bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder
Authors: Carlson Ryan J. , Quesnel Alicia , Wells Dawson , Brownstein Zippora , Gilony Dror , Gulsuner Suleyman , Leppig Kathleen A. , Avraham Karen B. , King Mary-Claire , Walsh Tom , Rubinstein Jay 
Published: May 2021

Objectives:
To better distinguish NOG-related-symphalangism spectrum disorder (NOG-SSD) from chromosomal 17q22 microdeletion syndromes and to inform surgical considerations in stapes surgery for patients with NOG-SSD.

Background:
Mutations in NOG cause a variety of skeletal syndromes that often include conductive hearing loss. Several microdeletions of chromosome 17q22 lead to severe syndromes with clinical characteristics that overlap NOG-SSD. Isolated deletion of NOG has not been described, and therefore the contribution of NOG deletion in these syndromes is unknown.

Methods:
Two families with autosomal dominant NOG-SSD exhibited stapes ankylosis, facial dysmorphisms, and skeletal and joint anomalies. In each family, NOG was evaluated by genomic sequencing and candidate mutations confirmed as damaging by in vitro assays. Temporal bone histology of a patient with NOG-SSD was compared with temporal bones of 40 patients diagnosed with otosclerosis.

Results:
Family 1 harbors a 555 kb chromosomal deletion encompassing only NOG and ANKFN1. Family 2 harbors a missense mutation in NOG leading to absence of noggin protein. The incus-footplate distance of the temporal bone was significantly longer in a patient with NOG-SSD than in patients with otosclerosis.

Conclusion:
The chromosomal microdeletion of family 1 led to a phenotype comparable to that due to a NOG point mutation and much milder than the phenotypes due to other chromosome 17q22 microdeletions. Severe clinical findings in other microdeletion cases are likely due to deletion of genes other than NOG. Based on temporal bone findings, we recommend that surgeons obtain longer stapes prostheses before stapes surgery in individuals with NOG-SSD stapes ankylosis.
Prevalence of Advanced Colorectal Neoplasia in Veterans
Authors: Imperiale Thomas F. , Daggy Joanne K. , Imler Timothy D. , Sherer Eric A. , Kahi Charles J. , Larson Jason , Cardwell Jon , Johnson Cynthia S. , Ahnen Dennis J. , Antaki Fadi , Ashley Christopher , Baffy Gyorgy , Dominitz Jason A. , Hou Jason , Korsten Mark A. , Nagar Anil , Promrat Kittichai , Robertson Douglas J. , Saini Sameer , Shergill Amandeep , Smalley Walter E. 
Published: May 2021

Goal:
We sought to quantify the independent effects of age, sex, and race/ethnicity on risk of colorectal cancer (CRC) and advanced neoplasia (AN) in Veterans.

Study:
We conducted a retrospective, cross-sectional study of Veterans aged 40 to 80 years who had diagnostic or screening colonoscopy between 2002 and 2009 from 1 of 14 Veterans Affairs Medical Centers. Natural language processing identified the most advanced finding and location (proximal, distal). Logistic regression was used to examine the adjusted, independent effects of age, sex, and race, both overall and in screening and diagnostic subgroups.

Results:
Among 90,598 Veterans [mean (SD) age 61.7 (9.4) y, 5.2% (n=4673) were women], CRC and AN prevalence was 1.3% (n=1171) and 8.9% (n=8081), respectively. Adjusted CRC risk was higher for diagnostic versus screening colonoscopy [odds ratio (OR)=3.79; 95% confidence interval (CI), 3.19-4.50], increased with age, was numerically (but not statistically) higher for men overall (OR=1.53; 95% CI, 0.97-2.39) and in the screening subgroup (OR=2.24; 95% CI, 0.71-7.05), and was higher overall for Blacks and Hispanics, but not in screening. AN prevalence increased with age, and was present in 9.2% of men and 3.9% of women [adjusted OR=1.90; 95% CI, 1.60-2.25]. AN risk was 11% higher in Blacks than in Whites overall (OR=1.11; 95% CI, 1.04-1.20), was no different in screening, and was lower in Hispanics (OR=0.74; 95% CI, 0.55-0.98). Women had more proximal CRC (63% vs. 39% for men; P=0.03), but there was no difference in proximal AN (38.3% for both genders).

Conclusions:
Age and race were associated with AN and CRC prevalence. Blacks had a higher overall prevalence of both CRC and AN, but not among screenings. Men had increased risk for AN, while women had a higher proportion of proximal CRC. These findings may be used to tailor when and how Veterans are screened for CRC.
Safety and Efficacy of Biological Therapy in Chronic Antibiotic Refractory Pouchitis
Authors: Chandan Saurabh , Mohan Babu P. , Kumar Anand , Khan Shahab R. , Chandan Ojasvini C. , Kassab Lena L. , Ponnada Suresh , Kochhar Gursimran S. 
Published: May 2021

Background:
Pouchitis is the most common long-term complication after ileal pouch-anal anastomosis in patients with ulcerative colitis. Those with ≥3 episodes of pouchitis/year and symptoms despite antibiotics are considered to have chronic antibiotic refractory pouchitis (CARP). While several agents including probiotics, steroids and immunomodulators have been used, treatment of CARP remains challenging. We conducted a systematic review and meta-analysis evaluating the safety and efficacy of various biological agents in treatment of CARP.

Methods:
Multiple databases were searched through June 2020 for studies that reported the efficacy and safety of biological therapy including antitumor necrosis factor-alpha agents [infliximab (IFX) and adalimumab (ADA)], vedolizumab (VDZ), and ustekinumab in CARP. We excluded studies on Crohn’s like and/or other inflammatory complications of the pouch. Meta-analysis was performed to calculate pooled rates of clinical as well as endoscopic improvement and remission.

Results:
We included 15 studies with 311 patients in our final analysis. Ninety-two patients were treated with IFX, 42 with ADA, 144 with VDZ and 33 with ustekinumab. Pooled rate of clinical improvement was 71.4%, 58.2%, 47.9% and clinical remission was 65.7%, 31%, 47.4% with IFX, ADA, and VDZ, respectively. Pooled rate of endoscopic improvement was achieved in 61.2% patients treated with VDZ while endoscopic remission was achieved in 70.3% patients treated with IFX. Adverse events were reported in 3.9% patients.

Conclusion:
Biologic therapy is safe and effective in the treatment of CARP.
Diaphragm Pacing and a Model for Respiratory Rehabilitation After Spinal Cord Injury
Authors: Cavka Kathryn , Fuller David D. , Tonuzi Geneva , Fox Emily J. 
Published: May 2021

Background and Purpose:
Cervical spinal cord injury (CSCI) can cause severe respiratory impairment. Although mechanical ventilation (MV) is a lifesaving standard of care for these patients, it is associated with diaphragm atrophy and dysfunction. Diaphragm pacing (DP) is a strategy now used acutely to promote MV weaning and to combat the associated negative effects. Initial reports indicate that DP also may promote neuromuscular plasticity and lead to improvements in spontaneous diaphragm activation and respiratory function. These outcomes suggest the need for reevaluation of respiratory rehabilitation for patients with CSCI using DP and consideration of new rehabilitation models for these patients and their unique care needs.

Summary of Key Points:
This article discusses the rationale for consideration of DP as a rehabilitative strategy, particularly when used in combination with established respiratory interventions. In addition, a model of respiratory rehabilitation and recovery (RRR) is presented, providing a framework for rehabilitation and consideration of DP as an adjuvant rehabilitation approach. The model promotes goals such as respiratory recovery and independence, and lifelong respiratory health, via interdisciplinary care, respiratory training, quantitative measurement, and use of adjuvant strategies such as DP. Application of the model is demonstrated through a description of an inpatient rehabilitation program that applies model components to patients with CSCI who require DP.

Recommendations for Clinical Practice:
As DP use increases for patients with acute CSCI, so does the need and opportunity to advance rehabilitation approaches for these patients. This perspective article is a critical step in addressing this need and motivating the advancement of rehabilitation strategies for CSCI patients. (See Video Abstract, Supplemental Digital Content, available at: http://links.lww.com/JNPT/A348).
Evaluation of the Utilization of FilmArray Meningitis/Encephalitis in Children With Suspected Central Nervous System Infection
Authors: Barros Domingues Renan , Mendes-Correa Maria Cássia , Vilela de Moura Leite Fernando Brunale , Vega dos Santos Márcio , Senne Soares Carlos Augusto 
Published: May 2021

Background
The etiology of central nervous system infections is often difficult to establish. FilmArray meningitis/encephalitis (ME) panel is a multiplex polymerase chain reaction for rapid identification of 14 pathogens. The aim of this study was to evaluate potential real-life contributions of the use of this method in the pediatric population.

Methods
We herein report the results obtained with FilmArray ME in a retrospective case series of 367 children with suspected central nervous system infection. We identified viral and bacterial agents by FilmArray, and we evaluated the potential diagnostic contributions of the use of the panel taking into account the cytological, biochemical, and microbiological results of the cerebrospinal fluid (CSF) analysis.

Results
The FilmArray ME panel detected a viral infection in 186 cases (50.7%) and a bacterial infection in 12 cases (3.3%). Fifty-three cases (28.4%) of viral infection had at least 1 CSF finding that could be mistaken for bacterial meningitis. Enterovirus was identified in 2 cases with normal CSF findings. Among 12 bacterial infection cases, only 6 (50%) had a positive result with conventional microbiology analysis (Gram stain and culture). The CSF findings suggestive of bacterial meningitis were found in all 6 cases in which FilmArray was the only method to identify bacterial etiological agent.

Conclusions
FilmArray ME panel identified an etiological agent in cases in which conventional CSF analysis failed, providing potential clinical contributions to the management of such cases.
Fully Automatic Deep Learning in Bi-institutional Prostate Magnetic Resonance Imaging
Authors: Netzer Nils , Weißer Cedric , Schelb Patrick , Wang Xianfeng , Qin Xiaoyan , Görtz Magdalena , Schütz Viktoria , Radtke Jan Philipp , Hielscher Thomas , Schwab Constantin , Stenzinger Albrecht , Kuder Tristan Anselm , Gnirs Regula , Hohenfellner Markus , Schlemmer Heinz-Peter , Maier-Hein Klaus H. , Bonekamp David 
Published: May 2021

Background
The potential of deep learning to support radiologist prostate magnetic resonance imaging (MRI) interpretation has been demonstrated.

Purpose
The aim of this study was to evaluate the effects of increased and diversified training data (TD) on deep learning performance for detection and segmentation of clinically significant prostate cancer–suspicious lesions.

Materials and Methods
In this retrospective study, biparametric (T2-weighted and diffusion-weighted) prostate MRI acquired with multiple 1.5-T and 3.0-T MRI scanners in consecutive men was used for training and testing of prostate segmentation and lesion detection networks. Ground truth was the combination of targeted and extended systematic MRI–transrectal ultrasound fusion biopsies, with significant prostate cancer defined as International Society of Urological Pathology grade group greater than or equal to 2. U-Nets were internally validated on full, reduced, and PROSTATEx-enhanced training sets and subsequently externally validated on the institutional test set and the PROSTATEx test set. U-Net segmentation was calibrated to clinically desired levels in cross-validation, and test performance was subsequently compared using sensitivities, specificities, predictive values, and Dice coefficient.

Results
One thousand four hundred eighty-eight institutional examinations (median age, 64 years; interquartile range, 58–70 years) were temporally split into training (2014–2017, 806 examinations, supplemented by 204 PROSTATEx examinations) and test (2018–2020, 682 examinations) sets. In the test set, Prostate Imaging–Reporting and Data System (PI-RADS) cutoffs greater than or equal to 3 and greater than or equal to 4 on a per-patient basis had sensitivity of 97% (241/249) and 90% (223/249) at specificity of 19% (82/433) and 56% (242/433), respectively. The full U-Net had corresponding sensitivity of 97% (241/249) and 88% (219/249) with specificity of 20% (86/433) and 59% (254/433), not statistically different from PI-RADS (P > 0.3 for all comparisons). U-Net trained using a reduced set of 171 consecutive examinations achieved inferior performance (P < 0.001). PROSTATEx training enhancement did not improve performance. Dice coefficients were 0.90 for prostate and 0.42/0.53 for MRI lesion segmentation at PI-RADS category 3/4 equivalents.

Conclusions
In a large institutional test set, U-Net confirms similar performance to clinical PI-RADS assessment and benefits from more TD, with neither institutional nor PROSTATEx performance improved by adding multiscanner or bi-institutional TD.
A Pilot Study of Multidimensional Diffusion MRI for Assessment of Tissue Heterogeneity in Prostate Cancer
Authors: Langbein Björn J. , Szczepankiewicz Filip , Westin Carl-Fredrik , Bay Camden , Maier Stephan E. , Kibel Adam S. , Tempany Clare M. , Fennessy Fiona M. 
Published: May 2021

Objectives
The objectives of this exploratory study were to investigate the feasibility of multidimensional diffusion magnetic resonance imaging (MddMRI) in assessing diffusion heterogeneity at both a macroscopic and microscopic level in prostate cancer (PCa).

Materials and Methods
Informed consent was obtained from 46 subjects who underwent 3.0-T prostate multiparametric MRI, complemented with a prototype spin echo–based MddMRI sequence in this institutional review board–approved study. Prostate cancer tumors and comparative normal tissue from each patient were contoured on both apparent diffusion coefficient and MddMRI-derived mean diffusivity (MD) maps (from which microscopic diffusion heterogeneity [MKi] and microscopic diffusion anisotropy were derived) using 3D Slicer. The discriminative ability of MddMRI-derived parameters to differentiate PCa from normal tissue was determined using the Friedman test. To determine if tumor diffusion heterogeneity is similar on macroscopic and microscopic scales, the linear association between SD of MD and mean MKi was estimated using robust regression (bisquare weighting). Hypothesis testing was 2 tailed; P values less than 0.05 were considered statistically significant.

Results
All MddMRI-derived parameters could distinguish tumor from normal tissue in the fixed-effects analysis (P < 0.0001). Tumor MKi was higher (P < 0.05) compared with normal tissue (median, 0.40; interquartile range, 0.29–0.52 vs 0.20–0.18; 0.25), as was tumor microscopic diffusion anisotropy (0.55; 0.36–0.81 vs 0.20–0.15; 0.28). The MKi could not be predicted (no significant association) by SD of MD. There was a significant correlation between tumor volume and SD of MD (R
2 = 0.50, slope = 0.008 μm2/ms per millimeter, P < 0.001) but not between tumor volume and MKi.

Conclusions
This explorative study demonstrates that MddMRI provides novel information on MKi and microscopic anisotropy, which differ from measures at the macroscopic level. MddMRI has the potential to characterize tumor tissue heterogeneity at different spatial scales.
Theta-Alpha Variability on Admission EEG Is Associated With Outcome in Pediatric Cerebral Malaria
Authors: Andrews Alexander , Zelleke Tesfaye , Harrar Dana , Izem Rima , Gai Jiaxiang , Postels Douglas 
Published: May 2021

Purpose:
Pediatric cerebral malaria has high rates of mortality and neurologic morbidity. Although several biomarkers, including EEG, are associated with survival or morbidity, many are resource intensive or require skilled interpretation for clinical use. Automation of quantitative interpretation of EEG may be preferable in resource-limited settings, where trained interpreters are rare. As currently used quantitative EEG factors do not adequately describe the spectrum of variability seen in studies from children with cerebral malaria, the authors developed and validated a new quantitative EEG variable, theta-alpha variability (TAV).

Methods:
The authors developed TAV, a new quantitative variable, as a composite of multiple automated EEG outputs. EEG records from 194 children (6 months to 14 years old) with cerebral malaria were analyzed. Independent EEG interpreters performed standard quantitative and qualitative analyses, with the addition of the newly created variable. The associations of TAV with other quantitative EEG factors, a qualitative assessment of variability, and outcomes were assessed.

Results:
Theta-alpha variability was not highly correlated with alpha, theta, or delta power and was not associated with qualitative measures of variability. Children whose EEGs had higher values of TAV had a lower risk of death (odds ratio = 0.934, 95% confidence interval = 0.902–0.966) or neurologic sequelae (odds ratio = 0.960, 95% confidence interval = 0.932–0.990) compared with those with lower values. Receiver operating characteristic analysis in predicting death at a TAV threshold of 0.244 yielded a sensitivity of 74% and specificity of 70% for an area under the receiver operating characteristic curve of 0.755.

Conclusions:
Theta-alpha variability is independently associated with outcome in pediatric cerebral malaria and can predict death with high sensitivity and specificity. Automated determination of this newly created EEG factor holds promise as a potential method to increase the clinical utility of EEG in resource-limited settings by allowing interventions to be targeted to those at higher risk of death or disability.
Combined VNS-RNS Neuromodulation for Epilepsy
Authors: Khankhanian Pouya , Lee Angelica M. , Drees Cornelia N. , Decker Barbara M. , Becker Danielle A. 
Published: May 2021

Summary:
The vagus nerve stimulator (VNS) and responsive nerve stimulator (RNS) are nonpharmacological devices approved for drug-resistant epilepsy. Vagus nerve stimulator was removed before placing an RNS in clinical trials. Two cases of bilateral mesial temporal epilepsy treated concurrently with VNS and bilateral mesial temporal RNS devices were reported. In each case, the VNS device was turned off temporarily, which allowed for a direct comparison of RNS recordings and efficacy with and without simultaneous VNS stimulation. Temporary VNS cessation lead to increased clinical and electrocorticographic seizures despite continued anti-seizure drugs and RNS stimulation. In one case, VNS eliminated seizures from one epileptogenic area, whereas VNS and RNS were required to treat seizures from the contralateral mesial temporal structure. In another case, VNS effectively decreased seizure spread to the symptomatogenic zone. These cases demonstrate synergistic neuromodulation with concurrent use of VNS and RNS in intractable bitemporal epilepsy.
Epidemic interventions: insights from classic results
Authors: Gog Julia R. , Hollingsworth T. Déirdre 
Published: May 2021

Analytical expressions and approximations from simple models have performed a pivotal role in our understanding of infectious disease epidemiology. During the current COVID-19 pandemic, while there has been proliferation of increasingly complex models, still the most basic models have provided the core framework for our thinking and interpreting policy decisions. Here, classic results are presented that give insights into both the role of transmission-reducing interventions (such as social distancing) in controlling an emerging epidemic, and also what would happen if insufficient control is applied. Though these are simple results from the most basic of epidemic models, they give valuable benchmarks for comparison with the outputs of more complex modelling approaches.
This article is part of the theme issue ‘Modelling that shaped the early COVID-19 pandemic response in the UK’.
Estimates of regional infectivity of COVID-19 in the United Kingdom following imposition of social distancing measures
Authors: Challen Robert , Tsaneva-Atanasova Krasimira , Pitt Martin , Edwards Tom , Gompels Luke , Lacasa Lucas , Brooks-Pollock Ellen , Danon Leon 
Published: May 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reproduction number has become an essential parameter for monitoring disease transmission across settings and guiding interventions. The UK published weekly estimates of the reproduction number in the UK starting in May 2020 which are formed from multiple independent estimates. In this paper, we describe methods used to estimate the time-varying SARS-CoV-2 reproduction number for the UK. We used multiple data sources and estimated a serial interval distribution from published studies. We describe regional variability and how estimates evolved during the early phases of the outbreak, until the relaxing of social distancing measures began to be introduced in early July. Our analysis is able to guide localized control and provides a longitudinal example of applying these methods over long timescales.
This article is part of the theme issue ‘Modelling that shaped the early COVID-19 pandemic response in the UK'.
Ultra-rare and common genetic variant analysis converge to implicate negative selection and neuronal processes in the aetiology of schizophrenia
Authors: Akingbuwa Wonuola A , Hammerschlag Anke R , Bartels Meike , Nivard Michel G , Middeldorp Christel M 
Published: May 2021

ABSTRACTBoth common and rare genetic variants (minor allele frequency > 1% and < 0.1% respectively) have been implicated in the aetiology of schizophrenia. In this study, we integrate single-cell gene expression data with publicly available Genome-Wide Association Study (GWAS) and exome sequenced data in order to investigate in parallel, the enrichment of common and (ultra-)rare variants related to schizophrenia in several functionally relevant gene-sets. Four types of gene-sets were constructed 1) protein-truncating variant (PTV)-intolerant (PI) genes 2) genes expressed in brain cell types and neurons ascertained from mouse and human brain tissue 3) genes defined by synaptic function and location and 4) intersection genes, i.e., PI genes that are expressed in the human and mouse brain cell gene-sets. We show that common as well as ultra-rare schizophrenia-associated variants are overrepresented in PI genes, in excitatory neurons from the prefrontal cortex and hippocampus, medium spiny neurons, and genes enriched for synaptic processes. We also observed stronger enrichment in the intersection genes. Our findings suggest that across the allele frequency spectrum, genes and genetic variants likely to be under stringent selection, and those expressed in particular brain cell types, are involved in the same biological pathways influencing the risk for schizophrenia.