bluuebunny/crossref_metadata_2025 huggingface dataset:
A Half-Century of Evidence-Based Cardiac Rehabilitation: A Historical Review
Authors: Shephard Roy J.
Published: September 2020

Objective:

To review the achievements of cardiac exercise rehabilitation programs retrospectively and to identify continuing challenges to their success.

Methods:

A review of files accumulated while working with the Toronto Rehabilitation Center, updated by articles identified by PUB-MED, OVID, and Google Scholar through February 2019.

Results:

After the early lead of Israeli physicians, cardiac rehabilitation began in Ontario during the 1960s and quickly attracted a large case load. Recurrence rates of the patients recruited were low relative to those receiving standard medical treatment, even after allowing for differences in risk factors at entry to programs. Controlled trials began but were individually of insufficient in size to show a significant reduction in recurrences or mortality. Subsequently, multiple meta-analyses demonstrated a 20% to 25% reduction of all-cause and cardiac mortality over the first few years of follow-up in patients who persisted with their rehabilitation. Compliance continued a problem at many centers, but special features of the Toronto cardiac rehabilitation program sustained a compliance of 82.8% over 3 years. Although vigorous exercise increased the immediate risks of a recurrence 5- to 10-fold, this was more than offset by the long-term benefits of enhanced physical condition, and cardiac deaths were a rarity during either supervised or home-based exercise sessions. About a half of patients developed a depression immediately after infarction, but if encouraged to persist with prescribed exercise, their quality of life progressively improved. Among the wide variety of mechanisms underlying the benefits of exercise, gains of aerobic power seemed particularly important. With sustained training, the physical condition of some younger patients progressed to the point of participating successfully in marathon events. Older patients also benefited from sustained training, but for them, optimal results were likely associated with less rigorous physical demands.

Conclusions:

Research conducted in Toronto and elsewhere has established the benefits of exercise-centered cardiac rehabilitation. However, there remains a need to define the optimum timing of program onset, and the frequency, intensity, and duration of supervised training sessions. Return to blue-collar occupations also needs to be boosted, and the limited participation of eligible patients in available programs remains a continuing challenge.
Clinician Knowledge of Societal Guidelines on Management of Gastrointestinal Complications in Esophageal Atresia
Authors: O’Donnell Jonathan E.M. , Purcell Michael , Mousa Hayat , Dall’Oglio Luigi , Rosen Rachel , Faure Christophe , Gottrand Frédéric , Krishnan Usha
Published: September 2020

Objectives:

The aim of this study was to assess whether clinicians approached the management of children with esophageal atresia (EA) in accordance with the 2016 European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)/North American Society of Paediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines on the management of gastrointestinal and nutritional complications in this cohort.

Methods:

We invited expert physicians and surgeons closely involved in the care of children with EA (members of the International network on esophageal atresia [INoEA], ESPGHAN EA working group, French national EA registry, European pediatric surgical association (EUPSA), and European rare disease reference network [ERNICA]) to participate in an anonymous online survey containing 15 multiple choice questions concerning the management of gastrointestinal and nutritional complications in children with EA. Questions were based on the management of gastroesophageal reflux disease (GERD) dysphagia, cyanotic spells, feeding and nutrition, anastamotic strictures, and transition to adult care as detailed in the 2016 guidelines.

Results:

Median concordance with ESPGHAN/NASPHAN EA Guidelines was 69% (16–100%, SD 16%) across all responders. Areas of greatest concordance were in the fields of surveillance endoscopy and medical management of GERD. Areas for potential educational opportunities include: the differential diagnosis and appropriate investigation of dysphagia and the diagnostic evaluation of extraesophageal symptoms.

Conclusions:

This survey highlights the importance of improving the understanding and adherence to the EA guidelines amongst clinicians involved in the care of these patients.
Corneal Health during Three Months of Scleral Lens Wear
Authors: Tse Vivien , Zhou Yixiu , Truong Tan , Lin Kristina , Tan Bo , Lin Meng C.
Published: September 2020

SIGNIFICANCE

This study evaluated the effects scleral lens wear has on corneal health using fluorometry and in vivo confocal microscopy. No subclinical changes on healthy corneas of young subjects were observed during 3 months of scleral lens wear.

PURPOSE

This study aimed to evaluate the effects 3 months of scleral lens wear has on the corneal epithelial barrier function, dendritic cell density, and nerve fiber morphology.

METHODS

Twenty-seven neophytes (mean [standard deviation] age, 21.4 [3.9] years) wore scleral lenses of a fluorosilicone acrylate material bilaterally (97 Dk, 15.6 to 16.0-mm diameter) for 3 months without overnight wear. Subjects were randomized to use either Addipak (n = 12) or PuriLens Plus (n = 15) during lens insertion. Measurements of corneal epithelial permeability to fluorescein were performed with automated scanning fluorophotometer (Fluorotron Master; Ocumetrics, Mountain View, CA) on the central cornea of the right eye and the temporal corneal periphery of the left eye. Images of the distributions of corneal nerve fibers and dendritic cells and nerve fibers were captured in vivo with a confocal laser scanning microscope (Heidelberg Retina Tomograph, Rostock Cornea Module; Heidelberg Engineering, Heidelberg, Germany) on the central and inferior peripheral cornea of the left eye. Corneal measurements and imaging were performed at baseline and after 1 and 3 months of lens wear.

RESULTS

The corneal permeability values in natural log, dendritic cell densities, and nerve fiber morphology did not significantly change from baseline to 1 and 3 months of lens wear, for both central and peripheral corneal regions (P > .05). Dendritic cell density at the inferior cornea was higher than the central cornea throughout the study (P < .001). No relationships were observed between each outcome measurements and the saline solution groups (P > .05).

CONCLUSIONS

Scleral lens wear for 3 months on healthy cornea of young subjects did not affect corneal epithelial barrier function, nerve fiber, and dendritic cell densities. Buffered and nonbuffered saline solutions impacted the corneal health in similar ways.
Criticality: A New Concept of Severity of Illness for Hospitalized Children
Authors: Rivera Eduardo A. Trujillo , Patel Anita K. , Chamberlain James M. , Workman T. Elizabeth , Heneghan Julia A. , Redd Douglas , Morizono Hiroki , Kim Dongkyu , Bost James E. , Pollack Murray M.
Published: September 2020

Objectives:

To validate the conceptual framework of “criticality,” a new pediatric inpatient severity measure based on physiology, therapy, and therapeutic intensity calibrated to care intensity, operationalized as ICU care.

Design:

Deep neural network analysis of a pediatric cohort from the Health Facts (Cerner Corporation, Kansas City, MO) national database.

Setting:

Hospitals with pediatric routine inpatient and ICU care.

Patients:

Children cared for in the ICU (n = 20,014) and in routine care units without an ICU admission (n = 20,130) from 2009 to 2016. All patients had laboratory, vital sign, and medication data.

Interventions:

None.

Measurements and Main Results:

A calibrated, deep neural network used physiology (laboratory tests and vital signs), therapy (medications), and therapeutic intensity (number of physiology tests and medications) to model care intensity, operationalized as ICU (versus routine) care every 6 hours of a patient’s hospital course. The probability of ICU care is termed the Criticality Index. First, the model demonstrated excellent separation of criticality distributions from a severity hierarchy of five patient groups: routine care, routine care for those who also received ICU care, transition from routine to ICU care, ICU care, and high-intensity ICU care. Second, model performance assessed with statistical metrics was excellent with an area under the curve for the receiver operating characteristic of 0.95 for 327,189 6-hour time periods, excellent calibration, sensitivity of 0.817, specificity of 0.892, accuracy of 0.866, and precision of 0.799. Third, the performance in individual patients with greater than one care designation indicated as 88.03% (95% CI, 87.72–88.34) of the Criticality Indices in the more intensive locations was higher than the less intense locations.

Conclusions:

The Criticality Index is a quantification of severity of illness for hospitalized children using physiology, therapy, and care intensity. This new conceptual model is applicable to clinical investigations and predicting future care needs.
Severity Trajectories of Pediatric Inpatients Using the Criticality Index
Authors: Rivera Eduardo A. Trujillo , Patel Anita K. , Zeng-Treitler Qing , Chamberlain James M. , Bost James E. , Heneghan Julia A. , Morizono Hiroki , Pollack Murray M.
Published: September 2020

Objectives:

To assess severity of illness trajectories described by the Criticality Index for survivors and deaths in five patient groups defined by the sequence of patient care in ICU and routine patient care locations.

Design:

The Criticality Index developed using a calibrated, deep neural network, measures severity of illness using physiology, therapies, and therapeutic intensity. Criticality Index values in sequential 6-hour time periods described severity trajectories.

Setting:

Hospitals with pediatric inpatient and ICU care.

Patients:

Pediatric patients never cared for in an ICU (n = 20,091), patients only cared for in the ICU (n = 2,096) and patients cared for in both ICU and non-ICU care locations (n = 17,023) from 2009 to 2016 Health Facts database (Cerner Corporation, Kansas City, MO).

Interventions:

None.

Measurements and Main Results:

Criticality Index values were consistent with clinical experience. The median (25–75th percentile) ICU Criticality Index values (0.878 [0.696–0.966]) were more than 80-fold higher than the non-ICU values (0.010 [0.002–0.099]). Non-ICU Criticality Index values for patients transferred to the ICU were 40-fold higher than those never transferred to the ICU (0.164 vs 0.004). The median for ICU deaths was higher than ICU survivors (0.983 vs 0.875) (p < 0.001). The severity trajectories for the five groups met expectations based on clinical experience. Survivors had increasing Criticality Index values in non-ICU locations prior to ICU admission, decreasing Criticality Index values in the ICU, and decreasing Criticality Index values until hospital discharge. Deaths had higher Criticality Index values than survivors, steeper increases prior to the ICU, and worsening values in the ICU. Deaths had a variable course, especially those who died in non-ICU care locations, consistent with deaths associated with both active therapies and withdrawals/limitations of care.

Conclusions:

Severity trajectories measured by the Criticality Index showed strong validity, reflecting the expected clinical course for five diverse patient groups.
Knee Extensor and Flexor Torque Variability During Maximal Strength Testing and Change in Knee Pain and Physical Function at 60-Mo Follow-Up
Authors: Schroeder Allison , Wang Na , Felson David T. , Lewis Cora E. , Nevitt Michael C. , Segal Neil A.
Published: September 2020

As the population ages, there is a growing burden owing to musculoskeletal diseases, such as knee osteoarthritis, and subsequent functional decline. In the absence of a cure, there is a need to identify factors amenable to intervention to prevent or slow this process. The Multicenter Osteoarthritis Study cohort was developed for this purpose. In this study, associations between variability in peak knee flexor and extensor torque at baseline and worsening of pain and physical function over the subsequent 60 mos were assessed in a cohort of 2680 participants. The highest quartile of baseline knee flexor torque variability was found to be associated longitudinally with worsening pain (fourth quartile ß estimate, mean ± SE, 0.49 ± 0.19; P = 0.0115; with R
2 = 0.28 and P for trend across quartiles = 0.0370) and physical function scores (fourth quartile ß estimate, mean ± SE, 1.39 ± 0.64; P = 0.0296; with R
2 = 0.25 and P for trend across quartiles = 0.0371), after adjusting for baseline knee osteoarthritis and maximum knee flexor torque. There were no associations between baseline knee extensor torque and worsening pain or physical function by 60 mos. The presence of greater variability in maximum knee flexor strength may identify patients who may benefit from therapies aimed at preventing worsening knee pain and physical function.
The Effect of Age and Competition Level on Subtle Motor Performance in Adolescents Medically Cleared Postconcussion
Authors: Crasta Jewel E. , Raja Altamash E. , Caffo Brian S. , Hluchan Christine M. , Suskauer Stacy J.
Published: September 2020

Objective

The aim of this study was to examine the effect of age and level of competition on subtle motor performance in adolescents who have recently been medically cleared postconcussion and never-injured controls.

Design

Thirty adolescents who were recently medically cleared postconcussion (12–18 yrs) and 30 never-concussed, typically developing controls were examined using the Revised Physical and Neurological Examination of Subtle Signs (PANESS) and the Immediate Post-Concussion Assessment and Cognitive Testing.

Results

Older age was associated with better Immediate Post-Concussion Assessment and Cognitive Testing scores in both groups, whereas only the control group showed improved motor performance on the PANESS with increasing age. Adolescents across both groups participating at a higher level of competition (school or travel level) had better motor performance on the PANESS than those participating at a lower level of competition (recreational level or no sports participation). Adolescents medically cleared postconcussion had greater motor deficits on the PANESS than controls did.

Conclusion

After medical clearance, adolescents with a history of recent concussion demonstrate alterations in the relationship between motor function and age. The PANESS merits further exploration as a measure that is sensitive to factors affecting motor performance, such as age and level of athletic competition, as well as to persistent subtle motor deficits in adolescents medically cleared postconcussion.
Multicenter validation of the American Association for the Surgery of Trauma grading scale for acute cholecystitis
Authors: Schuster Kevin M. , O’Connor Rick , Cripps Michael , Kuhlenschmidt Kali , Taveras Luis , Kaafarani Haytham M. , El Hechi Majed , Puri Ruchir , Mull Jennifer , Schroeppel Thomas J. , Rodriquez Jennifer , Cullinane Daniel C. , Cullinane Laura M. , Enniss Toby M. , Sensenig Rachel , Zilberman Brian , Crandall Marie
Published: September 2020

BACKGROUND

The American Association for the Surgery of Trauma (AAST) patient assessment committee has created grading systems for emergency general surgery diseases to assist with clinical decision making and risk adjustment during research. Single-institution studies have validated the cholecystitis grading system as associated with patient outcomes. Our aim was to validate the grading system in a multi-institutional fashion and compare it with the Parkland grade and Tokyo Guidelines for acute cholecystitis.

METHODS

Patients presenting with acute cholecystitis to 1 of 8 institutions were enrolled. Discrete data to assign the AAST grade were collected. The Parkland grade was collected prospectively from the operative surgeon from four institutions. Parkland grade, Tokyo Guidelines, AAST grade, and the AAST preoperative grade (clinical and imaging subscales) were compared using linear and logistic regression to the need for surgical “bailout” (subtotal or fenestrated cholecystectomy, or cholecystostomy), conversion to open, surgical complications (bile leak, surgical site infection, bile duct injury), all complications, and operative time.

RESULTS

Of 861 patients, 781 underwent cholecystectomy. Mean (SD) age was 51.1 (18.6), and 62.7% were female. There were six deaths. Median AAST grade was 2 (interquartile range [IQR], 1–2), and median Parkland grade was 3 (interquartile range [IQR], 2–4). Median AAST clinical and imaging grades were 2 (IQR, 2–2) and 1 (IQR, 0–1), respectively. Higher grades were associated with longer operative times, and worse outcomes although few were significant. The Parkland grade outperformed the AAST grade based on area under the receiver operating characteristic curve.

CONCLUSION

The AAST cholecystitis grading schema has modest discriminatory power similar to the Tokyo Guidelines, but generally lower than the Parkland grade, and should be modified before widespread use.

LEVEL OF EVIDENCE

Diagnostic study, level IV.
Predicting Early Extubation After Liver Transplantation: External Validation and Improved Generalizability of a Proposed Fast-track Score
Authors: Haque Mohammed E. , Badenoch Adam D. , Orlov David , Selzner Markus , McCluskey Stuart A.
Published: September 2020

Background.

Early extubation of liver transplantation recipients is a cornerstone of fast-track (FT) pathways. Identifying suitable candidates has previously been accomplished using perioperative variables to develop a FT probability score. The objective of this study was to externally validate a proposed FT score.

Methods.

Following Research Ethics Board approval, data were extracted on liver transplants conducted at a single center from 2009 to 2017. Data extracted included patient characteristics, intraoperative variables, and postoperative outcome variables. The proposed FT score utilized 9 variables: age, gender, body mass index, model of end-stage liver disease, retransplant, preoperative hospital admission, blood transfusion, operative time, and vasopressor use. We calculated the FT score in our cohort, and assessed the discrimination and calibration of the model. Score performance was explored by subgroup analyses, customization and altering the outcome definition.

Results.

The FT score was found to predict higher rates of successful FT than was observed in the external cohort (n = 1385) and had reduced discrimination (area under the receiver operating curve, 0.711; 95% confidence interval, 0.682-0.741) compared with the original internal validation cohort (area under the receiver operating curve, 0.830; 95% confidence interval, 0.789-0.871; P < 0.0001). Discrimination was improved by customizing the transfusion (P < 0.0001) components of the simplified score or by level 1 customization of all regression model coefficients (P < 0.0001). A time-based definition of FT (early extubation) did not alter the accuracy of the prediction score (P = 0.914), improving the model’s generalizability.

Conclusions.

The proposed FT score may help identify patients suitable for early extubation and FT pathways after liver transplantation in conjunction with clinical judgment.
Forensic genomics of a novel Klebsiella quasipneumoniae type from a neonatal intensive care unit in China reveals patterns of colonization, evolution and epidemiology
Authors: Perlaza-Jiménez Laura , Wu Qing , Torres Von Vergel L. , Zhang Xiaoxiao , Li Jiahui , Rocker Andrea , Lithgow Trevor , Zhou Tieli , Vijaykrishna Dhanasekaran
Published: September 2020

During March 2017, a neonatal patient with severe diarrhoea subsequently developed septicaemia and died, with

Klebsiella

isolated as the causative microorganism. In keeping with infection control protocols, the coincident illness of an attending staff member and three other neonates with

Klebsiella

infection triggered an outbreak response, leading to microbiological assessment of isolates collected from the staff member and all 21 co-housed neonates. Multilocus sequence typing and genomic sequencing identified that the isolates from the 21 neonates were of a new

Klebsiella

sequence type, ST2727, and taxonomically belonged to

K. quasipneumoniae

subsp.

similipneumoniae

(formerly referred to as KpIIB). Genomic characterization showed that the isolated ST2727 strains had diverged from other

K. quasipneumoniae

subsp.

similipneumoniae

strains at least 90 years ago, whereas the neonatal samples were highly similar with a genomic divergence of 3.6 months. There was no relationship to the

Klebsiella

isolate from the staff member. This demonstrates that no transmission occurred from staff to patient or between patients. Rather, the data suggest that ST2727 colonized each neonate from a common hospital source. Sequence-based analysis of the genomes revealed several genes for antimicrobial resistance and some virulence features, but suggest that ST2727 is neither extremely-drug resistant nor hypervirulent. Our results highlight the clinical significance and genomic properties of ST2727 and urge genome-based measures be implemented for diagnostics and surveillance within hospital environments. Additionally, the present study demonstrates the need to scale the power of genomic analysis in retrospective studies where relatively few samples are available.
Treatment with an Anti-CK2 Synthetic Peptide Improves Clinical Response in Covid-19 Patients with Pneumonia. A Randomized and Controlled Clinical Trial
Authors: Cruz Leticia R. , Baladrón Idania , Rittoles Aliusha , Díaz Pablo A. , Valenzuela Carmen , Santana Raúl , Vázquez Maria M. , García Ariadna , Chacón Deyli , Thompson Delvin , Perera Gustavo , González Ariel , Reyes Rafael , Torres Loida , Pérez Jesus , Valido Yania , Rodriguez Ralysmay , Vázquez Dania M. , Rosales Mauro , Ramón Ailyn C. , Pérez George V. , Guillén Gerardo , Muzio Verena , Perera Yasser , Perea Silvio E. ,   for the ATENEA-Co-300 group
Published: September 2020

Purpose

The instrumental role of CK2 in the SARS-Cov2 infection has pointed out this protein kinase as a promising therapeutic target in Covid-19. Anti-SARS-Cov2 activity has been reported by CK2 inhibitors in vitro; however, any anti-CK2 clinical approach has been investigated in Covid-19. This exploratory trial aimed to explore safety and putative clinical benefit of CIGB-325, an anti-CK2 peptide previously assessed in cancer.

Methods

A monocentric, parallel group design, therapeutic exploratory trial of intravenous CIGB-325 in adults hospitalized with Covid-19 was performed. Twenty patients were randomly assigned to receive CIGB-325 (2.5 mg/kg/day during 5-consecutive days) plus standard-of-care (10 patients) or standard-of-care (10 patients). Adverse events were classified by the WHO Adverse Reaction Terminology. Parametric and non-parametric statistical analyses were performed according to the type of variable. Considering the small sample size, differences between groups were estimated by Bayesian analysis.

Findings

CIGB-325 induced transient mild and/or moderate adverse events like pruritus, flushing and rash in some patients. Both therapeutic regimens were similar respect to SARS-Cov2 clearance in nasopharynx swabs over the time. However, CIGB-325 significantly reduced the median number of pulmonary lesions (9.5 to 5.5, p = 0.042) at day 7 and proportion of patients with such effect was also higher according to Bayesian analysis (pDif > 0; 0.951). Additionally, CIGB-325 significantly reduced the CPK (p = 0.007) and LDH (p = 0.028) plasma levels at day 7.

Implications

Our preliminary findings suggest that this anti-CK2 clinical approach could be combined with standard-of-care in Covid-19 thus warranting larger studies.
A dual antigen ELISA allows the assessment of SARS-CoV-2 antibody seroprevalence in a low transmission setting
Authors: Hicks Sarah M. , Pohl Kai , Neeman Teresa , McNamara Hayley A. , Parsons Kate M. , He Jin-shu , Ali Sidra A. , Nazir Samina , Rowntree Louise C. , Nguyen Thi H. O. , Kedzierska Katherine , Doolan Denise L. , Vinueas Carola G. , Cook Matthew C. , Coatsworth Nicholas , Myles Paul S. , Kurth Florian , Sander Leif E. , Mann Graham J. , Gruen Russell L. , George Amee J. , Gardiner Elizabeth E. , Cockburn Ian A. ,   the SARS-CoV-2 Testing in Elective Surgery Collaborators
Published: September 2020

Estimates of seroprevalence of SARS-CoV-2 antibodies have been hampered by inadequate assay sensitivity and specificity. Using an ELISA-based approach to that combines data about IgG responses to both the Nucleocapsid and Spike-receptor binding domain antigens, we show that near-optimal sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (0 to 0.72%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.
Impact of sleep fragmentation, heart failure, and their combination, on the gut microbiome
Authors: Khannous-Lleiffe Olfat , Willis Jesse R. , Saus Ester , Cabrera-Aguilera Ignacio , Almendros Isaac , Farré Ramon , Gozal David , Farré Nuria , Gabaldón Toni
Published: September 2020

Heart failure (HF) is a common condition associated with a high rate of hospitalizations and adverse outcomes. HF is characterized by impairments of the cardiac ventricular filling and/or ejection of blood capacity. Sleep fragmentation (SF) involves a series of short sleep interruptions that lead to fatigue and contribute to cognitive impairments and dementia. Both conditions are known to be associated with increased inflammation and dysbiosis of the gut microbiota. In the present study, male mice were distributed into four groups, and subjected for four weeks to either HF, SF, both HF and SF, or left unperturbed as controls. We used 16S metabarcoding to assess fecal microbiome composition before and after the experiments. Evidence for distinct alterations in several bacterial groups and an overall decrease in alpha diversity emerged in HF and SF treatment groups. Combined HF and SF conditions, however, showed no synergism, and observed changes were not always additive, suggesting that some of the individual effects of either HF or SF cancel each other out when applied concomitantly.

IMPORTANCE

The study demonstrates the potential of the gut microbiome as a source of molecular markers for the diagnosis, prevention, and treatment of both heart failure and sleep fragmentation conditions in isolation. Our results provide the first evidence of an antagonistic effect of the presence of both conditions in the gut microbiome dysbiosis, showing an attenuation of the alterations that are observed when considering them separately.
Impact of SARS-CoV-2 antibodies at delivery in women, partners and newborns
Authors: Egerup Pia , Olsen Line Fich , Christiansen Ann-Marie Hellerung , Westergaard David , Severinsen Elin Rosenbek , Hviid Kathrine Vauvert Römmelmayer , Kolte Astrid Marie , Boje Amalie Dyhrberg , Bertelsen Marie-Louise Mathilde Friis , Prætorius Lisbeth , Zedeler Anne , Nielsen Josefine Reinhardt , Bang Didi , Berntsen Sine , Ethelberg-Findsen Jeppe , Storm Ditte Marie , Bello-Rodríguez Judith , Ingham Andreas , Ollé-López Joaquim , Hoffmann Eva R , Wilken-Jensen Charlotte , Krebs Lone , Jørgensen Finn Stener , Westh Henrik , Jørgensen Henrik Løvendahl , Freiesleben Nina la Cour , Svarre Nielsen Henriette
Published: September 2020

Background

Only few studies have focused on serological testing for SARS-CoV-2 in pregnant women and no previous study has investigated the frequency in partners. The aim was to investigate the frequency and impact of SARS-CoV-2 in parturient women, their partners and newborns.

Methods

From April 4thto July 3rd, 2020, all parturient women, their partners and newborns were invited to participate in the study. Participating women and partners had a pharyngeal swab and a blood sample taken at admission and immediately after delivery a blood sample was drawn from the umbilical cord. The swabs were analyzed for SARS-CoV-2 RNA by PCR and the blood samples were analyzed for SARS-CoV-2 antibodies. Full medical history, obstetric- and neonatal information were available.

Results

A total of 1,361 parturient women, 1,236 partners and 1,342 newborns participated in the study. No associations between previous COVID-19 disease and obstetric- or neonatal complications were found. The adjusted serological prevalence was 2.9% in women and 3.8% in partners. The frequency of blood type A was significantly higher in women with antibodies compared to women without antibodies. 17 newborns had SARS-CoV-2 IgG antibodies, and none had IgM antibodies. Full serological data from 1,052 families showed an absolute risk of infection of 0.37 if the partner had antibodies. Only 55% of individuals with antibodies reported symptoms.

Conclusion

This large prospective cohort study reports no association between COVID-19 and obstetric- or neonatal complications. The family pattern showed a substantial increase in absolute risk for women living with a partner with antibodies.
Saliva cell type DNA methylation reference panel for epidemiology studies in children
Authors: Middleton Lauren Y. M. , Dou John , Fisher Jonah , Heiss Jonathan A. , Nguyen Vy K. , Just Allan C. , Faul Jessica , Ware Erin B. , Mitchell Colter , Colacino Justin A. , Bakulski Kelly M.
Published: September 2020

Saliva is a widely used biological sample, especially in pediatric research, containing a heterogenous mixture of immune and epithelial cells. Associations of exposure or disease with saliva DNA methylation can be influenced by cell-type proportions. Here, we developed a saliva cell-type DNA methylation reference panel to estimate interindividual cell-type heterogeneity in whole saliva studies. Saliva was collected from 22 children (7-16 years) and sorted into immune and epithelial cells, using size exclusion filtration and magnetic bead sorting. DNA methylation was measured using the Illumina MethylationEPIC BeadChip. We assessed cell-type differences in DNA methylation profiles and tested for enriched biological pathways. Immune and epithelial cells differed at 164,793 (20.7%) DNA methylation sites (t-test p < 10-8). Immune cell hypomethylated sites mapped to genes enriched for immune pathways (p < 3.2 × 10-5). Epithelial cell hypomethylated sites were enriched for cornification (p = 5.2 × 10-4), a key process for hard palette formation. Saliva immune and epithelial cells have distinct DNA methylation profiles which can drive whole saliva DNA methylation measures. A primary saliva DNA methylation reference panel, easily implemented with an R package, will allow estimates of cell proportions from whole saliva samples and improve epigenetic epidemiology studies by accounting for measurement heterogeneity by cell-type proportions.
SARS-CoV-2 N-antigenemia: A new COVID-19 marker and a potential alternative to nucleic acid amplification techniques
Authors: Le Hingrat Quentin , Visseaux Benoit , Laouenan Cédric , Tubiana Sarah , Bouadma Lila , Yazdanpanah Yazdan , Duval Xavier , Ichou Houria , Damond Florence , Bertine Mélanie , Benmalek Nabil ,   French COVID cohort management committee,   CoV-CONTACT study group, Choquet Christophe , Timsit Jean-François , Ghosn Jade , Charpentier Charlotte , Descamps Diane , Houhou-Fidouh Nadhira
Published: September 2020

Background

Molecular assays on nasopharyngeal swabs remain the cornerstone of COVID-19 diagnostic. Despite massive worldwide efforts, the high technicalities of nasopharyngeal sampling and molecular assays, as well as scarce resources of reagents, limit our testing capabilities. Several strategies failed, to date, to fully alleviate this testing process (e.g. saliva sampling or antigen testing on nasopharyngeal samples). We assessed the performances of a new ELISA microplate assay quantifying SARS-CoV-2 nucleocapsid antigen (N-antigen) in serum or plasma.

Methods

The specificity of the assay, determined on 63 non-COVID patients, was 98.4% (95% confidence interval [CI], 85.3 to 100). Performances were determined on 227 serum samples from 165 patients with RT-PCR confirmed SARS-CoV-2 infection included in the French COVID and CoV-CONTACT cohorts.

Findings

Sensitivity was 132/142, 93.0% (95% CI, 84.7 to 100), within the first two weeks after symptoms onset. A subset of 73 COVID-19 patients had a serum collected within 24 hours following or preceding a positive nasopharyngeal swab. Among patients with high nasopharyngeal viral loads, Ct value below 30 and 33, only 1/50 and 4/67 tested negative for N-antigenemia, respectively. Among patients with a negative nasopharyngeal RT-PCR, 8/12 presented positive N-antigenemia. The lower respiratory tract was explored for 6/8 patients, showing positive PCR in 5 cases.

Interpretation

This is the first demonstration of the N-antigen antigenemia during COVID-19. Its detection presented a robust sensitivity, especially within the first 14 days after symptoms onset and high nasopharyngeal viral loads. These findings have to be confirmed with higher representation of outpatients. This approach could provide a valuable new option for COVID-19 diagnosis, only requiring a blood draw and easily scalable in all clinical laboratories.
Predicting clinical outcome with phenotypic clusters in COVID-19 pneumonia: an analysis of 12,066 hospitalized patients from the Spanish registry SEMI-COVID-19
Authors: Rubio-Rivas Manuel , Corbella Xavier , Mora-Luján José María , Amigo Jose Loureiro , Sampalo Almudena López , Bergua Carmen Yera , Atiénzar Pedro Jesús Esteve , Díez García Luis Felipe , Ferrer Ruth Gonzalez , Canteli Susana Plaza , Piñeiro Antía Pérez , Rodríguez Begoña Cortés , Vidal Leyre Jorquer , Catalán Ignacio Pérez , Tellez Marta Leon , Martín Oterino José Ángel , González María Candelaria Martín , Serrano Carrillo de Albornoz José Luis , Sardon Eva Garcia , Pedrajas José Nicolás Alcalá , Diez-Canseco Anabel Martin-Urda , Giner MaJosé Esteban , Gómez Pablo Tellería , Gómez-Huelgas Ricardo , Ramos-Rincón José Manuel ,   for the SEMI-COVID-19 Network
Published: September 2020

(1) Background

This study aims to identify different clinical phenotypes in COVID-19 pneumonia using cluster analysis and to assess the prognostic impact among identified clusters in such patients.

(2) Methods

Cluster analysis including 11 phenotypic variables was performed in a large cohort of 12,066 COVID-19 patients, collected and followed-up from March 1, to July 31, 2020, from the nationwide Spanish SEMI-COVID-19 Registry.

(3) Results

Of the total of 12,066 patients included in the study, most were males (7,052, 58.5%) and Caucasian (10,635, 89.5%), with a mean age at diagnosis of 67 years (SD 16). The main pre-admission comorbidities were arterial hypertension (6,030, 50%), hyperlipidemia (4,741, 39.4%) and diabetes mellitus (2,309, 19.2%). The average number of days from COVID-19 symptom onset to hospital admission was 6.7 days (SD 7). The triad of fever, cough, and dyspnea was present almost uniformly in all 4 clinical phenotypes identified by clustering. Cluster C1 (8,737 patients, 72.4%) was the largest, and comprised patients with the triad alone. Cluster C2 (1,196 patients, 9.9%) also presented with ageusia and anosmia; cluster C3 (880 patients, 7.3%) also had arthromyalgia, headache, and sore throat; and cluster C4 (1,253 patients, 10.4%) also manifested with diarrhea, vomiting, and abdominal pain. Compared to each other, cluster C1 presented the highest in-hospital mortality (24.1% vs. 4.3% vs. 14.7% vs. 18.6%; p<0.001). The multivariate study identified phenotypic clusters as an independent factor for in-hospital death.

(4) Conclusion

The present study identified 4 phenotypic clusters in patients with COVID-19 pneumonia, which predicted the in-hospital prognosis of clinical outcomes.
Predictors of characteristics associated with negative first SARS-CoV-2 PCR testing despite final diagnosis of COVID-19, and association with treatment and outcomes. The COVID-19 RT-PCR Study
Authors: Lascarrou Jean-Baptiste , Colin Gwenhael , Le Thuaut Aurélie , Serck Nicolas , Ohana Mickael , Sauneuf Bertrand , Geri Guillaume , Mesland Jean-Baptiste , Ribeyre Gaetane , Hussenet Claire , Sophie Boureau Anne , Gille Thomas
Published: September 2020

Background

Reverse transcriptase-polymerase chain reaction (RT-PCR) testing is an important tool for the diagnosis of coronavirus disease 2019 (COVID-19). However, performance concerns have recently emerged, especially about its sensitivity.. We hypothesized that clinical, biological and radiological characteristics of patients with false negative first RT-PCR testing, despite final diagnosis of COVID-19, might differ from patients with positive first RT-PCR.

Methods

Case – control, multicenter study in which COVID-19 patients with negative first RT-PCR testing were matched to patients with positive first RT-PCR on age, gender and initial admission unit (ward or intensive care).

Results

Between March 30, and June 22, 2020, 80 cases and 80 controls were included. Neither proportion of death at hospital discharge, nor duration of hospital length stay differed between “case” and “control” patients (P = 0.80 and P = 0.54, respectively). In multivariate analysis, headache (adjusted OR: 0.07 [0.01; 0.49]; P = 0.007) and fatigue/malaise (aOR: 0.16 [0.03; 0.81]; P = 0.027) were associated with lower risk of false negative, whereas platelets > 207.103.mm−3 (aOR: 3.81 [1.10; 13.16]; P = 0.034) and CRP > 79.8 mg.L−1 (aOR: 4.00 [1.21; 13.19]; P = 0.023) were associated with higher risk of false negative.

Interpretation

Patients with suspected COVID-19 and higher inflammatory biological signs expected higher risk of false negative RT-PCR testing. Strategy of serial RT-PCR testings must be rigorously evaluated before adoption by clinicians.
Containment to outbreak tipping points in COVID-19
Authors: Arim Matías , Herrera-Esposito Daniel , Bermolen Paola , Cabana Álvaro , Fariello María Inés , Lima Mauricio , Romero Hector
Published: September 2020

Non-pharmaceutical interventions (NPIs) have been a cornerstone in managing emergent diseases such as COVID-191–4. However, despite their potential to contain or attenuate the epidemic, the effects of NPIs on disease dynamics are not well understood1,5–7. We show that saturation of NPIs with the increase in infected individuals, an expected consequence of limited contact tracing and healthcare capacities, produces a positive feedback in the disease growth rate and a threshold between two alternative states--containment and outbreak8. These alternative states were previously related with the strength of NPIs but not with the infection number2,9–11. Furthermore, the transition between these states involves an abrupt acceleration in disease dynamics, which we report here for several COVID-19 outbreaks around the world. The consequences of a positive feedback in population dynamics at low numbers is a phenomenon widely studied in ecology--the Allee effect. This effect is a determinant of extinction-outbreak states, geographic synchronization, spatial spread, and the effect of exogenous variables, as vaccination12–15. As countries are relaxing containing measures, recognizing an NPI-induced Allee effect may be essential for deploying containment strategies within and among countries16 and acknowledges the need for early warning indicators of approaching epidemic tipping points17.
Cryo-EM structure ofHelicobacter pyloriurease with a novel inhibitor in the active site at 2.0 Å resolution
Authors: Cunha Eva S. , Chen Xiaorui , Gaitero Marta Sanz , Mills Deryck J. , Luecke Hartmut
Published: September 2020

Infection of the human stomach byHelicobacter pyloriremains a worldwide problem and greatly contributes to peptic ulcer disease and gastric cancer. Without active intervention approximately 50% of the world population will continue to be infected with this gastric pathogen. Current eradication, called triple therapy, entails a proton-pump inhibitor and two broadband antibiotics, however resistance to either clarithromycin or metronidazole is greater than 25% and rising. Therefore, there is an urgent need for a targeted, high-specificity eradication drug. Gastric infection byH. pyloridepends on the expression of a nickeldependent urease in the cytoplasm of the bacteria. Here, we report the 2.01 Å resolution structure of the 1.1 MDa urease in complex with a novel inhibitor by cryo-electron microscopy and compare it to a β-mercaptoethanol-inhibited structure at 2.45 Å resolution. The structural information is of sufficient detail to aid in the development of inhibitors with high specificity and affinity.
Oncogenic KRAS engages an RSK1/NF1 complex in pancreatic cancer
Authors: Cheng Derek K. , Oni Tobiloba E. , Park Youngkyu , Thalappillil Jennifer S. , Ting Hsiu-Chi , Alagesan Brinda , Prasad Nadia , Rivera Keith D. , Pappin Darryl J. , Van Aelst Linda , Tuveson David A.
Published: September 2020

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC.

Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways and toxicity due to the targeting of normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil new potential therapeutic targets. Here, we used proximity labelling to identify protein interactors of active KRAS in PDAC cells. Fusions of wildtype (BirA-KRAS4B), mutant (BirA-KRAS4BG12D) and non-transforming and cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase were expressed in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 was enriched among proteins that selectively interacted with membrane-bound KRASG12D. RSK1 required the NF1 and SPRED proteins to interact with KRAS-GTP at the membrane. In both murine and human PDAC lines, membrane-targeted RSK1 was tolerated but inhibited cell proliferation following oncogenic KRAS abrogation to reveal a negative feedback role for membrane-localized RSK1 on wild-type KRAS. Inhibition of the wild-type KRAS, which has been previously proposed to suppress KRAS oncogenesis, may partially explain how RSK1 has been identified as a dependency in some KRAS mutant cells and may provide an additional function for NF1 in tumorigenesis.

Significance Statement

For decades, KRAS interactors have been sought after as potential therapeutic targets in KRAS mutant cancers, especially pancreatic adenocarcinoma (PDAC). Our proximity labeling screen with KRAS in PDAC cells highlight RSK1 as a notable mutant-specific interactor. Functionally, we show that RSK1 mediates negative feedback on wild-type KRAS in PDAC cells.
Low hatching success in the critically endangered kākāpō (Strigops habroptilus) is driven by early embryo mortality not infertility
Authors: Savage James L. , Crane Jodie M. S. ,   Kākāpō Recovery Team, Hemmings Nicola
Published: September 2020

In many endangered species, reproductive failure is a major barrier to recovery. The critically endangered kākāpō (Strigops habroptilus) exemplifies this challenge: 61% of their eggs fail to hatch, and of these 73% show no sign of development. Undeveloped eggs have previously been attributed to male infertility, but recent studies of non-threatened bird species suggest fertilisation failure is rare in the wild. The underlying causes of fertilisation failure and embryo death differ, so distinguishing between them is essential for effective conservation management. Here we show that the majority (72%, n=124) of undeveloped kākāpō eggs are fertilised, and combine this with conservation programme data on natural copulations, artificial inseminations, and paternity of developed eggs, to generate the most precise estimate to date of fertility in a wild population. We also demonstrate, for the first time in a wild bird, that artificial insemination results in greater numbers of sperm reaching the egg.
Peptide location fingerprinting reveals modification-associated biomarkers of ageing in human tissue proteomes
Authors: Ozols Matiss , Eckersley Alexander , Mellody Kieran T , Mallikarjun Venkatesh , Warwood Stacey , O’Cualain Ronan , Knight David , Watson Rachel EB , Griffiths Christopher EM , Swift Joe , Sherratt Michael J
Published: September 2020

Although dysfunctional protein homeostasis (proteostasis) is a key factor in many age-related diseases, the untargeted identification of structural modifications in proteins remains challenging. Peptide location fingerprinting is a proteomic analysis technique capable of identifying structural modification-associated differences in mass spectrometry (MS) datasets of complex biological samples. A new webtool (Manchester Peptide Location Fingerprinter), applied to photoaged and intrinsically aged skin proteomes, can relatively quantify peptides (spectral counting) and map statistically significant differences to regions within protein structures. New photoageing biomarkers were identified in multiple proteins including matrix components (collagens and proteoglycans), oxidation and protease modulators (peroxiredoxins and SERPINs) and cytoskeletal proteins (keratins). Crucially, for many extracellular biomarkers, structural modification-associated differences were not correlated with relative abundance (by ion intensity). By applying peptide location fingerprinting to published MS datasets, (identifying biomarkers including collagen V and versican in ageing tendon) we demonstrate the potential of the MPLF webtool to discover novel biomarkers.
A high-affinity calmodulin-binding site in the CyaA toxin translocation domain is essential for invasion into eukaryotic cells
Authors: Voegele Alexis , Sadi Mirko , O’Brien Darragh P , Gehan Pauline , Raoux-Barbot Dorothée , Davi Maryline , Hoos Sylviane , Brûlé Sébastien , Raynal Bertrand , Weber Patrick , Mechaly Ariel , Haouz Ahmed , Rodriguez Nicolas , Vachette Patrice , Durand Dominique , Brier Sébastien , Ladant Daniel , Chenal Alexandre
Published: September 2020

The molecular mechanisms and forces involved in the translocation of bacterial toxins into host cells have thus far remained elusive. The adenylate cyclase (CyaA) toxin fromBordetella pertussisdisplays a unique intoxication pathway in which its catalytic domain is directly translocated across target cell membranes. We have previously identified a translocation region in CyaA that contains a segment, P454 (residues 454–484), exhibiting membrane-active properties related to antimicrobial peptides. Herein, we show that this peptide is able to translocate across membranes and interact with calmodulin. Structural and biophysical analyses have revealed the key residues of P454 involved in membrane destabilization and calmodulin binding. Mutational analysis demonstrated that these residues play a crucial role in CyaA translocation into target cells. We have also shown that calmidazolium, a calmodulin inhibitor, efficiently blocks CyaA internalization. We propose that after CyaA binding to target cells, the P454 segment destabilizes the plasma membrane, translocates across the lipid bilayer and binds calmodulin. Trapping of the CyaA polypeptide chain by the CaM:P454 interaction in the cytosol may assist the entry of the N-terminal catalytic domain by converting the stochastic process of protein translocation into an efficient vectorial chain transfer into host cells.