bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Initial and Subsequent Injury in Young Infants
Authors: Thackeray Jonathan D. , Crichton Kristin G. , McPherson Paul , Izsak Eugene , Vavul-Roediger Lori , Kim Grace , Spencer Sandra , Baker Carrie , Eismann Emily A. , Shapiro Robert A. ,   on behalf of the TRAIN Collaborative
Published: May 2022

Objectives

The objective of this study was to identify opportunities to improve identification and evaluation of child abuse by (1) describing rates of initial and recurrent injury in young infants, (2) describing the frequency of a history of prior injury in young children evaluated by a child abuse pediatrician, and (3) identifying practice variation, including use of skeletal surveys as an example, in the identification and evaluation of injury across a network of 6 children’s hospitals.

Methods

Six children's hospitals identified infants with an initial injury and recurrent injury over a 1-year period using 2 methods: (1) diagnostic code method — infants 6 months or younger presenting with at least 1 diagnostic code for injury were tracked for 12 months to determine the frequency of recurrent injury, and (2) consult method — all available medical records of children 18 months or younger seen for an inpatient consultation for suspected child abuse were reviewed to identify history of a first injury at 6 months or younger.

Results

Using the diagnostic code method, 682 unique infants were identified with initial injuries, most commonly fractures (37.0%), bruising/ecchymosis (35.9%), and superficial injuries (28.3%). Forty-two infants (6.2%) returned with a second injury, and no demographic factors were significantly associated with the likelihood of a second injury. Using the consult method, 37 of 342 consults (10.8%) were identified as having a history of at least 1 initial injury. Of the initial injuries identified, the most common was bruising/ecchymosis (64.9%). The number of injuries identified with either method varied significantly across hospitals, as did completion of skeletal surveys for infants with bruising (range, 4.5%–71.1%; P < 0.001) and any injury (range, 4.4%–62.7%; P < 0.001).

Conclusions

Our study demonstrates that young infants who experience 1 injury often experience a second injury. There exists significant variability in the identification of injury and the completion of skeletal surveys across a network of 6 children's hospitals. A standardized quality improvement approach may improve identification of injury and reduce the variability in practice observed.
A Comprehensive Review on the Supraclavicular Flap for Head and Neck Reconstruction
Authors: Hamidian Jahromi Alireza , Horen Sydney R. , Miller Emily J. , Konofaos Petros
Published: May 2022

The supraclavicular artery flap (SCF) is a highly vascularized fasciocutaneous flap overlying the shoulder. The flap was first described in 1979 by Lamberty but did not gain popularity until much later due to lack of a reliable technique. The main advantages of using the SCF include avoiding microsurgical techniques, requiring only a single-stage operation, shorter operative time compared with alternative options, and a wider patient population including those with comorbidities who may be excluded from more extensive operations including free flaps surgeries. The SCF has been successfully performed on individuals with advanced age, poor nutrition, cachexia, obesity, diabetes, tobacco use, severe chronic obstructive pulmonary disease, hypertension, coronary artery disease, peripheral vascular disease, supraventricular tachycardia, atrial fibrillation, heart failure, asthma, and steroid use. The largest disadvantages of the SCF include the possibility of distal tip necrosis, size limitation without pre-expansion, and a moderately visible donor site scar. The following review and meta-analysis of the SCF details its use historically as both an island and a pedicle flap, and its application in head and neck reconstruction.
Corneal Neurotization
Authors: Swanson Marco A. , Swanson Roy D. , Kotha Vikas S. , Cai Yida , Clark Robert , Jin Alison , Kumar Anand R. , Davidson Edward H.
Published: May 2022

Background

Corneal neurotization describes reinnervation of the anesthetic or severely hypoesthetic cornea with a healthy local nerve or graft. Preliminary evidence has shown corneal neurotization to improve corneal sensation, visual acuity, and ocular surface health. Factors that improve patient selection and lead to better neurotization outcomes have yet to be elucidated, limiting ability to optimize perioperative decision-making guidelines.

Methods

A systematic review with meta-analysis was performed of the MEDLINE and Embase databases using variations of “corneal,” “nerve transfer,” “neurotization,” and “neurotization.” The primary outcomes of interest were corrected visual acuity, NK Mackie stage, and central corneal sensation. Regression analyses were performed to identify the effects of surgical technique, duration of denervation, patient age, and etiology of corneal pathology on neurotization outcomes.

Results

Seventeen studies were included. Corneal neurotization resulted in significant improvement in NK Mackie stage (0.84 vs 2.46, P < 0.001), visual acuity (logarithm of minimum angle of resolution scale: 0.98 vs 1.36, P < 0.001), and corneal sensation (44.5 vs 0.7, P < 0.001). Nerve grafting was associated with greater corneal sensation improvement than nerve transfer (47.7 ± 16.0 vs 35.4 ± 18.76, P = 0.03). Denervation duration was predictive of preneurotization visual acuity (logarithm of minimum angle of resolution scale; R
2 = 0.25, P = 0.001), and older age (ß = 0.30, P = 0.03) and acquired etiology (ß = 0.30, P = 0.03) were predictive of improved visual acuity.

Conclusions

Corneal neurotization provides significant clinical improvement in visual acuity, NK Mackie staging, and corneal sensation in patients who experience NK. Both nerve grafting and nerve transfer are likely to yield similar levels of benefit and ideally should be performed early to limit denervation time.
Patient Understanding of Provider Credentials and Selection of Plastic Surgery Providers
Authors: Parus Anamaria , Hartmann Thomas , Foley Brandon J. , Plank David M.
Published: May 2022

Background

Many physicians who are not board-certified plastic surgeons have started performing aesthetic procedures, leading to unsafe practices that jeopardize patients' health.

Methods

Patients of a cosmetic and reconstructive private plastic surgery practice were asked to complete a survey that assessed their understanding of plastic surgeon credentials and advertising practices, and what influences their choice of a plastic surgeon.

Results

Eighty-five patients completed the survey, with 37.2% reporting prior aesthetic surgery; 84.9% were unaware of the lack of legal regulations governing the advertising practices of physicians. When asked if a doctor can perform surgery to improve their appearance without being a board-certified plastic surgeon, 22.1% responded “yes,” 50% responded “no,” and 27.9% responded “I don't know;” 98.8% reported a sense of comfort knowing their provider is board-certified in plastic surgery. When asked what factors help them decide if a surgeon is knowledgeable and trustworthy, the overwhelming majority reported referral from patients and providers as the most important factor, followed by online ratings and reviews. When deciding whether to recommend a plastic surgeon, personal experience was the most important factor. When deciding who should perform their cosmetic procedure, the most important factor was experience, followed by plastic surgery board certification.

Discussion

Current physician advertising practices lack strict guidelines and are often misleading. Patients would benefit from more thorough education on these practices. Of the various plastic surgeon assessment factors, most patients rely heavily on feedback obtained from patients and providers.
Scalp Nodules and Deformed Great Toes
Authors: Karinja Sarah Jean , Mulliken John Butler
Published: May 2022

We report a case of fibrous scalp nodules and bilateral hallux valgus in an infant who one decade later was diagnosed with a rare life-threatening genetic disease.
Comorbidity Trends in Patients Requiring Sternectomy and Reconstruction
Authors: Soto Edgar , Kumbla Pallavi A. , Restrepo Ryan D. , Patel Jason J. , Davies James , Aliotta Rachel , Collawn Sherry S. , Denney Brad , Kilic Ali , Patcha Prasanth , Grant John H. , Fix R. Jobe , King Timothy W. , de la Torre Jorge I. , Myers Rene P.
Published: May 2022

Introduction

Comorbidity trends after median sternectomy were studied at our institution by Vasconze et al (Comorbidity trends in patients requiring sternectomy and reconstruction. Ann Plast Surg. 2005;54:5). Although techniques for sternal reconstruction have remained unchanged, the patient population has become more complex in recent years. This study offers insight into changing trends in this patient population.

Methods

A retrospective review was performed of patients who underwent median sternectomy followed by flap reconstruction at out institution between 2005 and 2020. Comorbidities, reconstruction method, average laboratory values, and complications were analyzed.

Results

A total of 105 patients were identified. Comorbidities noted were diabetes (27%), immunosuppression (16%), hypertension (58%), renal insufficiency (23%), chronic obstructive pulmonary disease (16%), and tobacco utilization (24%). The most common reconstruction methods were omentum (45%) or pectoralis major flaps (34%). Thirty-day mortality rates were 10%, and presence of at least 1 complication was 34% (hematoma, seroma, osteomyelitis, dehiscence, wound infection, flap failure, and graft exposure). Univariate analysis demonstrated that sex (P = 0.048), renal insufficiency, surgical site complication, wound dehiscence, and flap failure (P < 0.05) had statistically significant associations with mortality. In addition, body mass index, creatinine, and albumin had a significant univariate association with mortality (P < 0.05).

Conclusions

Similar to the original study, there is an association between renal insufficiency and mortality. However, the mortality rate is decreased to 10%, likely because of improved medical management of patients with increasing comorbidities (80% with greater than one comorbidity). This has led to the increased use of omentum as a first-line option. Subsequent wound dehiscence and flap failure demonstrate an association with mortality, suggesting that increasingly complex patients are requiring a method of reconstruction once used a last resort as a first-line option.
Complication Profile of Total Submuscular Versus Prepectoral Tissue Expander Placement
Authors: Soni Sara E. , Le Nicole K. , Buller Mitchell , Modica Ashley D. , Kumar Ambuj , Smith Paul D. , Laronga Christine
Published: May 2022

Background

We sought to compare the safety profile of prepectoral breast reconstruction with total submuscular tissue expander reconstruction, previously our standard. Primary outcomes of interest in this retrospective cohort study were incidence of infection, hematoma, seroma, mastectomy flap necrosis, and reconstruction loss.

Methods

Total submuscular and prepectoral with acellular dermal matrix reconstructions consecutively performed by a single surgeon (P.D.S.) between January 1, 2016, and December 31, 2019, were compared. Demographic and clinical characteristics, as well as complications and complication types, were extracted for all patients. A t test was used to assess differences in continuous variables. Multivariate logistics regression was used to assess the association between type of reconstruction and complication rate. The statistical significance was set at 0.05 for all comparisons.

Results

A total of 133 patients (234 breasts) were included. There was a significantly greater incidence of infection (16.5% vs 5.5%, P < 0.01) in the prepectoral/acellular dermal matrix cohort. However, reconstructive loss was low in both cohorts (2.5% and 3.0%, P = 0.83). Adjusted odds ratio for complications in the prepectoral cohort was 2.26, but this was not statistically significant (adjusted P = 0.24).

Conclusions

Prepectoral breast reconstruction shares an overall complication profile that is not greater than that of total submuscular reconstruction. It is associated with a greater risk of infection; however, the ability to salvage the reconstruction with early, aggressive intervention results in low rates of reconstructive loss, comparable with those of total submuscular reconstruction.
New Skin Flaps for Triangular Surgical Defects
Authors: Russo-de la Torre Francisco , Iglesias-Zamora María Eugenia , Linares-Barrios Mario , Vieira Ricardo , Lova-Navarro Miguel
Published: May 2022

Background

Most skin flaps are designed to repair circular surgical defects after skin tumor excisions, but few flaps have been described to reconstruct triangular defects.

Objective

The aim of this study was to describe new skin flaps for triangular surgical defects using an innovative experimental model.

Methods

We tested new flap designs in an experimental pig skin model using a tension sensor to measure maximum tension and tension augmentation when the flap is performed in an area of increased basal tension. The results were compared with those from classic flaps. Finally, the new flaps were performed on a series of patients with triangular surgical defects.

Results

Six new flaps with adequate levels of tension were obtained and named after their morphology: spider crab, mantis, toy windmill, nautilus, origami bird, and clover. These new flaps were successfully performed on a series of 40 patients; among them, spider crab and mantis flaps showed a better response to basal tension augmentation.

Conclusions

Six new flaps for triangular surgical defects were proposed and successfully performed in a series of 40 patients, using an experimental pig skin model and a tensiometer.
Does Oral Propranolol Improve the Final Outcome of All Involuted Infantile Hemangiomas? A Matched Retrospective Comparative Study
Authors: Chang Shih-Jen , Chang Hsiao-Fen , Qiu Yajing , Chang Lei , Jin Yunbo , Lin Xiaoxi
Published: May 2022

Background

Oral propranolol can effectively activate and accelerate infantile hemangioma (IH) involution; however, could the final outcome of oral propranolol treatment for IHs commensurate that of spontaneous involution?

Objective

This study aimed to investigate the long-term therapeutic effect of oral propranolol for IHs.

Methods

We present an individual matching comparative study with (1) oral propranolol therapy for mixed and deep IHs on the lips, nose, and parotid and (2) lesion type– and lesion location–matched untreated IHs as controls. Patients' follow-up photographs were assessed by 3 surgeons blinded of their treatment. Outcome measures were the quantification of the degree of sequelae ranging from 1 to 4 and the age at which IH achieved involution arrest.

Results

Ten groups of oral propranolol and untreated patients with matched lesions were assessed. Average age at which lesions stabilized and reached no change in appearance was 1.7 years old and 6.3 years old for propranolol group and untreated group (t = 5.663, P < 0.001). There was no significant difference in the quantified degree of sequelae for oral propranolol group and untreated group upon follow-up (1.60 vs 1.40, respectively; t = 1.259, P = 0.240).

Conclusions

Oral propranolol therapy accelerates IH involution but does not have a superior effect than spontaneous involution on the overall outcome of problematic IHs.
Lumbar Artery Perforator Flaps
Authors: Vonu Peter Michael , Chopan Mustafa , Sayadi Lohrasb , Chim Harvey W. , Leyngold Mark
Published: May 2022

Background

The lumbar artery perforator (LAP) flap has gained popularity as a versatile flap in reconstructive surgery; however, few studies have analyzed salient characteristics of this flap. We set out to provide a comprehensive appraisal of free tissue transfers of LAP flaps with specific attention to anatomic features and clinical outcomes.

Methods

Using preferred reporting items for systematic reviews and meta-analyses guidelines, we identified clinical, radiographic, and cadaveric studies of LAP flaps and assessed outcomes, complications, and anatomic parameters, such as pedicle length, diameter, location, and course.

Results

A total of 254 articles were initially reviewed, of which 18 met the final inclusion criteria. Ten studies were primarily concerned with anatomic characteristics, and most clinical studies related to breast reconstruction. The operative durations varied between 4.8 and 9.2 hours. Partial and total flap losses were estimated at 2.6% and 7.6%, respectively. Acute revision rates ranged from 16% to 24% related to hematoma, arterial thrombus, and venous thrombus. Donor-site seromas were frequently encountered in breast reconstruction with an incidence of 17% to 78%.

Conclusions

The LAP flap has demonstrated favorable outcomes in various reconstructive scenarios. The caudal perforators generally offer more pedicle length, greater pedicle diameter, and septocutaneous course and may be better suited for flap design. For breast reconstruction, the LAP flap is a useful alternative to abdominal-based flaps, and special attention should be given to optimizing pedicle length using interposition grafts and methods that minimize seroma formation at the donor site.
Outcome Analysis of Advanced Oral Cancers Requiring Large Composite Fibular Osteocutaneous Flap Reconstruction
Authors: Joshi Tanmay , Mantri Mayur , Hadgaonkar Sumit , Rao Neeraj , Dhondge Rajendra , Jaiswal Dushyant , Mathews Saumya , Qayyumi Burhanuddin , Chaturvedi Pankaj , Shankhdhar Vinay Kant
Published: May 2022

Background

Advanced oral cancer entailing extensive resection of large parts of the mucosa, bone, and skin require reconstructions with composite free flaps. Our aim was to analyze the outcomes of those oral squamous cell carcinomas requiring fibular osteocutaneous free flaps with large skin defects.

Methods

Perioperative course and histopathological and survival outcomes of 246 consecutive patients warranting composite fibular flaps from January 2010 to June 2015 at Tata Memorial Hospital, Mumbai, India, were retrospectively analyzed.

Results

Despite majority of T4 disease (88.2%) and stage IV disease (92%) patients, the 5-year overall survival was 52.1% and the 5-year recurrence-free survival was 48.6% with a median follow-up of 42 months with minimal complications.

Conclusions

Reconstruction with composite fibular osteocutaneous flaps has comparable outcomes of survival with acceptable complications in mega oral squamous cell carcinomas requiring extensive resection.
Chryseobacterium subflavum sp. nov., isolated from soil
Authors: Kong Delong , Wang Yan , Li Qingqing , Zhou Yanzheng , Jiang Xu , Xing Zhen , Wang Zhiye , Ruan Zhiyong
Published: May 2022

A Gram-stain-negative, aerobic, non-motile, rod-shaped bacterium, designated LAMRS1T, was isolated from a soil sample collected in Hebei Province, PR China. Strain LAMRS1T was able to grow optimally in the presence of 0.5 % (w/v) NaCl, at pH 7.5 and at 30 °C. On the basis of 16S rRNA gene sequence analysis, strain LAMRS1T was closely related to members of the genus

Chryseobacterium

, with highest levels of sequence similarity to

Chryseobacterium soli

DSM 19298T (97.9 %),

Chryseobacterium soldanellicola

DSM 17072T (97.6%) and

Chryseobacterium piperi

CTMT (97.5 %). The average nucleotide identity and digital DNA–DNA hybridization values between LAMRS1T and the closely related species of

C. soli

DSM 19298T,

C. soldanellicola

DSM 17072T and

C. piperi

CTMT were 78.1, 78.2 and 80.7 %, and 21.7, 22.0 and 23.7 %, respectively. The draft genome sequence of LAMRS1T was 4.61 Mb, with DNA G+C content of 36.2 mol%. The major isoprenoid quinone was menaquinone-6 and iso-C15 : 0, iso-C17 : 0 3-OH and summed feature 3 (C16 : 1
 ω6c and/or C16 : 1
 ω7c) constituted the major cellular fatty acids. The main polar lipids were phosphatidylethanolamine, four aminolipids, three glycolipids and seven unidentified lipids. On the basis of evidence presented in this study, strain LAMRS1T represents a novel species of the genus

Chryseobacterium

, for which the name Chryseobacterium subflavum sp. nov. is proposed. The type strain is LAMRS1T (=JCM 33868T=KCTC 72823T).
Projective LDDMM: Mapping Molecular Digital Pathology with Tissue MRI
Authors: Stouffer Kaitlin M. , Witter Menno P. , Tward Daniel J. , Miller Michael I.
Published: May 2022

Reconstructing dense 3D anatomical coordinates from 2D projective measurements has become a central problem in digital pathology for both animal models and human studies. We describe a new family of diffeomorphic mapping technologies called Projective LDDMM which generate diffeomorphic mappings of dense human MRI atlases at tissue scales onto sparse measurements at micron scales associated with histological and more general optical imaging modalities. We solve the problem of dense mapping surjectively onto histological sections by incorporating new technologies for crossing modalities that use non-linear scattering transforms to represent multiple radiomic-like textures at micron scales and incorporating a Gaussian mixture-model frame-work for modelling tears and distortions associated to each section. We highlight the significance of our method through incorporation of neuropathological measures and MRI, as relevant to the development of biomarkers for Alzheimer’s disease and one instance of the integration of imaging data across the scales of clinical imaging and digital pathology.
Analytical solution to the Flory-Huggins model
Authors: Qian Daoyuan , Michaels Thomas C. T. , Knowles Tuomas P. J.
Published: May 2022

A self-consistent analytical solution for binodal concentrations of the two-component Flory-Huggins model is derived. We show that this form extends the validity of the Ginzburg-Landau expansion away from the critical point to cover the whole phase space. Furthermore, this analytical solution reveals an exponential scaling law of the dilute phase binodal concentration as a function of interaction strength and chain length. We demonstrate explicitly the power of this approach by fitting experimental protein liquid-liquid phase separation boundaries to determine the effective chain length and the solute-solvent interaction energy. Moreover, we demonstrate that this strategy allows us to resolve the differences in the interaction energy contributions of individual amino acids. This analytical framework can serve as a new way to decode the protein sequence grammar for liquid-liquid phase separation.
A machine learning based predictive model for the diagnosis of sepsis
Authors: Delgado Sanchis Juan A. , Signol François , Perez-Cortes Juan-Carlos , García-López Eva M. , Mena-Mollá Salvador , Carbonell-Monleón Nieves , Rodríguez-Gimillo María , García-Giménez José Luis
Published: May 2022

The early recognition and treatment of sepsis is essential to increase the probability of survival of the patient. Sepsis is a complex and heterogeneous syndrome influenced by the site of infection, causative microorganisms, acute organ dysfunctions and co-morbidities. So, early diagnosis is a challenge in which complex physiologic, metabolic, biochemical markers and clinical signs must be evaluated simultaneously for a reliable and early identification of sepsis. In this paper, a list of relevant variables involved in sepsis diagnosis is provided. Furthermore, to help answering the question of whether a patient is suffering from sepsis when entering the emergency room, a model based on the machine learning gradient boosting algorithm is proposed. Using three histones H2B, H3, H4 and the activated protein C together with other variables a gradient boosting classifier was trained and evaluated with cross validation. Results show that the model can achieve up to a 97% mean per-class accuracy.
A methodology to generate epidemic scenarios for emerging infectious diseases based on the use of key calendar events
Authors: Acuña-Zegarra M. Adrian , Santana-Cibrian Mario , Hernandez-Vela Carlos E. Rodriguez , Mena Ramsés H. , Velasco-Hernández Jorge X.
Published: May 2022

This work presents a methodology to recreate the observed dynamics of emerging infectious diseases and to generate short-term forecasts for their evolution based on superspreading events occurring on key calendar dates. The method is illustrated by the COVID-19 pandemic dynamics in Mexico and Peru up to January 31, 2022. We also produce scenarios obtained through the estimation of a time-dependent contact rate, with the main assumption that the dynamic of the disease is determined by the mobility and social activity of the population during holidays and other important calendar dates. First, historical changes in the effective contact rate on predetermined dates are estimated. Then, this information is used to forecast scenarios under the assumption that the trends of the effective contact rate observed in the past will be similar on the same but future key calendar dates. All other conditions are assumed to remain constant in the time scale of the projections. One of the main features of the methodology is that it avoids the necessity of fixing values of the dynamic parameters for the whole prediction period. Results show that considering the key dates as reference information is useful to recreate the different outbreaks, slow or fast-growing, that an epidemic can present and, in most cases, make good short-term predictions.
Early life attachment in term and preterm infants
Authors: Jiménez-Sánchez Lorena , Ginnell Lorna , O’Carroll Sinéad , Ledsham Victoria , Corrigan Amy , Chua Yu Wei , Stoye David Q. , Sullivan Gemma , Hall Jill , Clemens Ann M. , Boardman James P. , Fletcher-Watson Sue
Published: May 2022

1

Background

Preterm birth is associated with atypical cognitive and socioemotional outcomes in childhood. Secure infant attachment protects against adverse outcomes, but could be modified by alterations in the early caregiving environment inherent to essential neonatal intensive care or co-morbidities of preterm birth. We aimed to test the hypothesis that preterm birth is associated with differences in infant attachment, and to investigate clinical, neurodevelopmental and socioeconomic variables that are associated with infant attachment.

Methods

82 preterm and 75 term infants with mean (range) gestational age at birth 29.5 (22.1 – 32.9) and 39.6 (36.4 – 42.1) weeks, respectively, completed the Still-Face Paradigm (SFP) at nine months of corrected age. Attachment dimensions and categories were obtained from infant responses to the SFP during the reunion episode using a published coding scheme, and an alternative principal component (PC) and clustering strategy. Neurodevelopment was assessed using the Vineland Adaptive Behavior Scales, and socioeconomic status was operationalized as neighborhood deprivation.

Results

Preterm and term infants significantly differed in fretfulness, attentional PC scores and in their distribution between attachment clusters (p-values ≤ 0.3); with preterm infants exhibiting less fretful and more neutral responses to the SFP. Preterm and term infants did not significantly differ in distress, attentiveness to caregivers, emotional PC scores, or in their distribution between attachment styles (p-values ≥ .13). In the whole sample, fretfulness correlated with socioeconomic deprivation (rs= −0.18, p-value = .02).

Conclusions

Data reveal subtle attachment differences between preterm and term infants at nine months of age, which may not always be captured by traditional approaches for categorizing attachment. Findings suggests that caregiver-infant attachment relationships may not be fully resilient to the effects of prematurity on the developing infant, but this depends on how attachment is measured. Our results highlight putative links between socioeconomic deprivation and infant attachment that warrant further study.
Forecast Intervals for Infectious Disease Models
Authors: Picard Rick , Osthus Dave
Published: May 2022

Forecast intervals for infectious disease transmission and mortality have long been overconfident — i.e., the advertised coverage probabilities of those intervals fell short of their subsequent performances. Further, there was no apparent relation between how good models claimed to be (as measured by their purported forecast uncertainties) and how good the models really were (as measured by their actual forecast errors). The main cause of this problem lies in the misapplication of textbook methods for uncertainty quantification. A solution lies in the creative use of predictive tail probabilities to obtain valid interval coverages. This approach is compatible with all probabilistic predictive models whose forecast error behavior does not change “too quickly” over time.
Unifying comprehensive genomics and transcriptomics in individual cells to illuminate oncogenic and drug resistance mechanisms
Authors: Marks Jeffrey R. , Zawistowski Jon S. , Salas-González Isai , Tate Tia A. , Morozova Tatiana V. , Blackinton Jeff G. , Arvapalli Durga M. , Velivela Swetha D. , Harton Gary L. , Gawad Charles , Weigman Victor J. , Hwang E. Shelley , West Jay A.A.
Published: May 2022

Discovering transcriptional variation in the absence of underlying genomic contributions hinders understanding of molecular mechanisms of disease. To assess this coordination in individual cells, we leveraged a new workflow, ResolveOME, exploiting the attributes of primary template-directed amplification (PTA) to enable accurate, complete-genome assessment of single-nucleotide variation in conjunction with full-transcript RNA-seq.

In cultured AML cells resistant to the FLT3 inhibitor quizartinib, we uncovered aFLT3missense mutation and matched transcript upregulation of AXL signal transduction and enhancer factor modulation driving resistance. In primary breast cancer cells, we detected oncogenicPIK3CAN345K mutations and heterogeneous classes of chromosomal loss and were empowered to interpret these genotypes with the crucial knowledge of cell identity and state derived from the transcriptome. The study reinforces the plasticity of the genome in conjunction with expected transcriptional modulation, leading to combinatorial alterations that affect cellular evolution that can be identified through application of this workflow to individual cells.
microbeSEG: A deep learning software tool with OMERO data management for efficient and accurate cell segmentation
Authors: Scherr Tim , Seiffarth Johannes , Wollenhaupt Bastian , Neumann Oliver , Schilling Marcel P. , Kohlheyer Dietrich , Scharr Hanno , Nöh Katharina , Mikut Ralf
Published: May 2022

In biotechnology, cell growth is one of the most important properties for the characterization and optimization of microbial cultures. Novel live-cell imaging methods are leading to an ever better understanding of cell cultures and their development. The key to analyzing acquired data is accurate and automated cell segmentation at the single-cell level. Therefore, we present microbeSEG, a user-friendly Python-based cell segmentation tool with a graphical user interface and OMERO data management. microbeSEG utilizes a state-of-the-art deep learning-based segmentation method and can be used for instance segmentation of a wide range of cell morphologies and imaging techniques, e.g., phase contrast or fluorescence microscopy. The main focus of microbeSEG is a comprehensible, easy, efficient, and complete workflow from the creation of training data to the final application of the trained segmentation model. We demonstrate that accurate cell segmentation results can be obtained within 45 minutes of user time. Utilizing public segmentation datasets or pre-labeling further accelerates the microbeSEG workflow. This opens the door for accurate and efficient data analysis of microbial cultures.
Characterization of metabolic changes associated with floral transition in Arabidopsis: RAFFINOSE SYNTHASE 5 contributes to determine the timing of floral transition
Authors: Praena Tamayo Jesús , Budzinski Ilara Gabriela Frasson , Delhomme Nicolas , Moritz Thomas , Madueño Francisco , Benlloch Reyes
Published: May 2022

Integration of environmental and endogenous cues triggers floral induction at the optimal time during the plant life cycle. Flowering is a tightly regulated process, which involves an intricated genetic network, as expected for a process crucial for plant fitness and survival. Individual metabolites are known to contribute to the determination of flowering time, including carbohydrates and hormones. However, a global analysis of metabolic changes associated with flowering was still lacking. We performed a metabolomic study to characterize global metabolic changes associated with photoperiodic floral induction. By using an inducible system, with the CONSTANS (CO) promoter driving the expression of CO fused to the rat glucocorticoid receptor (CO::GR), we induce flowering and identify metabolites that increase or decrease in leaves and apices during floral induction. Combining metabolomic with transcriptomic data, we identify that raffinose metabolism was altered in apices that are induced to flower. Loss-of-function mutants affecting RAFFINOSE SYNTHASE 5 (RS5), a key enzyme of the raffinose metabolism, show an early flowering phenotype. Also, RS5 expression changes during floral transition, suggesting a role for raffinose catabolism on the release of simple sugars at the apex. We propose that variation on the differential accumulation of raffinose and mono- and disaccharides during floral transition contributes to the induction of floral transition, by influencing expression of THEHALOSE-6-PHOSPHATE SYNTHASE 1 (TPS1) and SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 3 (SPL3), which affect expression of the florigen FLOWERING LOCUS T (FT).
DysRegNet: Patient-specific and confounder-aware dysregulated network inference
Authors: Kersting Johannes , Lazareva Olga , Louadi Zakaria , Baumbach Jan , Blumenthal David B. , List Markus
Published: May 2022

Gene regulation is frequently altered in diseases in unique and patient-specific ways. Hence, personalized strategies have been proposed to infer patient-specific gene-regulatory networks. However, existing methods do not scale well as they often require recomputing the entire network per sample. Moreover, they do not account for clinically important confounding factors such as age, sex, or treatment history. Finally, a user-friendly implementation for the analysis and interpretation of such net-works is missing.

We present DysRegNet, a method for inferring patient-specific regulatory alterations (dysregulations) from bulk gene expression profiles. We compared DysRegNet to SSN, a well-known sample-specific network approach. We demonstrate that both SSN and DysRegNet produce interpretable and biologically meaningful networks across various cancer types. In contrast to SSN, DysRegNet can scale to arbitrary sample numbers and highlights the importance of confounders in network inference, revealing an age-specific bias in gene regulation in breast cancer. DysRegNet is available as a Python package (https://github.com/biomedbigdata/DysRegNet_package), and analysis results for eleven TCGA cancer types are available through an interactive web interface (https://exbio.wzw.tum.de/dysregnet).
Colour polymorphism associated with a gene duplication in male wood tiger moths
Authors: Brien Melanie N. , Orteu Anna , Yen Eugenie C. , Galarza Juan A. , Kirvesoja Jimi , Pakkanen Hannu , Wakamatsu Kazumasa , Jiggins Chris D. , Mappes Johanna
Published: May 2022

Colour is often used as an aposematic warning signal, with predator learning expected to lead to a single colour pattern within a population. However, there are many puzzling cases where aposematic signals are also polymorphic. The wood tiger moth,Arctia plantaginis, displays bright hindwing colours associated with unpalatability, and males have discrete colour morphs which vary in frequency between localities. In Finland, both white and yellow morphs can be found, and these colour morphs also differ in behavioural and life-history traits. Here, we show that male colour is linked to an extra copy of ayellowfamily gene that is only present in the white morphs. This white-specific duplication, which we namevalkea, is highly upregulated during wing development, and CRISPR knockouts validate the role ofvalkeain producing white wing colour. We also characterise the pigments responsible for yellow, white and black colouration, showing that yellow is partly produced by pheomelanins, while black is dopamine-derived eumelanin. Our results add to a growing number of studies on the genetic architecture of complex and seemingly paradoxical polymorphisms, and the role of gene duplications and structural variation in adaptive evolution.
Single cell transcriptional landscape of long non-coding RNAs orchestrating mouse heart development
Authors: Ramos Thaís A. R. , Kim Soo Young , Gillette Thomas G. , Hill Joseph A. , Lavandero Sergio , do Rêgo Thaís G. , Maracaja-Coutinho Vinicius
Published: May 2022

Long non-coding RNAs (lncRNAs) comprise the most representative transcriptional units of the mammalian genome, and they’re associated with organ development that can be associated with the emergence of diseases, such as cardiovascular diseases. Thus, we used bioinformatic approaches, machine learning algorithms and statistical techniques to define lncRNAs involved in mammalian cardiac development. We used a single-cell transcriptome dataset generated from 4 embryonic and 4 postnatal stages. Our study identified 8 distinct cell types, novel marker transcripts (coding/lncRNAs) and also, differential expression and functional enrichment analysis reveal cardiomyocyte subpopulations associated with cardiac function; meanwhile modular co-expression analysis reveals cell-specific functional insights for lncRNAs during myocardial development, including a potential association with key genes related to disease and the “fetal gene program”. Our results evidence the role of particular lncRNAs in heart development, and highlights the usage of co-expression modular approaches in the cell-type functional definition.
NMDA-receptor-Fc-fusion constructs neutralize anti-NMDA receptor antibodies
Authors: Steinke Stephan , Kirmann Toni , Nerlich Jana , Weichard Iron , Kuhn Philip , Bullmann Torsten , Ritzau-Jost Andreas , Rizalar Filiz Sila , Prüss Harald , Haucke Volker , Geis Christian , Hust Michael , Hallermann Stefan
Published: May 2022

N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common subtype of autoimmune encephalitis characterized by a complex neuropsychiatric syndrome ranging from memory impairment and psychosis to coma. Patients develop an intrathecal immune response against NMDARs with antibodies that presumably bind to the amino-terminal domain (ATD) of the GluN1 subunit. The therapeutic response to immunotherapy is often delayed and does not directly interfere with intrathecal synthesis of pathogenic antibodies. Therefore, new therapeutic approaches for fast neutralization of NMDAR antibodies are needed. Here, we developed fusion constructs consisting of the Fc part of immunoglobulin G and the ATDs of either GluN1 or GluN2B or both, GluN1 and GluN2B, subunits. Surprisingly, both subunits were required to generate high-affinity epitopes. The construct with both subunits efficiently prevented NMDAR binding of patient-derived monoclonal antibodies and of patient cerebrospinal fluid containing high-titer NMDAR antibodies. Furthermore, it inhibited the internalization of NMDARs in rodent dissociated neurons and human induced pluripotent stem cells (iPSC)-derived neurons. Finally, the construct stabilized NMDAR currents recorded in rodent neurons. Our results demonstrate that both GluN1 and GluN2B subunits contribute to the main immunogenic region of the NMDAR and provide a promising strategy for fast and specific treatment of NMDAR encephalitis, which can complement immunotherapy.
Increased glucose availability sensitizes pancreatic cancer to chemotherapy
Authors: Vaziri-Gohar Ali , Hue Jonathan J. , Graor Hallie G. , Abbas Ata , Zarei Mehrdad , Hajihassani Omid , Titomihelakis George , Feczko John , Rathore Moeez , Wang Rui , Zarei Mahsa , Goudarzi Maryam , Zhang Renliang , Willard Belinda , Zhang Li , Wang Gi-Ming , Tatsuoka Curtis , Salvino Joseph M. , Bederman Ilya , Brunengraber Henri , Lyssiotis Costas A. , Brody Jonathan R. , Winter Jordan M.
Published: May 2022

Pancreatic cancer (Pancreatic Ductal Adenocarcinoma; PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, leaving chemotherapy as the best available systematic treatment. The discovery of safe and available adjuncts that improve chemotherapeutic efficacy would potentially improve survival outcomes. We show that a hyperglycemic state enhances the efficacy of conventional single- and multi-agent chemotherapies against PDAC. Molecular analyses of tumors exposed to relatively high glucose levels revealed that a key metabolic pathway, glutathione biosynthesis, is diminished and underlies chemo-sensitization by enhancing oxidative injury to cancer cells. Inhibition of this pathway under normal conditions phenocopied a hyperglycemic state by enhancing chemotherapeutic efficacy in mouse PDAC, while rescuing the pathway under high glucose abrogated the anti-tumor effects observed with chemotherapy.
Deep Learning-based Pseudo-Mass Spectrometry Imaging Analysis for Precision Medicine
Authors: Shen Xiaotao , Shao Wei , Wang Chuchu , Liang Liang , Chen Songjie , Zhang Sai , Rusu Mirabela , Snyder Michael P.
Published: May 2022

Liquid chromatography-mass spectrometry (LC-MS) based untargeted metabolomics provides systematic profiling of metabolic. Yet its applications in precision medicine (disease diagnosis) have been limited by several challenges, including metabolite identification, information loss, and low reproducibility. Here, we present the deepPseudoMSI project (https://www.deeppseudomsi.org/), which converts LC-MS raw data to pseudo-MS images and then processes them by deep learning for precision medicine, such as disease diagnosis. Extensive tests based on real data demonstrated the superiority of deepPseudoMSI over traditional approaches and the capacity of our method to achieve an accurate individualized diagnosis. Our framework lays the foundation for future metabolic-based precision medicine.
Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors
Authors: Cao Shuting , Hung Yu-Wen , Wang Yi-Chang , Chung Yiyin , Qi Yue , Ouyang Ching , Zhong Xiancai , Hu Weidong , Coblentz Alaysia , Maghami Ellie , Sun Zuoming , Lin H. Helen , Ann David K.
Published: May 2022

Rationale

Immunosuppression in the tumor microenvironment (TME) is key to the pathogenesis of solid tumors. Tumor cell-intrinsic autophagy is critical for sustaining both tumor cell metabolism and survival. However, the role of autophagy in the host immune system that allows cancer cells to escape immune destruction remains poorly understood. Here, we determined if attenuated host autophagy is sufficient to induce tumor rejection through reinforced adaptive immunity. Furthermore, we determined whether dietary glutamine supplementation, mimicking attenuated host autophagy, is capable of promoting antitumor immunity.

Methods

A syngeneic orthotopic tumor model in Atg5+/+ and Atg5flox/flox mice was established to determine the impact of host autophagy on the antitumor effects against mouse malignant salivary gland tumors (MSTs). Multiple cohorts of immunocompetent mice were used for oncoimmunology studies, including inflammatory cytokine levels, macrophage, CD4+, and CD8+ cells tumor infiltration at 14 days and 28 days after MST inoculation. In vitro differentiation and in vivo dietary glutamine supplementation were used to assess the effects of glutamine on Treg differentiation and tumor expansion.

Results

We showed that mice deficient in the essential autophagy gene, Atg5, rejected orthotopic allografts of isogenic MST cells. An enhanced antitumor immune response evidenced by reduction of both M1 and M2 macrophages, increased infiltration of CD8+ T cells, elevated IFN-γ production, as well as decreased inhibitory Tregs within TME and spleens of tumor-bearing Atg5flox/flox mice. Mechanistically, ATG5 deficiency increased glutamine level in tumors. We further demonstrated that dietary glutamine supplementation partially increased glutamine levels and restored potent antitumor responses in Atg5+/+ mice.

Conclusions

Dietary glutamine supplementation exposes a previously undefined difference in plasticity between cancer cells, cytotoxic CD8+ T cells and Tregs.
Effects of Full-cycle Exposure to Difenoconazole in Parental Zebrafish on the Liver-gut Axis of F0 and F1 Generations
Authors: Zhu Tao , Wang Siwen , Li Dong
Published: May 2022

To explore the effects of long-term exposure to low-dose difenoconazole (DCZ) on lipid metabolism in the liver-gut axis, we exposed zebrafish embryos to ambient concentrations of DCZ for 120 days and comprehensively analyzed the metabolic and microbial networks of the F0 and F1 generations using biochemical, metabolomic and metagenomics approaches. The changes of biochemical indexes indicated that DCZ exposure inhibited lipid synthesis, lipolysis and lipid transport of F0 males and females. In addition, the composition of gut microbes in males and females was significantly changed, which corresponds to changes in biochemical parameters in liver, intestine and serum. Metabolome analysis showed that pathways related to amino acid metabolism, ATP-binding cassette transporters, carbohydrate metabolism, and energy metabolism were downregulated in the gut of males and females. At 120 days post-fertilization, lipid synthesis, lipolysis and lipid transport of F1 males was upregulated; the composition of microbiota and metabolome of the F1males gut was significantly altered. Overall, we found that long-term exposure to low doses of DCZ inhibited the liver-gut axis in males and females, and the liver-gut axis in F1 males were disturbed even in F1 generation without DCZ exposure.
HematoNet: Expert Level Classification of Bone Marrow Cytology Morphology in Hematological Malignancy with Deep Learning
Authors: Tripathi Satvik , Augustin Alisha Isabelle , Sukumaran Rithvik , Dheer Suhani , Kim Edward
Published: May 2022

There have been few efforts made to automate the cytomorphological categorization of bone marrow cells. For bone marrow cell categorization, deep-learning algorithms have been limited to a small number of samples or disease classifications. In this paper, we proposed a pipeline to classify the bone marrow cells despite these limitations. Data augmentation was used throughout the data to resolve any class imbalances. Then, random transformations such as rotating between 0° to 90°, zooming in/out, flipping horizontally and/or vertically, and translating were performed. The model used in the pipeline was a CoAtNet and that was compared with two baseline models, EfficientNetV2 and ResNext50. We then analyzed the CoAtNet model using SmoothGrad and Grad-CAM, two recently developed algorithms that have been shown to meet the fundamental requirements for explainability methods. After evaluating all three models’ performance for each of the distinct morphological classes, the proposed CoAtNet model was able to outperform the EfficientNetV2 and ResNext50 models due to its attention network property that increased the learning curve for the algorithm which was represented using a precision-recall curve.