bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of copper-induced protein precipitation across the E. coli proteome
Authors: Robison Amy T R , Sturrock Grace R , Zaengle-Barone Jacqueline M , Wiebelhaus Nancy , Dharani Azim , Williams Isabella G , Fitzgerald Michael C , Franz Katherine J
Published: December 2022

Metal cations have been exploited for their precipitation properties in a wide variety of studies, ranging from differentiating proteins from serum and blood to identifying the protein targets of drugs. Despite widespread recognition of this phenomenon, the mechanisms of metal-induced protein aggregation have not been fully elucidated. Recent studies have suggested that copper's (Cu) ability to induce protein aggregation may be a main contributor to Cu-induced cell death. Here, we provide the first proteome-wide analysis of the relative sensitivities of proteins across the Escherichia coli proteome to Cu-induced aggregation. We utilize a metal-induced protein precipitation (MiPP) methodology that relies on quantitative bottom–up proteomics to define the metal concentration–dependent precipitation properties of proteins on a proteomic scale. Our results establish that Cu far surpasses other metals in promoting protein aggregation and that the protein aggregation is reversible upon metal chelation. The bulk of the Cu bound in the protein aggregates is Cu1+, regardless of the Cu2+ source. Analysis of our MiPP data allows us to investigate underlying biophysical characteristics that determine a protein's sensitivity to Cu-induced aggregation, which is independent of the relative concentration of protein in the lysate. Overall, this analysis provides new insights into the mechanism behind Cu cytotoxicity, as well as metal cation–induced protein aggregation.
Clustering analysis identifies two subgroups of women with fibromyalgia with different psychological, cognitive, health-related, and physical features but similar widespread pressure pain sensitivity
Authors: Fernández-de-las-Peñas César , Valera-Calero Juan Antonio , Arendt-Nielsen Lars , Martín-Guerrero José D , Cigarán-Méndez Margarita , Navarro-Pardo Esperanza , Pellicer-Valero Oscar J
Published: December 2022

Objective

Given that identification of groups of patients can help to better understand risk factors related to each group and to improve personalized therapeutic strategies, this study aimed to identify subgroups (clusters) of women with fibromyalgia syndrome (FMS) according to pain, pain-related disability, neurophysiological, cognitive, health, psychological, or physical features.

Methods

Demographic, pain, sensory, pain-related disability, psychological, health, cognitive, and physical variables were collected in 113 women with FMS. Widespread pressure pain thresholds were also assessed. K-means clustering was used to identify groups of women without any previous assumption.

Results

Two clusters exhibiting similar widespread sensitivity to pressure pain (pressure pain thresholds) but differing in the remaining variables were identified. Overall, women in one cluster exhibited higher pain intensity and pain-related disability; more sensitization-associated and neuropathic pain symptoms; higher kinesiophobia, hypervigilance, and catastrophism levels; worse sleep quality; higher anxiety/depressive levels; lower health-related function; and worse physical function than women in the other cluster.

Conclusions

Cluster analysis identified one group of women with FMS exhibiting worse sensory, psychological, cognitive, and health-related features. Widespread sensitivity to pressure pain seems to be a common feature of FMS. The present results suggest that this group of women with FMS might need to be treated differently.
Rationality is Not Coherence
Authors: Heinzelmann Nora
Published: December 2022

According to a popular account, rationality is a kind of coherence of an agent’s mental states and, more specifically, a matter of fulfilling norms of coherence. For example, in order to be rational, an agent is required to intend to do what they judge they ought to and can do. This norm has been called ‘Enkrasia’. Another norm requires that, ceteris paribus, an agent retain their intention over time. This has been called ‘Persistence of Intention’. This paper argues that thus understood norms of rationality may at times conflict. More specifically, Enkrasia and Persistence of Intention may place demands on the agent that are impossible to fulfil. In these cases, the framework of requirements does not provide us with norms that make us rational. A rival account, according to which rationality is a kind of responsiveness to one’s available reasons, can overcome the problem.
Incidence of septic arthritis in patients with ankylosing spondylitis and seropositive rheumatoid arthritis following TNF inhibitor therapy
Authors: Kim Hyung Woo , Han Minkyung , Jung Inkyung , Ahn Sung Soo
Published: December 2022

Objectives

Septic arthritis (SA) is a serious complication occurring in the joints, and its risk increases with immunosuppressive therapy. This study investigated whether TNF inhibitors increase the risk of SA in patients with AS and seropositive RA (SPRA).

Methods

We searched the South Korean Health Insurance Review and Assessment Service database for incident cases of AS and SPRA between 2010 and 2020. SA was defined using the diagnostic code M00 and hospital admission. Cox-proportional hazards analysis was conducted to compare the incidence of SA according to TNF inhibitor (infliximab, etanercept, adalimumab/golimumab) use during follow-up.

Results

Of the 145 129 patients analysed, 1170 (0.8%) developed SA during the follow-up period. Older age; male sex; SPRA diagnosis; comorbidities of hypertension (HTN), diabetes mellitus (DM) and chronic pulmonary disease (CPD); and infliximab and etanercept use increased the incidence of SA in the overall population. However, in patients with AS, only age and renal disease were predictors of SA, and TNF inhibitors did not increase the incidence of SA. Meanwhile, patients with SPRA treated with TNF inhibitors were prone to SA regardless of TNF inhibitor type, and age, HTN, DM and CPD were associated with SA. The incidence of SA was prominent after the first year of commencing TNF inhibitor therapy, for both AS and SPRA.

Conclusion

TNF inhibitors increase the incidence of SA, specifically in patients with SPRA, but not AS. Importantly, age, comorbidities and the early time period after starting TNF inhibitors were associated with SA, which should be considered simultaneously when initiating TNF inhibitor therapy.
Methadone Induction for a Patient With Precipitated Withdrawal in the Emergency Department: A Case Report
Authors: Church Benjamin , Clark Ryan , Mohn William , Potee Ruth , Friedmann Peter , Soares William E.
Published: December 2022

In the era of illicit fentanyl, reports on difficulties with buprenorphine inductions for patients with opioid use disorder are emerging. Methadone is the only other approved medication treatment with efficacy similar to buprenorphine but without risks of precipitated withdrawal. Unfortunately, outpatient methadone inductions can take days to weeks to complete, due in part to regulations that limit administration to opioid treatment programs. We describe a patient with opioid use disorder who presented to the emergency department in precipitated withdrawal who completed a same-day methadone induction with next-day dosing at an opioid treatment program as part of an emergency department methadone protocol. As opioid-related deaths rise, emergency department–initiated methadone is feasible for patients with opioid use disorder.
Difference between affected and unaffected sides of forearm bone length in children with congenital terminal transverse deficiencies at the level of carpal bone
Authors: Nishizaka Chika , Fujiwara Sayaka , Mano Hiroshi , Haga Nobuhiko
Published: December 2022

The forearm of the affected sideis often shorter than that of the unaffected side in children with congenital terminal transverse deficiencies at the level of proximal or distal carpals. The aim of this study is to clarify the characteristics of forearm bone length in those children, especially to quantify the difference in forearm bone length between affected and unaffected sides. The subjects were children with carpal partial transverse deficiencies. The lengths of the radius and the ulna were measured in the radiographs. The lengths of affected and unaffected sides (A/U) were compared in order to quantify the discrepancy. The A/U ratio was defined as the length of the affected side divided by that of the unaffected side. The A/U ratios ranged from 77.1 to 99.0% in the radii and from 74.1 to 99.6% in the ulnae. In both the radius and ulna, the A/U ratios were significantly lower than the left/right ratios of normal adults. Additionally, the A/U ratios of the ulna were significantly lower than the A/U ratios of the radius. The forearm bones of affected side are significantly shorter than those of unaffected side. Although the cause remains unclear, it is possible that not only congenital factors but also acquired factors such as infrequent use of the affected upper limb are involved. A future longitudinal study is necessary to investigate whether length discrepancies can be reduced by using prostheses to increase the frequency of use on the affected limb.
Do All Pediatric Femoral Shaft Fractures Need a Computed Tomography Scan of the Ipsilateral Femoral Neck? Calculating the Incidence of Concomitant Femoral Neck and Shaft Fractures
Authors: Pradhan Pratik , Townsend Tracy K. , Cook Danielle , Feldman Lanna , Canizares Maria Fernanda , Watkins Colyn , Shore Benjamin J.
Published: December 2022

Background:

In adults, the incidence of ipsilateral femoral neck fractures in the setting of femoral shaft fractures is reported to be as high as 9%; however, scant literature exists on the same clinical scenario in pediatric/adolescent populations. Therefore, the purpose of this study was to investigate the incidence of ipsilateral femoral neck fracture in the setting of femoral shaft fractures in children and adolescents treated in pediatric hospitals across the United States.

Methods:

The Pediatric Health Information System database was queried for patients aged 18 years or younger who were treated for a femoral neck, femoral shaft, and pertrochanteric femur fractures through an emergency department, inpatient, ambulatory surgery, or observation visit. Patients were identified using ICD-9 and ICD-10 diagnosis codes. Data from 49 pediatric hospitals between the years 2002 and 2020 were included. Incidence was calculated as the number of cases including the event divided by the total number of cases.

Results:

A total of 90,146 records were identified from a cohort of 55,733,855 (0.16%). Distal femur fractures, pathologic fractures, and periprosthetic fractures were excluded, resulting in 65,651 unique cases. Of the 65,651 cases, 7104 (11%) were identified as isolated neck fractures. The combined incidence of femoral neck or pertrochanteric femur fractures in the setting of a femoral shaft fracture was 82.3 per 10,000 cases (0.82%). Only 283 cases of concomitant femoral neck and shaft fractures were found among 55,169 femoral shaft fractures (0.5%).

Conclusions:

The incidence of ipsilateral femoral neck or pertrochanteric femur fractures in the setting of a femoral shaft fracture is 82.3 per 10,000 patients (0.82%) based on data from Pediatric Health Information System-participating institutions. The incidence of femoral neck/pertrochanteric femur fractures and femoral shaft fractures in children and adolescents is more than 10 times lower than reported for adults; therefore, the routine use of advanced diagnostic imaging in pediatric patients with femoral shaft fractures should be considered cautiously.

Level of Evidence:

Level IV; cross-sectional analysis.
Vitamin D deficiency in chronic obstructive pulmonary disease
Authors: Mullin Monica L.L. , Milne Stephen
Published: December 2022

Purpose of review

There is biological and epidemiological evidence supporting a role for vitamin D in the respiratory system, and vitamin D deficiency (VDD) may be associated with poor health outcomes in people with chronic obstructive pulmonary disease (COPD). This review summarizes recent findings relevant to the role of vitamin D in COPD.

Recent findings

The prevalence of VDD in people with COPD may be underestimated. Treatment of severe VDD [serum 25(OH)D3 < 10 ng/ml] may reduce the risk of COPD exacerbations. Vitamin D supplementation may also improve functional capacity and quality of life in people with COPD. However, there is no strong evidence that vitamin D supplementation slows the decline in lung function.

Although there are many known associations between vitamin D and COPD outcomes, the causal nature of these associations and the precise benefits of vitamin D supplementation remain unclear. High-quality randomized controlled trials are necessary.
Ethical Considerations Within the ESPGHAN Community
Authors: Crespo‐Escobar Paula , Tapsas Dimitrios , Roggero Paola , Sokal Etienne , Yahav Jacob
Published: December 2022

There are limited data on ethical issues related to the daily practice of members of the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). The role of the ESPGHAN Ethics Committee (EC) is to provide advice on such matters to its members. The present survey aimed to evaluate the current function, and reasons that ESPGHAN members consulted the ECs. One hundred and five participants from 24 different countries answered the questionnaire. Thirty‐five point seven percent of the participants used the ESGHAN EC to ask about clinical practice problems and patient‐related issues whereas 21.4% ask about human research questions. An important additional finding was that 66.3% of respondents consulted their hospital’s EC when they had ethical concerns and 17.4% consulted with other colleagues with expertise. This is the first survey in the ESPGHAN and Europe that analyses ethical issues that are important to members of the National Societies for Pediatric Gastroenterology Hepatology and Nutrition.
First-in-human free-flap tissue reconstruction using a dedicated microsurgical robotic platform
Authors: Innocenti Marco , Malzone Gerardo , Menichini Giulio
Published: December 2022

Background:

Microsurgery has become standard of care for increasingly complex techniques in tissue harvest, replantation, reconstruction, allotransplantation, and supermicrosurgery on submillimetric vessels. As techniques become more and more challenging, and are performed at smaller and smaller scale, there is greater potential application for robotic assistance in extreme motion scaling and tremor reduction.

Methods:

The Symani Surgical System (Medical Microinstruments, S.p.A, Calci, Pisa, Italy), a robotic platform designed for microsurgery, was used in a robotic-assisted microsurgical free-flap reconstruction using a perforator-to-perforator flap technique. This procedure employed robotic-assisted anastomosis of an artery and vein.

Findings:

The procedure was completed successfully, with vessels fully patent immediately following and 20 minutes after anastomosis. The flap was viable, no re-exploration of the anastomosis was necessary postoperatively and no flap loss occurred.

Interpretation:

This novel, dedicated robotic platform with wristed microsurgical instruments was shown to be feasible for carrying out robotic-assisted anastomosis of veins and arteries below 0.8mm in diameter, in the domain of supermicrosurgery. The system has the potential to open the field of microsurgery to new clinicians and to facilitate new microsurgical applications that were previously rendered inaccessible by the limits of manual precision and physiological tremor.

Funding:

The Symani System was loaned to the Plastic, Reconstructive and Microsurgery unit at CTO Careggi University Hospital by MMI SpA, and the necessary robotic instrumentation was provided free of charge for use in this case.
IDENTIFICATION OF SUBPHENOTYPES OF SEPSIS-ASSOCIATED LIVER DYSFUNCTION USING CLUSTER ANALYSIS
Authors: Miao He , Cui Zhigang , Guo Zhaotian , Chen Qianhui , Su Wantin , Sun Yongqiang , Sun Mu , Ma Xiaochun , Ding Renyu
Published: December 2022

Objectives: We attempted to identify and validate the subphenotypes of sepsis-associated liver dysfunction (SALD) using routine clinical information. Design: This article is a retrospective observational cohort study. Setting: We used the Medical Information Mart for Intensive Care IV database and the eICU Collaborative Research Database. Patients: We included adult patients (age ≥18 years) who developed SALD within the first 48 hours of intensive care unit (ICU) admission. We excluded patients who died or were discharged from the ICU within the first 48 hours of admission. Patients with abnormal liver function before ICU admission were also excluded. Measurements and Main Results: Patients in the MIMIC-IV 1.0 database served as a derivation cohort. Patients in the eICU database were used as validation cohort. We identified four subphenotypes of SALD (subphenotype α, β, γ, δ) using K-means cluster analysis in 5234 patients in derivation cohort. The baseline characteristics and clinical outcomes were compared between the phenotypes using one-way analysis of variance/Kruskal-Wallis test and the χ2 test. Moreover, we used line charts to illustrate the trend of liver function parameters over 14 days after ICU admission. Subphenotype α (n = 1,055) was the most severe cluster, characterized by shock with multiple organ dysfunction (MODS) group. Subphenotype β (n = 1,179) had the highest median bilirubin level and the highest proportion of patients with underlying liver disease and coexisting coagulopathy (increased bilirubin group). Subphenotype γ (n = 1,661) was the cluster with the highest mean age and had the highest proportion of patients with chronic kidney disease (aged group). Subphenotype δ (n = 1,683) had the lowest 28-day and in-hospital mortality (mild group). The characteristics of clusters in the validation cohort were similar to those in the derivation cohort. In addition, we were surprised to find that GGT levels in subphenotype δ were significantly higher than in other subphenotypes, showing a different pattern from bilirubin. Conclusions: We identified four subphenotypes of SALD that presented with different clinical features and outcomes. These results can provide a valuable reference for understanding the clinical characteristics and associated outcomes to improve the management of patients with SALD in the ICU.
Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration
Authors: Seddon Johanna M. , Rosner Bernard , De Dikha , Huan Tianxiao , Java Anuja , Atkinson John
Published: December 2022

PURPOSE

To evaluate associations between rare dysfunctional Complement Factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA) and neovascular disease (NV).

DESIGN

Prospective, longitudinal study

PARTICIPANTS

Patients aged 55-80 years at baseline identifying as white with non-advanced AMD in one or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV).CFIvariants were categorized using genotyping and sequencing platforms.

METHODS

Analyses were performed using the Seddon Longitudinal Cohort Study (N = 2116 subjects, 3901 eyes, mean follow-up 8.3 years) and the Age-Related Eye Disease Study (N = 2837 subjects, 5200 eyes, mean follow-up 9.2 years).CFIrare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, demographic, behavioral, and ocular factors were evaluated. Generalized Estimating Equations methods were used to assess the association betweenCFIrare variants and progression, independent of other genetic variants and covariates.

MAIN OUTCOME

Progression to AAMD, GA, or NV.

RESULTS

In the prospective cohort of 4953 subjects (9101 eyes with non-advanced AMD at baseline), 1% were type 1 rareCFIcarriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for non-carriers (P <0.001) while 30% of carriers versus 10% of non-carriers progressed to GA (P < 0.001); 18% of carriers compared to 11% of non-carriers progressed to NV (P = 0.049).CFIcarriers were more likely to have a family history of AMD (P for trend = 0.035) and a higher baseline AMD grade (P<0.001). After adjusting for all covariates,CFIcarrier status was associated with progression to GA (OR = 1.91; 95% CI = 1.03, 3.52) but not NV (OR = 0.96). Higher BMI was associated with progression amongCFIcarriers (BMI ≥25 vs <25; OR = 5.8; 95% CI 1.5, 22.3), but not for non-carriers (OR = 1.1; 95% CI = 0.9, 1.3), with P_interaction = 0.011.

CONCLUSIONS

Results suggest that carriers of rare dysfunctional type 1CFIvariants are at higher risk for progression to AAMD with GA.

PRÉCIS

Rare dysfunctional Complement Factor I (CFI) genetic variants are associated with a family history of AMD and increased risk of progression to advanced dry age-related macular degeneration (AMD) with geographic atrophy.
Deep learning Model for Recognizing Monkey Pox based on Dense net-121 Algorithm
Authors: Torky Mohamed , Bakheit Ali , Bakry Mohamed , Hassanien Aboul Ella
Published: December 2022

While the world is trying to get rid of the Covid 19 pandemic, the beginning of the monkeypox(MPX) pandemic has recently appeared and is threatening many countries of the world. MPX is a rare disease caused by infection with the MPX virus, and it is among the same family of pox viruses. The danger is that MPX causes pustules all over the body, which causes a revolting view to the body regions and works as a source of infection in case of skin contact between individuals. Pustules and rashes are common symptoms of many pox viruses and other skin diseases such as Measles, chicken pox, syphilis, Eczema, etc, Therefore, the medical and clinical diagnosis of monkeypox is one of the great challenges for doctors and specialists. In response to this need, Artificial intelligence can develop aid systems based on machine and deep learning algorithms for diagnosing these types of diseases based on datasets of skin images to those types of diseases. In this paper, a deep learning approach called Dense Net-121model is applied, tested, and compared with the convolution neural network (CNN) model for diagnosing monkeypox through a skin image dataset of MPX and Measles images. The most significant finding to emerge from this study is the superiority of the Dense Net-121 model over CNN in diagnosing MPX cases with a testing accuracy of 93%. These findings suggest a role for using more deep learning algorithms for accurately diagnosing MPX cases with bigger datasets of similar pustules and rashes diseases.
End-to-end protein-ligand complex structure generation with diffusion-based generative models
Authors: Nakata Shuya , Mori Yoshiharu , Tanaka Shigenori
Published: December 2022

Three-dimensional structures of protein-ligand complexes provide valuable insights into their interactions and are crucial for molecular biological studies and drug design. However, their high-dimensional and multimodal nature hinders end-to-end modeling, and earlier approaches depend inherently on existing protein structures. To overcome these limitations and expand the range of complexes that can be accurately modeled, it is necessary to develop efficient end-to-end methods. We introduce an equivariant diffusion-based generative model that learns the joint distribution of ligand and protein conformations conditioned on the molecular graph of a ligand and the sequence representation of a protein extracted from a pre-trained protein language model. Benchmark results show that this protein structure-free model is capable of generating diverse structures of protein-ligand complexes, including those with correct binding poses. Further analyses indicate that the proposed end-to-end approach is particularly effective when the ligand-bound protein structure is not available. The present results demonstrate the effectiveness and generative capability of our end-to-end complex structure modeling framework with diffusion-based generative models. We suppose that this framework will lead to better modeling of protein-ligand complexes, and we expect further improvements and wide applications.
LuxHMM: DNA methylation analysis with genome segmentation via Hidden Markov Model
Authors: Malonzo Maia H. , Lähdesmäki Harri
Published: December 2022

DNA methylation plays an important role in studying the epigenetics of various biological processes including many diseases. Although differential methylation of individual cytosines can be informative, given that methylation of neighboring CpGs are typically correlated, analysis of differentially methylated regions is often of more interest.

We have developed a probabilistic method and software, LuxHMM, that uses hidden Markov model (HMM) to segment the genome into regions and a Bayesian regression model, which allows handling of multiple covariates, to infer differential methylation of regions. Moreover, our model includes experimental parameters that describe the underlying biochemistry in bisulfite sequencing and model inference is done using either variational inference for efficient genome-scale analysis or Hamiltonian Monte Carlo (HMC).

Analyses of real and simulated bisulfite sequencing data demonstrate the competitive performance of LuxHMM compared with other published differential methylation analysis methods.
Genetic Predisposition to High Blood Pressure and Out-of-Office Hypertension: Insights from a Population Sample in Liechtenstein
Authors: Narula Sukrit , Mohammadi-Shemirani Pedrum , Aeschbacher Stefanie , Chong Michael R. , Le Ann , Thériault Sébastien , Grossman Kirsten , Paré Guillaume , Risch Lorenz , Risch Martin , Conen David
Published: December 2022

Genetic predisposition is a risk factor for office hypertension. We tested whether genetic background could identify individuals with ambulatory daytime hypertension in a sample of white Europeans from Liechtenstein. We evaluated two measures of predisposition to hypertension: family history and polygenic risk scores (PRS). Our analytic sample contained 1444 participants aged 25 to 41. Of the participants, 12% had office hypertension, while 37% had out-of-office hypertension. The correlation between blood pressure PRS and family history of hypertension was low (R2= 4.96×10−3), but both were strongly associated with ambulatory blood pressure (2.2 mmHg per 1 SD increase [95% CI: 1.6, 2.7] & 2.4 mmHg increase with positive family history [95% CI: 1.3, 3.4], respectively). The PRS provides incremental improvement in predicting ambulatory systolic blood pressure beyond a validated blood pressure prediction score (ΔAIC = - 33), whereas family history does not (ΔAIC = 1). However, the difference in performance between a baseline prediction algorithm for identifying ambulatory systolic daytime hypertension (positive likelihood ratio of 6.87 [95% CI: 5.56, 8.49]; negative likelihood ratio of 0.45 [95% CI: 0.39, 0.51]) and the same model with PRS integrated (positive likelihood ratio of 7.69 [95% CI: 6.18, 9.57]; negative likelihood ratio of 0.43 [95% CI: 0.37, 0.49]) was modest. In conclusion, in a white European sample from Liechtenstein, PRS and family history are distinct constructs that are associated with increased clinical and ambulatory blood pressure. Unlike family history, polygenic risk scores provide incremental information in the identification of individuals with ambulatory hypertension. However, these gains are modest and warrant further development to improve predictive utility at the point-of-care.
A Standardized Metric to Enhance Clinical Trial Design and Outcome Interpretation in Type 1 Diabetes
Authors: Ylescupidez Alyssa , Bahnson Henry T. , O’Rourke Colin , Lord Sandra , Speake Cate , Greenbaum Carla J.
Published: December 2022

The use of a standardized outcome metric enhances clinical trial interpretation and cross-trial comparison. If a disease course is predictable, comparing modeled predictions with outcome data affords the precision and confidence needed to accelerate precision medicine. We demonstrate this approach in type 1 diabetes (T1D) trials aiming to preserve endogenous insulin secretion measured by C-peptide. C-peptide is predictable given an individual’s age and baseline value; quantitative response (QR) adjusts for these variables and represents the difference between the observed and predicted outcome. Validated across 13 trials, the QR metric reduces each trial’s variance and increases statistical power. As smaller studies are especially subject to random sampling variability, using QR as the outcome introduces alternative interpretations of previous clinical trial results. QR can provide model-based estimates that quantify whether individuals or groups did better or worse than expected. QR also provides a purer metric to associate with biomarker measurements. Using data from more than 1,300 participants, we demonstrate the value of QR in advancing disease-modifying therapy in T1D. QR applies to any disease where outcome is predictable by pre-specified baseline covariates, rendering it useful for defining responders to therapy, comparing therapeutic efficacy, and understanding causal pathways in disease.
mTICI 1 vs mTICI 0 before endovascular stroke treatment in middle cerebral artery M1-occlusion – predictor for revascularization success and outcome?
Authors: Jesser Jessica , Weyland Charlotte S. , Potreck Arne , Neuberger Ulf , Breckwoldt Michael O. , Chen Min , Schönenberger Silvia , Bendszus Martin , Möhlenbruch Markus A.
Published: December 2022

Background

Endovascular stroke treatment (EST) has become the treatment of choice for middle cerebral artery (MCA) M1-segment occlusions. Little is known about the implications for revascularization success of occlusions with persisting antegrade perfusion before initiation of treatment (modified Treatment In Cerebral Ischemia (mTICI 1)) compared to a complete occlusion (mTICI 0). Here, we compared the impact of these two states of target vessel occlusion on recanalization success and clinical outcome.

Methods

Retrospective, single-center analysis of patients treated for M1-segment MCA occlusion with EST from 01/2015 until 05/2020 in a tertiary stroke center. Primary study endpoint was successful recanalization (mTICI 2c-3) after one thrombectomy attempt (first pass effect). Secondary endpoints were the clinical outcome (as modified Rankin Scale 90 days after stroke onset) and the complication rate. The two study groups were compared in univariate analysis including patient characteristics and procedural details.

Results

In this study, 422/581 patients (72.6 %) presented with complete M1-occlusion compared to 159/581 (27.4 %) with incomplete M1-occlusion. Neither did the rate of FPE differ between the study groups nor the rate of procedural complications (mTICI 0: 10 (2.4%), mTICI 1: 1 (0.6%), p = 0.304). Patients with incomplete initial occlusion showed a lower mRS at discharge (median (IQR) mTICI0: 4 (3-5) vs. mTICI1: 3 (2 – 6), p = 0.014), but a comparable mRS 90 days after stroke onset (mTICI0: 3 (2-6) vs. mTICI:1 4 (2-6), p = 0.479).

Conclusion

Complete M1-occlusions (mTICI 0) and incomplete occlusions (mTICI 1) show the same recanalization success and complication rate as well as a comparable clinical outcome. Thus, incomplete M1-occlusions should be treated with the same urgency as initial complete occlusions.
Orally administratedLactobacillus gasseriTM13 andLactobacillus crispatusLG55 Can Restore the Vaginal Health of Patients Recovering from Bacterial Vaginosis
Authors: Qi Fengyuan , Fan Shangrong , Fang Chao , Ge Lan , Lyu Jinli , Huang Zhuoqi , Zhao Shaowei , Zou Yuanqiang , Huang Liting , Liu Xinyang , Liang Yiheng , Zhang Yongke , Zhong Yiyi , Zhang Haifeng , Xiao Liang , Zhang Xiaowei
Published: December 2022

Bacterial vaginosis (BV) is a common infection of the lower genital tract with a vaginal microbiome dysbiosis caused by decreasing of lactobacilli. Previous studies suggested that supplementation with liveLactobacillusmay benefit the recovery of BV, while the outcomes vary in people from different regions. Herein, we aim to evaluate the effectiveness of oral Chinese-originLactobacilluswith adjuvant metronidazole (MET) on treating Chinese BV patients. In total, 67 Chinese women with BV were enrolled in this parallel controlled trial and randomly assigned to two study groups: a control group treated with MET vaginal suppositories for 7 days and a probiotic group treated with oralLactobacillus gasseriTM13 andLactobacillus crispatusLG55 as an adjuvant to MET for 30 days. By comparing the participants with Nugent scores ≥ 7 and < 7 on days 14, 30, and 90, we found that oral administration of probiotics did not improve BV cure rates (57.14% and 67.74% at day 14, 57.14% and 58.06% at day 30, 32.14% and 48.39% at day 90 for probiotic and control group respectively). However, the probiotics were effective in restoring vaginal health after cure by showing higher proportion of participants with Nugent scores < 4 in the probiotic group compared to the control group (87.50% and 71.43% on day 14, 93.75% and 88.89% on day 30, and 77.78% and 66.67% on day 90). The relative abundance of the probiotic strains was significantly increased in the gut microbiome of the probiotic group compared to the control group at day 14, but no significance was detected after 30 and 90 days. Also, the probiotics were not detected in vaginal microbiome, suggesting thatL. gasseriTM13 andL. crispatusLG55 mainly acted through the gut. A higher abundance ofPrevotella timonensisat baseline was significantly associated with long-term cure failure of BV and greatly contributed to the enrichment of the lipid IVA synthesis pathway, which could aggravate inflammation response. To sum up,L. gasseriTM13 andL. crispatusLG55 can restore the vaginal health of patients recovering from BV, and individualized intervention mode should be developed to improve BV cure rates.
Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation
Authors: Schweizer Lisa , Schaller Tina , Zwiebel Maximilian , Karayel Özge , Müller-Reif Johannes B. , Zeng Wen-Feng , Dintner Sebastian , Hirschbühl Klaus , Märkl Bruno , Claus Rainer , Mann Matthias
Published: December 2022

SARS-CoV-2 directly damages lung tissue via its infection and replication process and indirectly due to systemic effects of the host immune system. There are few systems-wide, untargeted studies of these effects on the different tissues of the human body and nearly all of them base their conclusions on the transcriptome. Here we developed a parallelized mass spectrometry (MS)-based proteomics workflow allowing the rapid, quantitative analysis of hundreds of virus-infected and FFPE preserved tissues. The first layer of response in all tissues was dominated by circulating inflammatory molecules. To discriminated between these systemic and true tissue-specific effects, we developed an analysis pipeline revealing that proteome alterations reflect extensive tissue damage, mostly similar to non-COVID diffuse alveolar damage. The next most affected organs were kidney and liver, while the lymph-vessel system was also strongly affected. Finally, secondary inflammatory effects of the brain correlated with receptor rearrangements and the degradation of neuronal myelin. Our results establish MS-based tissue proteomics as a promising strategy to inform organ-specific therapeutic interventions following COVID-19 infections.
Perception and Readiness Towards Inter-Professional Education Among Different Health Care Disciplines at Khyber Medical University Peshawar
Authors: Ud-din Yaser , Ghani Nasreen , Khatoon Zubaida , Zartasha  , Ali Haidar , Badshah Sadar , Hassan Syed , Ali Mehboob , Iqbal Naveed , Hameed Abdul , Shehzad Qaisar
Published: December 2022

Interprofessional learning (IPL) is an approach that teaches students diverse disciplines to communicate with each other about their professional knowledge in order to acquire a more complex one understanding of the current situation. According to WHO definition of IPE “it’s a process between two or more professionals learn about from, and with one another to permit effective association and enhance health outcome. The aim of this study was to measure perception and readiness towards IPE among different health care disciplines. A cross-sectional study was done with two hundred and eighteen post graduate Nursing, public health, physiotherapy, and basic medical sciences students from September,2020 to January,2021 at Khyber Medical University Peshawar Pakistan. Convenient sampling technique was used to collect data. The Readiness for Inter-Professional Learning Scale (RIPLS) and Interdisciplinary Education Perception Scale (IEPS) were used to measure the readiness and perception of students regarding inter-professional leaning. The data were analyzed using software Statistical Package for Social Science (SPSS) (Version 23). The RIPLS was completed by a total of 218 participants (response rate 100%, 61 Nursing students 28%, 51 physiotherapy students 23.4%, 53 public health students 24.3%, and 53 basic medical sciences students 24.3%). As shown in Table 1.1, the majority of respondents were male (51.4%) followed by female (48.6%). Most of the respondents were aged with a mean score of 27.92 ± 3.195. Moreover, majority of respondents have experience less than 5years (75.2%) and (22.8%) has experience above than 5years. Value of perception and readiness in Shapiro-Wilk is .000 which shows that the data variable is not normally distributed. correlation of students towards interprofessional learning by applying Spearman’ rho test. Students’ perception has strong positive correlation with their readiness, p value (.000). Also students’ readiness has strong positive correlation with their perception towards interprofessional learning. This study was to explore the readiness and perception of students towards interprofessional education in different health care students. IPL is beneficial for students to know other professionals to work together for teamwork and collaboration and it also increase communication between different health care professional and patients.
Trans-ethnic Genomic Informed Risk Assessment for Alzheimer’s disease: An International Hundred K+ Cohorts Consortium Study
Authors: Sleiman Patrick M. , Qu Hui-Qi , Connolly John J , Mentch Frank , Pereira Alexandre , Lotufo Paulo A , Tollman Stephen , Choudhury Ananyo , Ramsay Michele , Kato Norihiro , Ozaki Kouichi , Mitsumori Risa , Jeon Jae-Pil , Hong Chang Hyung , Son Sang Joon , Roh Hyun Woong , Lee Dong-gi , Mukadam Naaheed , Foote Isabelle F , Marshall Charles R , Butterworth Adam , Prins Bram P , Glessner Joseph T , Hakonarson Hakon
Published: December 2022

Background

Alzheimer’s disease (AD) is a complex multifactorial progressive dementia affecting all human populations. As a collaboration model between the International Hundred K+ Cohorts Consortium (IHCC) and the Davos Alzheimer Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for AD.

Methods

The GIRA model was created to include a polygenic risk score (PRS) calculated from the AD GWAS loci, theAPOEhaplotypes, and non-genetic covariates including age, sex and first 3 principal components of population substructure. The model was first validated using a ancestrally diverse dataset from the eMERGE network, and subsequently validated in a South-Asian population in the UK and 3 East-Asian populations. The distributions of the PRS scores were also explored in populations from 3 African regions. In two validation sites, the PRS was tested for associated with the levels of plasma proteomics markers.

Results

We created a trans-ethnic GIRA model for the risk prediction of AD and validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD, highlighting molecular mechanisms underlying the previously observed correlations between these clinical phenotypes.

Conclusions

As the initial effort by the IHCC to leverage existing large scale datasets in a collaborative setting with DAC, we developed a trans-ethnic GIRA for AD with the potential of identifying individuals at high risk of developing AD for future clinical applications. The PRS scores in this model also contribute new research discoveries for the molecular pathogenesis of AD as demonstrated by the proteomic data.
Variations in determining actual orientations of segmented deep brain stimulation leads using the manually refined DiODe algorithm: a retrospective study across different lead designs and medical institutions
Authors: Henry Kaylee R. , Miulli Milina , Nuzov Noa , Nolt Mark J. , Rosenow Joshua , Elahi Behzad , Pilitsis Julie G. , Golestanirad Laleh
Published: December 2022

Purpose

Directional deep brain stimulation (DBS) leads have become widely used in the past decade. Understanding the asymmetric stimulation provided by directional leads requires precise knowledge of the exact orientation of the lead in respect to its anatomical target. Recently, the DiODe algorithm was developed to automatically determine the orientation angle of leads from the artifact on postoperative computed tomography (CT) images. However, DiODe results are user-dependent. This study analyzed the significance of lead rotation as well as the user agreement of DiODe calculations across the two most common DBS systems and two independent medical institutions.

Methods

Data from 104 patients who underwent an anterior-facing unilateral/bilateral directional DBS implantation at either Northwestern Memorial Hospital (NMH) or Albany Medical Center (AMC) were retrospectively analyzed. Actual orientations of the implanted leads were independently calculated by three individual users using the DiODe algorithm in Lead-DBS and patients’ postoperative CT images. Deviation from the intended orientation and user agreement were assessed.

Results

All leads significantly deviated from the intended 0° orientation (p<0.001), regardless of DBS lead design (p<0.05) or institution (p<0.05). However, a bias of the implantation towards a single direction was seen for the Boston Scientific leads (p=0.014 at NMH, p=0.029 at AMC). A difference of 10° between at least two users occurred in 28% (NMH) and 39% (AMC) of all Boston Scientific and 53% (AMC) and 76% (NMH) of all St. Jude leads.

Conclusion

Our results show that there is a significant lead rotation from the intended surgical orientation across both DBS systems and both medical institutions, however, a bias towards a single direction was only seen in Boston Scientific leads. Additionally, these results raise questions into the user error that occurs when manually refining the orientation angles calculated with DiODe.
Association of close-range contact patterns with SARS-CoV-2: a household transmission study
Authors: Kleynhans Jackie , Dall’Amico Lorenzo , Gauvin Laetitia , Tizzoni Michele , Maloma Lucia , Walaza Sibongile , Martinson Neil A. , von Gottberg Anne , Wolter Nicole , Makhasi Mvuyo , Cohen Cheryl , Cattuto Ciro , Tempia Stefano ,   the SA-S-HTS Group
Published: December 2022

Background

Households are an important location for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, especially during periods where travel and work was restricted to essential services. We aimed to assess the association of close-range contact patterns with SARS-CoV-2 transmission.

Methods

We deployed proximity sensors for two weeks to measure face-to-face interactions between household members after SARS-CoV-2 was identified in the household, in South Africa, 2020 - 2021. We calculated duration, frequency and average duration of close range proximity events with SARS-CoV-2 index cases. We assessed the association of contact parameters with SARS-CoV-2 transmission using mixed effects logistic regression accounting for index and household member characteristics.

Results

We included 340 individuals (88 SARS-CoV-2 index cases and 252 household members). On multivariable analysis, factors associated with SARS-CoV-2 acquisition were index cases with minimum Ctvalue <30 (aOR 10.2 95%CI 1.4-77.4) vs >35, contacts aged 13-17 years (aOR 7.7 95%CI 1.0-58.2) vs <5 years and female contacts (aOR 2.3 95%CI 1.1-4.8). No contact parameters were associated with acquisition (aOR 1.0 95%CI 1.0-1.0) for all three of duration, frequency and average duration.

Conclusion

We did not find an association between close-range proximity events and SARS-CoV-2 household transmission. It may be that droplet-mediated transmission during close-proximity contacts play a smaller role than airborne transmission of SARS-CoV-2 in the household, due to high contact rates in households or study limitations.

Funding

Wellcome Trust (Grant number 221003/Z/20/Z) in collaboration with the Foreign, Commonwealth and Development Office, United Kingdom.
Nf1deficiency accelerates mammary development and promotes luminal-basal plasticity
Authors: Tovar Elizabeth A. , Arumugam Menusha , Essenburg Curt J. , Dischinger Patrick S. , Grit Jamie L. , Callaghan Megan E. , Sheridan Rachael T.C. , Turner Lisa , Esquibel Corinne R. , Feenstra Kristin , Madaj Zachary B. , Beddows Ian , Graveel Carrie R. , Steensma Matthew R.
Published: December 2022

The tumor suppressorNF1is a critical driver of sporadic breast cancer and NF-related breast cancers. We utilized distinctNf1-deficient immunocompetent rat models to investigateNf1function in mammary development and homeostasis. Here we demonstrate thatNf1deficiency dramatically accelerates mammary morphogenesis, alters TEB cell organization, and proliferation. Notably, we observed a shift in luminal-basal epithelial lineage commitment withinNf1-deficient lines with early tumor onset. In addition, we detected subpopulations of hybrid EMT cells (Ecad+/CK14+) within the invasive edge and stroma ofNf1-deficient tumors.Nf1deficiency restricted luminal progenitor potential and resulted in gene expression changes associated with decreased cell adhesion and increased EMT signatures. Together our findings support a model in whichNf1loss of function results in lineage plasticity throughout mammary morphogenesis and promotes EMT-mediated invasion. This study reveals a previously unknown role for the tumor suppressor neurofibromin in mammary homeostasis and phenotypic plasticity during breast cancer progression.
Full site-specific addressability in DNA origami-templated silica nanostructures
Authors: Wassermann Lea M. , Scheckenbach Michael , Baptist Anna V. , Glembockyte Viktorija , Heuer-Jungemann Amelie
Published: December 2022

DNA nanotechnology allows for the fabrication of nano-meter-sized objects with high precision and selective addressability as a result of the programmable hybridization of complementary DNA strands. Such structures can template the formation of other materials, including metals and complex silica nanostructures, where the silica shell simultaneously acts to protect the DNA from external detrimental factors. However, the formation of silica nanostructures with site-specific addressability has thus far not been explored. Here we show that silica nanostructures templated by DNA origami remain addressable for post silicification modification with guest molecules even if the silica shell measures several nm in thickness. We used the conjugation of fluorescently labelled oligonucleotides to different silicified DNA origami structures carrying a complementary ssDNA handle as well as DNA PAINT super-resolution imaging to show that ssDNA handles remain unsilicified and thus ensure retained addressability. We also demonstrate that not only handles, but also ssDNA scaffold segments within a DNA origami nanostructure remain accessible, allowing for the formation of dynamic silica nanostructures. Finally we demonstrate the power of this approach by forming 3D DNA origami crystals from silicified monomers. Our results thus present a fully site-specifically addressable silica nanostructure with complete control over size and shape.