bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinically relevant pretraining is all you need
Authors: Bear Don’t Walk IV Oliver J , Sun Tony , Perotte Adler , Elhadad Noémie
Published: May 2021

Clinical notes present a wealth of information for applications in the clinical domain, but heterogeneity across clinical institutions and settings presents challenges for their processing. The clinical natural language processing field has made strides in overcoming domain heterogeneity, while pretrained deep learning models present opportunities to transfer knowledge from one task to another. Pretrained models have performed well when transferred to new tasks; however, it is not well understood if these models generalize across differences in institutions and settings within the clinical domain. We explore if institution or setting specific pretraining is necessary for pretrained models to perform well when transferred to new tasks. We find no significant performance difference between models pretrained across institutions and settings, indicating that clinically pretrained models transfer well across such boundaries. Given a clinically pretrained model, clinical natural language processing researchers may forgo the time-consuming pretraining step without a significant performance drop.
Short communication: investigation of the feasibility of genomic selection in Icelandic Cattle
Authors: Gautason Egill , Sahana Goutam , Su Guosheng , Benjamínsson Baldur Helgi , Jóhannesson Guðmundur , Guldbrandtsen Bernt
Published: May 2021

Icelandic Cattle is a local dairy cattle breed in Iceland. With about 26,000 breeding females, it is by far the largest among the indigenous Nordic cattle breeds. The objective of this study was to investigate the feasibility of genomic selection in Icelandic Cattle. Pedigree-based best linear unbiased prediction (PBLUP) and single-step genomic best linear unbiased prediction (ssGBLUP) were compared. Accuracy, bias, and dispersion of estimated breeding values (EBV) for milk yield (MY), fat yield (FY), protein yield (PY), and somatic cell score (SCS) were estimated in a cross validation-based design. Accuracy (r^) was estimated by the correlation between EBV and corrected phenotype in a validation set. The accuracy (r^) of predictions using ssGBLUP increased by 13, 23, 19, and 20 percentage points for MY, FY, PY, and SCS for genotyped animals, compared with PBLUP. The accuracy of nongenotyped animals was not improved for MY and PY, but increased by 0.9 and 3.5 percentage points for FY and SCS. We used the linear regression (LR) method to quantify relative improvements in accuracy, bias (Δ^), and dispersion (b^) of EBV. Using the LR method, the relative improvements in accuracy of validation from PBLUP to ssGBLUP were 43%, 60%, 50%, and 48% for genotyped animals for MY, FY, PY, and SCS. Single-step GBLUP EBV were less underestimated (Δ^), and less overdispersed (b^) than PBLUP EBV for FY and PY. Pedigree-based BLUP EBV were close to unbiased for MY and SCS. Single-step GBLUP underestimated MY EBV but overestimated SCS EBV. Based on the average accuracy of 0.45 for ssGBLUP EBV obtained in this study, selection intensities according to the breeding scheme of Icelandic Cattle, and assuming a generation interval of 2.0 yr for sires of bulls, sires of dams and dams of bulls, genetic gain in Icelandic Cattle could be increased by about 50% relative to the current breeding scheme.
Enforcement against the Biggest Banks
Authors: Zaring David
Published: May 2021

Being a big bank means the regular payment of huge fines to a number of different regulators, paired with profuse apologies, and promises to do better next time. This article makes use of a hand-collected dataset to show how this enforcement worked in the United States after the passage of the Dodd-Frank Wall Street Reform Act. American regulators have tended to hunt the big banks in packs, with multiple regulators pursuing fines against financial institutions for the same misconduct. Regulators frequently enforce in a ‘viral’ manner: once they sanction one bank for a type of misconduct, the chances that they will sanction another bank for the same sort of misconduct increases. Some regulators like to bundle a variety of different unlawful actions by banks into one global settlement. Enforcement by the Department of Justice can result in spectacularly expensive settlements compared to the level of enforcement by primary banking regulatory agencies; overall, Department of Justice sanctions in dollars dwarf those of all other agencies policing part of what a bank does. American enforcement, despite suspicion to the contrary, does not appear to protect domestic banks and discriminate against foreign ones. Although this article’s primary goal is to make sense of the federal government’s overall enforcement practices, one recommendation is made: criminal prosecutors should consult with safety and soundness regulators before unveiling indictments and settlements against banks.
The limitations of external measurements for aging small mammals: the cautionary example of the Lesser Treeshrew (Scandentia: Tupaiidae: Tupaia minor Günther, 1876)
Authors: Woodman Neal , Miller-Murthy Ananth , Olson Link E , Sargis Eric J
Published: May 2021

Age is a basic demographic characteristic vital to studies of mammalian social organization, population dynamics, and behavior. To eliminate potentially confounding ontogenetic variation, morphological comparisons among populations of mammals typically are limited to mature individuals (i.e., those assumed to have ceased most somatic growth). In our morphometric studies of treeshrews (Scandentia), adult individuals are defined by the presence of fully erupted permanent dentition, a common criterion in specimen-based mammalogy. In a number of cases, however, we have had poorly sampled populations of interest in which there were potentially useful specimens that could not be included in samples because they lacked associated skulls. Such specimens typically are associated with external body and weight measurements recorded by the original collectors, and we sought to determine whether these data could be used successfully as a proxy for age or at least to establish maturity. We analyzed four traditional external dimensions (head-and-body length, tail length, hind foot length, and ear length) and weight associated with 103 specimens from two allopatric populations of the Lesser Treeshrew (Tupaia minor Günther, 1876) from Peninsular Malaysia and from Borneo, which we treated as separate samples (populations). Individuals were assigned to one of eight age categories based on dental eruption stage, and measurements were compared among groups. In general, mean sizes of infants and subadults were smaller than those of adults, but the majority of subadults fell within the range of variation of adults. The large overlap among infants, subadults, and adults in external measurements and weight indicates that such measures are poor proxies for age in this species, probably for treeshrews in general, and possibly for other small mammals. This has significant implications for any investigation wherein relative age of individuals in a given population is an important consideration.
Niche partitioning in small mammals: interspecific and biome-level analyses using stable isotopes
Authors: Bubadué Jamile , Cáceres Nilton , Melo Geruza , Sponchiado Jonas , Battistella Thaís , Newton Jason , Meloro Carlo
Published: May 2021

Small mammal assemblages from South America provide a unique opportunity to measure coexistence and niche partitioning between marsupials and placentals. We tested how these two major clades partition environmental resources by comparing stable isotopic ratios of similar sized Didelphidae and Sigmodontinae in four Brazilian biomes: Pampas grassland, Pantanal wetland, Cerrado woodland savanna, and Atlantic Forest. Generally, didelphid isotopic niche follows a scaling law, because we found an association between δ15N enrichment and body mass. Sigmodontines that primarily partition the environment via forest strata showed a greater intake of C4 or/and crassulacean acid metabolism (CAM) plants than didelphids, as reflected by their wider trophic niche. Values of δ13C were highest in savannas and grasslands (Cerrado and Pampas biomes), and values of δ15N were highest in the Atlantic Forest (in sigmodontines) and Pampas (in didelphids). While assessing patterns between the two major Brazilian biomes (Atlantic Forest and Cerrado), we found evidence of a broader trophic niche for both clades in the Cerrado. In the Atlantic Forest, niche occupation by Didelphidae was completely enclosed within the Sigmodontinae trophic niche. Both clades showed less overlap in the Cerrado, a less productive environment. Our results highlight the importance of a comparative framework and the use of stable isotopes for testing ecological questions related to how small mammalian communities partition their niche.
Long-term clinical outcomes of patients receiving proton beam therapy for caudate lobe hepatocellular carcinoma
Authors: Iizumi Takashi , Okumura Toshiyuki , Sekino Yuta , Takahashi Hiroaki , Tsai Yu-Lun , Takizawa Daichi , Ishida Toshiki , Hiroshima Yuichi , Nakamura Masatoshi , Shimizu Shosei , Saito Takashi , Numajiri Haruko , Mizumoto Masashi , Nakai Kei , Sakurai Hideyuki
Published: May 2021

Hepatocellular carcinoma (HCC) located in the caudate lobe (caudate HCC) is rare; however, patients with this type of tumour have poorer prognoses than those with HCC in other segments. Despite many published reports on the clinical usefulness of proton beam therapy (PBT) for HCC, data on the clinical outcomes of patients undergoing PBT for caudate HCC remain scarce. Therefore, the present study aimed to investigate the outcomes of this group of patients. Thirty patients with caudate HCC who underwent definitive PBT between February 2002 and February 2014 were retrospectively analysed. The total irradiation doses ranged from 55 to 77 (median 72.6) Gy relative biological dose. The median follow-up period was 37.5 (range, 3.0–152.0) months. The overall survival (OS) rates at one, three and five years were 86.6%, 62.8% and 46.1%, respectively. According to univariate and multivariate analyses, Child-Pugh A (P < 0.01), having a single tumour (P = 0.02) and a low serum alpha-fetoprotein level (AFP; P < 0.01) were significant factors predicting longer survival. The local control (LC) rates at one, three and five years were 100%, 85.9% and 85.9%, respectively, while the corresponding progression-free survival (PFS) rates were 65%, 27.5% and 22%, respectively. No grade 3 or worse adverse events were observed. PBT is effective and safe for the treatment of caudate HCC, and should therefore be considered a feasible option for intervention in patients with this disease.
Extrinsic compression of the right external iliac artery secondary to iliac vein stenting
Authors: Subramaniam Syva Imayan , Fung Adrian T , Taylor David C
Published: May 2021

Symptomatic extrinsic compression of the external iliac artery (EIA) is a rare complication of surgical intervention. Previous cases of EIA compression have presented in the postoperative period after orthopedic surgery or vascular stenting. We report a case of right EIA compression postvenous stenting causing acute limb ischemia.
Evidence for Selection in the Abundant Accessory Gene Content of a Prokaryote Pangenome
Authors: Whelan Fiona J , Hall Rebecca J , McInerney James O
Published: May 2021

A pangenome is the complete set of genes (core and accessory) present in a phylogenetic clade. We hypothesize that a pangenome’s accessory gene content is structured and maintained by selection. To test this hypothesis, we interrogated the genomes of 40 Pseudomonas species for statistically significant coincident (i.e., co-occurring/avoiding) gene patterns. We found that 86.7% of common accessory genes are involved in ≥1 coincident relationship. Further, genes that co-occur and/or avoid each other—but are not vertically inherited—are more likely to share functional categories, are more likely to be simultaneously transcribed, and are more likely to produce interacting proteins, than would be expected by chance. These results are not due to coincident genes being adjacent to one another on the chromosome. Together, these findings suggest that the accessory genome is structured into sets of genes that function together within a given strain. Given the similarity of the Pseudomonas pangenome with open pangenomes of other prokaryotic species, we speculate that these results are generalizable.
Translational accuracy of a tethered ribosome
Authors: Fabret Celine , Namy Olivier
Published: May 2021

Ribosomes are evolutionary conserved ribonucleoprotein complexes that function as two separate subunits in all kingdoms. During translation initiation, the two subunits assemble to form the mature ribosome, which is responsible for translating the messenger RNA. When the ribosome reaches a stop codon, release factors promote translation termination and peptide release, and recycling factors then dissociate the two subunits, ready for use in a new round of translation. A tethered ribosome, called Ribo-T, in which the two subunits are covalently linked to form a single entity, was recently described in Escherichia coli. A hybrid ribosomal RNA (rRNA) consisting of both the small and large subunit rRNA sequences was engineered. The ribosome with inseparable subunits generated in this way was shown to be functional and to sustain cell growth. Here, we investigated the translational properties of Ribo-T. We analyzed its behavior during amino acid misincorporation, −1 or +1 frameshifting, stop codon readthrough, and internal translation initiation. Our data indicate that covalent attachment of the two subunits modifies the properties of the ribosome, altering its ability to initiate and terminate translation correctly.
A structural intermediate pre-organizes the add adenine riboswitch for ligand recognition
Authors: St-Pierre Patrick , Shaw Euan , Jacques Samuel , Dalgarno Paul A , Perez-Gonzalez Cibran , Picard-Jean Frédéric , Penedo J Carlos , Lafontaine Daniel A
Published: May 2021

Riboswitches are RNA sequences that regulate gene expression by undergoing structural changes upon the specific binding of cellular metabolites. Crystal structures of purine-sensing riboswitches have revealed an intricate network of interactions surrounding the ligand in the bound complex. The mechanistic details about how the aptamer folding pathway is involved in the formation of the metabolite binding site have been previously shown to be highly important for the riboswitch regulatory activity. Here, a combination of single-molecule FRET and SHAPE assays have been used to characterize the folding pathway of the adenine riboswitch from Vibrio vulnificus. Experimental evidences suggest a folding process characterized by the presence of a structural intermediate involved in ligand recognition. This intermediate state acts as an open conformation to ensure ligand accessibility to the aptamer and folds into a structure nearly identical to the ligand-bound complex through a series of structural changes. This study demonstrates that the add riboswitch relies on the folding of a structural intermediate that pre-organizes the aptamer global structure and the ligand binding site to allow efficient metabolite sensing and riboswitch genetic regulation.
NetGO 2.0: improving large-scale protein function prediction with massive sequence, text, domain, family and network information
Authors: Yao Shuwei , You Ronghui , Wang Shaojun , Xiong Yi , Huang Xiaodi , Zhu Shanfeng
Published: May 2021

With the explosive growth of protein sequences, large-scale automated protein function prediction (AFP) is becoming challenging. A protein is usually associated with dozens of gene ontology (GO) terms. Therefore, AFP is regarded as a problem of large-scale multi-label classification. Under the learning to rank (LTR) framework, our previous NetGO tool integrated massive networks and multi-type information about protein sequences to achieve good performance by dealing with all possible GO terms (>44 000). In this work, we propose the updated version as NetGO 2.0, which further improves the performance of large-scale AFP. NetGO 2.0 also incorporates literature information by logistic regression and deep sequence information by recurrent neural network (RNN) into the framework. We generate datasets following the critical assessment of functional annotation (CAFA) protocol. Experiment results show that NetGO 2.0 outperformed NetGO significantly in biological process ontology (BPO) and cellular component ontology (CCO). In particular, NetGO 2.0 achieved a 12.6% improvement over NetGO in terms of area under precision-recall curve (AUPR) in BPO and around 2.6% in terms of $\mathbf {F_{max}}$ in CCO. These results demonstrate the benefits of incorporating text and deep sequence information for the functional annotation of BPO and CCO. The NetGO 2.0 web server is freely available at http://issubmission.sjtu.edu.cn/ng2/.
G2PDeep: a web-based deep-learning framework for quantitative phenotype prediction and discovery of genomic markers
Authors: Zeng Shuai , Mao Ziting , Ren Yijie , Wang Duolin , Xu Dong , Joshi Trupti
Published: May 2021

G2PDeep is an open-access web server, which provides a deep-learning framework for quantitative phenotype prediction and discovery of genomics markers. It uses zygosity or single nucleotide polymorphism (SNP) information from plants and animals as the input to predict quantitative phenotype of interest and genomic markers associated with phenotype. It provides a one-stop-shop platform for researchers to create deep-learning models through an interactive web interface and train these models with uploaded data, using high-performance computing resources plugged at the backend. G2PDeep also provides a series of informative interfaces to monitor the training process and compare the performance among the trained models. The trained models can then be deployed automatically. The quantitative phenotype and genomic markers are predicted using a user-selected trained model and the results are visualized. Our state-of-the-art model has been benchmarked and demonstrated competitive performance in quantitative phenotype predictions by other researchers. In addition, the server integrates the soybean nested association mapping (SoyNAM) dataset with five phenotypes, including grain yield, height, moisture, oil, and protein. A publicly available dataset for seed protein and oil content has also been integrated into the server. The G2PDeep server is publicly available at http://g2pdeep.org. The Python-based deep-learning model is available at https://github.com/shuaizengMU/G2PDeep_model.
Thunor: visualization and analysis of high-throughput dose–response datasets
Authors: Lubbock Alexander L R , Harris Leonard A , Quaranta Vito , Tyson Darren R , Lopez Carlos F
Published: May 2021

High-throughput cell proliferation assays to quantify drug-response are becoming increasingly common and powerful with the emergence of improved automation and multi-time point analysis methods. However, pipelines for analysis of these datasets that provide reproducible, efficient, and interactive visualization and interpretation are sorely lacking. To address this need, we introduce Thunor, an open-source software platform to manage, analyze, and visualize large, dose-dependent cell proliferation datasets. Thunor supports both end-point and time-based proliferation assays as input. It provides a simple, user-friendly interface with interactive plots and publication-quality images of cell proliferation time courses, dose–response curves, and derived dose–response metrics, e.g. IC50, including across datasets or grouped by tags. Tags are categorical labels for cell lines and drugs, used for aggregation, visualization and statistical analysis, e.g. cell line mutation or drug class/target pathway. A graphical plate map tool is included to facilitate plate annotation with cell lines, drugs and concentrations upon data upload. Datasets can be shared with other users via point-and-click access control. We demonstrate the utility of Thunor to examine and gain insight from two large drug response datasets: a large, publicly available cell viability database and an in-house, high-throughput proliferation rate dataset. Thunor is available from www.thunor.net.
Relevance of gastrointestinal manifestations in a large Spanish cohort of patients with systemic lupus erythematosus: what do we know?
Authors: Tejera Segura Beatriz , Altabás González Irene , Rúa-Figueroa Iñigo , Pérez Veiga Natalia , Del Campo Pérez Victor , Olivé-Marqués Alejandro , Galindo María , Calvo Jaime , Ovalles-Bonilla Juan Gabriel , Fernández-Nebro Antonio , Menor-Almagro Raúl , Tomero Eva , del Val del Amo Natividad , Uriarte Isacelaya Esther , Martínez-Taboada Víctor Manuel , Andreu Jose L , Boteanu Alina , Narváez Javier , Movasat Atusa , Montilla Carlos , Senabre Gallego Jose Miguel , Hernández-Cruz Blanca , Andrés Mariano , Salgado Eva , Freire Mercedes , Machín García Sergio , Moriano Clara , Expósito Lorena , Pérez Velásquez Clara , Velloso-Feijoo M L , Cacheda Ana Paula , Lozano-Rivas Nuria , Bonilla Gema , Arévalo Marta , Jiménez Inmaculada , Quevedo-Vila Víctor , Manero-Ruiz Francisco J , García de la Peña Lefebvre Paloma , Vázquez-Rodríguez Tomás Ramón , Ibañez-Rua Jesús , Cobo-Ibañez Tatiana , Pego-Reigosa Jose María
Published: May 2021

Objective

SLE can affect any part of the gastrointestinal (GI) tract. GI symptoms are reported to occur in >50% of SLE patients. To describe the GI manifestations of SLE in the RELESSER (Registry of SLE Patients of the Spanish Society of Rheumatology) cohort and to determine whether these are associated with a more severe disease, damage accrual and a worse prognosis.

Methods

We conducted a nationwide, retrospective, multicentre, cross-sectional cohort study of 3658 SLE patients who fulfil ≥4 ACR-97 criteria. Data on demographics, disease characteristics, activity (SLEDAI-2K or BILAG), damage (SLICC/ACR/DI) and therapies were collected. Demographic and clinical characteristics were compared between lupus patients with and without GI damage to establish whether GI damage is associated with a more severe disease.

Results

From 3654 lupus patients, 3.7% developed GI damage. Patients in this group (group 1) were older, they had longer disease duration, and were more likely to have vasculitis, renal disease and serositis than patients without GI damage (group 2). Hospitalizations and mortality were significantly higher in group 1. Patients in group 1 had higher modified SDI (SLICC Damage Index). The presence of oral ulcers reduced the risk of developing damage in 33% of patients.

Conclusion

Having GI damage is associated with a worse prognosis. Patients on a high dose of glucocorticoids are at higher risk of developing GI damage which reinforces the strategy of minimizing glucocorticoids. Oral ulcers appear to decrease the risk of GI damage.
Cerebral mansoni schistosomiasis: a systematic review of 33 cases published from 1989 to 2019
Authors: Bruscky Igor Silvestre , Bruscky Dayanne Mota Veloso , de Melo Fabio Lopes , Medeiros Zulma Maria , Correia Carolina da Cunha
Published: May 2021

Background

We investigated the epidemiology, clinical presentation and outcomes of individuals affected by cerebral schistosomiasis.

Methods

This systematic review was planned in accordance with current guidelines for performing comprehensive systematic reviews and meta-analysis, including the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline.

Results

Most of patients presented with seizures (48.5%), which is a non-specific symptom despite its high prevalence. There was no specific clinical manifestation that could help the diagnosis, which was made in 69.7% by histopathological analysis of brain tissue.

Conclusions

Seizures are a non-specific symptom to diagnose patients with cerebral schistosomiasis and accurate clinical indicators need to be derived through further studies.
Contamination and Translocation of Deoxynivalenol and Its Derivatives Associated with Fusarium Crown Rot of Wheat in Northern China
Authors: Fan Xuefeng , Yan Zhen , Yang Meixin , Waalwijk Cees , van der Lee Theo , van Diepeningen Anne , Brankovics Balazs , Chen Wanquan , Feng Jie , Zhang Hao
Published: May 2021

Fusarium crown rot (FCR) is one of the most important wheat diseases in northern China. The main causal agent of FCR, Fusarium pseudograminearum, can produce mycotoxins such as type B trichothecenes. Therefore, FCR could be an additional source of mycotoxin contamination during wheat production. Field inoculation experiments demonstrated that FCR disease severity strongly impacts the distribution pattern of trichothecenes in different wheat tissues. Mycotoxins were mainly observed in lower internodes, and a low amount was detected in the upper parts above the fourth internode. However, high levels of trichothecene accumulation were detected in the upper segments of wheat plants under field conditions, which would threaten the feed production. The variation of mycotoxin content among sampling sites indicated that besides disease severity, other factors like climate, irrigation, and fungicide application may influence the mycotoxin accumulation in wheat. A comprehensive survey of deoxynivalenol (DON) and its derivatives in wheat heads with FCR symptoms in natural fields was conducted at 80 sites in seven provinces in northern China. Much higher levels of mycotoxin were observed compared with inoculation experiments. The mycotoxin content varied greatly among sampling sites, but no significant differences were observed if compared at province level, which indicated the variation is mainly caused by local conditions. Trace amounts of mycotoxin appeared to be translocated to grains, which revealed that FCR infection in natural fields poses a relatively small threat to contamination of grains but a larger one to plant parts that may be used as animal feed. To our knowledge, this is the first report of trichothecene accumulation in wheat stems and heads, as well as grains after FCR infection in natural field conditions. These investigations provide novel insights into food and feed safety risk caused by FCR in northern China.
Is There a Role for Perioperative Pelvic Radiotherapy in Surgically Resected Stage IV Rectal Cancer?
Authors: Kwon Jeanny , Kim Jun-Sang , Kim Byoung Hyuck
Published: May 2021

Objectives:

This study aimed to determine whether perioperative pelvic radiotherapy (RT) improves outcomes in stage IV rectal cancer patients treated with primary surgical resection and systemic chemotherapy and to identify predictive factors for selection of patients for these approaches.

Materials and Methods:

We searched the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed between 2010 and 2015 with stage IV rectal cancer, but without brain or bone metastases. After applying the exclusion criteria, a total of 26,132 patients were included in the analysis; propensity score matching was used to balance their individual characteristics.

Results:

Overall, 3283 (12.6%) patients received perioperative RT; the 3-year overall survival (OS) rates were 43.6% in the surgery group and 50.5% in the surgery with RT group (P<0.001). The survival benefit of RT was maintained after propensity score matching and multivariate adjustment (hazard ratio: 0.70; 95% confidence interval: 0.66-0.81; P<0.001). Interaction testing of the prognostic variables showed a significant interaction between RT and the presence of lung metastasis (P<0.001): the benefit of RT was observed only in patients without lung metastases (3 y OS 52.1% vs. 44.1%, P<0.001), but it was observed regardless of liver metastases. In addition, we developed a web-based calculator (http://bit.do/mRC_surv) to provide individualized estimates of OS benefit based on the receipt of perioperative pelvic RT.

Conclusions:

Perioperative pelvic RT significantly improved OS rates, especially in patients without lung metastases. We successfully developed a nomogram and web-based calculator that could predict survival benefit with the addition of RT for these patients.
Bayesian Forecasting for Intravenous Tobramycin Dosing in Adults With Cystic Fibrosis Using One Versus Two Serum Concentrations in a Dosing Interval
Authors: Drennan Philip G. , Thoma Yann , Barry Lucinda , Matthey Johan , Sivam Sheila , van Hal Sebastiaan J.
Published: May 2021

Background:

Intravenous tobramycin treatment requires therapeutic drug monitoring (TDM) to ensure safety and efficacy when used for prolonged treatment, as in infective exacerbations of cystic fibrosis. The 24-hour area under the concentration–time curve (AUC24) is widely used to guide dosing; however, there remains variability in practice around methods for its estimation. The objective of this study was to determine the potential for a sparse-sampling strategy using a single postinfusion tobramycin concentration and Bayesian forecasting to assess the AUC24 in routine practice.

Methods:

Adults with cystic fibrosis receiving once-daily tobramycin had paired concentrations measured 2 hours (c1) and 6 hours (c2) after the end of infusion as routine monitoring. AUC24 exposures were estimated using Tucuxi, a Bayesian forecasting application that incorporates a validated population pharmacokinetic model. Simulations were performed to estimate AUC24 using the full data set using c1 and c2, compared with estimates using depleted data sets (c1 or c2 only), with and without concentration data from earlier in the course. The agreement between each simulation condition and the reference was assessed graphically and numerically using the median difference (∆) AUC24 and (relative) root mean square error (rRMSE) as measures of bias and accuracy, respectively.

Results:

A total of 55 patients contributed 512 concentrations from 95 tobramycin courses and 256 TDM episodes. Single concentration methods performed well, with median ∆AUC24 <2 mg·h·L−1 and rRMSE of <15% for sequential c1 and c2 conditions.

Conclusions:

Bayesian forecasting implemented in Tucuxi, using single postinfusion concentrations taken 2–6 hours after tobramycin administration, yield similar exposure estimates to more intensive (two-sample) methods and are suitable for routine TDM practice.
Irregular Astigmatism Management Using SPOT Scleral Lenses in the Treatment of Corneal Ectasia and Penetrating Keratoplasty
Authors: Navel Valentin , Barriere Jean-Vincent , Joubert Romain , Coutu Adrien , Watson Stephanie L. , Lambert Céline , Dutheil Frédéric , Chiambaretta Frédéric
Published: May 2021

Purpose:

To evaluate the outcome of SPOT scleral lenses in the management of irregular astigmatism in patients with corneal ectasia and penetrating keratoplasty. Second, we analyzed patients' characteristics and tolerance, comfort, and geometries of fitted lenses.

Method:

Over a 5-year period, we included patients experiencing irregular astigmatism fitted with SPOT scleral contact lenses, from the University Hospital of Clermont-Ferrand, France. Data collected included corneal diseases, refractive error, best-corrected visual acuity (VA) with SPOT lenses, geometry of the lens, number of adjustment consultations, and the duration of follow-up. Comfort, quality of vision, less handling, and satisfaction were evaluated using visual analog scales after a 6-month follow-up period.

Results:

Sixty-five patients were included, analyzing 107 eyes. Eighty percent of patients still daily wore lenses after a follow-up of 22.3±13.8 months. Visual acuity improved by 0.47±0.51 logarithm of the minimum angle of resolution (average increase of 5 lines) (P<0.001) after wearing scleral lenses. Comfort, quality of vision, less handling, and satisfaction of contact lenses were excellent (>75/100). Contact lenses were daily worn 10.0±4.1 hr/day. Most patients wore size M (17 mm) lenses (53.3% of patients), with an average sagittal height of 5.2±1.2 mm. Internal toricity was used in 30% of cases. Best geometry was found after 2.69±0.87 consultations.

Conclusion:

SPOT scleral contact lenses are an effective and well tolerated method to improve the VA of patients with irregular astigmatism.
Healthcare-associated Pediatric Cutaneous Mucormycosis at Texas Children’s Hospital, 2012–2019
Authors: Foster Catherine E. , Revell Paula A. , Campbell Judith R. , Marquez Lucila
Published: May 2021

Cutaneous mucormycosis in children is an opportunistic fungal infection associated with significant morbidity and mortality. We describe characteristics of 12 patients with healthcare-associated cutaneous mucormycosis at Texas Children’s Hospital and results of an outbreak investigation. A definitive source was not identified. Skin lesions near medical device securement sites should raise concern for mucormycosis in patients with underlying medical conditions.
Comparison of corneal surgically induced astigmatism calculations based on keratometry measurements made by 2 biometric devices
Authors: Abulafia Adi , Rein Adi Porat , Weill Yishay , Zadok David , Mourits Maarten P. , Lapid-Gortzak Ruth
Published: May 2021

Purpose:

To compare calculated corneal surgically induced astigmatism (SIA) by means of anterior-based keratometry (K) and total keratometry (TK) measurements made by 2 biometric devices.

Setting:

Ophthalmology Department, Shaare Zedek Medical Center, Jerusalem, Israel.

Design:

Retrospective, consecutive case series.

Methods:

The medical records of patients who had undergone cataract surgery through a 2.4 mm temporal clear corneal incision by a single surgeon between March 2018 and November 2020 were retrospectively reviewed. Patients for whom there were preoperative and postoperative K measurements assessed by 2 biometric devices, optical low-coherence reflectometry (OLCR) (Lenstar LS900, Haag-Streit, software v. eye suite i/9.1.0.0) and swept-source optical coherence tomography (SS-OCT) (IOLMaster700, Carl Zeiss Meditec AG, software v. 1.80.6.60340), were identified. Corneal SIA (mean vector value) was calculated by vector analysis for 3 groups: SS-OCT(K), SS-OCT(TK), and OLCR(K). Bivariate analyses were applied for comparisons.

Results:

147 eyes of 123 patients (73 right eyes and 74 left eyes) were enrolled in the study. The right eye corneal SIA values were 0.09 diopters (D) @ 136 degrees, 0.09 D @ 141 degrees, and 0.07 D @ 123 degrees for the SS-OCT(K), SS-OCT(TK), and OLCR, respectively. The corresponding left eye corneal SIA values were 0.13 D @ 120 degrees, 0.11 D @ 123 degrees, and 0.08 D @ 120 degrees. There were no statistically significant differences between the mean vector value and variance of the corneal SIA for the right (P = .78 and P = .65) and the left (P = .75 and P = .37) eyes of the 3 groups.

Conclusions:

Corneal SIA values were low (0.07 to 0.13 D) and similar for the SS-OCT and the OLCR biometric devices with standard K measurements. TK measurements yielded similar corneal SIA values compared with anterior corneal-based measurements.
Visual outcome after rhegmatogenous retinal detachment repair surgery in patients with multifocal vs monofocal intraocular lenses
Authors: Freissinger Sigrid , Vounotrypidis Efstathios , Stetzer Eva , Bayer Iris , Shajari Mehdi , Kreutzer Thomas , Keidel Leonie , Kern Christoph , Priglinger Siegfried , Wolf Armin
Published: May 2021

Purpose:

To evaluate functional outcome after retinal detachment (RD) repair surgery in eyes with a multifocal intraocular lens (mIOL).

Setting:

Ludwig-Maximilians-University, Munich, Germany.

Design:

Single-center case control study.

Methods:

52 pseudophakic eyes with successful anatomical outcome after surgical RD repair were included. Retrospectively, 21 mIOL eyes were compared with a matched group of 21 monofocal eyes over 6 weeks. Prospectively, corrected distance visual acuity (CDVA) was evaluated over 12 months in these eyes. Furthermore, uncorrected distance, intermediate, and near visual acuity (UDVA, UIVA, and UNVA, respectively), defocus curves, and patient-reported outcomes were evaluated at 1 year in 24 mIOL eyes.

Results:

52 eyes of 48 patients comprised the study. The mean CDVA (logMAR) improved significantly from 1.35 ± 1.38 to 0.29 ± 0.37 at 6 weeks and remained stable at 12 months postoperatively in monofocal eyes (P = .001) and from 1.16 ± 1.2 to 0.37 ± 0.29 (6 weeks) and 0.20 ± 0.36 (12 months) in mIOL eyes (P = .001). Univariate factorial analysis of variance showed no statistically significant differences in CDVA at 6 weeks or 12 months postoperatively for IOL type or for preoperative macular status (P > .05). In the prospective cohort of 24 mIOL eyes, a mean CDVA of 0.13 ± 0.33 logMAR, UDVA of 0.21 ± 0.34 logMAR, UIVA of 0.17 ± 0.28 logMAR, and UNVA of 0.23 ± 0.32 logMAR was achieved. Macular status did not affect final outcome significantly (P > .05). Most patients stated they usually did not need spectacles; no patient wanted mIOL replacement.

Conclusions:

1 year after successful anatomical repair after 23-gauge vitrectomy with gas tamponade, functionality of mIOL was restored, and CDVA was comparable with that of patients with monofocal IOL.
Sympathectomy decreases pain behaviors and nerve regeneration by downregulating monocyte chemokine CCL2 in dorsal root ganglia in the rat tibial nerve crush model
Authors: Zhu Xiaoyan , Xie Wenrui , Zhang Jingdong , Strong Judith A. , Zhang Jun-Ming
Published: May 2021

Peripheral nerve regeneration is associated with pain in several preclinical models of neuropathic pain. Some neuropathic pain conditions and preclinical neuropathic pain behaviors are improved by sympathetic blockade. In this study, we examined the effect of a localized “microsympathectomy,” ie, cutting the gray rami containing sympathetic postganglionic axons where they enter the L4 and L5 spinal nerves, which is more analogous to clinically used sympathetic blockade compared with chemical or surgical sympathectomy. We also examined manipulations of CCL2 (monocyte chemoattractant protein 1), a key player in both regeneration and pain. We used rat tibial nerve crush as a neuropathic pain model in which peripheral nerve regeneration can occur successfully. CCL2 in the sensory ganglia was increased by tibial nerve crush and reduced by microsympathectomy. Microsympathectomy and localized siRNA-mediated knockdown of CCL2 in the lumbar dorsal root ganglion had very similar effects: partial improvement of mechanical hypersensitivity and guarding behavior, reduction of regeneration markers growth-associated protein 43 and activating transcription factor 3, and reduction of macrophage density in the sensory ganglia and regenerating nerve. Microsympathectomy reduced functional regeneration as measured by myelinated action potential propagation through the injury site and denervation-induced atrophy of the tibial-innervated gastrocnemius muscle at day 10. Microsympathectomy plus CCL2 knockdown had behavioral effects similar to microsympathectomy alone. The results show that local sympathetic effects on neuropathic pain may be mediated in a large part by the effects on expression of CCL2, which in turn regulates the regeneration process.
First Annual Conference on New Health Practitioners
Authors: Sadler Alfred M. , Piemme Thomas E.
Published: May 2021

The First National Conference on New Health Practitioners was a seminal event in the development of the fledgling PA profession. Sponsored by the Association of Physician Assistant Programs and the American Academy of Physician Assistants, it was achieved by the cooperation of leaders committed to the success of the new profession. This article reveals, in a manner never before detailed, how this conference milestone was planned and what took place, and emphasizes its importance to the field. The meeting, held in April of 1973, was groundbreaking, attracting, among the 252 participants, the leadership of the American Medical Association, the National Board of Medical Examiners, the Federation of State Medical Boards, the Association of American Medical Colleges, the American Nurses Association, and federal agencies within the Department of Health, Education and Welfare, responsible for promoting and funding PA education, as well as PAs and PA educators. This remarkable participation, and conference program, have long deserved a more explicit accounting than they have had to date. Details for this article were enhanced when one of the authors (Piemme) discovered, among his archive of personal documents (from almost 50 years ago), 2 items originally generated by the US Air Force that provide more insight into details of the conference. One is a robust conference planning document outlining in detail both the organizational elements and the programmatic elements of the conference. The other is a final financial statement from the conference organizing committee.
Survival Outcomes of Acinar Cell Pancreatic Cancer
Authors: Shaib Walid L. , Zakka Katerina , Huang Weixing , Chen Zhengjia , Alese Olatunji B. , Wu Christina , Akce Mehmet , El-Rayes Bassel F.
Published: May 2021

Objectives

Acinar cell pancreatic carcinomas (ACPCs) are rare neoplasms accounting for 1% to 2% of pancreatic tumors in adults. The objective of this study is to evaluate the benefit of chemotherapy in the adjuvant setting in resected ACPC and in the palliative setting for metastatic ACPC.

Methods

Data were obtained from all US hospitals that contributed to the National Cancer Database between 2004 and 2014. Cases were identified using the histology code 8550.

Results

A total of 593 patients with ACPC were identified. The mean age was 64.4 years (range, 18–90 years), with a male preponderance (72.8%, n = 432). Localized stage disease comprised 52.3% (n = 310) of patients. Among localized ACPC patients, 88.0% (n = 191) underwent surgery and 50.6% (n = 91) received adjuvant chemotherapy. The 5-year overall survival in those who received adjuvant treatment was slightly higher than those who did not receive adjuvant treatment (46.7% vs 44.8%, P = 0.3271). Among advanced-stage ACPC patients, 67.6% received chemotherapy, which translated into improved 5-year overall survival compared with no chemotherapy (8.1% vs 0%, P < 0.0001).

Conclusions

Chemotherapy in the palliative setting for advanced-stage ACPC patients was associated with improved survival. Adjuvant therapy did not translate into significant survival benefit.
The Clinical Applicability of Primary Thromboprophylaxis in Ambulatory Patients With Pancreatic Cancer
Authors: Sandow Lyndsey Paige , Cannon Laura A. , Weston Natalie Rose , Aung Kyaw Lwin , Oo Thein Hlaing
Published: May 2021

Thromboembolism is a leading cause of death in ambulatory patients with cancer. Patients with pancreatic adenocarcinoma have a very high risk of developing venous thromboembolism, especially within the first 6 months of diagnosis. Although primary thromboprophylaxis could reduce this risk, there are unresolved questions concerning choice of agents for anticoagulation, duration of anticoagulation treatment, and criteria for patient selection. Furthermore, the current clinical guidelines on primary thromboprophylaxis in ambulatory patients with pancreatic cancer are ambiguous. This review seeks out to understand and critically appraise the evidence supporting the use of primary thromboprophylaxis in patients with pancreatic cancer and its clinical applicability.
Diagnostic Accuracy of Computed Tomography Scores in Chronic Pancreatitis
Authors: Nordaas Ingrid Kvåle , Dimcevski Georg , Gilja Odd Helge , Havre Roald Flesland , Haldorsen Ingfrid S. , Engjom Trond
Published: May 2021

Objectives

Computed tomography (CT) is the most commonly used imaging modality when diagnosing chronic pancreatitis (CP). We aimed to evaluate the diagnostic accuracy of CT scores for diagnosing CP.

Methods

One hundred eighteen patients were retrospectively included from an observational cohort study that comprised patients referred because of suspected CP. Patients were categorized as CP or non-CP using a modified Mayo score based on biochemistry, clinical presentation, and findings on endoscopic ultrasound and/or transabdominal ultrasound. The CT scans were scored according to the modified Cambridge classification and the unweighted CT score. Diagnostic performance indices were calculated using the modified Mayo score as reference standard.

Results

Seventy-six of the 118 patients fulfilled the CP diagnostic criteria (Mayo score ≥4). The modified Cambridge classification and the unweighted CT score yielded sensitivities of 63% and 67% and specificities of 91% and 91%, respectively, and similar areas under the receiver operating characteristic curves (95% confidence interval) of 0.79 (0.71–0.88)/0.81 (0.73–0.89), respectively (P, not significant).

Conclusions

Both CT scores had similar, moderate accuracies for diagnosing CP. The limitation in diagnostic accuracy makes CT ineligible as a single method to diagnose CP, supporting that the diagnostic process for CP needs to incorporate other imaging methods and/or markers for better diagnostics.
Genetic Variants in Patients With a Family History of Pancreatic Cancer
Authors: Zhu Huili , Welinsky Sara , Soper Emily R. , Brown Karen L. , Abul-Husn Noura S. , Lucas Aimee L.
Published: May 2021

Objectives

Up to 15% of pancreatic cancer is hereditary. We aim to study the prevalence of pathogenic germline variants (PGVs) in patients referred for genetic counseling with a family history (FH) of pancreatic cancer.

Methods

We performed a retrospective single institution cohort study of individuals who underwent cancer genetic counseling with a FH of pancreatic cancer.

Results

We identified 314 patients. Genetic testing was performed in 291 (92.7%) and 187 (59.6%) underwent expanded multigene panel testing. Fifty-four PGVs were found in 53 (16.9%) individuals; PGVs in BRCA1/2 (37%) were most common. Seventy-two variants of uncertain significance (VUS) were found in 58 (18.5%) individuals; VUS in ATM (16.7%) were the most common. Of the 112 (35.4%) with a first-degree family member with pancreatic cancer, 14 PGVs were identified in 14 (12.5%) individuals and 28 VUS were identified in 21 (18.8%) individuals. After genetic testing, 47 (15.0%) individuals met International Cancer of the Pancreas Screening criteria and 67 (21.3%) met American College of Gastroenterology criteria for pancreatic surveillance.

Conclusions

Genetic testing of individuals with a FH of pancreatic cancer represents an opportunity to identify individuals who may be candidates for pancreatic surveillance.
Heat Shock Protein 90 Inhibitor Effects on Pancreatic Cancer Cell Cultures
Authors: Gulla Aistė , Kazlauskas Egidijus , Liang Hong , Strupas Kestutis , Petrauskas Vytautas , Matulis Daumantas , Eshleman James R.
Published: May 2021

Objectives

Pancreatic ductal adenocarcinoma is one of the deadliest cancers for which few curative therapies are available to date. Heat shock protein 90 (Hsp90) inhibitors have shown activity against numerous cancers in vitro; therefore, we tested whether they could be used to target pancreatic ductal adenocarcinoma.

Methods

Inhibitors of Hsp90 ATPase activity were applied on low-passage pancreatic cell line cultures (Panc10.05, Panc215, A6L) in a dose-response manner, and the inhibitor in vitro effect on cell growth was evaluated. Seven of novel Hsp90 inhibitors based on resorcinol fragment and 5 commercially available Hsp90 inhibitors (17-AAG, AT-13387, AUY-922, ganetespib, and rifabutin) as well as control compound triptolide were tested yielding IC50 values in 2- and 3-dimensional assays.

Results

The novel Hsp90 inhibitors exhibited strong effects on all 3 tested pancreatic cell line cultures (Panc10.05, Panc215, A6L) reaching the IC50 of 300 to 600 nM in 2- and 3-dimensional assays.

Conclusions

Novel Hsp90 inhibitors can be developed as antipancreatic cancer agents. Their chemical structures are simpler, and they are likely to exhibit lower side effects than the much more complex inhibitors used as controls.