bluuebunny/crossref_metadata_2025 huggingface dataset:
Immediate Breast Reconstruction with a Deep Inferior Epigastric Perforator Flap in the Lithotomy Position
Authors: Tamura Shihoko , Satake Toshihiko , Muto Mayu , Shibuya Mai , Narui Kazutaka , Kobayashi Shinji , Ishikawa Takashi , Maegawa Jiro
Published: December 2019

Mastectomy and flap harvesting can be accomplished simultaneously in immediate deep inferior epigastric perforator (DIEP) flap breast reconstruction. However, this is not always possible, particularly in a teaching institution, where supervisors, trainees, and assistants must participate in the surgery, because there is not enough working space for breast and plastic surgeons to perform surgery together. We attempted to overcome this problem by placing the patient in the lithotomy position and have reported the outcomes. We evaluated patients who underwent unilateral immediate DIEP flap breast reconstruction in the supine or lithotomy position between October 2014 and July 2016. The surgeries were performed by the same inexperienced plastic surgeon in our hospital. In the lithotomy position, 1 plastic surgeon stands between the patient’s legs and 1 stands beside the abdomen, and they perform DIEP flap harvesting simultaneously with mastectomy performed by 3 breast surgeons. After mastectomy, breast reconstruction is performed by 4 plastic surgeons. The supine position was used in the first 8 patients, and the lithotomy position was used in the following 8 patients. The mean operative time was 11 hours 21 minutes in the supine group and 8 hours 52 minutes in the lithotomy group, with a significant difference (P = 0.027). Breast reconstruction with a DIEP flap in the lithotomy position is useful for teaching institutions because it provides sufficient working space and allows simultaneous procedures without prolonging operative time. However, issues such as pressure sores, nerve palsy, and difficulty in patient placement still exist.
Death by Implants: Critical Analysis of the FDA-MAUDE Database on Breast Implant-related Mortality
Authors: Abi-Rafeh Jad , Safran Tyler , Al-Halabi Becher , Dionisopolous Tassos
Published: December 2019

Introduction:

Since the 1992 moratorium by the Food and Drug Administration (FDA), the debate on the association of breast implants with systemic illnesses has been ongoing. Breast implant-associated anaplastic large cell lymphoma has also raised significant safety concerns in recent years.

Methods:

A systematic search of the Manufacturer and User Facility Device Experience (MAUDE) database was performed to identify all cases of breast implant-associated deaths reported to the FDA.

Results:

The search identified 50 reported cases of apparent implant-related mortality; breast implant-associated anaplastic large cell lymphoma comprised the majority of fatal outcomes (n = 21, 42%), followed by lymphoma (n = 4, 8%), breast cancer (n = 3, 6%), pancreatic cancer (n = 2, 4%), implant rupture (n = 2, 4%), and postoperative infections (n = 2, 4%). Single cases (n = 1, 2% each) of leukemia, small bowel cancer, lung disease, pneumonia, autoimmune and joint disease, amyotrophic lateral sclerosis, liver failure, and sudden death, and 2 cases (4%) of newborn deaths, to mothers with breast implants, were also identified. A literature review demonstrated that 54% of alleged implant-related deaths were not truly associated with breast implant use: the majority of these reports (82%) originated from the public and third-party sources, rather than evidence-based reports by health-care professionals and journal articles.

Conclusions:

Although there exists a need for more comprehensive reporting in federal databases, the information available should be considered for a more complete understanding of implant-associated adverse outcomes. With only 46% of FDA-reported implant-related deaths demonstrated to be truly associated with breast implant use, there exists a need for public awareness and education on breast implant safety.
Patient Representation in Medical Literature: Are We Appropriately Depicting Diversity?
Authors: Massie Jonathan P. , Cho Daniel Y. , Kneib Cameron J. , Burns Jacob R. , Crowe Christopher S. , Lane Megan , Shakir Afaaf , Sobol Danielle L. , Sabin Janice , Sousa Janelle D. , Rodriguez Eduardo D. , Satterwhite Thomas , Morrison Shane D.
Published: December 2019

Background:

Racial disparities exist in the accessibility, delivery, and quality of healthcare. Clinical images are central to plastic surgery, but choice of images in the literature is susceptible to implicit biases. The objective of this study was to determine if published images reflect the racial demographic of patients.

Methods:

A search for color photographs and rendered graphics depicting human skin was completed in 6 plastic surgery journals and the New England Journal of MedicineImages in Clinical Medicinefor each decade between 1992 and 2017. For each article, images were categorized as white or nonwhite based on Fitzpatrick Scale (1–3 versus 4–6). Additionally, the authors’ geographic region was documented. Proportional data and average number of nonwhite images per article were compared. Regression analyses were performed to assess the correlation of time and geographic region on nonwhite images.

Results:

In total, 24,209 color photographs and 1,671 color graphics were analyzed. In plastic surgery journals, 22% of photographs were nonwhite and the average number of photographs per article with white skin was 5.4 compared with 1.6 with nonwhite skin (P< 0.0001). There was a significant increase in nonwhite photographs over time (r= 0.086,P< 0.001) and association of nonwhite photographs with international authors (r= 0.12,P< 0.001).

Conclusions:

Roughly 60%–70% of the world population and 30% of US cosmetic patients are nonwhite. Images in plastic surgery literature reflect neither racial demographics by global region nor the patient population seeking surgery. To advance equitable care, images should better represent the racial composition of the populations served.
Short-term Safety of Augmentation Mammaplasty Using the BellaGel Implants in Korean Women
Authors: Sung Jung Youp , Jeong Jeong Pil , Moon Dong Seung , Kim Min Soo , Kim Ho Chan , Choi Woo Sik , Song Keun Yeong , Kim Hye Jin , Lim Hyung Guhn , Kim Jae Hong
Published: December 2019

Background:

Asian women are stereotypically characterized by a slim body, smaller breasts and areolae, and larger nipples when compared with White women. They would therefore be vulnerable to displacement of a breast implant if they receive larger implants. They are also prone to hypertrophic and prolonged hyperemic scars. Surgeons should therefore be aware of Asian women’s breast anatomy, healing tendency, and preferences. We conducted this multicenter, retrospective study to assess the short-term safety of the BellaGel implants in Korean women.

Methods:

We evaluated a total of 637 women (n = 637; 1,274 breasts) for incidences of postoperative complications and the cumulative Kaplan–Meier complication-free survival.

Results:

Overall, there were 12 cases (1.9%) of postoperative complications; these include 6 cases (0.9%) of hematoma, 2 cases (0.3%) of infection, and 4 cases (0.6%) of seroma. Moreover, there was no significant difference in the cumulative complication-free survival at 120 weeks between the 4 types of the BellaGel implants (χ2 = 2.289, P = 0.513).

Conclusion:

In conclusion, we describe the short-term safety of augmentation mammaplasty using the BellaGel implants in Korean women. But further prospective, large-scale, multicenter studies with a long period of follow-up are warranted to establish our results.
A Novel Surgical Technique for Resuspension of Digital Pulp Tissue after Degloving Injuries
Authors: Gehring Michael B. , Yang Kai J. , Cusic Jenna G. , Ramamurthi Aishu , Matloub Hani S. , Argenta Anne E.
Published: December 2019

Adherence of pulp tissue to the underlying distal phalanx is required for fundamental actions including grip, proprioception, and fine motor skills. Disruption of the fibrous septa causes sliding between the distal phalanx and overlying soft tissues, hindering basic hand function. The authors present a novel surgical technique in which the fibrous pulp septa are resuspended to the distal phalanx with bone anchors and sclerosing agents after a closed degloving injury.
Electroencephalographic Patterns During Common Nursing Interventions in Neurointensive Care: A Descriptive Pilot Study
Authors: Elf Kristin , Carlsson Tommy , Rivas Liliana Santeliz , Widnersson Emma , Nyholm Lena
Published: December 2019

Background: Many patients with neurological insults requiring neurointensive care have an increased risk of acute symptomatic seizures. Various nursing interventions performed when caring for these patients may elicit pathological cerebral electrical activity including seizures and stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs). The aim was to explore changes in electroencephalogram (EEG) due to neurointensive care nursing interventions. Methods: A convenience sample was recruited between November 2015 and April 2016, consisting of 12 adult patients with impaired consciousness due to a neurosurgical condition. Continuous EEG and simultaneous video recordings of nursing interventions were collected 48 continuous hours for each patient. Two analysts categorized the video recordings for common nursing interventions, and a neurophysiologist analyzed the EEGs. Results: In total, 976 nursing interventions were observed. Epileptiform activity was observed in 4 patients (33%), during 1 nursing intervention episode each (0.4%). The 4 observed episodes of epileptiform activity occurred during multiple simultaneous nursing interventions (n = 3) and hygienic interventions (n = 1). Stimulus-induced rhythmic, periodic, or ictal discharges were observed in 1 patient (8%), in 1 single nursing intervention (0.1%). The observed SIRPIDs occurred during repositioning of the patient. All patients had muscle artifacts, during 353 nursing interventions (36.3%). The duration of nursing interventions was longer for those with simultaneous muscle artifacts (median, 116 seconds) than those without muscle artifacts, epileptiform activity, or SIRPIDs (median, 89.0 seconds). With regard to epileptiform activity and SIRPIDs, the median durations of the nursing interventions were 1158 and 289 seconds, respectively. Conclusion: The results of this pilot study indicate that muscle artifacts seem prevalent during nursing interventions and may be a sign of stress. Nurses should be aware of the risk of inducing stress by performing regular nursing interventions in daily practice, consider shorter or fewer interventions at a time in sensitive patients, and administer sedation accordingly. Considering that this was a pilot study, more research that investigates correlations between EEG patterns and nursing interventions in larger samples is needed.
Prehabilitation
Authors: Harris Rachel E. , Duncan Hazel , Buchanan Elaine , Cardigan Tracey , Garrick Vikki , Curtis Lee , Gervais Lisa , Barclay Andrew , Haddock Graham , Hansen Richard , Tayler Rachel , Walker Gregor , Russell Richard K.
Published: December 2019

Exclusive enteral nutrition (EEN) is effective in inducing remission in paediatric Crohn Disease (CD) and has been shown to reduce inflammation and improve outcomes in adult CD patients when used before resectional surgery. This retrospective study demonstrates that preoperative EEN is achievable in paediatric CD patients undergoing right hemicolectomy and is associated with positive peri‐operative outcomes. Seventeen patients (8 who received preoperative EEN and 9 who did not) were included in the study. Six of 8 (75.0%) managed EEN orally; 1 via nasogastric tube and another via a previously sited gastrostomy. Use of preoperative EEN was associated with a decreased rate of moderate/severe disease on resection pathology (5/8 [62.5%] vs 9/9 [100%]; P = 0.04). Larger studies are required to determine the wider potential benefits of preoperative EEN on postoperative outcomes within paediatric practice.
Psychotic Symptoms Predict Suicidal Behavior Postdischarge in High Risk Psychiatric Inpatients
Authors: BARZILAY SHIRA , ASSOUNGA KRYSTEL , KIM HAE-JOON , RUDNER ELVIRA , YASEEN ZIMRI , GALYNKER IGOR
Published: December 2019

Background:

Psychotic disorders, as well as psychotic symptoms, are associated with a greater lifetime risk of suicidal behavior (SB). It is not known, however, whether psychotic symptoms are independent predictors for short-term SB.

Methods:

Data were collected from 201 psychiatric inpatients at Mount Sinai Beth Israel Hospital. Self-reported psychotic symptoms were assessed using the Brief Symptom Inventory (BSI). Postdischarge SB defined as an aborted, interrupted, or actual suicide attempt was assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), during the 4 to 8 weeks following discharge from an inpatient psychiatric unit (n=127, 63% retention). Logistic regressions were performed to assess the relationships between psychotic symptoms and SB, controlling for primary psychiatric disorders.

Results:

Self-reported psychotic symptoms were associated with subsequent postdischarge SB. There was no significant difference between the SB versus no SB groups on the basis of primary psychiatric disorder. Self-reported psychotic symptoms remained an independent and significant predictor of postdischarge SB when the analysis controlled for primary psychiatric disorder.

Conclusions:

These results suggest that psychotic symptoms are a dimensional predictor of near-term postdischarge SB and are a necessary component of suicide risk assessment during inpatient hospitalization, independent of psychiatric diagnosis.
Psychotherapy in Psychiatry: Fighting Alternative Facts
Authors: Plakun Eric M. , VILLELA RENATA M.
Published: December 2019

In the Canadian province of Ontario, the Ministry of Health and Long-Term Care is proposing to impose arbitrary limits on access to psychotherapy provided by physicians. This column presents and debunks 3 myths associated with this ill-conceived proposal: (1) that long-term psychotherapy costs the health care system too much money, making it necessary for the government to curb this spending; (2) that long-term psychotherapy is a non–evidence-based treatment being needlessly spent on the worried well; and (3) that we need to focus on quick treatments, not long ones.
Catatonia Due to Tacrolimus Toxicity 16 Years After Renal Transplantation: Case Report and Literature Review
Authors: SIKAVI DANIEL , MCMAHON JENNIFER , FROMSON JOHN A.
Published: December 2019

Tacrolimus, a potent posttransplant immunosuppressant, has been associated with major neuropsychiatric complications, including catatonia and psychosis. We report a novel case of tacrolimus-induced encephalopathy that developed 16 years after renal transplantation while the drug was at a therapeutic level. Discontinuation of tacrolimus and switching to an alternative immunosuppressant resulted in significant clinical improvement over 1 week. Our experience illustrates the possibility of acute neurotoxicity from tacrolimus even when the patient has tolerated the drug for 16 years and drug levels are within the therapeutic range. This case also highlights the importance of collaboration between psychiatry and transplant clinicians.
Kidney Transplant Outcomes in Patients With Adenine Phosphoribosyltransferase Deficiency
Authors: Runolfsdottir Hrafnhildur Linnet , Palsson Runolfur , Agustsdottir Inger M. Sch. , Indridason Olafur S. , Li Jennifer , Dao Myriam , Knebelmann Bertrand , Milliner Dawn S. , Edvardsson Vidar O.
Published: December 2019

Background.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare, hereditary cause of kidney stones and chronic kidney disease (CKD) which is characterized by 2,8-dihydroxyadenine renal parenchymal crystal deposition. The aim of this study was to examine outcomes of kidney transplantation in APRT deficiency patients.

Methods.

Included were 13 patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, 2 from Westmead Hospital in Sydney, Australia, and 2 from Necker Hospital in Paris, France. The CKD-EPI and CKiD equations were used to calculate glomerular filtration rate estimates. Allograft survival was analyzed employing the Kaplan-Meier method. The Wilcoxon-Mann-Whitney test was used to compare alllograft outcomes according to xanthine oxidoreductase (XOR) inhibitor treatment status at transplantation.

Results.

Seventeen patients (9 females) received 22 kidney transplants. Age at first transplantation was 47.2 (14.9–67.0) years. Ten patients received XOR inhibitor therapy pretransplant (11 allografts), while 8 patients did not receive such treatment before transplantation (11 allografts). Two-year allograft survival was 91% and 55% in the 2 groups, respectively (P = 0.16). The median (range) estimated glomerular filtration rate at 2 years posttransplant was 61.3 (24.0–90.0) mL/min/1.73 m2 when XOR inhibitor therapy was initiated before transplantation, and 16.2 (10.0–39.0) mL/min/1.73 m2 (P = 0.009) when such treatment was not administered pretransplant.

Conclusions.

Kidney allograft outcomes are good in APRT deficiency patients beginning XOR inhibitor therapy pretransplant. Delay in such treatment is a major cause of premature graft loss in these patients. Increased awareness among clinicians is imperative, promoting early diagnosis of APRT deficiency and pharmacotherapy initiation before kidney transplantation.
The making of calibration sausage exemplified by recalibrating the transcriptomic timetree of jawed vertebrates
Authors: Marjanović David
Published: December 2019

Molecular divergence dating has the potential to overcome the incompleteness of the fossil record in inferring when cladogenetic events (splits, divergences) happened, but needs to be calibrated by the fossil record. Ideally but unrealistically, this would require practitioners to be specialists in molecular evolution, in the phylogeny and the fossil record of all sampled taxa, and in the chronostratigraphy of the sites the fossils were found in. Paleontologists have therefore tried to help by publishing compendia of recommended calibrations, and molecular biologists unfamiliar with the fossil record have made heavy use of such works (in addition to using scattered primary sources and copying from each other). Using a recent example of a large node-dated timetree inferred from molecular data, I reevaluate all thirty calibrations in detail, present the current state of knowledge on them with its various uncertainties, rerun the dating analysis, and conclude that calibration dates cannot be taken from published compendia or other secondary or tertiary sources without risking strong distortions to the results, because all such sources become outdated faster than they are published: 50 of the sources I cite to constrain calibrations were published in 2019, half of the total of 276 after mid-2016, and 90% after mid-2005. It follows that the present work cannot serve as such a compendium either; in the slightly longer term, it can only highlight known and overlooked problems. Future authors will need to solve each of these problems anew through a thorough search of the primary paleobiological and chronostratigraphic literature on each calibration date every time they infer a new timetree; and that literature is not optimized for that task, but largely has other objectives.
The association of neurofibromatosis and autism symptomatology is confounded by behavioral problems
Authors: Morotti Hadley , Mastel Sarah , Keller Kory , Barnard Rebecca A. , Hall Trevor , O’Roak Brian J. , Fombonne Eric
Published: December 2019

Aim

to evaluate if autism symptoms and diagnoses are raised in children with neurofibromatosis type 1 (NF1), to which levels, and to determine if co-occurring symptomatology accounts for this elevation.

Method

We interrogated our hospital electronic medical records. We collected parental reports of autism symptomatology, adaptive behavior, and co-occurring behavioral and emotional problems on a subsample of 45 children (9 years 2 months, 49% male). Age- and sex-matched controls with (N=180) or without ASD (N=180) were drawn from the Simons Simplex Collection and compared cross-sectionally to participants with NF1.

Results

Diagnoses of ADHD (8.8%), not of ASD (2.1%), were raised among 968 children with NF1 identified through electronic search. Mean Social Responsiveness Score (55.9) was below the cut-off of 60 for significant autism symptoms. Participants with NF1 had significantly more autism and behavioral symptoms than typically developing (TD) controls, and significantly less than controls with autism, with one exception: ADHD symptom levels were similar to those of autistic controls. When emotional, ADHD, and communication scores were covaried, the difference between participants with NF1 and TD controls disappeared almost entirely.

Interpretation

Our results do not support an association between NF1 and autism, both at the symptom and disorder levels.

What this paper adds

Diagnoses of ADHD, not of ASD, were raised among children with NF1.

Increases in autism symptoms did not reach clinically significant thresholds.

Co-occurring ADHD symptoms accounted for increased autism questionnaire scores.

Adaptive behavior in NF1 participants showed normal socialization but lower communication proficiency.
Use of directed acyclic graphs (DAGs) in applied health research: review and recommendations
Authors: Tennant Peter WG , Harrison Wendy J , Murray Eleanor J , Arnold Kellyn F , Berrie Laurie , Fox Matthew P , Gadd Sarah C , Keeble Claire , Ranker Lynsie R , Textor Johannes , Tomova Georgia D , Gilthorpe Mark S , Ellison George TH
Published: December 2019

Background

Directed acyclic graphs (DAGs) are an increasingly popular approach for identifying confounding variables that require adjustment when estimating causal effects. This review examined the use of DAGs in applied health research to inform recommendations for improving their transparency and utility in future research.

Methods

Original health research articles published during 1999-2017 mentioning “directed acyclic graphs” or similar or citing DAGitty were identified from Scopus, Web of Science, Medline, and Embase. Data were extracted on the reporting of: estimands, DAGs, and adjustment sets, alongside the characteristics of each article’s largest DAG.

Results

A total of 234 articles were identified that reported using DAGs. A fifth (n=48, 21%) reported their target estimand(s) and half (n=115, 48%) reported the adjustment set(s) implied by their DAG(s).

Two-thirds of the articles (n=144, 62%) made at least one DAG available. Diagrams varied in size but averaged 12 nodes (IQR: 9-16, range: 3-28) and 29 arcs (IQR: 19-42, range: 3-99). The median saturation (i.e. percentage of total possible arcs) was 46% (IQR: 31-67, range: 12-100). 37% (n=53) of the DAGs included unobserved variables, 17% (n=25) included super-nodes (i.e. nodes containing more than one variable, and a 34% (n=49) were arranged so the constituent arcs flowed in a consistent direction.

Conclusions

There is substantial variation in the use and reporting of DAGs in applied health research. Although this partly reflects their flexibility, it also highlight some potential areas for improvement. This review hence offers several recommendations to improve the reporting and use of DAGs in future research.
Bone changes assessed with High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) in early inflammatory arthritis: a 12-month cohort study
Authors: Brunet Scott C. , Finzel Stephanie , Engelke Klaus , Boyd Steven K. , Barnabe Cheryl , Manske Sarah L.
Published: December 2019

Objectives

We sought to determine the sensitivity of high resolution peripheral quantitative computed tomography (HR-pQCT) to detect change and identify erosions in comparison with conventional radiography (CR) in early inflammatory arthritis patients. We also explored which prognostic factors contribute to bone damage assessed by HR-pQCT in the first year of diagnosis.

Methods

46 patients with arthritic symptoms less than one year, and a clinical diagnosis of inflammatory arthritis were prospectively imaged at baseline and 12-months. HR-pQCT scans of the 2nd and 3rd MCP joints and CR of the hands and feet were performed. Joint space width (JSW), total bone mineral density (Tt.BMD), erosion presence and volume were assessed with HR-pQCT. Scan-rescan precision was assessed to define an individual-level least significant change (LSC) criterion. Regression analyses explored prognostic factors for bone damage progression.

Results

We observed no significant group-level changes in JSW, Tt.BMD or erosion volume. 20% or fewer joints demonstrated individual-level changes greater than the LSC criterion for mean JSW, Tt.BMD and erosion volume. HR-pQCT detected more erosions than CR in the 2nd and 3rd MCP. Increased symptom duration at diagnosis was associated (p < 0.10) with lower JSW minimum and higher JSW standard deviation.

Conclusions

We have demonstrated stability in erosion, bone density and JSW over 12-months in most patients receiving treatment for inflammatory arthritis using a LSC criterion, although patients with longer symptom duration prior to treatment initiation had demonstrable negative effects on JSW estimates. HR-pQCT captures bone damage and progression undetectable by CR in the imaged joints.
Lactoferrin Reverses Methotrexate Driven Epithelial Barrier Defect by Inhibiting TGF-β Mediated Epithelial to Mesenchymal Transition
Authors: Wallach Thomas E. , Srivastava Vasudha , Reyes Efren , Klein Ophir D. , Gartner Zev J.
Published: December 2019

BACKGROUND AND AIMS

Methotrexate is an important tool in the arsenal of oncologists, gastroenterologists, and rheumatologists. At low doses it induces intestinal barrier dysfunction that may induce side effects such as gastrointestinal discomfort and liver injury. Previous studies suggest that lactoferrin can improve barrier function in a variety of contexts. This study set out to determine the mechanism of methotrexate induced barrier dysfunction and assess the effect of lactoferrin and other components of human breast milk on this dysfunction.

METHODS

Using a murine enteroid model and Caco2 spheroids, we measured flux of basolateral-administered fluorescent dextran into the lumen. Barrier dysfunction was induced using methotrexate (220 nM) or lipopolysaccharide (20 nM). Human lactoferrin was added at 0.8 mg/ml (10 µM). RNAseq was performed on exposed samples.

RESULTS

Lactoferrin blocks methotrexate-induced barrier dysfunction in murine enteroids. Similar results were observed when barrier dysfunction was induced in Caco2 spheroids with methotrexate and LPS, but not ML7. RNAseq revealed activation of TGF-β response genes and epithelial-mesenchymal transition (EMT) by methotrexate, which normalized in the presence of lactoferrin. TGF-β receptor inhibition (RepSox) blocked methotrexate induced barrier dysfunction in Caco2 spheroids. 20 nM TGF-β induced barrier dysfunction in Caco2 spheroids which was also inhibited by lactoferrin.

CONCLUSIONS

Methotrexate induces barrier dysfunction by activation of an EMT program promoted by TGF-β signaling and inhibited by lactoferrin. Lactoferrin is also protective of barrier function in an LPS-induced model. The likely mechanism of this effect is blockade of EMT programs induced by TGF-β.
NFIA regulates granule recruitment and exocytosis in the adult pancreas
Authors: Scavuzzo Marissa A. , Chmielowiec Jolanta , Teaw Jessica , Yang Diane , Hill Matthew C. , Waksmunski Andrea R. , Duraine Lita , Camunas-Soler Joan , Dai Xiaoqing , King Jordon C. , Quake Stephen R , MacDonald Patrick E. , Catic Andre , Borowiak Malgorzata
Published: December 2019

After food ingestion, pancreatic cells secrete zymogen and hormone-containing granules to precisely control digestion and blood glucose levels. Identifying regulators of this process is paramount to combatting multiple pancreatic diseases. Here we show that pancreatic deletion of the transcription factor nuclear factor IA (NFIA) leads to hyperglycemia, hypoinsulinemia, and hypolipidemia. Surprisingly, insulin and digestive enzymes are produced in the absence of NFIA, however, they are not secreted properly and instead accumulate inside pancreatic cells. In NFIA-deficient mice we saw a reduction of insulin granules in the ready releasable pool and the first-phase insulin response was impaired. We found that NFIA binds to and activatesRab39b,a Rab GTPase critical for exocytosis. Re-expression ofRab39bin NFIA knockout islets restored glucose-stimulated insulin secretion. In sum, the NFIA-Rab39b axis regulates pancreatic physiology throughgranule recruitment and docking, linking NFIA to a new process with potential effects in diabetes, pancreatitis, and lipid disorders.
Antimetastatic dsRNA mimics identified by live imaging of pathogenic neolymphangiogenesis
Authors: Olmeda David , Cerezo-Wallis Daniela , Calvo Tonantzin G. , Alonso Direna , Cañón Estela , Ibarz Nuria , Muñoz Javier , Ortega Sagrario , Soengas María S.
Published: December 2019

The crosstalk between cancer cells and the lymphatic vasculature has long been proposed to define competency for metastasis. Nevertheless, the discovery of selective blockers of lymphovascular niches has been compromised by the paucity of experimental systems for whole-body analyses of tumor progression. Here we present immunocompetent and immunodeficient mouse models for live imaging of melanoma-induced neolymphangiogenesis (driven by Vegfr3) as a cost-effective platform for drug screeningin vivo. Spatio-temporal analyses in autochthonous melanomas and patient-derived xenografts identified double stranded RNA mimics (dsRNA nanoplexes) as potent repressors of lymphangiogenesis and metastasis. Mechanistically, dsRNA nanoplexes were found to suppress lymphangiogenic drivers in both tumor cells and their associated lymphatic vasculature (via MIDKINE and Vegfr3, respectively). This dual inhibitory action, driven by type I interferon, was not shared by FDA-approved antimelanoma treatments or by lymphangiogenic blockers in clinical testing. These results underscore the power of Vegfr3-lymphoreporters for pharmacological testing in otherwise aggressive cancers.

RELEVANCE

Although tumor-induced lymphangiogenesis has long been associated with metastasis, selective targeting of this process has been compromised by the paucity of experimental platforms for whole-body imaging of tumor progression and drug response. Here we present animal models engineered for spatio-temporal analyses of neolymphangiogenesis in clinically relevant autochthonous melanomas and patient-derived xenografts, and identify a unique action of double stranded-RNA nanoplexes as potent repressors of lymphatic dissemination and metastatic relapse.
Prediction of condition-specific regulatory maps inArabidopsisusing integrated genomic data
Authors: Song Qi , Lee Jiyoung , Akter Shamima , Grene Ruth , Li Song
Published: December 2019

Recent advances in genomic technologies have generated large-scale protein-DNA interaction data and open chromatic regions for multiple plant species. To predict condition specific gene regulatory networks using these data, we developed theConditionSpecificRegulatory network inference engine (ConSReg), which combines heterogeneous genomic data using sparse linear model followed by feature selection and stability selection to select key regulatory genes. UsingArabidopsisas a model system, we constructed maps of gene regulation under more than 50 experimental conditions including abiotic stresses, cell type-specific expression, and stress responses in individual cell types. Our results show that ConSReg accurately predicted gene expressions (average auROC of 0.84) across multiple testing datasets. We found that, (1) including open chromatin information from ATAC-seq data significantly improves the performance of ConSReg across all tested datasets; (2) choice of negative training samples and length of promoter regions are two key factors that affect model performance. We applied ConSReg toArabidopsissingle cell RNA-seq data of two root cell types (endodermis and cortex) and identified five regulators in two root cell types. Four out of the five regulators have additional experimental evidence to support their roles in regulating gene expression inArabidopsisroots. By comparing regulatory maps in abiotic stress responses and cell type-specific experiments, we revealed that transcription factors that regulate tissue levels abiotic stresses tend to also regulate stress responses in individual cell types in plants.
Conservative management of women with cervical intraepithelial neoplasia grade 2 in Denmark: a cohort study
Authors: Skorstengaard M , Lynge E , Suhr J , Napolitano G
Published: December 2019

Objective

Assess the progression, persistence, and regression of cervical intraepithelial neoplasia grade 2 (CIN2) after new guidelines on conservative treatment, compared with previous practice.

Design

Nationwide register‐based cohort study.

Setting

Denmark.

Population

Women aged 18–44 years diagnosed with CIN2 on biopsy: 6721 in 2008–2011 and 6399 in 2014–2017.

Methods

Register data were retrieved from before (2008–2011) and after (2014–2017) the introduction of new guidelines. Histology diagnoses at second visit were used to assess progression (CIN3+), persistence (CIN2), or regression (CIN1/normal).

Main outcome measures

Proportion of CIN2 by type of management. Relative risk (RR) and corresponding 95% confidence intervals (95% CIs) for progression, persistence, and regression at second visit in 2014–2017, versus 2008–2011.

Results

The proportion of CIN2 managed conservatively increased from 29.6% in 2008–2011 to 53.3% in 2014–2017 (RR 1.81, 95% CI 1.73–1.89). Time to second visit increased by 2 months. Regression increased from 23.5 to 30.2% (RR 1.29, 95% CI 1.22–1.36), whereas persistence and progression decreased, from 42.6 to 34.9% (RR 0.82, 95% CI 0.78–0.86) and from 28.0 to 22.8% (RR 0.81, 95% CI 0.77–0.86), respectively. In 2008–2011, women managed conservatively had a regression rate of 41.8%, persistence rate of 40.9%, and progression rate of 16.6%. In 2014–2017, these rates were 46.7, 35.5, and 17.1%, respectively.

Conclusion

After implementation of the new guidelines, conservative management became more frequent, and is now used for more than half of women with CIN2. Lesion regression became more frequent, now experienced by 47% of women managed conservatively. Similar regression rates were seen in women younger and older than 30 years, suggesting that conservative management is justifiable for women of childbearing age.

Tweetable abstract

In Denmark, more than half of women with CIN2 are managed conservatively, and half of these women experience lesion regression.
Teachers’ attitudes towards inclusion and their self‐efficacy for inclusive practices as predictors of willingness to implement peer tutoring
Authors: Avramidis Elias , Toulia Anastasia , Tsihouridis Charilaos , Strogilos Vasilis
Published: December 2019

The attitudes teachers hold towards inclusion are one of the most widely researched themes in the field of inclusive education. Contrary to the most attitudinal studies which are solely focusing on examining the impact of a host of factors in the formation of teacher attitudes, the present study sought to link the reported attitudes towards inclusion and teachers’ self‐efficacy for inclusive practices with an actual inclusive instructional approach, that of peer tutoring. Participants were 225 Greek general teachers and 69 special education counterparts who responded to a questionnaire consisting of the Core Perspectives Scale from the My Thinking about Inclusion scale, the Teacher Efficacy for Inclusive Practice scale and other scales measuring their attitudes towards peer tutoring. Results indicated that general teachers held neutral attitudes towards inclusion while their special education counterparts held significantly more positive ones. General teachers were found to be less positive in their self‐efficacy for inclusive practices than the special education counterparts with the exception of the managing behaviour dimension. General teachers emphasised mainly the social gains achieved by students participating in a peer tutoring program. Moreover, they considered peer tutoring as an effective means for including students with diverse needs in their classrooms. Importantly, this study found that teachers’ attitudes towards inclusion and their self‐efficacy for inclusive practices largely predict their willingness to implement a peer tutoring program in their classrooms. The paper concludes with highlighting the need to offer teachers professional development courses that positively influence their attitudes and enhance their sense of self‐efficacy in implementing peer tutoring.
Japanese and Finnish teachers’ perceptions and self‐efficacy in inclusive education
Authors: Yada Akie , Savolainen Hannu
Published: December 2019

It has been indicated that teachers’ perceptions of the most suitable educational environment for students with different disabilities depends on the type and severity of students’ disability. Although the perceptions are found to be different by country, research comparing Japanese teachers’ perceptions and perceptions of teachers from other countries is limited. In addition, much less is known about relationships between the perceptions and teachers’ self‐efficacy (TSE). This study examines whether teachers’ perceptions differ by country (Japan and Finland), severity of disability and disability type. Moreover, the correlations between perceptions and self‐efficacy for inclusive practices are investigated. Quantitative data were collected through a survey from 359 Japanese and 872 Finnish teachers. The first finding on teachers’ perceptions is that Finnish teachers’ overall perceptions were more inclusive than those of Japanese teachers’. Second, the teachers in both countries preferred segregated environments for students with severe disabilities more than for students with moderate disabilities. Finally, teachers’ perceptions were different depending on students’ type of disability in both countries. Correlations between teachers’ perceptions and self‐efficacy showed that teachers with high self‐efficacy recommended more inclusive placements in both Japan and Finland. However, TSE was correlated only with perceptions of students with moderate disabilities in Japan. These findings mean that even the Japanese teachers with high self‐efficacy thought that students with severe disabilities were better educated in segregated educational settings. The findings are discussed from the viewpoint of sociocultural contexts, which offers useful insights for developing inclusive education.
The impact of ι‐ and κ‐carrageenan addition on freezing process and ice crystals structure of strawberry sorbet frozen by various methods
Authors: Kamińska‐Dwórznicka Anna , Janczewska‐Dupczyk Agnieszka , Kot Anna , Łaba Sylwia , Samborska Katarzyna
Published: December 2019

The aim of this work was to study the influence of ι‐ and κ‐carrageenan addition to strawberry sorbet prepared by various freezing methods (cryostat and conventional freezer) on freezing kinetics and ice crystals structure. Four variants of strawberry‐based sorbet were prepared: with no additive, with 0.1% addition of ι‐ and κ‐carrageenan, and 1:1 blend of both. Freezing curves and freezing time, as well as the size and morphology of ice crystals, were analyzed. The addition of carrageenan stabilizers resulted in freezing process elongation. Reference samples were characterized by different dynamics of the freezing process. The addition of carrageenan increased the final temperature of the samples, compared to the reference sample (even 2.6 °C of difference). Additives reduced ice crystals growth. The most efficient was mixture of both fractions of carrageenan––the samples in this variant frozen in conventional freezer were characterized by the smallest ice crystals diameter––average 5.44 µm, while for the reference sample it was 17.79 µm.

Practical Application

This research can give a new path for the carrageenan's hydrolysates application––not only for dairy products. Iota carrageenan fraction was recommended for dairy products according to its water‐holding capacity in the presence of calcium ions. This study showed that mix of ι‐ and κ‐carrageenan could bring positive results to such product as sorbet without any milk proteins addition. This experiment data could also be helpful when optimizing frozen desserts production in small gastronomy––especially the temperature and time of freezing modifications.
AnUstilago maydischassis for itaconic acid production without by‐products
Authors: Becker Johanna , Hosseinpour Tehrani Hamed , Gauert Marc , Mampel Jörg , Blank Lars M. , Wierckx Nick
Published: December 2019

Ustilago maydisis a promising yeast for the production of a range of valuable metabolites, including itaconate, malate, glycolipids and triacylglycerols. However, wild‐type strains generally produce a potpourri of all of these metabolites, which hinders efficient production of single target chemicals. In this study, the diverse by‐product spectrum ofU. maydiswas reduced through strain engineering using CRISPR/Cas9 and FLP/FRT, greatly increasing the metabolic flux into the targeted itaconate biosynthesis pathway. With this strategy, a marker‐free chassis strain could be engineered, which produces itaconate from glucose with significantly enhanced titre, rate and yield. The lack of by‐product formation not only benefited itaconate production, it also increases the efficiency of downstream processing improving cell handling and product purity.
Anti‐SOX1 antibody‐positive paraneoplastic neurological syndrome presenting with Lambert‐Eaton myasthenic syndrome and small cell lung cancer: A case report
Authors: Li Chunyang , Wang Xiaolei , Sun Lihua , Deng Hui , Han Yanqiu , Zheng Wenqi
Published: December 2019

Paraneoplastic neurological syndromes (PNS) are rare disorders affecting any part of the central, peripheral or autonomic nervous system that occur in association with cancer. Among cancer patients, less than 1% overall develop PNS. Anti‐SOX1 antibodies' positive paraneoplastic neurological disorders are rare and are usually associated with small cell lung cancer (SCLC). Here, we report a case of a 61‐year‐old male patient who presented with an unusual anti‐SOX1 positive PNS. The right tibialis anterior showed noticeable low‐amplitude motor unit potentials and high amplitude motor potentials in electrodiagnostic study, suggesting the presence of Lambert‐Eaton myasthenic syndrome (LEMS). Typical MRI and PET‐CT found a hyperintense lesion with contrast enhancement in the thorax in front of 5–6 centrum of vertebrae, and thoracoscopic biopsy revealed pathological findings for SCLC. The patient underwent several lines of chemotherapy and radiotherapy and survived for 15 months after the diagnosis of SCLC.
1,25‐Dihydroxyvitamin D protects against age‐related osteoporosis by a novel VDR‐Ezh2‐p16 signal axis
Authors: Yang Renlei , Chen Jie , Zhang Jiao , Qin Ran , Wang Rong , Qiu Yue , Mao Zhiyuan , Goltzman David , Miao Dengshun
Published: December 2019

To determine whether 1,25‐dihydroxyvitamin D (1,25(OH)2D) can exert an anti‐osteoporosis role through anti‐aging mechanisms, we analyzed the bone phenotype of mice with 1,25(OH)2D deficiency due to deletion of the enzyme, 25‐hydroxyvitamin D 1α‐hydroxylase, while on a rescue diet. 1,25(OH)2D deficiency accelerated age‐related bone loss by activating the p16/p19 senescence signaling pathway, inhibiting osteoblastic bone formation, and stimulating osteoclastic bone resorption, osteocyte senescence, and senescence‐associated secretory phenotype (SASP). Supplementation of exogenous 1,25(OH)2D3 corrected the osteoporotic phenotype caused by 1,25(OH)2D deficiency or natural aging by inhibiting the p16/p19 pathway. The proliferation, osteogenic differentiation, and ectopic bone formation of bone marrow mesenchymal stem cells derived from mice with genetically induced deficiency of the vitamin D receptor (VDR) were significantly reduced by mechanisms including increased oxidative stress, DNA damage, and cellular senescence. We also demonstrated that p16 deletion largely rescued the osteoporotic phenotype caused by 1,25(OH)2D3 deficiency, whereas 1,25(OH)2D3 could up‐regulate the enzyme Ezh2 via VDR‐mediated transcription thereby enriching H3K27me3 and repressing p16/p19 transcription. Finally, we demonstrated that treatment with 1,25(OH)2D3 improved the osteogenic defects of human BM‐MSCs caused by repeated passages by stimulating their proliferation and inhibiting their senescence via the VDR‐Ezh2‐p16 axis. The results of this study therefore indicate that 1,25(OH)2D3 plays a role in preventing age‐related osteoporosis by up‐regulating Ezh2 via VDR‐mediated transcription, increasing H3K27me3 and repressing p16 transcription, thus promoting the proliferation and osteogenesis of BM‐MSCs and inhibiting their senescence, while also stimulating osteoblastic bone formation, and inhibiting osteocyte senescence, SASP, and osteoclastic bone resorption.
Identification of genetic loci associated with growth traits at weaning in yak through a genome‐wide association study
Authors: Jia C. , Li C. , Fu D. , Chu M. , Zan L. , Wang H. , Liang C. , Yan P.
Published: December 2019

A multilocus GWAS was performed to explore the genetic architecture of four growth traits in yak. In total, 354 female yaks for which measurements of body weight (BW), withers height (WH), body length (BL) and chest girth (CG) at weaning were available underwent genotyping with the Illumina BovineHD BeadChip (770K). After quality control, we retained 98 688 SNPs and 354 animals for GWAS analysis. We identified seven, 18, seven and nine SNPs (corresponding to seven, 17, seven and eight candidate genes) associated with BW, WH, BL and CG at weaning respectively. Interestingly, most of these candidate genes were reported to be involved in growth‐related processes such as muscle formation, lipid deposition, feed efficiency, carcass composition and development of the central and peripheral nervous system. Our results offer novel insight into the molecular architecture underpinning yak growth traits. Further functional analyses are thus warranted to explore the molecular mechanisms whereby these genes affect these traits of interest.
Extracellular matrix composition of different spleen compartments of fruit bats
Authors: Hanadhita Desrayni , Rahma Anisa , Wahid Muhammad R. , Mayasari Ni Luh Putu I. , Satyaningtijas Aryani S. , Hondo Eiichi , Agungpriyono Srihadi
Published: December 2019

The distribution and composition of extracellular matrix (ECM) of the spleen in two species of fruit bats, namely Cynopterus titthaecheilus and Rousettus leschenaultii, were examined by histochemistry and immunohistochemistry. Reticular fibres accompanied by laminin were identified to make up the splenic stromal network. Types I and III collagen were identified in various spleen compartments with varying intensities. Thin and short elastin fibres were scattered in several parts of the spleen. Visualization of the ECM of the spleen can better demonstrate spleen compartmentalization. The alleged vascular space structure in the fruit bats spleen was the sinus structure that was strengthened by the presence of reticular fibres that limit the sinus basement membrane. The present study identified periellipsoidal lymphoid sheath (PELS)‐like structure in fruit bats spleen that had never been identified in mammals before. In addition to describing the structure, this study highlighted the variations in ECM composition of the spleen between species that can provide new insight into the phylogenetic study of spleen morphology.
The clinical spectrum of dermatomyositis and the new autoantibodies – with regard to two clinical cases with distinct associations
Authors: Calvão da Silva Joana Cruz Matos , Santiago Luís , Brites Maria Manuel , Gonçalo Margarida
Published: December 2019

Dermatomyositis is a rare idiopathic inflammatory myopathy associated with different autoantibodies (anti‐MDA5, anti‐TIF1‐γ) which are linked with typical and distinct phenotypes of dermatomyositis. We describe two cases that illustrate these diverse cutaneous and systemic manifestations.