bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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.
Safety and tolerability of lumateperone for the treatment of schizophrenia: a pooled analysis of late-phase placebo- and active-controlled clinical trials
Authors: Kane John M , Durgam Suresh , Satlin Andrew , Vanover Kimberly E , Chen Richard , Davis Robert , Mates Sharon
Published: May 2021

Lumateperone, an antipsychotic that is US Food and Drug Administration-approved for the treatment of schizophrenia, has a novel mechanism of action that may confer beneficial effects with improved tolerability. This pooled analysis of three randomized, double-blind, placebo-controlled trials was conducted to evaluate the safety and tolerability of lumateperone 42 mg. The pooled population comprised 1073 patients with an acute exacerbation of schizophrenia randomized to placebo (n = 412), lumateperone 42 mg (n = 406) or risperidone 4 mg (n = 255). Treatment-emergent adverse events (TEAEs) were predominantly mild and rates of discontinuation due to TEAEs with lumateperone 42 mg (0.5%) were similar to placebo (0.5%) and lower than risperidone (4.7%). The only TEAEs that occurred at a rate of ≥5% and twice placebo for lumateperone were somnolence/sedation and dry mouth. Mean change from baseline in metabolic parameters and prolactin were similar to or reduced in lumateperone 42 mg relative to placebo-treated patients and were smaller than risperidone. Mean change in weight and rates of extrapyramidal symptoms-related TEAEs were similar for lumateperone 42 mg and placebo-treated patients and less than for risperidone-treated patients. This pooled analysis demonstrates the safety and favorable tolerability profile of lumateperone 42 mg.
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’.
Challenges in control of COVID-19: short doubling time and long delay to effect of interventions
Authors: Pellis Lorenzo , Scarabel Francesca , Stage Helena B. , Overton Christopher E. , Chappell Lauren H. K. , Fearon Elizabeth , Bennett Emma , Lythgoe Katrina A. , House Thomas A. , Hall Ian ,   University of Manchester COVID-19 Modelling Group
Published: May 2021

Early assessments of the growth rate of COVID-19 were subject to significant uncertainty, as expected with limited data and difficulties in case ascertainment, but as cases were recorded in multiple countries, more robust inferences could be made. Using multiple countries, data streams and methods, we estimated that, when unconstrained, European COVID-19 confirmed cases doubled on average every 3 days (range 2.2–4.3 days) and Italian hospital and intensive care unit admissions every 2–3 days; values that are significantly lower than the 5–7 days dominating the early published literature. Furthermore, we showed that the impact of physical distancing interventions was typically not seen until at least 9 days after implementation, during which time confirmed cases could grow eightfold. We argue that such temporal patterns are more critical than precise estimates of the time-insensitive basic reproduction number
R
0
for initiating interventions, and that the combination of fast growth and long detection delays explains the struggle in countries' outbreak response better than large values of
R
0
alone. One year on from first reporting these results, reproduction numbers continue to dominate the media and public discourse, but robust estimates of unconstrained growth remain essential for planning worst-case scenarios, and detection delays are still key in informing the relaxation and re-implementation of interventions.

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

Both 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.
Improvements in clinical signs of Parkinson’s disease using photobiomodulation: A prospective proof-of-concept study
Authors: Liebert Ann , Bicknell Brian , Laakso E-Liisa , Heller Gillian , Jalilitabaei Parastoo , Tilley Sharon , Mitrofanis John , Kiat Hosen
Published: May 2021

BACKGROUND

Parkinson’s disease (PD) is a progressive neurodegenerative disease with no cure and few treatment options. Its incidence is increasing due to aging populations, longer disease duration and potentially as a COVID-19 sequela. Photobiomodulation (PBM) has been successfully used in animal models to reduce the signs of PD and to protect dopaminergic neurons.

OBJECTIVE

To assess the effectiveness of PBM to mitigate clinical signs of PD in a prospective proof-of-concept study, using a combination of transcranial and remote treatment, in order to inform on best practice for a larger randomized placebo-controlled trial (RCT).

METHODS

Twelve participants with idiopathic PD were recruited. Six were randomly chosen to begin 12 weeks of transcranial, intranasal, neck and abdominal PBM. The remaining 6 were waitlisted for 14 weeks before commencing treatment. After the 12-week treatment period, all participants were supplied with PBM devices to continue home treatment. Participants were assessed for mobility, fine motor skills, balance and cognition before treatment began, after 4 weeks of treatment, after 12 weeks of treatment and the end of the home treatment period. A Wilcoxon Signed Ranks test was used to assess treatment effectiveness at a significance level of 5%.

RESULTS

Measures of mobility, cognition, dynamic balance and fine motor skill were significantly improved (p<0.05) with PBM treatment for 12 weeks and up to one year. Many individual improvements were above the minimal clinically important difference, the threshold judged to be meaningful for participants. Individual improvements varied but many continued for up to one year with sustained home treatment. There was a demonstrable Hawthorne Effect that was below the treatment effect. No side effects of the treatment were observed.

CONCLUSIONS

PBM was shown to be a safe and potentially effective treatment for a range of clinical signs and symptoms of PD. Improvements were maintained for as long as treatment continued, for up to one year in a neurodegenerative disease where decline is typically expected. Home treatment of PD by the person themselves or with the help of a carer might be an effective therapy option. The results of this study indicate that a large RCT is warranted.

TRIAL REGISTRATION

Australian New Zealand Clinical Trials Registry, registration number: ACTRN12618000038291p, registered on 12/01/2018
Psychometric properties of the Sleep Hygiene Index in a large Italian community sample
Authors: Zagaria Andrea , Ballesio Andrea , Musetti Alessandro , Lenzo Vittorio , Quattropani Maria C. , Borghi Lidia , Margherita Giorgia , Saita Emanuela , Castelnuovo Gianluca , Filosa Maria , Palagini Laura , Plazzi Giuseppe , Lombardo Caterina , Franceschini Christian
Published: May 2021

Objective/Background

Poor sleep hygiene is considered an exacerbating and perpetuating factor of sleep disturbances and is also associated with poor mental health. The Sleep Hygiene Index (SHI) is a self-report measure assessing adherence to sleep hygiene practices. The aim of this study was to estimate the psychometric properties of the SHI in an Italian representative sample of the general population, following a formative measurement approach.

Patients/Methods

Participants (n=6276; M=33.62, SD=13.45) completed the SHI alongside measures of sleep disturbance, depression, anxiety, and stress. To consider the item formative nature, sets of item-composites weighted by means of canonical correlation analysis was created and a confirmatory factor analysis (CFA) was implemented. Factorial invariance tests were computed considering both presence of sleep problems and presence of emotional distress symptoms as grouping variables.

Results and Conclusions

CFA confirmed the unidimensional structure of SHI. Internal consistency was acceptable (ω=0.752). Test-retest reliability at 8-10 months presented an ICC of 0.666. SHI significantly correlated with sleep, depression, anxiety and stress symptoms (r range from 0.358 to 0.500). Configural and metric invariance were reached for both grouping variables. Partial scalar invariance was obtained only across emotional distress groups. People with emotional symptoms reported higher latent means on the sleep hygiene dimension. Findings support the validity and reliability of the Italian version of the SHI. Importantly, the SHI showed robust psychometric properties both in healthy individuals and in individual reporting mental health symptoms. Thus, it is advisable to use this version of the SHI in both research and clinical practice.
A Study On Clinical Profile And Semiology In Complex Partial Seizures And Its Radiological Correlation
Authors: Nandini Priyanka B. , Elongovan S. , Thangaraj M.
Published: May 2021

Background

Epilepsy is the second most common and frequently encountered neurological disorder which poses huge threat to known healthcare systems worldwide also causing financial, socio economic burden to the community. Complex Partial Seizures are a form of focal epileptic seizures that may impair consciousness.

Aim and objectives

Our motivation for the study was to understand the extent of patients with complex partial seizures associated with medial temporal lobe sclerosis.

Materials and methods

We performed a cross sectional study about patients with complex partial seizures in Thanjavur medical college and hospital about their clinical profile and neuro-radiological correlation.

Statistical analysis and results

Through our multimodal study with EEG, MRI on N=118 (female / male, age range, Most common age group-10-20 years, mean age of 23 years, SD-14 years, 66% males), we observed that atypical febrile seizures and fever provoked seizures has more association (18%) to complex partial seizures and to medial temporal lobe sclerosis in comparison to 12% in an earlier study.

Conclusion

We believe this study summarizes the complex partial seizure features, origin, and their link to Medial Temporal lobe Sclerosis in our subject pool from Thajavur, India.

Limitation

There are some limitations to our study, especially with no video EEG monitoring and no invasive EEG recording. We aim to improve them in our future studies.
Spatially refined time-varying reproduction numbers of SARS-CoV-2 in Arkansas and Kentucky and their relationship to population size and public health policy, March – November, 2020
Authors: Politis Maria D. , Hua Xinyi , Ogwara Chigozie A. , Davies Margaret R. , Adebile Temitayo M. , Sherman Maya P. , Zhou Xiaolu , Chowell Gerardo , Spaulding Anne C. , Fung Isaac Chun-Hai
Published: May 2021

Purpose

To examine the time-varying reproduction number, Rt, for COVID-19 in Arkansas and Kentucky and investigate the impact of policies and preventative measures on the variability in Rt.

Methods

Arkansas and Kentucky county-level COVID-19 cumulative case count data (March 6-November 7, 2020) were obtained. Rt was estimated using the R package ‘EpiEstim’, by county, region (Delta, non-Delta, Appalachian, non-Appalachian), and policy measures.

Results

The Rt was initially high, falling below 1 in May or June depending on the region, before stabilizing around 1 in the later months. The median Rt for Arkansas and Kentucky at the end of the study were 1.15 (95% credible interval [CrI], 1.13, 1.18) and 1.10 (95% CrI, 1.08, 1.12), respectively, and remained above 1 for the non-Appalachian region. Rt decreased when facial coverings were mandated, changing by -10.64% (95% CrI, -10.60%, -10.70%) in Arkansas and -5.93% (95% CrI, -4.31%, -7.65%) in Kentucky. The trends in Rt estimates were mostly associated with the implementation and relaxation of social distancing measures.

Conclusions

Arkansas and Kentucky maintained a median Rt above 1 during the entire study period. Changes in Rt estimates allows quantitative estimates of potential impact of policies such as facemask mandate.
A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank
Authors: Park Joseph , Packard Elizabeth A , Levin Michael G , Judy Renae L ,   Regeneron Genetics Center, Damrauer Scott M , Day Sharlene M , Ritchie Marylyn D , Rader Daniel J
Published: May 2021

‘Genome-first’ approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into ‘gene burdens’ for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these ‘positive control’ genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41,759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.
Impact of Sepsis Identification and Treatment Time on In-Hospital Mortality, Length of Stay, and Hours in the Intensive Care Unit
Authors: Sudat Sylvia EK
Published: May 2021

Objective

The objective of this study was to examine the impact of timely treatment and identification of sepsis on patient outcomes at Sutter Health, a mixed-payer healthcare system in northern California, US.

Methods

This observational, retrospective analysis considered electronic health record (EHR) data for individuals who presented with sepsis during 2016-17 at any of Sutter Health’s 22 emergency departments (ED). Impacts were assessed for the timing of broad-spectrum antibiotic and intravenous (IV) fluid initiation, first vital signs, sepsis screening, and lactate results. Outcomes were in-hospital mortality, hospital length of stay (LOS) and intensive care unit (ICU) hours for patients discharged alive.

Results

The final sample size was 35,847 (N=9,638 severe sepsis, N=5,309 septic shock). Early fluid initiation had the largest estimated impacts: a mortality reduction of 2.85%[2.03%,3.68%] overall and 2.94%[1.44%,4.48%] for severe sepsis (within 1 hour of sepsis presentation), and 14.66%[9.23%,20.07%] for septic shock (within 3 hours); reduced LOS (days) 1.39[1.08,1.71] overall, 2.30[1.31,3.21] severe sepsis, 3.07[1.21,4.94] septic shock; and fewer ICU hours 25.93[16.95,34.66] overall, 35.06[14.7,56.99] severe sepsis, 41.99[15.70,70.68] septic shock (within 3 hours). Sepsis screening within 30 minutes was also associated with mortality reductions (3.88%[2.96%,4.90%] overall, 1.74%[0.08%,3.50%] severe sepsis, 6.78%[3.12%,10.33%] septic shock). The greatest improvement opportunity was estimated for joint initiation of antibiotics and IV fluids, with a modest additional mortality reduction of 0.80%[0.47%,1.17%] overall, 0.77%[0.34%,1.19%] severe sepsis, 2.94%[1.83%,3.97%] septic shock; LOS reduction of 0.37[0.28,0.46] overall, 0.29[0.17,0.43] severe sepsis, 0.25[0.01,0.51] septic shock (within 1 hour); ICU hours reduction of 4.85[3.26,6.57] overall, 5.07[2.55,7.67] severe sepsis, 3.85[1.69,6.24] septic shock (within 3 hours).
Ileal derived organoids from Crohn’s disease patients show unique transcriptomic and secretomic signatures
Authors: Niklinska-Schirtz Barbara Joanna , Venkateswaran Suresh , Anbazhagan Murugadas , Kolachala Vasantha L , Prince Jarod , Dodd Anne , Chinnadurai Raghavan , Gibson Gregory , Denson Lee A. , Cutler David J. , Jegga Anil G. , Matthews Jason D. , Kugathasan Subra
Published: May 2021

Background

We used patient derived organoids (PDOs) to study the epithelial-specific transcriptional and secretome signatures of the ileum during CD with varying phenotypes to screen for disease profiles and potential druggable targets.

Methods

RNA sequencing was performed on isolated intestinal crypts and 3-week-old PDOs derived from ileal biopsies of CD patients (n= 8 B1, inflammatory; n= 8 B2, stricturing disease) and non-IBD controls (n= 13). Differentially expressed (DE) genes were identified by comparing CD vs control, B1 vs B2, and inflamed vs non-inflamed. DE genes were used for computational screening to find candidate small molecules that could potentially reverse B1and B2 gene signatures. The secretome of a second cohort (n= 6 non-IBD controls, n=7 CD; 5 non-inflamed, 2 inflamed) was tested by Luminex using cultured organoid conditioned media.

Results

We found a 90% similarity in both the identity and abundance of protein coding genes between PDOs and intestinal crypts (15,554 transcripts of 19,900 genes). DE analysis identified 814 genes among disease group (CD vs non-IBD control), 470 genes different between the CD phenotypes, and 5 FDR significant genes between inflamed and non-inflamed CD. The PDOs showed both similarity and diversity in the levels and types of soluble cytokines and growth factors they released. Perturbagen analysis revealed potential candidate compounds to reverse B2 disease phenotype to B1 in PDOs.

Conclusion

PDOs are similar at the transcriptome level with the in vivo epithelium and retain disease-specific gene expression for which we have identified secretome products, druggable targets and corresponding pharmacological agents. Targeting the epithelium could reverse a stricturing phenotype and improve outcomes.
PONT: A Protocol for Online Neuropsychological Testing
Authors: Saban William , Ivry Richard B.
Published: May 2021

A major challenge for neuropsychological research arises from the fact that we are dealing with a limited resource: The patients. Not only is it difficult to identify and recruit these individuals, but their ability to participate in research projects can be limited by their medical condition. As such, sample sizes are small and considerable time (e.g., 2 yrs) is required to complete a study. To address limitations inherent to lab-based neuropsychological research, we developed a protocol for online neuropsychological testing (PONT). We describe the implementation of PONT and provide the required information and materials for recruiting participants, conducting remote neurological evaluations, and testing patients in an automated, self-administered manner. The protocol can be easily tailored to target a broad range of patient groups, especially those that can be contacted via support groups or multi-site collaborations. To highlight the operation of PONT and describe some of the unique challenges that arise in on-line neuropsychological research, we summarize our experience using PONT in a research program involving individuals with Parkinson’s disease and spinocerebellar ataxia. In a 10-month period, by contacting 646 support group coordinators, we were able to assemble a participant pool with over 100 patients in each group from across the United States. Moreover, we completed six experiments (n>300) exploring their performance on a range of tasks examining motor and cognitive abilities. The efficiency of PONT in terms of data collection, combined with the convenience it offers the participants, promises a new approach that can increase the impact of neuropsychological research.
In-field genetic stock identification of overwintering coho salmon in the Gulf of Alaska: Evaluation of Nanopore sequencing for remote real-time deployment
Authors: Deeg Christoph M. , Sutherland Ben J. G. , Ming Tobi J. , Wallace Colin , Jonsen Kim , Flynn Kelsey L. , Rondeau Eric B. , Beacham Terry D. , Miller Kristina M.
Published: May 2021

Genetic stock identification (GSI) by single nucleotide polymorphism (SNP) sequencing has become the gold standard for stock identification in Pacific salmon, which are found in mixed-stocks during the oceanic phase of their lifecycle. Sequencing platforms currently applied require large batch sizes and multi-day processing in specialized facilities to perform genotyping by the thousands. However, recent advances in third-generation single-molecule sequencing platforms, like the Oxford Nanopore minION, provide base calling on portable, pocket-sized sequencers and hold promise for the application of real-time, in-field stock identification on variable batch sizes. Here we report and evaluate utility and comparability of at-sea stock identification of coho salmon Oncorhynchus kisutch based on targeted SNP amplicon sequencing on the minION platform during the International Year of the Salmon Signature Expedition to the Gulf of Alaska in the winter of 2019. Long read sequencers are not optimized for short amplicons, therefore we concatenate amplicons to increase coverage and throughput. Nanopore sequencing at-sea yielded stock assignment for 50 of the 80 assessed individuals. Nanopore-based SNP calls agreed with Ion Torrent based genotypes in 83.25%, but assignment of individuals to stock of origin only agreed in 61.5% of individuals highlighting inherent challenges of Nanopore sequencing, such as resolution of homopolymer tracts and indels. However, poor representation of assayed coho salmon in the queried baseline dataset contributed to poor assignment confidence on both platforms. Future improvements will focus on lowering turnaround time, accuracy, throughput, and cost, as well as augmentation of the existing baselines, specifically in stocks from coastal northern BC and Alaska. If successfully implemented, Nanopore sequencing will provide an alternative method to the large-scale laboratory approach. Genotyping by amplicon sequencing in the hands of diverse stakeholders could inform management decisions over a broad expanse of the coast by allowing the analysis of small batches in remote areas in near real-time.
Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 and Spike Protein Subunit 1
Authors: Cory Theodore J. , Emmons Russell S. , Yarbro Johnathan R. , Davis Kierstin L. , Pence Brandt D.
Published: May 2021

A hallmark of COVID-19 is a hyperinflammatory state that is associated with severity. Various anti-inflammatory therapeutics have shown mixed efficacy in treating COVID-19, and the mechanisms by which hyperinflammation occurs are not well understood. Previous research indicated that monocytes, a key innate immune cell, undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response in monocytes. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism that was associated with production of pro-inflammatory cytokines including interleukin-6 and tumor necrosis factor-α. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production in monocytes, and abrogated glycolytic and mitochondrial metabolism. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments in monocytes. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.
Long-term repair of porcine articular cartilage using cryopreservable, clinically compatible human embryonic stem cell-derived chondrocytes
Authors: Petrigliano Frank A. , Liu Nancy Q. , Lee Siyoung , Tassey Jade , Sarkar Arijita , Lin Yucheng , Li Liangliang , Yu Yifan , Geng Dawei , Zhang Jiankang , Shkhyan Ruzanna , Bogdanov Jacob , Van Handel Ben , Ferguson Gabriel B. , Lee Youngjoo , Hinderer Svenja , Tseng Kuo-Chang , Kavanaugh Aaron , Crump J. Gage , Pyle April D. , Schenke-Layland Katja , Billi Fabrizio , Wang Liming , Lieberman Jay , Hurtig Mark , Evseenko Denis
Published: May 2021

Osteoarthritis (OA) impacts hundreds of millions of people worldwide, with those affected incurring significant physical and financial burdens. Injuries such as focal defects to the articular surface are a major contributing risk factor for the development of OA. Current cartilage repair strategies are moderately effective at reducing pain but often replace damaged tissue with biomechanically inferior fibrocartilage. Here we describe the development, transcriptomic ontogenetic characterization and quality assessment at the single cell level, as well as the scaled manufacturing of an allogeneic human pluripotent stem cell-derived articular chondrocyte formulation that exhibits long-term functional repair of porcine articular cartilage. These results define a new potential clinical paradigm for articular cartilage repair and mitigation of the associated risk of OA.
Machine learning prediction of cognition from functional connectivity: Are feature weights reliable?
Authors: Tian Ye , Zalesky Andrew
Published: May 2021

Cognitive performance can be predicted from an individual’s functional brain connectivity with modest accuracy using machine learning approaches. As yet, however, predictive models have arguably yielded limited insight into the neurobiological processes supporting cognition. To do so, feature selection and feature weight estimation need to be reliable to ensure that important connections and circuits with high predictive utility can be reliably identified. We comprehensively investigate feature weight test-retest reliability for various predictive models of cognitive performance built from resting-state functional connectivity networks in healthy young adults (n=400). Despite achieving modest prediction accuracies (r=0.2-0.4), we find that feature weight reliability is generally poor for all predictive models (ICC<0.3), and significantly poorer than predictive models for overt biological attributes such as sex (ICC ≈ 0.5). Larger sample sizes (n=800), the Haufe transformation, non-sparse feature selection/regularization and smaller feature spaces marginally improve reliability (ICC<0.4). We elucidate a tradeoff between feature weight reliability and prediction accuracy and find that univariate statistics are marginally more reliable than feature weights from predictive models. Finally, we show that measuring agreement in feature weights between cross-validation folds provides inflated estimates of feature weight reliability. We thus recommend for reliability to be estimated out-of-sample, if possible. We argue that rebalancing focus from prediction accuracy to model reliability may facilitate mechanistic understanding of cognition with machine learning approaches.
Cysteine Mutants of the Major Facilitator Superfamily-Type Transporter CcoA Provide insight into Copper Import
Authors: Khalfaoui-Hassani Bahia , Trasnea Petru-Iulian , Steimle Stefan , Koch Hans-Georg , Daldal Fevzi
Published: May 2021

CcoA belongs to the widely distributed bacterial copper (Cu) importer subfamily CalT (CcoA-like Transporters) of the Major Facilitator Superfamily (MFS), and provides cytoplasmic Cu needed for cbb3-type cytochrome c oxidase (cbb3-Cox) biogenesis. Earlier studies have supported a 12 transmembrane helices (TMH) topology of CcoA with the well-conserved Met233xxxMet237 and His261xxxMet265 motifs in its TMH7 and TMH8, respectively. Of these residues, Met233 and His261 are essential for Cu uptake and cbb3-Cox production, whereas Met237 and Met265 contribute partly to these processes. CcoA also contains five Cys residues of unknown role, and remarkably, its structural models predict that three of these are exposed to the highly oxidizing periplasm. Here, we first demonstrate that elimination of both Met237 and Met265 completely abolishes Cu uptake and cbb3-Cox production, indicating that CcoA requires at least one of these two Met residues for activity. Second, using scanning mutagenesis to probe plausible metal-interacting Met, His and Cys residues of CcoA we found that the periplasm-exposed Cys49 located at the end of TMH2, the Cys247 on a surface loop between TMH7 and THM8, and the C367 located at the end of TMH11 are important for CcoA function. Analyses of the single and double Cys mutants revealed the occurrence of a disulfide bond in CcoA in vivo, possibly related to conformational changes it undergoes during Cu import as MFS-type transporter. Our overall findings suggested a model linking Cu import for cbb3-Cox biogenesis with a thiol: disulfide oxidoreduction step, advancing our understanding of the mechanisms of CcoA function.

Importance

Copper (Cu) is a redox-active micronutrient that is both essential and toxic. Its cellular homeostasis is critical for supporting cuproprotein maturation while avoiding excessive oxidative stress. The Cu importer CcoA is the prototype of the widespread CalT subfamily of the MFS-type transporters. Hence, understanding its molecular mechanism of function is significant. Here we show that CcoA undergoes a thiol: disulfide oxidoreduction cycle, which is important for its Cu import activity.
Antibody Response to CoronaVac Vaccine in Indonesian COVID-19 Survivor
Authors: Kemal Rahmat Azhari , Sari Dita Kartika , Paulina Ariza Julia
Published: May 2021

Several studies have shown that individuals with previous history of SARS-CoV-2 infection had boosted antibody response after single dose of mRNA or adenovirus-vectored vaccines. We wondered whether single dose CoronaVac, a whole-inactivated vaccine, could be considered for COVID-19 survivors in Indonesia. We measured IgG anti-RBD titre among 18 survivors and 37 non-survivors. Among survivors, there were 9 survivors with positive antibody titre (seropositive) before vaccination and 9 seronegative survivors. All respondents received two doses of CoronaVac vaccine at 14-days interval. We found no significant antibody titre difference between non-survivor at 14 or 28 days after second dose as well as seronegative survivor at at 14 days after second dose. Seropositive survivors were rapidly boosted after first dose with higher antibody titer than non-survivors and seronegative survivors after second dose. However, antibody titer did not differ between first and second dose among seropositive survivors. Seropositive COVID-19 survivors could receive single dose of CoronaVac vaccine which could potentially ease the vaccine supply constrain. A long-term follow-up must be conducted to observe difference in antibody response and persistence.

Article Summary Line

Seropositive COVID-19 survivors had significantly higher antibody response after first dose of CoronaVac vaccine compared to non-survivors and seronegative survivors after second dose of vaccine.
Fear, Anxiety, Stress, and Depression of novel coronavirus (COVID-19) pandemic among patients and their healthcare workers
Authors: Parchani Ashwin , Vidhya K , Panda Prasan Kumar , Rawat Vikram Singh , Bahurupi Yogesh Arvind , Kalita Deepjyoti , Kumar Harsh , Dr Naveen
Published: May 2021

Background

Disease pandemics are known to cause psychological distress. The ensuing mental health issues are not only restricted to the patients and their relatives/friends but affect the healthcare workers (HCWs) as well. Our study aims to assess these psychological trends during the COVID-19 pandemic between the two most affected population groups, that is, patients and frontline healthcare workers.

Methods

A survey questionnaire including scales to assess fear, anxiety, stress, depression - PSS 10, and DASS 21 was distributed and sent to all COVID-19 suspected/confirmed individuals and healthcare workers at a tertiary care center along with a second visit after 14 days of answering the first questionnaire and this continued as follow up. Data were analyzed with the SPSS Version 23 using various tests of significance.

Results

In the community, COVID-19 patients in the age group 41-50 with respiratory tract symptoms and those who were home isolated/quarantined experienced a greater tendency of mental health problems. Healthcare workers posted in COVID-19 designated areas of the hospital displayed higher levels of stress, anxiety, and depression.

Conclusion

The high degree of uncertainty associated with novel pathogens has a profound effect on the psychological state of suspected/confirmed cases as well as healthcare workers. Within the community, individuals suspected of having COVID-19 display a significant mental health burden, while HCWs also experience an unprecedented amount of stress during such enduring situations.

Key points

Question

What is the psychological impact among patients and their healthcare workers during the COVID-19 pandemic?

Findings

In this observational study based on PSS 10 and DASS 21 questionnaire that included 156 patients and 226 health care workers, the patients in the age group 41-50 with respiratory tract symptoms and those who were home isolated/quarantined experienced a greater tendency of mental health problems. Similar burden was observed among health care workers.

Meaning

In a COVID-19 pandemic both population groups displayed higher levels of fear, anxiety, stress, and depression.