly impacts the molecular clock machinery. Chromatin accessibility proved highly plastic and dynamically affected by SD. Distal regions, rather than promoters, display dynamics corresponding to gene transcription, implying that changes in mRNA expression result from constantly accessible promoters under the influence of distal enhancers or repressors.Srfwas predicted as a transcriptional regulator driving immediate response, suggesting thatSrfactivity mirrors the build-up and release of sleep pressure. Our results demonstrate that a single, short SD has long-term aftereffects at the genomic regulatory level. Such effects might accumulate with repeated sleep restrictions, thereby contributing to their adverse health effects.

Significance statement

When and how long we sleep is determined by the time-of-day and how long we have been awake, which are tracked molecularly by a circadian and a sleep-wake driven process, respectively. We measured the long-term consequences of a short-term sleep deprivation (SD) on gene expression and regulation in the mouse brain, and used mathematical models to determine the relative contributions of the circadian and sleep-wake driven processes. We find that many genes, including most of the genes that constitute the molecular circadian clock, are perturbed by SD long after the mice ceased showing behavioral signs of sleep loss. Our results have implications for human health, given the high prevalence of insufficient and poor quality sleep in our contemporary society.
Enhancer-dependence of gene expression increases with developmental age
Authors: Cai Wenqing , Huang Jialiang , Zhu Qian , Li Bin E. , Seruggia Davide , Zhou Pingzhu , Nguyen Minh , Fujiwara Yuko , Xie Huafeng , Yang Zhenggang , Hong Danni , Ren Pengfei , Xu Jian , Pu William T. , Yuan Guo-Cheng , Orkin Stuart H.
Published: June 2019

How overall principles of gene regulation (the “logic”) may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic and topological profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1 and Myb occupancy. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes employ distal enhancers for long-range regulation through enhancer-promoter looping, confirmed by Gata1 HiChIP. Genome editing demonstrated distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer-dependence of transcription, we observed a progressive reliance on enhancer control with increasing age of ontogeny among diverse primary cells and tissues of mouse and human origin. Our findings highlight fundamental and conserved differences in regulatory logic at distinct developmental stages, characterized by simpler promoter-centric regulation in embryonic cells and combinatorial enhancer-driven control in adult cells.

Highlights

Regulation of embryonic-specific erythroid genes is promoter-centric through Gata1

Adult-specific control is combinatorial enhancer-driven and requires Myb

Adult specific genes have increased enhancer-promoter chromatin interactions

Enhancer-dependence increases progressively with increasing developmental age
Super-resolution Imaging Reveals 3D Structure and Organizing Mechanism of Accessible Chromatin
Authors: Xie Liangqi , Dong Peng , Qi Yifeng , De Marzio Margherita , Chen Xingqi , Banala Sambashiva , Legant Wesley R. , English Brian P. , Hansen Anders S. , Schulmann Anton , Lavis Luke D. , Betzig Eric , Casellas Rafael , Chang Howard Y. , Zhang Bin , Tjian Robert , Liu Zhe
Published: June 2019

Access to cis-regulatory elements packaged in chromatin is essential for directing gene expression and cell viability. Here, we report a super-resolution imaging strategy, 3D ATAC-PALM, that enables direct visualization of the entire accessible genome. We found that active chromosomal segments are organized into spatially-segregated accessible chromatin domains (ACDs). Rapid depletion of CTCF or Cohesin (RAD21 subunit) induced enhanced ACD clustering, reduced physical separation between intrachromosomal ACDs, and differentially regulated ACD compaction. Experimental perturbations and polymer modeling suggest that dynamic protein-protein and protein-DNA interactions within ACDs couple with loop extrusion to organize ACD topology. Dysorganization of ACDs upon CTCF or Cohesin loss alters transcription factor binding and target search dynamics in living cells. These results uncover fundamental mechanisms underpinning the formation of 3D genome architecture and its pivotal function in transcriptional regulation.
Distinguishing coalescent models - which statistics matter most?
Authors: Freund Fabian , Siri-Jégousse Arno
Published: June 2019

Modelling genetic diversity needs an underlying genealogy model. To choose a fitting model based on genetic data, one can perform model selection between classes of genealogical trees, e.g. Kingman’s coalescent with exponential growth or multiple merger coalescents. Such selection can be based on many different statistics measuring genetic diversity. A random forest based Approximate Bayesian Computation is used to disentangle the effects of different statistics on distinguishing between various classes of genealogy models. For the specific question of inferring whether genealogies feature multiple mergers, a new statistic, the minimal observable clade size, is introduced. When combined with classical site frequency based statistics, it reduces classification errors considerably.
Aging-Associated Decrease in the Histone Acetyltransferase KAT6B Causes Myeloid-Biased Hematopoietic Stem Cell Differentiation
Authors: Khokhar Eraj Shafiq , Borikar Sneha , Eudy Elizabeth , Stearns Tim , Young Kira , Trowbridge Jennifer J.
Published: June 2019

Aged hematopoietic stem cells (HSCs) undergo biased lineage priming and differentiation toward production of myeloid cells. A comprehensive understanding of gene regulatory mechanisms causing HSC aging is needed to devise new strategies to sustainably improve immune function in aged individuals. Here, a focused shRNA screen of epigenetic factors reveals that the histone acetyltransferase Kat6b regulates myeloid cell production from hematopoietic progenitor cells. Within the stem and progenitor cell compartment, Kat6b is most highly expressed in long-term (LT)-HSCs and is significantly decreased with aging at the transcript and protein levels. Knockdown of Kat6b in young LT-HSCs causes skewed production of myeloid cells both in vitro and in vivo. Transcriptome analysis identifies enrichment of aging and macrophage-associated gene signatures alongside reduced expression of self-renewal and multilineage priming signatures. Together, our work identifies KAT6B as an epigenetic regulator of LT-HSC aging and a novel target to improve aged immune function.
Exome-wide assessment of the functional impact and pathogenicity of multinucleotide mutations
Authors: Kaplanis Joanna , Akawi Nadia , Gallone Giuseppe , McRae Jeremy F. , Prigmore Elena , Wright Caroline F. , Fitzpatrick David R. , Firth Helen V. , Barrett Jeffrey C. , Hurles Matthew E. ,   on behalf of the Deciphering Developmental Disorders study
Published: June 2019

Approximately 2% of de novo single-nucleotide variants (SNVs) appear as part of clustered mutations that create multinucleotide variants (MNVs). MNVs are an important source of genomic variability as they are more likely to alter an encoded protein than a SNV, which has important implications in disease as well as evolution. Previous studies of MNVs have focused on their mutational origins and have not systematically evaluated their functional impact and contribution to disease. We identified 69,940 MNVs and 91 de novo MNVs in 6688 exome-sequenced parent–offspring trios from the Deciphering Developmental Disorders Study comprising families with severe developmental disorders. We replicated the previously described MNV mutational signatures associated with DNA polymerase zeta, an error-prone translesion polymerase, and the APOBEC family of DNA deaminases. We estimate the simultaneous MNV germline mutation rate to be 1.78 × 10−10 mutations per base pair per generation. We found that most MNVs within a single codon create a missense change that could not have been created by a SNV. MNV-induced missense changes were, on average, more physicochemically divergent, were more depleted in highly constrained genes (pLI ≥ 0.9), and were under stronger purifying selection compared with SNV-induced missense changes. We found that de novo MNVs were significantly enriched in genes previously associated with developmental disorders in affected children. This shows that MNVs can be more damaging than SNVs even when both induce missense changes, and are an important variant type to consider in relation to human disease.
Ethical Leadership and Unethical Pro‐Organisational Behaviour: The Mediating Mechanism of Reflective Moral Attentiveness
Authors: Miao Qing , Eva Nathan , Newman Alexander , Nielsen Ingrid , Herbert Kendall
Published: June 2019

This study examines the mediating effects of reflective moral attentiveness on the relationship between ethical leadership and subordinates’ unethical pro‐organisational behaviour (UPB). Based on two‐wave survey data obtained from 233 employees in 60 teams from Chinese government agencies, we found that ethical leadership was positively related to reflective moral attentiveness. In addition, we found that reflective moral attentiveness mediated the relationship between ethical leadership and UPB, such that ethical leadership negatively influenced subordinates’ unethical pro‐organisational behaviour through enhancing reflective moral attentiveness.
Post‐mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms
Authors: Fransen Nina L. , Crusius Jakob B. A. , Smolders Joost , Mizee Mark R. , van Eden Corbert G. , Luchetti Sabina , Remmerswaal Ester B. M. , Hamann Jörg , Mason Matthew R. J. , Huitinga Inge
Published: June 2019

Over the last few decades, several common single nucleotide polymorphisms (SNPs) have been identified that correlate with clinical outcome in multiple sclerosis (MS), but the pathogenic mechanisms underlying the clinical effects of these SNPs are unknown. This is in part because of the difficulty in the functional translation of genotype into disease‐relevant mechanisms. Building on our recent work showing the association of clinical disease course with post‐mortem MS lesion characteristics, we hypothesized that SNPs that correlate with clinical disease course would also correlate with specific MS lesion characteristics in autopsy tissue. To test this hypothesis, 179 MS brain donors from the Netherlands Brain Bank MS autopsy cohort were genotyped for 102 SNPs, selected based on their reported associations with clinical outcome or their associations with genes that show differential gene expression in MS lesions. Three SNPs linked to MS clinical severity showed a significant association between the genotype and either the proportion of active lesions (rs2234978/FAS and rs11957313/KCNIP1) or the proportion of mixed active/inactive lesions (rs8056098/CLEC16A). Three SNPs linked to MS pathology‐associated genes showed a significant association with either proportion of active lesions (rs3130253/MOG), incidence of cortical gray matter lesions (rs1064395/NCAN) or the proportion of remyelinated lesions (rs5742909/CTLA4). In addition, rs2234978/FAS T‐allele carriers showed increased FAS gene expression levels in perivascular T cells and perilesional oligodendrocytes, cell types that have been implicated in MS lesion formation. Thus, by combining pathological characterization of MS brain autopsy tissue with genetics, we now start to translate genotypes linked to clinical outcomes in MS into mechanisms involved in MS lesion pathogenesis.