bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and Radiological Outcome of Vancouver B2 Fracture Treated With Open Reduction and Internal Fixation. A Multicenter Cohort Analysis
Authors: Biberthaler Peter , Pflüger Patrick , Wurm Markus , Hanschen Marc , Kirchhoff Chlodwig , Aderinto Joseph , Whitwell George , Giannoudis Peter V. , Kanakaris Nikolaos
Published: February 2022

Objectives:

To determine whether open reduction and internal fixation (ORIF) of periprosthetic Vancouver B2 fractures can lead to successful fracture healing in selected patients, when attention is given to the surgical exposure and the creation of a balanced extramedullary construct.

Design:

Retrospective.

Setting:

Two Level-1 trauma centers in Germany and United Kingdom.

Methods:

Patients with a B2 fracture receiving solely ORIF using a polyaxial locking plate were included for analysis. Patients with other fracture types, or treated with other methods, or with follow-up less than 12 months were excluded. Clinical characteristics, including the Charlson index, the American Society for Anesthesiologists score, and their preinjury functional levels, were recorded. Main outcome measures were 1-year mortality, revision rate, and radiological healing according to the Beals–Tower criteria.

Results:

A total of 32 patients (mean age ,79 ± 12 years) were enrolled. Six patients died within the first year (1-year mortality: 19%), and 5 were unavailable for follow-up studies. The remaining 21 patients had a mean follow-up of 30 months. Of 21, 20 had an excellent/good result using the criteria of Beals–Tower. One patient required revision surgery due to loosening and secondary subsidence of the stem.

Conclusion:

ORIF can be offered to selected patients suffering from B2 fractures, especially if their functional demand is limited, and perioperative risk high for revision arthroplasty. In this challenging cohort of patients, ORIF was a safe and effective therapeutic option.

Level of Evidence:

Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
What Is the Therapeutic Reference Range for Levetiracetam? Grand Round/A Case Study
Authors: Couderc Sylvain , Chouchane Mondher , Saint-Marcoux Franck
Published: February 2022

The Therapeutic Drug Monitoring guidelines of Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie had proposed a therapeutic reference range of 10–40 mg/L for levetiracetam in 2011. In the first version of the 2017 update, it was changed to 20–40 mg/L; however, 5 months later, in an erratum version, it was changed back to 10–40 mg/L. In this study, the authors agree with the range to 10–40 mg/L but discuss to what extent a wider interval may be proposed for certain patients.
Effects of E2/P4 oral capsules on bone turnover in women with vasomotor symptoms
Authors: McClung Michael R. , Kagan Risa , Graham Shelli , Bernick Brian , Mirkin Sebastian , Constantine Ginger
Published: February 2022

Objective:

To evaluate bone turnover markers (BTM) in the REPLENISH trial (NCT01942668).

Methods:

REPLENISH evaluated oral estradiol/progesterone (E2/P4) for the treatment of moderate to severe vasomotor symptoms (VMS) in postmenopausal women with a uterus. Eligible women for this analysis had ≥50 moderate to severe VMS/wk, were <5 years since last menstrual period, and had BTM measurements at baseline, and months 6 and 12. Percent changes for three BTM (bone-specific alkaline phosphatase [BSAP], C-terminal telopeptide of type I collagen [CTX-1], and N-terminal propeptide of type I procollagen [P1NP]) assessed by immunoassay methods were evaluated from baseline to months 6 and 12 for the 1 mg E2/100 mg P4, 0.5 mg E2/100 mg P4, and placebo groups.

Results:

A total of 157 women (40-61 y, 69% White) were analyzed. Mean baseline values ranged from 14.0 to 14.3 U/L for BSAP, 0.34 to 0.39 ng/mL for CTX-1, and 76.9 to 79.3 ng/mL for PINP. Mean differences in percent change from baseline for both E2/P4 doses versus placebo significantly decreased at months 6 and 12 and ranged from −8% to −16% for BSAP (all, P < 0.05), −30% to −41% for CTX-1 (all, P ≤ 0.001), and −14% to −29% for PINP (all, P < 0.01).

Conclusions:

REPLENISH data provide support for a potential skeletal benefit of E2/P4 when it is used for the treatment of moderate to severe VMS. Further studies are warranted.

Video Summary
: http://links.lww.com/MENO/A894.
Safety and efficacy of compounded bioidentical hormone therapy (cBHT) in perimenopausal and postmenopausal women: a systematic review and meta-analysis of randomized controlled trials
Authors: Liu Yi , Yuan Ying , Day A.J. , Zhang Wen , John Princy , Ng Danielle J. , Banov Daniel
Published: February 2022

Importance:

More information is needed about the efficacy and safety of compounded bioidentical hormone therapy (cBHT) in the published literature. A thorough synthesis of existing data is not currently available.

Objective:

To provide a systematic review and meta-analysis of the existing evidence related to the safety and efficacy of commonly prescribed cBHT preparations in perimenopausal and postmenopausal women.

Evidence Review:

PubMed, ClinicalTrials.gov, and The Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials (RCTs) comparing cBHT with a placebo or FDA-approved products in perimenopausal or postmenopausal women were eligible. The risk of bias was assessed by the Cochrane risk of bias tool. The primary safety outcome was changes in lipid profile and glucose metabolism, and the primary efficacy outcome was the change of vaginal atrophy symptoms. The secondary outcomes included the change of endometrial thickness, risk of adverse events, vasomotor symptoms, change of serum hormone levels, and change of bone mineral density.

Findings:

A total of 29 RCTs reported in 40 articles containing 1,808 perimenopausal and postmenopausal women were included. Two risk factors of cardiovascular disease, lipid profile, and glucose metabolism, were evaluated with cBHT. The results showed that compounded androgen was not associated with change of lipid profile or glucose metabolism. There was no change in endometrial thickness or serious adverse events. There were more androgenic side effects with compounded dehydroepiandrosterone compared with placebo as expected. Other safety measures including clinical cardiovascular events, endometrial biopsy, and risk of breast cancer were not studied. cBHT in the form of compounded vaginal androgen was found to significantly improve vaginal atrophy symptoms (SMD -0.66 [95% CI, -1.28 to -0.04]; I2
= 86.70%). This finding was supported by the association between compounded vaginal androgen and improved female sexual function scores. The changes of serum hormone levels were also evaluated. Despite the variations in absorption from different types of compounded hormones, routes, and strengths, the trends were consistent with published data from FDA-approved products.

Conclusions and Relevance:

This review found that cBHT used in primarily short-term RCTs is not associated with adverse changes in lipid profile or glucose metabolism. cBHT in the form of vaginal androgens appears beneficial for vaginal atrophy symptoms. There are insufficient RCTs of cBHT to assess clinical risk of breast cancer, endometrial cancer, or cardiovascular disease. Long-term studies with clinical endpoints are needed.
A Conceptual Model of the Influence of Mindfulness-Based Interventions on Stress and Quality of Life in Patients With Chronic Conditions
Authors: Prather Jenifer G. , Baughman Brandon , Alexandrov Anne W. , Grimes Stanfill Ansley
Published: February 2022

Individuals with chronic conditions are susceptible to stress-related health complications. Left unattended, chronic stress exacerbates inflammation, diminishes quality of life (QOL), and increases all-cause mortality. Here, we suggest a theoretical framework promoting the use of mindfulness-based interventions (MBIs) in patients with chronic conditions and a conceptual model of how MBIs may influence stress and QOL.
Working Hours and Depressive and Anxiety Symptoms According to Shift Work and Gender
Authors: Lee Yesung , Park Hwanjin
Published: February 2022

Objectives:

We aimed to analyze the relationship between long working hours and depressive and anxiety symptoms according to gender and shift work.

Methods:

After dividing shift and day workers according to sex, multiple logistic regression analysis was performed to investigate the relationship between weekly working hours and both depressive and anxiety symptoms.

Results:

Both depressive and anxiety symptoms were significantly higher in weekly working 40 to 52 and more than 52 hours compared with working fewer than 40 hours in female day workers. Male day workers and both male and female shift workers, showed the association between weekly working more than 52 hours and both depressive and anxiety symptoms, compared with working fewer than 40 hours.

Conclusions:

Our study demonstrated a significant association between long working hours and depression and anxiety symptoms, regardless of gender and shift work schedule.
The potential of artificial intelligence-based applications in kidney pathology
Authors: Büllow Roman D. , Marsh Jon N. , Swamidass S. Joshua , Gaut Joseph P. , Boor Peter
Published: February 2022

Purpose of review

The field of pathology is currently undergoing a significant transformation from traditional glass slides to a digital format dependent on whole slide imaging. Transitioning from glass to digital has opened the field to development and application of image analysis technology, commonly deep learning methods (artificial intelligence [AI]) to assist pathologists with tissue examination. Nephropathology is poised to leverage this technology to improve precision, accuracy, and efficiency in clinical practice.

Recent findings

Through a multidisciplinary approach, nephropathologists, and computer scientists have made significant recent advances in developing AI technology to identify histological structures within whole slide images (segmentation), quantification of histologic structures, prediction of clinical outcomes, and classifying disease. Virtual staining of tissue and automation of electron microscopy imaging are emerging applications with particular significance for nephropathology.

AI applied to image analysis in nephropathology has potential to transform the field by improving diagnostic accuracy and reproducibility, efficiency, and prognostic power. Reimbursement, demonstration of clinical utility, and seamless workflow integration are essential to widespread adoption.
Bacterial diarrhoea
Authors: Kotloff Karen L.
Published: February 2022

Purpose of review

This review describes recent findings about the burden of bacterial diarrhoea and its potential complications, newer diagnostics, the emerging threat of multidrug resistance, and the promise of vaccines in development.

Recent findings

Introduction of rotavirus vaccines in over 110 countries has changed the landscape of diarrheal pathogens. In upper middle and high-income countries, the incidence of rotavirus-specific and all-cause gastroenteritis has declined substantially, and norovirus has become the major pathogen in many settings. Bacterial pathogens cause approximately 10–15% of episodes, most often Shigella, nontyphoidal Salmonella (NTS) Campylobacter and Shiga toxin-producing Escherichia coli (STEC). In lower income countries, bacterial pathogens remain a major cause of medically attended diarrhoea with Shigella, Campylobacter and enterotoxigenic Escherichia coli (ETEC) predominating. Multidrug-resistant strains of Shigella, NTS and, Campylobacter have emerged globally requiring judicious use of antibiotics according to current guidance.

Management of bacterial diarrhoea includes standard fluid and electrolyte therapy, vigilance for potential complications, and use of antibiotics for children who have moderate-severe illness due to pathogens for which efficacy has been demonstrated, or for those at high risk for severe disease. The threat of multiply resistant strains provides impetus for preventive strategies such as development of vaccines.
Surgical management of complex neonatal airway abnormalities
Authors: Tuliszewski Robert M. , Brigger Matthew T.
Published: February 2022

Purpose of review

The neonatal airway is subject to a variety of developmental abnormalities with a wide range of complexity. Symptomatic pathologies present in a spectrum ranging from simple noisy breathing or poor feeding to frank respiratory distress. Diagnosis requires a high index of suspicion, characterization of noisy breathing, and identification of obstructive symptoms such as increased work of breathing, retractions, and difficulty feeding. Surgical management is directed by the pathology.

Recent findings

The past several years have seen an expansion of surgical innovation as endoscopic and open techniques have evolved. We reviewed articles related to neonatal and infant airway diagnoses since 2020 with the goal of providing a current review and update of developing techniques. Specifically, we discuss some of the exciting trends in surgical management of vocal fold paralysis, laryngeal clefts, subglottic stenosis, tracheobronchomalacia as well as the role of ex utero intrapartum therapy (EXIT procedures).

An underlying theme in evolving surgical management is the exciting advancements in technology, including 3-D printing, and expansion of minimally invasive endoscopic techniques. Though some of these developments are in the initial stages of utilization, they may be potential sources to transform surgical management in the future.
Transplant in acute alcoholic hepatitis: a relative contraindication
Authors: Jakhete Neha , Abutaleb Ameer , Shetty Kirti
Published: February 2022

Purpose of review

The aim of this review is to provide a critical analysis of liver transplantation for alcoholic hepatitis, with an emphasis on barriers to long-term success in current implementation strategies across the United States.

Recent findings

Alcohol-associated liver disease is the most rapidly increasing indication for liver transplantation in the USA. Its most severe form, acute alcoholic hepatitis, has a rising incidence particularly in the young, and is associated with a high mortality risk. Although excellent outcomes following liver transplantation for alcoholic hepatitis can be achieved, several barriers limit its routine use. These constraints include risk of allograft dysfunction, the recognition of alcohol use disorder as a multisystem disease and ethical considerations.

Although liver transplantation is an important option in a carefully selected group of candidates, it should not be considered the standard of care in this condition. Consistency, transparency and consensus are necessary to formulate and implement policy changes at the national level. Following liver transplantation, wraparound services are important for relapse prevention, and to ensure long-term success and survival in this challenging group of patients.
Interleukin-17A is associated with flow-mediated dilation and interleukin-4 with carotid plaque in persons with HIV
Authors: Wanjalla Celestine N. , Temu Tecla M. , Mashayekhi Mona , Warren Christian M. , Shepherd Bryan E. , Gangula Rama , Fuseini Hubaida , Bailin Samuel , Gabriel Curtis L. , Gangula Pandu , Madhur Meena S. , Kalams Spyros , Mallal Simon A. , Harrison David G. , Beckman Joshua A. , Koethe John R.
Published: February 2022

Objective:

Chronic inflammation contributes to the high burden of cardiovascular disease (CVD) in persons with HIV (PWH). HIV has broad effects on innate and adaptive immune cells, including innate lymphoid cells (ILCs) and CD4+ T-helper cells. At present, the relationship between CVD and plasma cytokines reflecting ILC/T-helper responses in PWH is not well defined. We investigated relationships between plasma cytokines and subclinical atherosclerosis.

Design:

A cross-sectional study.

Methods:

We recruited 70 PWH on a single antiretroviral regimen (efavirenz, teno- fovir, and emtricitabine) with at least 12 months of suppressed viremia and 30 HIVnegative controls. We quantified plasma cytokines and chemokines, including inter- feron-g, interleukin (IL)-4, IL-13, and IL-17A, markers of macrophage activation, and markers of endothelial activation using multiplex assays and ELISA. Cytokines were grouped using Ward's hierarchical clustering. Brachial artery flow-mediated dilation (FMD) and carotid plaque burden were determined using ultrasound. Multivariable linear regression and negative binomial regression analyses were used to assess the relationships of plasma biomarkers and endpoints adjusted for CVD risk factors.

Results:

We identified three distinct clusters in PWH, one containing Th1/Th2/ILC1/ ILC2 type cytokines, one with Th17/ILC3/macrophage-related cytokines, and a less specific third cluster. Lower FMD was associated with higher plasma IL-17A and macrophage inflammatory protein-1 a. In contrast, IL-4, a Th2/ILC2 type cytokine, was associated with carotid plaque. When HIV-negative controls were added to the models clustering was more diffuse, and these associations were attenuated or absent.

Conclusion:

Th17/ILC3 and Th2/ILC2-mediated immune mechanisms may have distinct roles in endothelial dysfunction and atherosclerotic plaque formation, respectively, in PWH.
Perioperative Renin–Angiotensin System Inhibitors Improve Major Outcomes of Heart Failure Patients Undergoing Cardiac Surgery
Authors: Zhang Yan-Qing , Liu Xiao-Gang , Ding Qian , Berguson Mark , Morris Rohinton J. , Liu Hong , Goldhammer Jordan E.
Published: February 2022

Objective:

The aim of this study was to study the association of perioperative administration of renin angiotensin system inhibitors (RASi) and clinical outcomes of patients with heart failure (HF) undergoing cardiac surgery.

Summary Background Data:

It is controversial whether the perioperative RASi should be administered in HF patients undergoing cardiac surgery.

Methods:

A total of 2338 patients with HF and undergoing CABG and/or valve surgeries at multiple hospitals from 2001 to 2015 were identified from STS database. After adjustment using propensity score and instrumental variable, logistic regression was conducted to analyze the influence of preoperative continuation of RASi (PreRASi) on short-term in-hospital outcomes. Independent risk factors of 30-day mortality, major adverse cardiovascular events (MACE), and renal failure were analyzed by use of stepwise logistic regression. The effects of pre- and postoperative use of RASi (PostRASi) on long-term mortality were analyzed using survival analyses. Stepwise Cox regression was conducted to analyze the independent risk factors of 6-year mortality. The relationships of HF status and surgery type with perioperative RASi, as well as PreRASi-PostRASi, were also evaluated by subgroup analyses.

Results:

PreRASi was associated with lower incidences of 30-day mortality [P < 0.0001, odds ratio (OR): 0.556, 95% confidence interval (CI) 0.405−0.763], stroke (P =0.035, OR: 0.585, 95% CI: 0.355−0.962), renal failure (P =0.007, OR: 0.663, 95% CI: 0.493–0.894). Both PreRASi (P =0.0137) and PostRASi (P =0.007) reduced 6-year mortality compared with the No-RASi groups.

Conclusions:

Pre- and postoperative use of RASi was associated with better outcomes for the patients who have HF and undergo CABG and/or valve surgeries. Preoperative continuation and postoperative restoration are warranted in these patients.
A Nationwide Prospective Clinical Trial on Active Surveillance in Patients With Non-intraabdominal Desmoid-type Fibromatosis
Authors: Schut Anne-Rose W. , Timbergen Milea J. M. , van Broekhoven Danique L. M. , van Dalen Thijs , van Houdt Winan J. , Bonenkamp Johannes J. , Sleijfer Stefan , Grunhagen Dirk J. , Verhoef Cornelis
Published: February 2022

Objective:

To assess tumor behavior and the efficacy of active surveillance (AS) in patients with desmoid-type fibromatosis (DTF).

Summary of Background Data:

AS is recommended as initial management for DTF patients. Prospective data regarding the results of AS are lacking.

Methods:

In this multicenter prospective cohort study (NTR4714), adult patients with non-intraabdominal DTF were followed during an initial AS approach for 3 years. Tumor behavior was evaluated according to Response Evaluation Criteria in Solid Tumors. Cumulative incidence of the start of an active treatment and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Factors predictive for start of active treatment were assessed by Cox regression analyses.

Results:

A total of 105 patients started with AS. Median tumor size at baseline was 4.1cm (interquartile range 3.0–6.6). Fifty-seven patients had a T41A CTNNB1 mutation; 14 patients a S45F CTNNB1 mutation. At 3 years, cumulative incidence of the start of active treatment was 30% (95% confidence interval [CI] 21–39) and PFS was 58% (95% CI 49–69). Median time to start active treatment and PFS were not reached at a median follow-up of 33.7 months. During AS, 32% of patients had stable disease, 28% regressed, and 40% demonstrated initial progression. Larger tumor size (≥5 cm; hazard ratio = 2.38 [95% CI 1.15–4.90]) and S45F mutation (hazard ratio = 6.24 [95% CI 1.92–20.30]) were associated with the start of active treatment.

Conclusions:

The majority DTF patients undergoing AS do not need an active treatment and experience stable or regressive disease, even after initial progression. Knowledge about the natural behavior of DTF will help to tailor the follow-up schedule to the individual patient.
Sabulibacter ruber gen. nov., sp. nov., a novel bacterium in the family Hymenobacteraceae, isolated from desert soil
Authors: Lian Wen-Hui , Li Shuai , Lin Zhi-Liang , Han Jia-Rui , Mohamad Osama Abdalla Abdelshafy , Li Li , Lin Ying , Hozzein Wael N. , Dong Lei , Li Wen-Jun
Published: February 2022

A novel Gram-stain-negative, aerobic, oxidase-positive, catalase-positive, non-motile, short rod-shaped, red-pigmented strain, designated as SYSU D00434T, was isolated from a dry sandy soil sample collected from the Gurbantunggut desert in Xinjiang, north-west PR China. Strain SYSU D00434T was found to grow at 4–37 °C (optimum, 28–30 °C), pH 6.0–8.0 (optimum, pH 7.0) and with 0–1.5 % (w/v) NaCl (optimum, 0–0.5 %). The predominant respiratory quinone was MK-7 and the major fatty acids (>10 %) were C16 : 1
 ω5c, iso-C15 : 0, summed feature 3 (C16 : 1
 ω6c and/or C16 : 1
 ω7c) and summed feature 4 (anteiso-C17 : 1 B and/or iso-C17 : 1 I). The polar lipids consisted of phosphatidylethanolamine, two unidentified polar lipids, two unidentified aminolipids, two unidentified phospholipids and two unidentified glycolipids. The genomic DNA G+C content of strain SYSU D00434T was 50.6 mol%. Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain SYSU D00434T belonged to the family

Hymenobacteraceae

, and shared a sequence similarity of less than 94.6 % to all validly named taxa. Based on the phenotypic, phylogenetic and chemotaxonomic properties, strain D00434T is proposed to represent a new species of a new genus, named Sabulibacter ruber gen. nov., sp. nov., within the family

Hymenobacteraceae

. The type strain is SYSU D00434T (=CGMCC 1.18624T=KCTC 82276T=MCCC 1K04975T).
Genomic and phenotypic analyses of diverse non-clinical Acinetobacter baumannii strains reveals strain-specific virulence and resistance capacity
Authors: Hamidian Mohammad , Maharjan Ram P. , Farrugia Daniel N. , Delgado Natasha N. , Dinh Hue , Short Francesca L. , Kostoulias Xenia , Peleg Anton Y. , Paulsen Ian T. , Cain Amy K.
Published: February 2022

Acinetobacter baumannii

is a critically important pathogen known for its widespread antibiotic resistance and ability to persist in hospital-associated environments. Whilst the majority of

A. baumannii

infections are hospital-acquired, infections from outside the hospital have been reported with high mortality. Despite this, little is known about the natural environmental reservoir(s) of

A. baumannii

and the virulence potential underlying non-clinical strains. Here, we report the complete genome sequences of six diverse strains isolated from environments such as river, soil, and industrial sites around the world. Phylogenetic analyses showed that four of these strains were unrelated to representative nosocomial strains and do not share a monophyletic origin, whereas two had sequence types belonging to the global clone lineages GC1 and GC2. Further, the majority of these strains harboured genes linked to virulence and stress protection in nosocomial strains. These genotypic properties correlated well with in vitro virulence phenotypic assays testing resistance to abiotic stresses, serum survival, and capsule formation. Virulence potential was confirmed in vivo, with most environmental strains able to effectively kill Galleria mellonella greater wax moth larvae. Using phenomic arrays and antibiotic resistance profiling, environmental and nosocomial strains were shown to have similar substrate utilisation patterns although environmental strains were distinctly more sensitive to antibiotics. Taken together, these features of environmental

A. baumannii

strains suggest the existence of a strain-specific distinct gene pools for niche specific adaptation. Furthermore, environmental strains appear to be equally virulent as contemporary nosocomial strains but remain largely antibiotic sensitive.
Reciprocally rewiring and repositioning the Integration Host Factor (IHF) subunit genes in Salmonella enterica serovar Typhimurium: impacts on physiology and virulence
Authors: Pozdeev German , Beckett Michael C. , Mogre Aalap , Thomson Nicholas R. , Dorman Charles J.
Published: February 2022

The Integration Host Factor (IHF) is a heterodimeric nucleoid-associated protein that plays roles in bacterial nucleoid architecture and genome-wide gene regulation. The ihfA and ihfB genes encode the subunits and are located 350 kbp apart, in the Right replichore of the

Salmonella

chromosome. IHF is composed of one IhfA and one IhfB subunit. Despite this 1 : 1 stoichiometry, MS revealed that IhfB is produced in 2-fold excess over IhfA. We re-engineered

Salmonella

to exchange reciprocally the protein-coding regions of ihfA and ihfB, such that each relocated protein-encoding region was driven by the expression signals of the other’s gene. MS showed that in this 'rewired' strain, IhfA is produced in excess over IhfB, correlating with enhanced stability of the hybrid ihfB–ihfA mRNA that was expressed from the ihfB promoter. Nevertheless, the rewired strain grew at a similar rate to the wild-type and was similar in competitive fitness. However, compared to the wild-type, it was less motile, had growth-phase-specific reductions in SPI-1 and SPI-2 gene expression, and was engulfed at a higher rate by RAW macrophage. Our data show that while exchanging the physical locations of its ihf genes and the rewiring of their regulatory circuitry are well tolerated in

Salmonella

, genes involved in the production of type 3 secretion systems exhibit dysregulation accompanied by altered phenotypes.
A Novel de novo TP63 Mutation in Whole Exome Sequencing of a Syrian Family with Oral Cleft and Ectrodactyly
Authors: Simpson Claire L. , Kimble Danielle C. , Chandrasekharappa Settara C. ,   NISC Comparative Sequencing Program, Alqosayer Khalid , Holzinger Emily , Carrington Blake , McElderry John , Sood Raman , Al-Souqi Ghaith , Albacha-Hejazi Hasan , Bailey-Wilson Joan E.
Published: February 2022

Oral clefts and ectrodactyly are common, heterogeneous birth defects. We performed whole exome sequencing (WES) analysis in a Syrian family. The proband presented with both orofacial clefting and ectrodactyly. A paternal side second-degree relative with only an oral cleft was deceased and unavailable for analysis. Variant annotation, Mendelian inconsistencies, and novel variants in known cleft genes were examined. Candidate variants were validated using Sanger sequencing. Twentyeight candidate de novo events were identified, one of which is in a known oral cleft and ectrodactyly gene, TP63 (c.956G>T, p.Arg319Leu), and confirmed by Sanger sequencing. A triallelic SNV was also found in HLA-DRB5, which is similar to and overlaps the known oral cleft gene HLA-DRB1.

TP63 mutations are associated with multiple autosomal dominant orofacial clefting and limb malformation disorders. The p.Arg319Leu mutation seen in this patient is de novo but also novel. A known mutation 1bp upstream (rs121908839, c.955C>T, p.Arg319Cys) causes ectrodactyly, providing evidence that mutating this codon is deleterious. It is unclear whether this patient’s mutation is responsible for the entire phenotype. Generation and characterization of tp63 knockout zebrafish showed necrosis and rupture of the head at 3 days postfertilization. The embryonic phenotype could not be rescued by injection of zebrafish or human mRNA. Further functional analysis is needed to determine what proportion of the phenotype is due to this mutation.
Direct and indirect mortality impacts of the COVID-19 pandemic in the US, March 2020-April 2021
Authors: Lee Wha-Eum , Park Sang Woo , Weinberger Daniel M , Olson Donald , Simonsen Lone , Grenfell Bryan T. , Viboud Cécile
Published: February 2022

Excess mortality studies provide crucial information regarding the health burden of pandemics and other large-scale events. Here, we used time series approaches to separate the direct contribution of SARS-CoV-2 infections on mortality from the indirect consequences of pandemic interventions and behavior changes in the United States. We estimated deaths occurring in excess of seasonal baselines stratified by state, age, week and cause (all causes, COVID-19 and respiratory diseases, Alzheimer’s disease, cancer, cerebrovascular disease, diabetes, heart disease, and external causes, including suicides, opioids, accidents) from March 1, 2020 to April 30, 2021. Our estimates of COVID-19 excess deaths were highly correlated with SARS-CoV-2 serology, lending support to our approach. Over the study period, we estimate an excess of 666,000 (95% Confidence Interval (CI) 556000, 774000) all-cause deaths, of which 90% could be attributed to the direct impact of SARS-CoV-2 infection, and 78% were reflected in official COVID-19 statistics. Mortality from all disease conditions rose during the pandemic, except for cancer. The largest direct impacts of the pandemic were seen in mortality from diabetes, Alzheimer’s, and heart diseases, and in age groups over 65 years. In contrast, the largest indirect consequences of the pandemic were seen in deaths from external causes, which increased by 45,300 (95% CI 30,800, 59,500) and were statistically linked to the intensity of non-pharmaceutical interventions. Within this category, increases were most pronounced in mortality from accidents and injuries, drug overdoses, and assaults and homicides, while the rate of death from suicides remained stable. Younger age groups suffered the brunt of these indirect effects. Overall, on a national scale, the largest consequences of the COVID-19 pandemic are attributable to the direct impact of SARS-CoV-2 infections; yet, the secondary impacts dominate among younger age groups, in periods of stricter interventions, and in mortality from external causes. Further research on the drivers of indirect mortality is warranted to optimize interventions in future pandemics.
Quantifying the economic impact of Peristenus relictus establishment on host Lygus hesperus populations in California organic strawberry
Authors: Nieto Diego J. , Bick Emily , Pickett Charles H.
Published: February 2022

Lygus hesperus is a key pest in California-grown strawberries, in part because it lacks specialized natural enemies. In response, the specialist European nymphal parasitoid Peristenus relictus was released, and subsequently established, along the California Central Coast. A simulation model, based on field-collected L. hesperus immigration rates and 16 years of parasitism data, compared simulated pest populations with and without parasitism by P. relictus. After 10 years, L. hesperus population reductions exceeded 95% in weeds and alfalfa, and 70% in strawberry. These simulated results were in agreement with field-based P. relictus longitudinal studies. The averted value loss associated with L. hesperus, due to the establishment of P. relictus, is estimated at $1,901 per acre in organic strawberry.
Development of methylation-based biomarkers for breast cancer detection by model training and validation in synthetic cell-free DNA
Authors: de Procé Sophie Marion , Adamowicz Martyna , Dutta Prasun , Warlow Sophie J. , Moss Joshua , Shemer Ruth , Dor Yuval , Robert Christelle , Aitman Timothy J.
Published: February 2022

Circulating tumour-derived DNA (ctDNA) carries the genetic and epigenetic characteristics of the tumour from which it is derived and can give information about the biology and tissue origins of the underlying tumour. DNA methylation is an epigenetic mark that is specific to individual tissues and, as methylation profiles are disrupted in tumours, they can indicate the tissue of origin and cancer type of ctDNA. We have developed a set of methylation biomarkers for detecting breast cancer in plasma cell-free DNA (cfDNA). First, we mined publicly available methylation datasets to create synthetic methylation profiles that were modelled to reflect cfDNA from healthy subjects and cancer patients. These profiles were restricted to the most differentially methylated CpGs between breast tumour samples and haematopoietic cells. Regularised logistic regression models were trained using 10-fold cross-validation on synthetic cfDNA datasets with distinct fractions of breast tumour DNA spiked in silico into healthy cfDNA with the addition of 10% of a mix of different tissues. Initial validation with synthetic cfDNA permitted detection of breast cancer-derived DNA with as little as 0.25% tumour DNA spiked in silico into healthy subject cfDNA with an area under ROC curve (AUC) of 0.63. Performances of classifiers increased with increased fractions of spike-in tumour DNA (AUCs 0.77 and 0.93 at tumour DNA fractions 0.5% and 1% respectively). We then combined the most discriminative CpG markers from our models with methylation markers of breast cancer that had already been published to obtain a single marker set. In vitro testing of MCF-7 breast cancer cell line DNA spiked into leukocyte DNA showed highly significant correlation for individual markers between laboratory-measured and published methylation data for MCF-7 and leukocytes (R > 0.89, P < 2.2 × 10−16). These preliminary data indicate promising results for detection of breast cancer cell line DNA using this methylation marker set, which now require testing in cfDNA from breast cancer patients and healthy controls.
A novel consensus-based computational pipeline for rapid screening of antibody therapeutics for efficacy against SARS-CoV-2 variants of concern including omicron variant
Authors: Kumar Naveen , Kaushik Rahul , Zhang Kam Y. J. , Uversky Vladimir N. , Srivastava Pratiksha , Sahu Upasana , Sood Richa , Bhatia Sandeep
Published: February 2022

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to evolve carrying flexible amino acid substitutions in the spike protein’s receptor binding domain (RBD). These substitutions modify the binding of the SARS-CoV-2 to human angiotensin-converting enzyme 2 (hACE2) receptor and have been implicated in altered host fitness, transmissibility and efficacy against antibody therapeutics and vaccines. Reliably predicting the binding strength of SARS-CoV-2 variants RBD to hACE2 receptor and neutralizing antibodies (NAbs) can help assessing their fitness, and rapid deployment of effective antibody therapeutics, respectively. Here, we introduced a two-step computational framework with three-fold validation that first identified dissociation constant as a reliable predictor of binding affinity in hetero-dimeric and –trimeric protein complexes. The second step implements dissociation constant as descriptor of the binding strengths of SARS-CoV-2 variants RBD to hACE2 and NAbs. Then, we examined several variants of concern (VOCs) such as Alpha, Beta, Gamma, Delta, and Omicron and demonstrated that these VOCs RBD bind to the hACE2 with enhanced affinity. Furthermore, the binding affinity of Omicron variant’s RBD was reduced with majority of the RBD-directed NAbs, which is highly consistent with the experimental neutralization data. By studying the atomic contacts between RBD and NAbs, we revealed the molecular footprints of four NAbs (GH-12, P2B-1A1, Asarnow_3D11, and C118) — that may likely neutralize the recently emerged omicron variant — facilitating enhanced binding affinity. Finally, our findings suggest a computational pathway that could aid researchers identify a range of current NAbs that may be effective against emerging SARS-CoV-2 variants.
Predicting COVID-19 outbreak using open mobility data for minimal disruption on the country’s economy
Authors: Morales-Fajardo Héctor , Rodríguez-Arce Jorge
Published: February 2022

COVID-19 is an infectious disease caused by the SARS-COV-2 coronavirus, which was discovered in late 2019. Within a few months, COVID-19 was declared a global pandemic by the WHO. Several countries adopted social distancing measures, such as self-quarantine, workplace and mobility restrictions, reducing the probability of contact between non-infected and infected people. In general, these measures have a negative impact on low-income economies and small and medium businesses. During the outbreak, several predictive models have been proposed in order to assess the level of saturation that health services might have. Nevertheless, none of them considers information on the people’s mobility to assess the effectiveness of the social distancing policies. In this study, the authors propose a prediction method based on people’s open mobility data from Apple© and Google© databases to project potential scenarios and monitor case growth. The proposed method shows the importance of monitoring daily case increase for the first 4-6 weeks of the pandemic wave. Active monitoring is crucial to determine the reduction in mobility and proper actions. The results can contribute to health authorities for making timely decisions, preventing the spread of viruses while balancing the reduction of mobility with minimal disruption in people’s economies in future outbreaks.
Introducing CARATE: Finally speaking chemistry through learning hidden wave-function representations on graph-based attention and convolutional neural networks
Authors: Kleber Julian Manuel
Published: February 2022

Computer-Aided Drug Design is advancing to a new era. Recent developments in statistical modelling, including Deep Learning, Machine Learning and high throughput simulations, enable workflows and deductions not achievable 20 years ago. The key interaction for many small molecules in the context of medicinal chemistry is via bio-molecules. The interaction between a small molecule and a biological system therefore manifests itself at multiple time and length scales. While the human chemist quite intuitively grasps the concept of multiple scales, most of the computer technologies do not relate multiple scales easily. Numerous methods that try to tackle multiple scales in the realm of computational sciences have been developed. However, up to now it was not clear that the problem of multiple scales is not only a mere matter of computational abilities but even more a matter of accurate representation. Current representations of chemicals lack the descriptiveness necessary for modern modelling questions. This work introduces a novel representation of small and large molecules. The representation is obtained by the biochemical and pharmaceutical encoder (CARATE). Furthermore, the regression and classification abilities of the learned representation by CARATE are evaluated against benchmarking datasets (ZINC, ALCHEMY, MCF-7, MOLT-4, YEAST, Enzymes, Proteins) and compared to other baseline approaches. CARATE outperforms other graph-based algorithms on classification tasks of large biomolecules and small molecules, as well as on quantum chemical regression tasks of small molecules.
Next-generation intranasal Covid-19 vaccine: a polymersome-based protein subunit formulation that provides robust protection against multiple variants of concern and early reduction in viral load of the upper airway in the golden Syrian hamster model
Authors: Lam Jian Hang , Shivhare Devendra , Chia Teck Wan , Chew Suet Li , Sinsinbar Gaurav , Aw Ting Yan , Wong Siamy , Venkatraman Shrinivas , Lim Francesca Wei Inng , Vandepapeliere Pierre , Nallani Madhavan
Published: February 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (Covid-19), an ongoing global public health emergency. Despite the availability of safe and efficacious vaccines, achieving herd immunity remains a challenge due in part to rapid viral evolution. Multiple variants of concern (VOCs) have emerged, the latest being the heavily mutated Omicron, which exhibits the highest resistance to neutralizing antibodies from past vaccination or infection. Currently approved vaccines generate robust systemic immunity, yet poor immunity at the respiratory tract. We have demonstrated that a polymersome-based protein subunit vaccine with wild type (WT) spike protein and CpG adjuvant induces robust systemic immunity (humoral and T cell responses) in mice. Both antigen and adjuvant are encapsulated in artificial cell membrane (ACM) polymersomes – synthetic, nanoscale vesicles that substantially enhance the immune response through efficient delivery to dendritic cells. In the present study, we have formulated a vaccine candidate with the spike protein from Beta variant and assessed its immunogenicity in golden Syrian hamsters. Two doses of ACM-Beta spike vaccine administered via intramuscular (IM) injection evoke modest serum neutralizing titers that are equally efficacious towards WT and Beta viruses. In contrast, the ACM-WT spike vaccine induces a predominantly WT-specific serum neutralizing response with pronounced reduction in potency towards the Beta variant. Remarkably, immunogenicity of the ACM-Beta spike vaccine is greatly enhanced through intranasal (IN) administration. Following IN challenge with the Beta variant, IM-immunized hamsters are fully protected from disease but not infection, displaying similar peak viral RNA loads in oral swabs as non-vaccinated controls. In contrast, hamsters IN vaccinated with ACM-Beta spike vaccine are protected from disease and infection, exhibiting a ∼100-fold drop in total and subgenomic RNA load as early as day 2 post challenge. We further demonstrate that nasal washes from IN-but not IM-immunized animals possess virus neutralizing activity that is broadly efficacious towards Delta and Omicron variants. Altogether, our results show IN administration of ACM-Beta spike vaccine to evoke systemic and mucosal antibodies that cross-neutralize multiple SARS-CoV-2 VOCs. Our work supports IN administration of ACM-Beta spike vaccine for a next-generation vaccination strategy that not only protects against disease but also an infection of the respiratory tract, thus potentially preventing asymptomatic transmission.
Quantitative fate mapping: Reconstructing progenitor field dynamics via retrospective lineage barcoding
Authors: Fang Weixiang , Bell Claire M. , Sapirstein Abel , Asami Soichiro , Leeper Kathleen , Zack Donald J. , Ji Hongkai , Kalhor Reza
Published: February 2022

Natural and induced somatic mutations that accumulate in the genome during development record the phylogenetic relationships of cells; however, whether these lineage barcodes can capture the dynamics of complex progenitor fields remains unclear. Here, we introduce quantitative fate mapping, an approach to simultaneously map the fate and quantify the commitment time, commitment bias, and population size of multiple progenitor groups during development based on a time-scaled phylogeny of their descendants. To reconstruct time-scaled phylogenies from lineage barcodes, we introduce Phylotime, a scalable maximum likelihood clustering approach based on a generalizable barcoding mutagenesis model. We validate these approaches using realistically-simulated barcoding results as well as experimental results from a barcoding stem cell line. We further establish criteria for the minimum number of cells that must be analyzed for robust quantitative fate mapping. Overall, this work demonstrates how lineage barcodes, natural or synthetic, can be used to obtain quantitative fate maps, thus enabling analysis of progenitor dynamics long after embryonic development in any organism.
Rapid Knowledgebase Construction and Hypotheses Generation Using Extractive Literature Search
Authors: Launer-Wachs Shaked , Taub-Tabib Hillel , Goldberg Yoav , Shamay Yosi
Published: February 2022

As knowledgebases become increasingly important for structuring vast amounts of scientific knowledge and making it accessible to researchers, their construction entails expensive multi-year projects involving teams of bio-curators, computer scientists, or both. This restricts the coverage of existing knowledgebases to a limited set of popular topics, leaving a long tail of more specialized interests uncovered.

We present a methodology and a supporting tool to allow individual researchers or small teams, without background in bio-curation or computer science, to mine the scientific literature and construct ad-hoc, personalized, and literature-anchored knowledgebases, that are tailored around their specific research interests and support their scientific goals. The time investment involved in creating a knowledgebase ranges from a few hours to a few weeks, depending on the desired coverage and accuracy.

We demonstrate the methodology by constructing knowledgebases for different purposes: a high-level overview of challenges and controversies in a field (the cancer frontiers knowledgebase); a mapping of main concepts and interactions in a field, to support lab-internal hypothesis generation (tissue engineering and regeneration, cancer surgery and radiotherapy knowledgebases); and a comprehensive and accurate knowledgebase designated as an online up-to-date resource for the wider research community (the cell specific drug delivery knowledgebase). In each case we show how the structured knowledgebase, coupled with effective visualizations, facilitates effective data exploration, hypothesis generation and meta-analysis.

We implement the method as part of an open source web-based platform for knowledgebase construction, available publicly and freely at https://spike-kbc.apps.allenai.org.