bluuebunny/crossref_metadata_2025 huggingface dataset:
Geometric Profiling of Corneal Limbal Dermoids for the Prediction of Surgical Outcomes
Authors: Kim Kyoung Woo , Kim Mee Kum , Khwarg Sang In , Oh Joo Youn
Published: July 2020

Purpose:

To search for novel geometric parameters for corneal limbal dermoids that enable the prediction of clinical and surgical outcomes.

Methods:

We reviewed the medical records and anterior segment photographs of 85 eyes of 85 patients with corneal limbal dermoids that had been surgically excised. Patients were assigned to the following 4 cohorts (multiple assignments allowed): postoperative visual acuity (cohort 1, n = 65), amblyopia (cohort 2, n = 67), postoperative scar formation (cohort 3, n = 51), and preoperative spontaneous progression of dermoids (cohort 4, n = 39). For geometric profiling, 11 geometric parameters of lesions, including orientation, angular width, and 9 ratio parameters, were preoperatively defined in each patient based on the digital anterior-segment photographs. Each geometric parameter and demographic variable were analyzed for correlation with postoperative outcomes (cohorts 1–3) and preoperative spontaneous dermoid progression (cohort 4).

Results:

The mean patient age at surgery was 6.0 ± 6.3 years. Among the geometric and demographic parameters analyzed, the invaded angular axis of dermoid to corneal diameter ratio had the highest r coefficient (r = 0.728) in cohort 1 and best stratified patients in cohort 2 (cutoff > 0.48) and cohort 3 (cutoff > 0.56). No parameters were correlated with spontaneous dermoid progression in cohort 4.

Conclusions:

We devised geometric parameters to evaluate corneal limbal dermoids before surgery for the prediction of surgical outcomes. The invaded angular axis of dermoid to corneal diameter ratio value was the most significant factor associated with postoperative visual acuity, amblyopia development, and postoperative scarring.
A Patient With Bilateral Conjunctivitis Positive for SARS-CoV-2 RNA in a Conjunctival Sample
Authors: Sirakaya Ender , Sahiner Mustafa , Aslan Sirakaya Hatice
Published: July 2020

Purpose:

To present a patient with bilateral conjunctivitis, testing positive for viral RNA of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in both nasopharyngeal and conjunctival samples.

Methods:

A 40-year-old man with bilateral acute conjunctivitis and suspicious signs of coronavirus disease 2019 (COVID-19) presented to the hospital. A detailed ophthalmic examination was performed. Samples obtained from conjunctival and nasopharyngeal swabs were tested by reverse transcription PCR (RT-PCR) for the detection of SARS-CoV-2 virus. Ocular findings and duration of the presence of viral RNA in the conjunctival specimens were evaluated at follow-up visits.

Results:

Slit-lamp biomicroscopy revealed bilateral acute follicular conjunctivitis. The RT-PCR assay demonstrated the presence of viral RNA in the nasopharyngeal and conjunctival specimens at the initial visit and at the 4-day follow-up. Conjunctivitis findings were decreased after 4 days and recovered completely without any sequelae within10 days. The PCR results of both nasopharyngeal and conjunctiva specimens were negative for the viral RNA at 10 days.

Conclusions:

Bilateral conjunctivitis is rare in patients infected with COVID-19. Although it is difficult to detect viral RNA from conjunctival swabs, conjunctival secretions may be a source of contamination, and protective measures must be taken.
Pediatric Inflammatory Multisystem Syndrome With Central Nervous System Involvement and Hypocomplementemia Following SARS-COV-2 Infection
Authors: Regev Tslil , Antebi Maayan , Eytan Danny , Shachor-Meyouhas Yael , Ilivitzki Anat , Aviel Yonatan Butbul , Ben-Ari Josef
Published: July 2020

Pediatric inflammatory multisystem syndromes associated with Severe Acute Respiratory Syndrome Coronavirus 2 are emerging in recent reports. We describe a patient with critical illness consistent with atypical Kawasaki disease with cardiac dysfunction and abdominal involvement presenting weeks after Severe Acute Respiratory Syndrome Coronavirus 2 infection. Our patient showed unique central nervous system involvement with small vessel vasculitis and profound hypocomplementemia, both not previously reported in case descriptions and may hint at possible disease mechanisms.
Understanding the relationship between features associated with pain-related disability in people with painful temporomandibular disorder: an exploratory structural equation modeling approach
Authors: Miller Vanessa E. , Chen Ding-Geng , Barrett Deborah , Poole Charles , Golightly Yvonne M. , Sanders Anne E. , Ohrbach Richard , Greenspan Joel D. , Fillingim Roger B. , Slade Gary D.
Published: July 2020

Pain-related disability is a multifaceted construct that refers to the impact of pain on an individual's capacity to fulfill their self-defined and social roles. This research examined the relationship between clinical, psychological, and pain sensitivity factors and pain-related disability among adults with chronic temporomandibular disorder (TMD). We analyzed data from a cross-sectional community-based sample of 1088 men and women with chronic TMD. We first constructed and tested a measure of pain-related disability (ie, pain impact), including a variable assessing presenteeism, created measurement models of jaw limitation, psychological unease (negative affect, somatic symptoms, and catastrophizing), and experimental pain sensitivity (eg, pressure pain threshold, thermal tolerance, and mechanical pressure pain threshold). Subsequently, latent variables were combined in a structural equation model. Participants (n = 1088) were 18 to 44 years old (mean 29.2, SD ± 7.8) whose chronic TMD had persisted, on average, for 6.9 years (SD ± 6.4). A model of pain-related disability, jaw limitation, and psychological unease was created and refined with exploratory model revisions to account for correlation among variables. Estimation of the final model indicated excellent fit with the data (root-mean-square error of approximation = 0.048, root-mean-square error of approximation 90% confidence interval [CI] 0.043-0.053, comparative fit index = 0.956, standardized root-mean-square residual = 0.040). Jaw functional limitation and psychological unease was strongly related to pain-related disability. Experimental pain sensitivity was removed from our model because of weak direct effect and the burden of performing experimental pain sensitivity testing in a clinical setting. The final model explained 78% of the variance in pain-related disability.
Patient Length of Stay Under the Two-Midnight Rule: Assessing the Accuracy of Providers’ Predictions
Authors: Lindor Rachel A. , Bellolio Fernanda , Madsen Bo E. , Newman James S. , Lohse Christine M. , Jeffery Molly M. , Boon Ashton L. , Goyal Deepi G. , Sadosty Annie T.
Published: July 2020

EXECUTIVE SUMMARY

We sought to determine emergency medicine physicians’ accuracy in designating patients’ disposition status as “inpatient” or “observation” at the time of hospital admission in the context of Medicare’s Two-Midnight rule and to identify characteristics that may improve the providers’ predictions. We conducted a 90-day observational study of emergency department (ED) admissions involving adults aged 65 years and older and assessed the accuracy of physicians’ disposition decisions. Logistic regression models were fit to explore associations and predictors of disposition. A total of 2,257 patients 65 and older were admitted through the ED. The overall error rate in physician designation of observation or inpatient was 36%. Diagnoses most strongly associated with stays lasting less than two midnights included diverticulitis, syncope, and nonspecific chest pain. Diagnoses most strongly associated with stays lasting two or more midnights included orthopedic fractures, biliary tract disease, and back pain. ED physicians inaccurately predicted patient length of stay in more than one third of all patients. Under the Two-Midnight rule, these inaccurate predictions place hospitals at risk of underpayment and patients at risk of significant financial liability. Further work is needed to increase providers’ awareness of the financial repercussions of their admission designations and to identify interventions that can improve prediction accuracy.
Using Technology to Combat Clinician Burnout
Authors: Davis Matthew J.
Published: July 2020

EXECUTIVE SUMMARY

Physician burnout is a major problem affecting healthcare providers. It not only influences clinician mental health but also clinical outcomes, patient satisfaction, and the financial standing of a health system. A combination of web and mobile applications can be used to treat clinician burnout by effectively reducing stress, anxiety, and depression. When included in a well-structured program, these technology-based tools provide improved access to mental health treatments for clinicians, help remove the stigma of therapy, and reduce clinician burnout caused by job stressors.
Fire Service Organizational-Level Characteristics Are Associated With Adherence to Contamination Control Practices in Florida Fire Departments
Authors: Louzado-Feliciano Paola , Griffin Kevin A. , Santiago Katerina M. , Schaefer Solle Natasha , Koru-Sengul Tulay , Grant Casey , Niemczyk Neal , Lee David J. , Kobetz Erin N. , Caban-Martinez Alberto J.
Published: July 2020

Objectives:

To characterize the types of contamination control practices followed by Florida fire departments and examine the association between fire department organizational-level characteristics and adherence to contamination control practices.

Methods:

Using a cross-sectional study design, a survey was administered to 142 Florida firefighters. Validated survey measures assessed organizational level characteristics and 32 recommended national contamination control practices.

Results:

An average of 18.9 contamination control practices (standard deviation = 5.54; min = 3; max = 30) were reported by fire departments of which, wearing personal protective equipment (PPE) according to manufacturer instructions (98.9%) and access to special machine for cleaning (91%) were most cited. Fire departments with one or more health and safety officers had significantly higher implementation of contamination control practices (P = 0.032).

Conclusion:

Health and safety officers may have a positive impact on the number of contamination control practices followed in Florida fire departments.
Vedolizumab Trough Levels in Children With Anti‐Tumor Necrosis Factor Refractory Inflammatory Bowel Disease
Authors: Aardoom Martine A. , Jongsma Maria M.E. , de Vries Annick , Wolthoorn Jasja , de Ridder Lissy , Escher Johanna C.
Published: July 2020

Objectives:

Inflammatory bowel disease (IBD) can be successfully treated with vedolizumab. Studies in adult IBD patients have shown that differences in response to vedolizumab may be related to variability in vedolizumab trough levels, but in children with pediatric‐onset IBD data regarding vedolizumab trough levels are not available. Thus far, the role of trough levels in pediatric‐onset IBD treatment remains unclear. We aimed to investigate predictors of vedolizumab trough levels in pediatric‐onset IBD patients.

Methods:

Data from anti‐tumor necrosis factor refractory pediatric‐onset IBD patients who received vedolizumab were collected retrospectively. Vedolizumab trough levels were measured in serum samples collected before each infusion. A linear mixed model was conducted to analyze factors that influence trough levels.

Results:

Twenty‐six pediatric‐onset IBD patients (14 ulcerative colitis [UC]), 9 Crohn Disease [CD], 3 IBD‐unclassified [IBD‐U]) received 258 vedolizumab infusions. Mean vedolizumab trough level at week 6 was 29.9 μg/mL (SD 17.8), and 11.5 μg/mL (SD 4.9) during maintenance therapy. CD patients had significantly lower trough levels than IBD‐U patients (β 15.2; 95% confidence interval [CI] −1.1 to 29.2; P = 0.036). Higher fecal calprotectin (β −0.009; 95% CI −0.02 to −0.003; P = 0.007) and C‐reactive protein levels (β −0.4; 95% CI −0.72 to −0.04; P = 0.027) were associated with lower trough levels, whereas shortening of time between infusions led to higher trough levels (β −0.77; 95% CI −0.9 to 0.64; P < 0.001).

Conclusions:

In this group of pediatric‐onset IBD patients, trough levels were significantly lower in CD patients compared with UC/IBD‐U patients. Higher levels of inflammatory markers were associated with lower vedolizumab trough levels.
Intervention and Mechanisms of Alanyl‐glutamine for Inflammation, Nutrition, and Enteropathy
Authors: Moore Sean R. , Quinn Laura A. , Maier Elizabeth A. , Guedes Marjorie M. , Quetz Josiane S. , Perry Madeline , Ramprasad Chethan , Lanzarini Lopes Gabriela M.L. , Mayneris‐Perxachs Jordi , Swann Jonathan , Soares Alberto M. , Filho José Q. , Junior Francisco S. , Havt Alexandre , Lima Noelia L. , Guerrant Richard L. , Lima Aldo A.M.
Published: July 2020

Objective:

Determine the minimum dosage of alanyl‐glutamine (Ala‐Gln) required to improve gut integrity and growth in children at risk of environmental enteropathy (EE).

Methods:

This was a double‐blinded randomized placebo‐controlled dose‐response trial. We enrolled 140 children residing in a low‐income community in Fortaleza, Brazil. Participants were 2 to 60 months old and had weight‐for‐age (WAZ), height‐for‐age (HAZ), or weight‐for‐height (WHZ) z‐scores less than −1. We randomized children to 10 days of nutritional supplementation: Ala‐Gln at 3 g/day, Ala‐Gln at 6 g/day, Ala‐Gln at 12 g/day, or an isonitrogenous dose of glycine (Gly) placebo at 12.5 g/day. Our primary outcome was urinary lactulose‐mannitol excretion testing. Secondary outcomes were anthropometry, fecal markers of inflammation, urine metabolic profiles, and malabsorption (spot fecal energy).

Results:

Of 140 children, 103 completed 120 days of follow‐up (24% dropout). In the group receiving the highest dose of Ala‐Gln, we detected a modest improvement in urinary lactulose excretion from 0.19% on day 1 to 0.17% on day 10 (P = 0.05). We observed significant but transient improvements in WHZ at day 10 in 2 Ala‐Gln groups, and in WHZ and WAZ in all Ala‐Gln groups at day 30. We detected no effects on fecal inflammatory markers, diarrheal morbidity, or urine metabolic profiles; but did observe modest reductions in fecal energy and fecal lactoferrin in participants receiving Ala‐Gln.

Conclusions:

Intermediate dose Ala‐Gln promotes short‐term improvement in gut integrity and ponderal growth in children at risk of EE. Lower doses produced improvements in ponderal growth in the absence of enhanced gut integrity.
Rapid Increase in Clearance of Phenobarbital in Neonates on Extracorporeal Membrane Oxygenation: A Pilot Retrospective Population Pharmacokinetic Analysis
Authors: Michaličková Danica , Pokorná Pavla , Tibboel Dick , Slanař Ondřej , Knibbe Catherijne A. J. , Krekels Elke H. J.
Published: July 2020

Objectives:

This study characterizes the changes in the pharmacokinetics of phenobarbital associated with extracorporeal membrane oxygenation treatment in neonates, to illustrate our findings and provide guidance on dosing.

Design:

Retrospective pilot population pharmacokinetic analysis.

Setting:

Neonatal ICU.

Patients:

Thirteen critically ill neonates (birth body weight, 3.21 kg [2.65–3.72 kg]; postnatal age at start of treatment: 2 d [0–7 d]; gestational age: 38 wk [38–41 wk]) receiving venovenous or venoarterial extracorporeal membrane oxygenation.

Interventions:

Phenobarbital administered in a loading dose of 7.5 mg/kg (8.5–16 mg/kg) and maintenance dose of 6.9 mg/kg/d (4.5–8.5 mg/kg/d).

Measurements and Main Results:

Therapeutic drug monitoring data were available, yielding 5, 31, and 19 phenobarbital concentrations before, during, and after extracorporeal membrane oxygenation, respectively. Population pharmacokinetic analysis was performed using NONMEM 7.3.0 (ICON Development Solutions, Ellicott City, MD). Maturation functions for clearance and volume of distribution were obtained from literature. In a one-compartment model, clearance and volume of distribution for a typical neonate off extracorporeal membrane oxygenation and with a median birth body weight (3.21 kg) at median postnatal age (2 d) were 0.0096 L/hr (relative se = 11%)) and 2.72 L (16%), respectively. During extracorporeal membrane oxygenation, clearance was found to linearly increase with time. Upon decannulation, phenobarbital clearance initially decreased and subsequently increased slowly driven by maturation. Extracorporeal membrane oxygenation-related changes in volume of distribution could not be identified, possibly due to sparse data collection shortly after extracorporeal membrane oxygenation start. According to the model, target attainment is achieved in the first 12 days of extracorporeal membrane oxygenation with a regimen of a loading dose of 20 mg/kg and a maintenance dose of 4 mg/kg/d divided in two doses with an increase of 0.25 mg/kg every 12 hours during extracorporeal membrane oxygenation treatment.

Conclusions:

We found a time-dependent increase in phenobarbital clearance during the first 12 days of extracorporeal membrane oxygenation treatment in neonates, which results in continuously decreasing phenobarbital exposure and increases the risk of therapeutic failure over time. Due to high unexplained variability, frequent and repeated therapeutic drug monitoring should be considered even with the model-derived regimen.
Prediction of Acquired Morbidity Using Illness Severity Indices in Pediatric Intensive Care Patients*
Authors: Senna Stephanie , Ong Chengsi , Wong Judith Ju-Ming , Allen John Carson , Sultana Rehena , Lee Jan Hau
Published: July 2020

Objectives:

To assess the ability of two illness severity scores, Pediatric Logistic Organ Dysfunction Score 2 and Pediatric Index of Mortality 3, in predicting PICU-acquired morbidity.

Design:

Retrospective chart review conducted from April 2015 to March 2016.

Setting:

Single-center study in a multidisciplinary PICU in a tertiary pediatric hospital in Singapore.

Patients:

The study included all index admissions of patients 0–18 years old to the PICU during the study period.

Interventions:

None.

Measurements and Main Results:

Three outcomes were assessed at hospital discharge: mortality, survival with new morbidity defined as an increase in the Functional Status Scale score of greater than or equal to 3 points from baseline, and survival without morbidity. Of 577 consecutive admissions, 95 were excluded: 82 readmissions, 10 patients greater than or equal to 18 years old, two patients with missing baseline data, and one transferred to another PICU. Of 482 patients, there were 37 hospital deaths (7.7%) and 39 (8.1%) with acquired new morbidity. Median admission Pediatric Logistic Organ Dysfunction Score 2 and Pediatric Index of Mortality 3 scores differed among the three outcome groups. In addition, differences were found in emergency admission and neurologic diagnosis rates, PICU mechanical ventilation usage rates, and PICU length of stay. The highest proportion of neurologic diagnoses was observed in the new morbidity group. The final model simultaneously predicted risks of mortality, survival with new morbidity and survival without morbidity using admission Pediatric Logistic Organ Dysfunction Score 2 score, admission type, neurologic diagnosis, and preexisting chronic disease. Pediatric Logistic Organ Dysfunction Score 2 was superior to Pediatric Index of Mortality 3 in predicting risks of mortality and new morbidity, as indicated by volume under surface values of 0.483 and 0.362, respectively.

Conclusions:

Risk of mortality, survival with new morbidity, and survival without morbidity can be predicted simultaneously using admission Pediatric Logistic Organ Dysfunction Score 2, admission type, admission diagnosis, and preexisting chronic disease. Future independent studies will be required to validate the proposed model before clinical implementation.
What is new with hand hygiene?
Authors: Stadler Rahel Noemi , Tschudin-Sutter Sarah
Published: July 2020

Purpose of review

Healthcare-associated infections (HAIs) challenge healthcare systems worldwide. As healthcare workers’ hands are considered the main vector for transmission of pathogens, effective hand hygiene is the single most important action to prevent HAIs. We sought to highlight new developments and advances in hand hygiene.

Recent findings

Hand hygiene compliance averages at 38%. A sustained increase of compliance with a subsequent decrease of HAIs may be achieved by national, systematic and rigorous education, and auditing programs. Periodically deployed self-operating hand hygiene surveillance systems coupled with personalized reminders could facilitate such efforts. Alcohol-based hand-rub (ABHR) solutions remain the hand hygiene gold standard, but are modified in texture and composition to better meet healthcare workers’ preferences. Modifications of the hand hygiene procedure have been proposed targeting both time and technique of hand rub application. Reducing rub-time from 30 to 15 s and simplifying the technique to consist of three rather than six steps yielded encouraging results in terms of microbiological efficacy and higher compliance.

Implementation and promotion of compliance are the major concerns of today's research on hand hygiene. Developments towards better surveillance and systematic education, improved ABHR formulation and streamlining of hand hygiene actions are paving the way ahead.
Long-Term Patient-Reported Outcomes of Visual Field Defects and Compensatory Mechanisms in Patients After Cerebral Hemispherectomy
Authors: Meer Elana A. , Chen Monica F. , Jones Monika , Mathern Gary W. , Pineles Stacy L.
Published: July 2020

Background:

In cases of intractable epilepsy resistant to drug therapy, hemispherectomy is often the only treatment option to mitigate seizures; however, the true long-term subjective visual outcomes are relatively unexplored. In this study, we sought to determine and characterize patient-reported visual function years after hemispherectomy.

Methods:

This was an observational study conducted on a large cohort of children with seizure disorder treated with cerebral hemispherectomy. An online survey was sent to parents with questions to assess subjective visual function with a variety of questions from presence of visual field defects after hemispherectomy, to improvement over time, compensatory mechanisms used, and development of strabismus.

Results:

This survey was emailed to 248 parents of previously evaluated children who agreed to be re-surveyed, 48 (20%) of which responded. The average age at hemispherectomy was approximately 5 (±4) years, and the average time after hemispherectomy was 7 (±5) years. Thirty-nine patients (81%) were seizure-free after 1 surgery and 85% (n = 41) were seizure-free after ≥1 surgeries. Thirty-four (71%) experienced a visual field defect after surgery, but 25 (52%) experienced subjective improvement over time. Thirty-eight (79%) used compensatory mechanisms, such as head tilting, with 16 (33%) patients experiencing subjective improvement over time. Twenty-seven (56%) patients experienced a decrease in visual acuity after surgery with 12 (25%) experiencing subjective improvement over time.

Conclusion:

In a large cohort examining patient-reported visual outcomes years after hemispherectomy, most patients experienced strabismus and/or visual field defects. However, more than half reported improvements and compensatory mechanisms (exotropic strabismus and ipsilateral esotropic strabismus) over time, presumably to enhance visual field function. By exploring subjective visual and cognitive function, this paper uniquely characterizes patient-reported improvements over time, and provides motivation for larger longitudinal studies using more quantitative measures of visual function and improvement after hemispherectomy.
The
Endeavour
journal of Lieutenant Zachary Hicks 1768–1771
Authors: Hunting Penelope
Published: July 2020

In May 1768 Lieutenant Zachary Hicks joined His Majesty's Bark
Endeavour
under the command of Lieutenant James Cook. For the next 3 years, as the
Endeavour
circumnavigated the world, Hicks represented Cook to local governors and chiefs, he led expeditions, observed the transit of Venus at Tahiti and, whenever Cook was on shore, Hicks was in charge of the ship. In April 1770 he was the first to sight Australia and Cook named Point Hicks after him. The 250
th
anniversary of this event in 2020 and the 250
th
commemoration of Hicks's death in 2021 is an appropriate time to draw attention to his Journal.
Complex ecological interactions across a focus of cutaneous leishmaniasis in Eastern Colombia: novel description ofLeishmaniaspecies, hosts and phlebotomine fauna
Authors: Sandoval-Ramírez Claudia M. , Hernández Carolina , Teherán Aníbal A. , Gutierrez-Marin Reinaldo , Martínez-Vega Ruth A. , Morales Duvan , Hoyos-Lopez Richard , Araque-Mogollón Astrid , Ramírez Juan David
Published: July 2020

This study aimed to analyse the patterns of diversity, blood sources andLeishmaniaspecies of phlebotomines in a focus of cutaneous leishmaniasis in Arboledas, Eastern Colombia. In total, 1729 phlebotomines were captured in two localities (62.3% Siravita and 37.7% Cinera) and five environments of Norte de Santander. We identified 18 species of phlebotomines:Pintomyia ovallesi(29.8%),Psychodopygus davisi(20.3%),Pi. spinicrassa(18.5%) andLutzomyia gomezi(15.8%) showed the highest abundance. Species diversities were compared between Cinera (15.00) and Siravita (20.00) and among five microenvironments: forest remnants (19.49), coffee plantations (12.5), grassland (12.99), cane plantations (11.66) and citrus plantations (12.22).LeishmaniaDNA was detected in 5.8% (80/1380) of females, corresponding mainly toPi.ovallesi(22/80; 27.2%),Lu.gomezi(17/80; 21.3%) andPi.spinicrassa(11/80; 13.8%).Leishmaniaspecies were 63.1%L. braziliensis, 18.5%L.panamensis, 13.2%L.infantumand 6.1%L.amazonensis. The most frequent feeding sources wereHomo sapiens(50%),Bos taurus(13.8%) andCanis lupus familiaris(10.3%). This focus of cutaneous leishmaniasis has a high diversity ofLeishmania-carrying phlebotomines that feed on domestic animals. The transmission of leishmaniasis to human hosts was mainly associated withLu.gomezi,Pi.ovallesiandL.braziliensis.
Genetic analysis ofBoletus edulissuggests that intra-specific competition may reduce local genetic diversity as a woodland ages
Authors: Hoffman J. I. , Nagel R. , Litzke V. , Wells D. A. , Amos W.
Published: July 2020

Ectomycorrhizal fungi are key players in terrestrial ecosystems yet their mating systems and population dynamics remain poorly understood. We investigated the fine-scale relatedness structure and genetic diversity ofBoletus edulis, one of the world's most commercially important wild mushrooms. Microsatellite genotyping of fruiting bodies from 14 different sites around Bielefeld in Germany revealed little in the way of population structure over a geographic scale of several kilometres. However, on a more local scale we found evidence for elevated relatedness as well as inbreeding. We also observed a significant negative association between the genetic diversity of fruit and the age of the trees under which they were sampled. Taken together, our results suggest that as genets mature, they compete and potentially create conditions under which further spores struggle to become established. By implication, even though this species is widely picked, propagules remain common enough to create strong competition when new habitats become available.
Association between temporal muscle thickness and clinical outcomes in patients with newly diagnosed glioblastoma
Authors: An Geon , Ahn Stephen , Park Jae-Sung , Jeun Sin-Soo , Hong Yong-Kil
Published: July 2020

Purpose

Temporal muscle thickness (TMT) has been suggested as a novel biomarker that can represent sarcopenia in head and neck malignancies. This study investigated the association of TMT with clinical outcomes in patients with newly diagnosed glioblastoma (GBM).

Materials and Methods

Using electronic medical records, all GBM patients between 2008 and 2018 at Seoul St. Mary’s Hospital were reviewed. Total 177 patients met our eligibility criteria.

Results

The thinner group who had TMT less than the median showed shorter overall survival (OS) and progression-free survival (PFS) than the thicker group who had TMT more than median (OS; 11.0 versus 18.0 months, p < 0.001, and PFS; 6.0 versus 11.0 months, p < 0.001). In the multivariate analysis, the thinner group had negative associations with OS and PFS (OS; HR 2.63 (1.34-2.63), p < 0.001, and PFS; HR 2.21 (1.34-2.50), p = 0.002). We also performed propensity score matching between the thinner and thicker groups to minimize the potential bias. The thinner group showed shorter OS and PFS (OS; 13.5 versus 19.0 months, p = 0.006, and PFS; 6.5 versus 9.0 months, p = 0.028) and had negative associations with OS and PFS than the thicker group (OS; HR 1.90 (1.19-3.03), p = 0.008, and PFS; HR 1.70 (1.07-2.70), p = 0.026) in matched patients.

Conclusion

Our findings suggest that TMT can be a useful prognostic biomarker for clinical outcomes in GBM patients. Further preclinical and clinical studies could help elucidate this association of sarcopenia with clinical outcomes in GBM patients.
APOE-stratified genome-wide association study suggests potential novel genes for late-onset Alzheimer’s disease in East-Asian descent
Authors: Kang Sarang , Gim Jungsoo , Gunasekaran Tamil Iniyan , Choi Kyu Yeong , Lee Jang Jae , Seo Eun Hyun , Ko Pan-Woo , Chung Ji Yeon , Choi Seong-Min , Lee Young Min , Jeong Jee Hyang , Park Kyung Won , Song Min Kyung , Lee Ho-Won , Kim Ki Woong , Choi Seong Hye , Lee Dong Young , Kim Sang Yun , Kim Hoowon , Kim Byeong C. , Ikeuchi Takeshi , Lee Kun Ho
Published: July 2020

In this study, we report two new possible susceptible genes for late-onset Alzheimer’s disease identified through an APOE-stratified genome-wide association analysis (GWAS) using East Asian samples. In the discovery phase, we performed a GWAS of Alzheimer’s disease in 2,291 Korean seniors from the Gwangju Alzheimer’s and Related Dementias (GARD) cohort study. A successive replication analysis with a Japanese sample of size 1,956 suggested three novel susceptible SNPs in two genes: LRIG1 and CACNA1A. This study demonstrates that the discovery of AD-associated variants can be accomplished in non-European ethnic groups with a more homogeneous genetic background using samples comprising fewer subjects.
Ultrametric model for covid-19 dynamics: an attempt to explain slow approaching herd immunity in Sweden
Authors: Khrennikov Andrei
Published: July 2020

We present a mathematical model of infection dynamics that might explain slower approaching the herd immunity during the covid-19 epidemy in Sweden than it was predicted by a variety of other models; see graphs Fig. 2. The new model takes into account the hierarchic structure of social clusters in the human society. We apply the well developed theory of random walk on the energy landscapes represented mathematically with ultrametric spaces. This theory was created for applications to spin glasses and protein dynamics. To move from one social cluster (valley) to another, the virus (its carrier) should cross a social barrier between them. The magnitude of a barrier depends on the number of social hierarchy’s levels composing this barrier. As the most appropriate for the recent situation in Sweden, we consider linearly increasing (with respect to hierarchy’s levels) barriers. This structure of barriers matches with a rather soft regulations imposed in Sweden in March 2020. In this model, the infection spreads rather easily inside a social cluster (say working collective), but jumps to other clusters are constrained by social barriers. This model’s feature matches with the real situation during the covid-19 epidemy, with its cluster spreading structure. Clusters need not be determined solely geographically, they are based on a number of hierarchically ordered social coordinates. The model differs crucially from the standard mathematical models of spread of disease, such as the SIR-model. In particular, our model describes such a specialty of spread of covid-19 virus as the presence of “super-spreaders” who by performing a kind of random walk on a hierarchic landscape of social clusters spreads infection. In future, this model will be completed by adding the SIR-type counterpart. But, the latter is not a specialty of covid-19 spreading.
Repurposed Drugs Block Toxin-Driven Platelet Clearance by the Hepatic Ashwell-Morell Receptor to ClearStaphylococcus aureusBacteremia
Authors: Sun Josh , Uchiyama Satoshi , Olson Joshua , Morodomi Yosuke , Cornax Ingrid , Ando Nao , Kohno Yohei , Kyaw May M. T. , Aguilar Bernice , Haste Nina M. , Kanaji Sachiko , Kanaji Taisuke , Rose Warren E. , Sakoulas George , Marth Jamey D. , Nizet Victor
Published: July 2020

Staphylococcus aureus(SA) bloodstream infections cause high morbidity and mortality (20-30%) despite modern supportive care. In a human bacteremia cohort, development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta®), a commonly prescribed P2Y12 receptor inhibitor used post-myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thus providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu®) provided similar therapeutic benefit. Thus a “toxin-platelet-AMR” regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof-of-concept for repurposing two FDA-approved drugs as adjunctive therapies to improve patient outcomes.
AXL is a key factor for cell plasticity and promotes metastasis in pancreatic cancer
Authors: Du Wenting , Huang Huocong , Wang Zhaoning , Toombs Jason E. , Phinney Natalie Z. , Zhang Yuqing , Beg Muhammad S. , Wilkie Thomas M. , Lorens James B. , Brekken Rolf A.
Published: July 2020

Pancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the US, has a high metastatic rate and is associated with persistent immune suppression. AXL, a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, has been identified as a driver of metastasis and immune suppression in multiple cancer types. Here we use single cell RNA sequencing to reveal that AXL is expressed highly in tumor cells that have a mesenchymal-like phenotype and that AXL expression correlates with classic markers of mesenchymal tumor cells. We demonstrate thatAXL-deficiencyextends survival, reduces primary and metastatic burden and enhances sensitivity to gemcitabine in an autochthonous model of PDA. PDA inAXL-deficientmice displayed a more differentiated histology, higher nucleoside transporter expression and a more active immune microenvironment compared to PDA inwild-typemice. Finally, we demonstrate that AXL-positive mesenchymal tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target for PDA patients.
KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease
Authors: Nam Min-Ho , Park Jong-Hyun , Song Hyo Jung , Choi Ji Won , Kim Siwon , Jang Bo Ko , Yoon Hyung Ho , Heo Jun Young , Cho Doo-Wan , Yang Young-Su , Han Su-Cheol , Kim Sangwook , Oh Soo-Jin , Jeon Sang Ryong , Park Ki Duk , Lee C. Justin
Published: July 2020

Background and Purpose

Monoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinson’s disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD.

Experimental Approach

We designed and synthesized α-aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates.

Key Results

KDS2010 showed the highest potency, specificity, and reversibility among the α-aminoamide derivatives, with high bioavailability (>100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates.

Conclusion and Implications

KDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD.

Representative Schematic

What is already known

KDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor.

MAO-B is critical for PD pathology through astrocytic GABA and H2O2synthesis.

What this study adds

KDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD.

KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates.

What is the clinical significance?

KDS2010 is a safe and promising therapeutic candidate for Parkinson’s disease.

Reversible MAO-B inhibitors could be more effective for treatment of Parkinson’s disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.
RNF219 interacts with CCR4-NOT in regulating stem cell differentiation
Authors: Du Hao , Chen Chen , Wang Yan , Yang Yang , Che Zhuanzhuan , Liu Xiaoxu , Meng Siyan , Guo Chenghao , Xu Manman , Fang Haitong , Lin Chengqi , Luo Zhuojuan
Published: July 2020

Regulation of RNA stability plays a crucial role in gene expression control. Deadenylation is the initial rate-limiting step for the majority of RNA decay events. Here, we show that RING Finger Protein 219 (RNF219) interacts with the CCR4-NOT deadenylase complex. RNF219-CCR4-NOT exhibits deadenylation activityin vitro. RNA-seq analyses identify some of the 2-cell specific genes and the neuronal genes significantly down-regulated upon RNF219 knockdown, while up-regulated after depletion of the CCR4-NOT subunit CNOT10 in mouse embryonic stem (ES) cells. RNF219 depletion leads to impaired neuronal lineage commitment during ES cell differentiation. Our study suggests that RNF219 is a novel interacting partner of CCR4-NOT, and required for maintenance of ES cell pluripotency.
A High-efficacy CRISPRi System for Gene Function Discovery inZymomonas mobilis
Authors: Banta Amy B. , Enright Amy L. , Siletti Cheta , Peters Jason M.
Published: July 2020

Zymomonas mobilisis a promising biofuel producer due to its high alcohol tolerance and streamlined metabolism that efficiently converts sugar to ethanol.Z. mobilisgenes are poorly characterized relative to model bacteria, hampering our ability to rationally engineer the genome with pathways capable of converting sugars from plant hydrolysates into valuable biofuels and bioproducts. Many of the unique properties that makeZ. mobilisan attractive biofuel producer are controlled by essential genes; however, these genes cannot be manipulated using traditional genetic approaches (e.g., deletion or transposon insertion) because they are required for viability. CRISPR interference (CRISPRi) is a programmable gene knockdown system that can precisely control the timing and extent of gene repression, thus enabling targeting of essential genes. Here, we establish a stable, high-efficacy CRISPRi system inZ. mobilisthat is capable of perturbing all genes—including essentials. We show thatZ. mobilisCRISPRi causes either strong knockdowns (>100-fold) using single guide RNA (sgRNA) spacers that perfectly match target genes, or partial knockdowns using spacers with mismatches. We demonstrate the efficacy ofZ. mobilisCRISPRi by targeting essential genes that are universally conserved in bacteria, key to the efficient metabolism ofZ. mobilis, or underlie alcohol tolerance. OurZ. mobilisCRISPRi system will enable comprehensive gene function discovery, opening a path to rational design of biofuel production strains with improved yields.

IMPORTANCE

Biofuels produced by microbial fermentation of plant feedstocks provide renewable and sustainable energy sources that have the potential to mitigate climate change and improve energy security. Engineered strains of the bacteriumZ. mobiliscan convert sugars extracted from plant feedstocks into next generation biofuels such as isobutanol; however, conversion by these strains remains inefficient due to key gaps in our knowledge about genes involved in metabolism and stress responses such as alcohol tolerance. Here, we develop CRISPRi as a tool to characterize gene function inZ. mobilis. We identify genes that are essential for growth, required to ferment sugar to ethanol, and involved in resistance to alcohol. OurZ. mobilisCRISPRi system makes it straightforward to define gene function and can be applied to improve strain engineering and increase biofuel yields.
Simple phenotypic tests to improve accuracy in screening chromosomal and plasmid-mediated colistin resistance in gram-negative bacilli
Authors: Pasteran Fernando , Danze Diego , Menocal Alejandra , Cabrera Carla , Castillo Ignacio , Albornoz Ezequiel , Lucero Celeste , Rapoport Melina , Ceriana Paola , Corso Alejandra
Published: July 2020

CLSI and EUCAST recommends that only broth microdilution (BMD) should be used for routine colistin susceptibility testing, however, it could be difficult to perform in resource-poor settings. The purpose of this study was to evaluate the accuracy of an agar spot test (COL-AS) and a colistin drop test (COL-DT) as compared to BMD. COL-AS and COL-DT were challenged with a collection of 271 Gram-negative bacilli clinical isolates: 195 Enterobacterales (including 63 mcr-1 positive strains), 37 Acinetobacter spp. and 39 P. aeruginosa. For COL-AS, 3.0µg/ml (final concentration) of colistin was added to a Mueller-Hinton agar plate and subsequently swabbed with a 0.5 McFarland suspension of tested strain within 1cm2 spot. For COL-DT, 10µl of a 16µg/ml colistin solution was dripped on the surface of a Mueller-Hinton agar plate, previously inoculated with a lawn of tested strain (0.5 McFarland). Colistin solution was made either, by dissolving powder or by disk elution in CA-MHB. Overall, 141/271 (52%) isolates were categorized as colistin resistant by reference BMD. COL-AS yielded a categorical agreement (CA) of 95.5% compared to BMD, with 0.7% very major errors and 3.8% major errors. COL-DR yielded a CA of 96.2% compared to BMD, with 0.7% and 0% very major errors and 3.1% and 3.8% major errors, for colistin powder and disk elution solutions, respectively. Most major errors occurred for mcr-1 producing strains with MICs that fluctuated from 2 to 4 μg/ml. In conclusion, we developed and validated methods suited to the systematic screening of resistance to colistin in gram negative bacilli.

Clinical relevance

colistin continues to be one of the last-line therapeutic options to treat carbapenemase-producing gram negative bacilli. The BMD reference methodology, the only one accepted by current standards for evaluating colistin sensitivity, is difficult to implement in laboratories from low-resource countries. In this work, we propose two simple methodologies to screen for colistin resistance, with a performance equivalent to the reference method in detecting resistance to colistin, both of plasmid (mcr) and chromosomal nature. Furthermore, the methods validated here allowed a better identification of those producers of mcr producer with borderline MICs. These screening tests can be routinely performed in addition to the tests currently in use. showed long stability during storage and some of them do not require colistin powder as the source of antibiotic, an important limitation in low-resource countries.
Ranking the effectiveness of worldwide COVID-19 government interventions
Authors: Haug Nils , Geyrhofer Lukas , Londei Alessandro , Dervic Elma , Desvars-Larrive Amélie , Loreto Vittorio , Pinior Beate , Thurner Stefan , Klimek Peter
Published: July 2020

Non-pharmaceutical interventions (NPIs) to mitigate the spread of SARS-CoV-2 were often implemented under considerable uncertainty and a lack of scientific evidence. Assessing the effectiveness of the individual interventions is critical to inform future preparedness response plans. Here we quantify the impact of 4,579 NPIs implemented in 76 territories on the effective reproduction number,Rt, of COVID-19. We use a hierarchically coded data set of NPIs and propose a novel modelling approach that combines four computational techniques, which together allow for a worldwide consensus rank of the NPIs based on their effectiveness in mitigating the spread of COVID-19. We show how the effectiveness of individual NPIs strongly varies across countries and world regions, and in relation to human and economic development as well as different dimensions of governance. We quantify the effectiveness of each NPI with respect to the epidemic age of its adoption, i.e., how early into the epidemics. The emerging picture is one in which no one-fits-all solution exists, and no single NPI alone can decreaseRtbelow one and that a combination of NPIs is necessary to curb the spread of the virus. We show that there are NPIs considerably less intrusive and costly than lockdowns that are also highly effective, such as certain risk communication strategies and voluntary measures that strengthen the healthcare system. By allowing to simulate “what-if” scenarios at the country level, our approach opens the way for planning the most likely effectiveness of future NPIs.