bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of In Vivo Protein Folding Probability on Local Fitness Landscapes
Authors: Faber Matthew S , Wrenbeck Emily E , Azouz Laura R , Steiner Paul J , Whitehead Timothy A 
Published: August 2019

Abstract
It is incompletely understood how biophysical properties like protein stability impact molecular evolution and epistasis. Epistasis is defined as specific when a mutation exclusively influences the phenotypic effect of another mutation, often at physically interacting residues. In contrast, nonspecific epistasis results when a mutation is influenced by a large number of nonlocal mutations. As most mutations are pleiotropic, the in vivo folding probability—governed by basal protein stability—is thought to determine activity-enhancing mutational tolerance, implying that nonspecific epistasis is dominant. However, evidence exists for both specific and nonspecific epistasis as the prevalent factor, with limited comprehensive data sets to support either claim. Here, we use deep mutational scanning to probe how in vivo enzyme folding probability impacts local fitness landscapes. We computationally designed two different variants of the amidase AmiE with statistically indistinguishable catalytic efficiencies but lower probabilities of folding in vivo compared with wild-type. Local fitness landscapes show slight alterations among variants, with essentially the same global distribution of fitness effects. However, specific epistasis was predominant for the subset of mutations exhibiting positive sign epistasis. These mutations mapped to spatially distinct locations on AmiE near the initial mutation or proximal to the active site. Intriguingly, the majority of specific epistatic mutations were codon dependent, with different synonymous codons resulting in fitness sign reversals. Together, these results offer a nuanced view of how protein folding probability impacts local fitness landscapes and suggest that transcriptional–translational effects are as important as stability in determining evolutionary outcomes.
Pulmonary Hypertension as a Primary Presentation for Schistosomiasis, a Case Report of Unusual Presentation
Authors: Hussein Mogahed Ismail Hassan 
Published: August 2019

Abstract
The combination of schistosomiasis and pulmonary hypertension (PH) was always recognized as a very rare one; in medical literature, PH is considered as a manifestation of hepatosplenic schistosomiasis but not a manifestation of schistosomal infection until recently. Only 18.5% of patients that have a documented hepatosplenic schistosomiasis were found with PH. Schistosomiasis rarely causes PH without evident hepatosplenic manifestations. Here, we are reporting a case of a patient whose first clinical presentation was features of PH. We use this case as an opportunity to outline pathological mechanisms, causes and classification of PH. A structured and thorough workup for PH is emphasized. It is important to exclude all other secondary causes to be able to diagnose primary PH especially in the absence of a positive family history and advanced diagnostic technology.
Fertilization-Coupled Sperm Nuclear Fusion Is Required for Normal Endosperm Nuclear Proliferation
Authors: Maruyama Daisuke , Higashiyama Tetsuya , Endo Toshiya , Nishikawa Shuh-ichi 
Published: August 2019

Abstract
Angiosperms exhibit double fertilization, a process in which one of the sperm cells released from the pollen tube fertilizes the egg, while the other sperm cell fertilizes the central cell, giving rise to the embryo and endosperm, respectively. We have previously reported two polar nuclear fusion-defective double knockout mutants of Arabidopsis thaliana immunoglobulin binding protein (BiP), a molecular chaperone of the heat shock protein 70 (Hsp70) localized in the endoplasmic reticulum (ER), (bip1 bip2) and its partner ER-resident J-proteins, ERdj3A and P58IPK (erdj3a p58ipk). These mutants are defective in the fusion of outer nuclear membrane and exhibit characteristic seed developmental defects after fertilization with wild-type pollen, which are accompanied by aberrant endosperm nuclear proliferation. In this study, we used time-lapse live-cell imaging analysis to determine the cause of aberrant endosperm nuclear division in these mutant seeds. We found that the central cell of bip1 bip2 or erdj3a p58ipk double mutant female gametophytes was also defective in sperm nuclear fusion at fertilization. Sperm nuclear fusion was achieved after the onset of the first endosperm nuclear division. However, division of the condensed sperm nucleus resulted in aberrant endosperm nuclear divisions and delayed expression of paternally derived genes. By contrast, the other double knockout mutant, erdj3b p58ipk, which is defective in the fusion of inner membrane of polar nuclei but does not show aberrant endosperm nuclear proliferation, was not defective in sperm nuclear fusion at fertilization. We thus propose that premitotic sperm nuclear fusion in the central cell is critical for normal endosperm nuclear proliferation.
Negation, expressivism, and intentionality
Authors: Pérez Carballo Alejandro 
Published: August 2019

AbstractMany think that expressivists have a special problem with negation. I disagree. For if there is a problem with negation, I argue, it is a problem shared by those who accept some plausible claims about the nature of intentionality. Whether there is any special problem for expressivists turns, I will argue, on whether facts about what truth-conditions beliefs have can explain facts about basic inferential relations among those beliefs. And I will suggest that the answer to this last question is, on most plausible attempts at solving the problem of intentionality, ‘no’.
Impact of adding tacrolimus to initial treatment of interstitial pneumonitis in polymyositis/dermatomyositis: a single-arm clinical trial
Authors: Takada Kazuki , Katada Yoshinori , Ito Satoshi , Hayashi Taichi , Kishi Jun , Itoh Kenji , Yamashita Hiroyuki , Hirakata Michito , Kawahata Kimito , Kawakami Atsushi , Watanabe Norihiko , Atsumi Tatsuya , Takasaki Yoshinari , Miyasaka Nobuyuki 
Published: August 2019

Abstract

Objective
Interstitial pneumonia is common and has high short-term mortality in patients with PM and DM despite glucocorticoid (GC) treatment. Retrospective studies suggested that the early use of immunosuppressive drugs with GCs might improve its short-term mortality.

Methods
A multicentre, single-arm, 52-week-long clinical trial was performed to test whether the initial combination treatment with tacrolimus (0.075 mg/kg/day, adjusted for the target whole-blood trough levels between 5 and 10 ng/ml) and GCs (0.6–1.0 mg/kg/day of prednisolone followed by a slow taper) improves short-term mortality of PM/DM-interstitial pneumonia patients. The primary outcome was overall survival. We originally intended to compare, by using propensity-score matching, the outcome data of clinical trial patients with that of historical control patients who were initially treated with GCs alone.

Results
The 52-week survival rate with the combination treatment (N = 26) was 88.0% (95% CI, 67.3, 96.0). Safety profiles of the combination treatment were consistent with those known for tacrolimus and high-dose GCs individually. Serious adverse events occurred in 11 patients (44.0%), which included four opportunistic infections. Only 16 patients, including only 1 deceased patient, were registered as historical controls, which precluded meaningful comparative analysis against the clinical trial patients.

Conclusion
Our study provided findings which suggest that initial treatment with tacrolimus and GCs may improve short-term mortality of PM/DM-interstitial pneumonia patients with manageable safety profiles. This was the first prospective clinical investigation conducted according to the Good Clinical Practice Guideline of the International Conference on Harmonization for the treatment of this potentially life-threatening disease.

Trial registration
ClinicalTrials.gov, http://clinicaltrials.gov, NCT00504348.
Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice
Authors: Hill Thomas , Conolly Rory B 
Published: August 2019

Abstract
Traditional methods for carcinogenicity testing rely heavily on the rodent bioassay as the standard for identification of tumorigenic risk. As such, identification of species-specific outcomes and/or metabolism are a frequent argument for regulatory exemption. One example is the association of tumor formation in the mouse lung after exposure to Cyp2F2 ligands. The adverse outcome pathway (AOP) framework offers a theoretical platform to address issues of species specificity that is consistent, transparent, and capable of integrating data from new approach methodologies as well as traditional data streams. A central premise of the AOP concept is that pathway progression from the molecular initiating event (MIE) implies a definable “response-response” (R-R) relationship between each key event (KE) that drives the pathway towards a specific adverse outcome (AO). This article describes an AOP for lung cancer in the mouse from an MIE of Cyp2F2-specific reactive metabolite formation, advancing through KE that include protein and/or nucleic acid adducts, diminished Club Cell 10 kDa (CC10) protein expression, hyperplasia of CC10 deficient Club cells, and culminating in the AO of mixed-cell tumor formation in the distal airways. This tumor formation is independent of route of exposure and our AOP construct is based on overlapping mechanistic events for naphthalene, styrene, ethyl benzene, isoniazid, and fluensulfone in the mouse. This AOP is intended to accelerate the explication of an apparent mouse-specific outcome and serve as a starting point for a quantitative analysis of mouse-human differences in susceptibility to the tumorigenic effects of Cyp2F2 ligands.
Associations Between Parity, Breastfeeding, and Risk of Maternal Type 2 Diabetes Among Postmenopausal Women
Authors: Luo Juhua , Hendryx Michael , LeBlanc Erin S. , Shadyab Aladdin H. , Qi Lihong , Sealy-Jefferson Shawnita , Manson JoAnn E. 
Published: August 2019

OBJECTIVE:
To examine associations among parity, breastfeeding history, and risk of developing type 2 diabetes among postmenopausal women.

METHODS:
A prospective cohort study was conducted. One hundred thirty-six thousand six hundred fifty-two postmenopausal women aged 50–79 years participating in the Women's Health Initiative recruited from 40 clinical centers throughout the United States between 1993 and 1998, without baseline cancer or diabetes were followed for 14.2 years. Parity and breastfeeding data were collected by questionnaires administrated to all participants at baseline. Incident diabetes was assessed via validated self-report of physician-diagnosed diabetes treated with insulin or other hypoglycemic medications. Multivariable Cox proportional hazards regression models were used to assess associations between parity, breastfeeding and diabetes incidence, and racial–ethnic differences in the associations.

RESULTS:
During follow-up, 18,812 cases of incident diabetes were identified. Overall, a greater number of term pregnancies was associated with increased risk of diabetes (P for trend=.002), and longer duration of breastfeeding was associated with lower risk of diabetes (P for trend <.01). After further adjusting for adult weight gain among a subset of the cohort (n=75,558) with 9,110 cases, the association between parity and risk of diabetes were attenuated and became nonsignificant. Also, parous women with fewer than five term pregnancies did not have increased diabetes risk when breastfeeding for 3 months or more per child, which was associated with less weight gain.

CONCLUSION:
The results of this large, prospective study showed that the association between parity and risk of type 2 diabetes was most likely confounded by adult weight gain among postmenopausal women.
Strategies for Prescribing Aspirin to Prevent Preeclampsia
Authors: Mallampati Divya , Grobman William , Rouse Dwight J. , Werner Erika F. 
Published: August 2019

OBJECTIVE:
To evaluate the cost effectiveness of various preeclampsia screening and aspirin prophylaxis strategies, including a strategy based on biomarker and ultrasound measures.

METHODS:
We designed a decision analysis to compare preeclampsia-related costs and effects of four strategies for aspirin use in pregnancy initiated before 16 weeks of gestation to prevent preeclampsia. The four strategies were: 1) no aspirin use, 2) biomarker and ultrasound measure–predicated use, 3) use based on the U.S. Preventive Services Task Force guidelines, and 4) universal aspirin use. Our outcomes were preeclampsia-related costs and number of cases per 100,000 pregnant women. Using a threshold of $90,843 per case of preeclampsia, one-way, two-way, and Monte-Carlo sensitivity analyses incorporating varying probabilities of risk reduction due to aspirin use, aspirin-related side effects, and costs were performed to identify ranges at which costs and risks of aspirin-related complications shifted the preferred strategy.

RESULTS:
Compared with universal aspirin administration, the use of U.S. Preventive Services Task Force guidelines is associated with $8,011,725 higher health care costs and 346 additional cases of preeclampsia per 100,000 pregnant women; biomarker and ultrasound screening is associated with an additional $19,216,551 and 308 additional cases. Similarly, no aspirin use is associated with an increased cost of $18,750,381 and 762 additional cases. Thus, universal aspirin use dominated all three other strategies. In a Monte Carlo simulation of 10,000 pregnant women, universal aspirin was the preferred strategy in 91% of simulations. The U.S. Preventive Task Force screen was preferred in 8.5% of simulations, and biomarker and ultrasound screening and no aspirin were preferred in 0% and 0.5% of simulations, respectively.

CONCLUSION:
Over a broad range of assumptions, universal aspirin administration is associated with fewer cases of preeclampsia and fewer costs relative to no aspirin administration and aspirin administration based on serum and ultrasound measures or clinical risk factors.
Small-Group, Community-Member Intervention for Urinary and Bowel Incontinence
Authors: Brown Heidi W. , Braun Emilie J. , Wise Meg E. , Myers Shannon , Li Zhanhai , Sampene Emmanuel , Jansen Sierra M. , Moberg D. Paul , Mahoney Jane E. , Rogers Rebecca G. 
Published: August 2019

OBJECTIVE:
To evaluate the effects of Mind Over Matter: Healthy Bowels, Healthy Bladder, a small-group intervention, on urinary and bowel incontinence symptoms among older women with incontinence.

METHODS:
In this individually randomized group treatment trial, women aged 50 years and older with urinary, bowel incontinence, or both, were randomly allocated at baseline to participate in Mind Over Matter: Healthy Bowels, Healthy Bladder immediately (treatment group) or after final data collection (waitlist control group). The primary outcome was urinary incontinence (UI) improvement on the Patient Global Impression of Improvement at 4 months. Validated instruments assessed incontinence, self-efficacy, depression, and barriers to care-seeking. Intent-to-treat analyses compared differences between groups. Target sample size, based on an anticipated improvement rate of 45% in treated women vs 11% in the control group, 90% power, type I error of 0.05, with anticipated attrition of 25%, was 110.

RESULTS:
Among 121 women randomized (62 treatment group; 59 control group), 116 (95%) completed the 4-month assessment. Most participants were non-Hispanic white (97%), with a mean age of 75 years (SD 9.2, range 51–98); 66% had attended some college. There were no significant between-group differences at baseline. At 4 months, 71% of treated women vs 23% of women in the control group reported improved UI on Patient Global Impression of Improvement (P<.001); 39% vs 5% were much improved (P<.001). Regarding bowel incontinence, 55% of treated women vs 27% of women in the control group improved on Patient Global Impression of Improvement (P<.005), with 35% vs 11% reporting much improvement (P<.005). Treated women improved significantly more than women in the control group on all validated instruments of incontinence severity, quality of life, and self-efficacy. Care-seeking rates were similar between groups.

CONCLUSION:
Participation in a small-group intervention improves symptoms of both urinary and bowel incontinence in older women. Mind Over Matter is a feasible model with potential to bring effective behavioral solutions to the community.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT03140852.
Influence of Social Media on the Decision to Undergo a Cosmetic Procedure
Authors: Arab Khalid , Barasain Omar , Altaweel Abdullah , Alkhayyal Jawaher , Alshiha Lulwah , Barasain Rana , Alessa Rania , Alshaalan Hayfaa 
Published: August 2019

Background:
There is a rise of cosmetic procedures in Saudi Arabia. Social media have become a popular means of advertisements for cosmetic professional providers. There are currently no studies that determine the relationship between viewing cosmetic surgery advertisements and considering undergoing cosmetic procedures in female university students in Saudi Arabia.

Methods:
A cross-sectional study was conducted using an online survey. This survey determined the use of social media, cosmetic-related accounts followed by the respondent, and attitudes toward advertising for cosmetic treatments on social media. It also determines the influence of these accounts on female university students to consider undergoing cosmetic treatments in the future. The survey was distributed on multiple social media platforms and by Email.

Results:
Out of 816 completed questionnaires, 48.5% reported being influenced by social media to consider undergoing cosmetic procedures. Respondents (51.4%) follow plastic surgeons on social media (P < 0.001). The most common reported number of hours of social media use per day was >5 hours per day (53.2%; P < 0.026). Statistical significance was considered in relation to reporting being influenced by social media to consider undergoing cosmetic procedures in the future.

Conclusions:
Our findings revealed that viewing cosmetic surgery–related material on social media, spending longer hours on social media platforms, and having negative self-views when viewing social media are associated with an increased likelihood of considering undergoing cosmetic procedures in the future. Future studies using a validated questionnaire that assesses the likelihood of being influenced by social media to undergo cosmetic treatments are encouraged.
Rhinoplasty and External Nasal Splinting: Is It Really a Must?
Authors: Challita Raymond , Shouman Mohamad , Ghanime George 
Published: August 2019

Background:
Rhinoplasty is a common and challenging procedure. Lateral osteotomy is routinely performed in most cases. Most of the surgeons have the habit of applying external nasal splints to stabilize the nasal tissues and bone in their new position postrhinoplasty. These splints are widely used despite the absence of any evidence supporting this practice. Moreover, these splints have a lot of disadvantages, so we conducted this study to evaluate the cosmetic result in their absence.

Patients and Methods:
A retrospective cross-sectional study was performed. Medical records of 211 patients operated on for rhinoplasty by the same surgeon from 2015 to 2017 were reviewed. All patients were operated using open technique. After surgery, a Steri-Strips dressing with an overlying layer of surgical tape was applied to the nose without the use of an external nasal splint. Most of the patients were followed up for 18 months. Complication rates, revision rates, and nasal bone widths were recorded.

Results:
Complication rates and revision rates were as follows: skin infection 0.99%, skin necrosis 0.99%, and secondary revision 3.48%. Finally 79.60% of patients had a decrease in their nasal bone width postsurgery.

Conclusion:
Based on the present study, external nasal splinting postrhinoplasty should not be routinely used. Satisfactory cosmetic results can be obtained while avoiding the complications, cost, and bulky dressings associated with external splints.
Creating a Defined Process to Improve the Timeliness of Serious Safety Event Determination and Root Cause Analysis
Authors: Donnelly Lane F. , Palangyo Tua , Bargmann-Losche Jessey , Rogers Kiley , Wood Mathew , Shin Andrew Y. 
Published: August 2019

Introduction:
Serious Safety Events (SSEs) are defined as events in which there is a deviation from clinically accepted performance standards, causation, and significant patient harm or death. Given the nature of SSEs, it is important that the processes for declaration of SSEs, the performance of a root cause analysis (RCA), and action plan formation occur quickly, such that the window for potential recurrence of similar events is as small as possible. This manuscript describes a process put in place to improve the timeliness of SSE determination and RCA conduction and evaluates the effect of the process change on these parameters.

Methods:
A causal analysis was performed of the baseline process to determine factors contributing to long process times. A new process was created and implemented both for the SSE determination process and the RCA completion process. We calculated the mean time for the pre-implementation phase (April 2016–December 2017) and the post-implementation phase (March 2018–January 2019) for both SSE determination and RCA completion. We evaluated differences with a two-sided t test assuming unequal variances.

Results:
Comparing pre- versus post- implementation phases, the mean time for SSE determination for events that met the SSE criteria decreased from 38.4 to 4.8 days (P < 0.0001), determination for events that did not meet the SSE criteria decreased from 38.4 to 3.8 days (P < 0.0001), and RCA completion time dropped from 118.0 to 26.2 days (P < 0.0001).

Conclusions:
A targeted intervention can significantly reduce SSE determination and RCA conduction times.
Diagnosis and Treatment of Scalp Arteriovenous Malformations With Intracranial Extension
Authors: Kanth Aditi M. , Ricci Joseph A. , Adetayo Oluwaseun A. 
Published: August 2019

Abstract
Scalp arteriovenous malformations (AVMs) are rare entities that may present as large, tortuous vascular lesions with resultant craniofacial deformity. Radiologic findings include feeding arteries and veins associated with dilated tortuous vessels. Intracranial extension is rare. A 5-year-old African American male presented with an occipital mass presumed to be a dermoid cyst on referral. Further workup revealed the presence of a scalp AVM that demonstrated extension into the left sigmoid sinus. Radiologic and intraoperative images are presented. Literature search revealed only 4 patients with scalp AVM extending intracranially into the sagittal sinus, 2 of which were managed with coagulation and division of the feeding vessels and the other 2 underwent preoperative embolization. Our patient is the 1st to be reported to have sigmoid sinus extension. Scalp AVMs with intracranial extension are rare, and require further preoperative workup. Following ultrasound evaluation, computed tomography angiography, magnetic resonance angiography, magnetic resonance imaging, or cerebral angiography can be considered. Treatment entails resection, but preoperative embolization is increasingly used, mirroring patients without intracranial extension. Further studies are needed to evaluate the efficacy and risk profile of these treatments.