bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Prophylactic Cholecystectomy After Endoscopic Sphincterotomy for Biliary Stone Disease
Authors: McCarty Thomas R. , Farrelly James , Njei Basile , Jamidar Priya , Muniraj Thiruvengadam
Published: June 2020

Objective:

The aim of this study was to perform a structured systematic review and meta-analysis to evaluate the effectiveness and complication rate of cholecystectomy deferral versus prophylactic cholecystectomy among patients post-endoscopic biliary sphincterotomy for common bile duct stones.

Background:

Although previous reports suggest a decreased risk of biliary complications with prophylactic cholecystectomy, biliary endoscopic cholangiopancreatography (ERCP) with sphincterotomy may provide a role for deferring cholecystectomy with the gallbladder left in situ.

Methods:

Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed through August 2019 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. Measured outcomes included: mortality, recurrent biliary pain or cholecystitis, pancreatitis, cholangitis, and eventual need for cholecystectomy. Random effects models were used to determine pooled effect size and corresponding 95% confidence intervals (CIs).

Results:

Nine studies (n = 1605) were included. A total of 53.8% (n = 864) patients had deferred cholecystectomy post-sphincterotomy. Deferral cholecystectomy as compared to prophylactic cholecystectomy resulted in a significant increased risk of mortality [odds raio (OR) 2.56 (95% confidence interval, CI 1.54–4.23); P < 0.0001; I
2 = 18.49]. Patients who did not undergo prophylactic cholecystectomy developed more recurrent biliary pain or cholecystitis [OR 5.10 (95% CI 3.39–7.67); P < 0.0001; I
2 = 0.00]. Rate of pancreatitis [OR 3.11 (95% CI 0.99–9.83); P = 0.053; I
2 = 0.00] and cholangitis [OR 1.49 (95% CI 0.74–2.98); P = 0.264; I
2 = 0.00] was unaffected. Overall, 26.00% (95% CI 14.00–40.00) of patients with deferred prophylactic cholecystectomy required eventual cholecystectomy.

Conclusions:

Prophylactic cholecystectomy remains the preferred strategy compared to a deferral approach with gallbladder in situ post-sphincterotomy for patients with bile duct stones. Future studies may highlight a subset of patients (ie, those with large balloon biliary dilation) that may not require cholecystectomy.
Trends in Female Authorship in High Impact Surgical Journals Between 2008 and 2018
Authors: Hart Kamber L. , Boitano Laura T. , Tanious Adam , Conrad Mark F. , Eagleton Matthew J. , Lillemoe Keith D. , Perlis Roy H. , Srivastava Sunita D.
Published: June 2020

Objective:

This study evaluates the distribution of authorship by sex over the last 10 years among the top 25 surgical journals.

Summary of Background Data:

Despite an increase in women entering surgical residency, there remains a sex disparity in surgical leadership. Scholarly activity is the foundation for academic promotion. However, few studies have evaluated productivity by sex in surgical literature.

Methods:

Original research in the 25 highest-impact general surgery/subspecialty journals were included (1/2008–5/2018). Journals with <70% identified author sex were excluded. Articles were categorized by sex of first, last, and overall authorship. We examined changes in proportions of female first, last, and overall authorship over time, and analyzed the correlation between these measurements and journal impact factor.

Results:

There were 71,867 articles from 19 journals included. Sex was successfully predicted for 87.3% of authors (79.1%–92.5%). There were significant increases in the overall percentage of female authors (β = 0.55, P < 0.001), female first authors (β = 0.97, P < 0.001), and female last authors (β = 0.53, P < 0.001) over the study period. Notably, all cardiothoracic subspecialty journals did not significantly increase the proportion of female last authors over the study period. There were no correlations between journal impact factor and percentage of overall female authors (r

s
= 0.39, P = 0.09), female first authors (r

s
= 0.29, P = 0.22), or female last author (r

s
= 0.35, P = 0.13).

Conclusions:

This study identifies continued but slow improvement in female authorship of high-impact surgical journals during the contemporary era. However, the improvement was more apparent in the first compared to senior author positions.
Injuries associated with electronic nicotine delivery systems: A systematic review
Authors: Vyncke Tom , De Wolf Edward , Hoeksema Henk , Verbelen Jozef , De Coninck Petra , Buncamper Marlon , Monstrey Stan , Claes Karel E.Y.
Published: June 2020

BACKGROUND

Since its introduction on the market in 2007, the number of reports on injuries caused by the overheating, ignition, or explosion of electronic nicotine delivery systems (ENDSs) has increased significantly. These injuries appear to have different causes, the most important one being lithium-ion battery overheating to the point of ignition or explosion.

METHODS

A literature search for all relevant studies concerning ENDS-related traumatic injuries of all kinds was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses protocol. The search started with the first introduction of ENDSs in 2007 and ended February 2020. Articles included were reports on patients who sustained flame, chemical, or traumatic injuries of the skin, soft tissue, and/or bone, related to the use of ENDSs.

RESULTS

This systematic review includes 180 patients from 41 case series and reports, published between 2016 and 2020. The mean age was 30.8 years (range, 17–59 years) with an overall male predominance (168 of 180 patients, 93%). In most injuries, multiple anatomical sites were affected, with the thigh/lower limb being the most commonly injured area (77%) followed by the upper limb/hand (43%). Eighty-two patients (51%) required a surgical treatment, 70 patients (43%) were managed conservatively with dressings or ointments, and 9 patients (6%) underwent enzymatic debridement. Thirty-five percent of all patients underwent skin grafting.

CONCLUSION

Injuries from overheating, ignition, or explosion of ENDSs are an emerging, underreported, and underresearched issue. There is a need for increased regulation of ENDSs and improved surveillance of related injuries. Both health care providers and consumers should be made aware of the risks and be advised about how to safely handle these devices. In contrast to other articles, this systematic review includes all types of injuries related to ENDS overheating, ignition, and explosion. To our knowledge, this is the most extensive systematic review performed to date.

LEVEL OF EVIDENCE

Review article, level III.
Save it—don’t waste it! Maximizing utilization of erythrocytes from previously stored whole blood
Authors: Pulliam Kasiemobi E. , Joseph Bernadin , Veile Rosalie A. , Friend Lou Ann , Makley Amy T. , Caldwell Charles C. , Lentsch Alex B. , Goodman Michael D. , Pritts Timothy A.
Published: June 2020

BACKGROUND

Recent military and civilian experience suggests that fresh whole blood may be the preferred for treatment of hemorrhagic shock, but its use is limited by its 21-day shelf life. The red blood cell storage lesion and coagulation status of packed red blood cells (pRBCs) salvaged from expired whole blood are unknown. We hypothesized that pRBCs can be salvaged from previously stored whole blood.

METHODS

Cold stored, low-titer, O-positive, nonleukoreduced, whole blood units were obtained at 21 days of storage. Erythrocytes were separated by centrifugation, resuspended in AS-3, and stored for 21 additional days as salvaged pRBCs. The red blood cell storage lesion parameters of microvesicles, Band-3, free hemoglobin, annexin V, and erythrocyte osmotic fragility were measured and compared with pRBCs prepared at the time of donation and stored in AS-3 for 42 days (standard pRBCs). In additional experiments, murine pRBCs were prepared from expired whole blood units and compared with those stored under standard conditions. Mice underwent hemorrhage and resuscitation with standard and salvaged pRBC units, and serum cytokines and free hemoglobin were determined.

RESULTS

There were no significant differences in microvesicle formation or cell-free hemoglobin concentration between salvaged and standard pRBCs. There was decreased Band-3 and increased phosphatidylserine in the salvaged units as well as greater osmotic fragility. Salvaged pRBCs maintained consistent clot firmness. After hemorrhage and resuscitation in a murine model, salvaged pRBCs did not demonstrate increased serum cytokine levels.

CONCLUSION

Salvaged pRBCs from previously stored whole blood accumulate the red blood cell storage lesion in a similar fashion to standard pRBCs and maintain consistent coagulability when reconstituted with plasma. Salvaged pRBCs are not associated with an increased inflammatory response when used for resuscitation in a murine model. Salvaged pRBCs may be a viable product for utilization in the treatment of traumatic hemorrhagic shock.
Contemporary management of traumatic cervical and thoracic esophageal perforation: The results of an Eastern Association for the Surgery of Trauma multi-institutional study
Authors: Raff Lauren A. , Schinnerer Eric A. , Maine Rebecca G. , Jansen Jan , Noorbakhsh Matthew R. , Spigel Zachary , Campion Eric , Coleman Julia , Saquib Syed , Carroll Joseph T. , Jacobson Lewis E. , Williams Jamie , Young Andrew Joseph , Pascual Jose , Burruss Sigrid , Gordon Darnell , Robinson Bryce R.H. , Nahmias Jeffry , Kutcher Matthew E. , Bugaev Nikolay , Jeyamurugan Kokila , Bosarge Patrick
Published: June 2020

BACKGROUND

Traumatic esophageal perforation is rare and associated with significant morbidity and mortality. There is substantial variability in diagnosis and treatment. Esophageal stents have been increasingly used for nontraumatic perforation; however, stenting for traumatic perforation is not yet standard of care. The purpose of this study was to evaluate current management of traumatic esophageal perforation to assess the frequency of and complications associated with esophageal stenting.

METHODS

This was an Eastern Association for the Surgery of Trauma multi-institutional retrospective study from 2011 to 2016 of patients with traumatic cervical or thoracic esophageal injury admitted to one of 11 participating trauma centers. Data were collected and sent to a single institution where it was analyzed. Patient demographics, injury characteristics, initial management, complications, and patient mortality were collected. Primary outcome was mortality; secondary outcomes were initial treatment, esophageal leak, and associated complications.

RESULTS

Fifty-one patients were analyzed. Esophageal injuries were cervical in 69% and thoracic in 31%. Most patients were initially managed with operative primary repair (61%), followed by no intervention (19%), esophageal stenting (10%), and wide local drainage (10%). Compared with patients who underwent operative primary repair, patients managed with esophageal stenting had an increased rate of esophageal leak (22.6% vs. 80.0%, p = 0.02). Complication rates were higher in blunt compared with penetrating mechanisms (100% vs. 31.8%, p = 0.03) despite similar Injury Severity Score and neck/chest/abdomen Abbreviated Injury Scale. Overall mortality was 9.8% and did not vary based on location of injury, mechanism of injury, or initial management.

CONCLUSION

Most patients with traumatic esophageal injuries still undergo operative primary repair; this is associated with lower rates of postoperative leaks as compared with esophageal stenting. Patients who have traumatic esophageal injury may be best managed by direct repair and not esophageal stenting, although further study is needed.

LEVEL OF EVIDENCE

Therapeutic, level IV.
Prehospital end-tidal carbon dioxide predicts massive transfusion and death following trauma
Authors: Campion Eric M. , Cralley Alexis , Robinson Caitlin , Sauaia Angela , Pieracci Fredric M. , Lawless Ryan A. , Platnick Barry , Robinson James , Edwards David , McVaney Kevin , Moore Ernest E. , Cohen Mitchell J. , Coleman Jamie J. , Fox Charles , Burlew Clay Cothren
Published: June 2020

BACKGROUND

The lack of an accurate marker of prehospital hemorrhagic shock limits our ability to triage patients to the correct level of care, delays treatment in the emergency department, and inhibits our ability to perform prehospital interventional research in trauma. End-tidal carbon dioxide (ETCO2) is the measurement of alveolar carbon dioxide concentration at end expiration and is measured noninvasively in the ventilator circuit for intubated patients in continuous manner. Several hospital-based studies have been able to demonstrate that either low or decreasing levels of ETCO2 as well as disparities between ETCO2 and plasma carbon dioxide correlate with increasing mortality in trauma. We hypothesized that prehospital ETCO2 values will be predictive of mortality and need for massive transfusion following injury.

METHODS

This is a single-center retrospective study from an urban level 1 trauma center. We reviewed all intubated adult patients transported for injury who had prehospital ETCO2 values available. Unadjusted comparisons of continuous variables were done with the Wilcoxon two-sample test. The predictive performance of prehospital ETCO2, the prehospital shock index, and prehospital systolic blood pressure were assessed and compared using areas under the receiver operating characteristic curves. Optimal cutoffs were estimated by maximizing the Youden index. Massive transfusion was defined as >10 U of blood or death in 24 hours.

RESULTS

A total of 173 patients were identified with prehospital ETCO2 values during the 2-year study period. Population was 78.5% male with a median age of 37.5 years (interquartile range, 23.5–53.5 years). Injury mechanism was penetrating in 22.8%. This cohort had a median Injury Severity Score of 26 (interquartile range, 17–36), massive transfusion rate of 34.7%, and mortality of 42.1%. In the evaluation of prediction of postinjury mortality and massive transfusion, ETCO2 outperformed systolic blood pressure and shock index, but these differences did not reach statistical significance.

CONCLUSION

End-tidal carbon dioxide is a novel prehospital predictor of mortality and massive transfusion after injury.

LEVEL OF EVIDENCE

Prognostic/Epidemiologic, level III.
Multicolor Imaging for the Detection of Inner Nuclear Layer Microcysts Secondary to Optic Nerve Atrophy
Authors: Jimenez-Rolando Belen , Carreño Ester , Alonso-Peralta Miguel A. , Lopez-Molina Maria I. , Fernandez-Sanz Guillermo
Published: June 2020

Inner nuclear layer (INL) microcysts have been reported in diseases affecting the optic nerve. The new ocular imaging techniques detect minimal structural alterations at the macula and correlate these findings to different etiologies with less invasive procedures. The relationship between ganglion cells distribution at the macula and chiasmal nerve fibers enables the diagnosis and location of neurological lesions by new generation optical coherence tomography (SD-OCT) imaging devices. We report the evaluation of a patient with a history of optic nerve trauma and macular INL microcysts with multicolor SD-OCT technology that shows a pattern that localizes the lesion to the left optic nerve and proximal segment of the chiasm.
Papilledema Secondary to Neurologic Lyme Borreliosis: A Meta-Case Series
Authors: Vaysbrot Elizaveta E. , Bannuru Raveendhara R. , Christopher Mia-Cara , Osani Mikala C. , Halperin John J.
Published: June 2020

Background:

Papilledema can be a manifestation of neurologic Lyme borreliosis (LB). The clinical manifestations and progression of these cases have not been comprehensively documented to date. We aimed to describe clinical and diagnostic features and to assess patient outcomes in cases of papilledema secondary to neurologic LB.

Methods:

We searched MEDLINE, EMBASE, and the Cochrane Database from inception to August 2019. We did not restrict our search by study design or by publication date, status, or language.

Results:

Twenty-eight studies describing 46 cases of papilledema secondary to neurologic LB were included. Common clinical features included cranial neuropathy (68%) and diplopia (61%). Most patients did not recall tick bite (71%) and were afebrile (74%). Brain imaging was normal in 64% cases. Cerebrospinal fluid analysis showed lymphocytic pleocytosis (77%). Initial treatment with intravenous ceftriaxone was given in 52% of cases and resulted in a 100% resolution rate. Concomitant treatment with acetazolamide resulted in favorable outcomes.

Conclusions:

For patients in endemic regions who describe symptoms suggestive of intracranial hypertension and papilledema, especially accompanied by facial nerve palsy and other cranial nerve palsies, underlying neurologic LB should be considered.
Absence of Decussation in Optic Pathway Inflammation in Neuromyelitis Optica and Its Implications for Astrocyte Localization
Authors: Harvey Joshua P. , Hart Jonathan , Palace Jacqueline , O'Sullivan Eoin P.
Published: June 2020

A 39-year-old woman presented with acute visual loss in her right eye. Brain and orbit MRI demonstrated T2 hyperintensity along a long section of her right optic nerve, chiasm, and tract with no evidence of decussation of the inflammation. Subsequent seropositivity for the aquaporin 4 antibody confirmed a diagnosis of neuromyelitis optica. Posterior pathway involvement is typical in neuromyelitis optica and supports the hypothesis that the condition is an astrocytopathy. Furthermore, the absence of decussation in the condition may be a function of astrocyte localization within the chiasm.
The Value of Macular Optical Coherence Tomography in Watchful Waiting of Suprasellar Masses: A 2-Year Observational Study
Authors: Jørstad Øystein Kalsnes , Wigers Andreas Reidar , Marthinsen Pål Bache , Evang Johan Arild , Moe Morten Carstens
Published: June 2020

Background:

A possible benefit of optical coherence tomography (OCT) in the approach to tumors involving the optic chiasm may be the ability to foresee visual deterioration. This study investigated the value of OCT in watchful waiting for compressive optic neuropathy as the primary management of suprasellar masses.

Methods:

The research was conducted as a 2-year observational study of a patient cohort with conservatively managed mass lesions involving the optic chiasm on MRI. Threshold perimetry and macular OCT were performed at baseline and each follow-up examination. Univariate Cox regression was used to determine the effect of baseline and longitudinal covariates upon development of visual field (VF) loss compatible with chiasmal dysfunction.

Results:

Nineteen eyes of 19 patients were included. The optic chiasm–tumor relationship on baseline MRI was abutment in 6 cases and compression in 13 cases. Seven eyes developed VF loss. None of the baseline covariates were predictors of VF loss. The longitudinal decrease in mean macular ganglion cell complex (mGCC) thickness on OCT was 2.5 μm/yr for eyes that developed VF loss and 0.2 μm/yr for eyes that did not develop VF loss (P = 0.02). The hazard ratio for VF loss per 1-μm/yr decrease in mGCC thickness was 1.30 (95% confidence interval [CI] 1.04–1.62; P = 0.02) for the inferior nasal quadrant and 1.45 (95% CI 1.02–2.07; P = 0.04) for the inferior temporal quadrant.

Conclusions:

OCT offers a valuable complement to perimetry in monitoring for compressive optic neuropathy. Longitudinal mGCC thinning can anticipate VF loss.
Follow-up of Nonarteritic Anterior Ischemic Optic Neuropathy With Optical Coherence Tomography Angiography
Authors: Aghsaei Fard Masoud , Ghahvechian Hossein , Subramanian Prem S.
Published: June 2020

Background:

Peripapillary and macular microvasculature alterations after nonarteritic ischemic optic neuropathy (NAION) have been investigated in several studies. We aimed to explore the vascular changes from acute NAION (aNAION) to chronic NAION (cNAION).

Methods:

This prospective observational study composed of 16 eyes with aNAION and 40 healthy age-matched controls. Eyes with NAION were followed up for more than 6 months after acute event. Optical coherence tomography angiography (OCTA) was used to evaluate peripapillary and macular vessel densities (VDs). The customized software was used for calculating deep retinal VD to attenuate the large superficial vessel projection effect.

Result:

The mean age of patients with NAION and controls was 56.13 ± 13.2 and 54.46 ± 15.5 years, respectively (P = 0.195). Radial peripapillary capillary density was significantly lower in both eyes with aNAION and eyes with cNAION than healthy eyes. Peripapillary capillary density decreased significantly from the acute to the chronic phase of NAION with values of 41.77 ± 4.05% and 34.35 ± 7.30%, respectively (P < 0.001). The mean superficial macular VD was 46.83 ± 3.47% in aNAION and 44.49 ± 4.50% in cNAION eyes with no significant difference between them (P = 0.252), but both were lower than control eyes. Deep macular VD was not affected in aNAION and cNAION eyes compared with control eyes. Correlation analysis in eyes with cNAION revealed that there were significant correlations between peripapillary nerve fiber layer and the capillary density (r = 0.772, P < 0.001) and between ganglion cell complex thickness and corresponding superficial macular VD.

Conclusions:

Although a decrease in peripapillary capillary density in aNAION eyes with active disc edema progressed when evaluated in the cNAION state, progressive VD loss was not observed in the macular area, suggesting a nonprogressive nature of macular vessel involvement in NAION.
Abnormal Vestibular–Ocular Reflexes in Children With Cortical Visual Impairment
Authors: Mansukhani Sasha A. , Ho Mai-Lan , Brodsky Michael C.
Published: June 2020

Background:

To determine whether the vestibular–ocular reflexes (VORs) can be affected by central nervous system injury in children with cortical visual impairment (CVI).

Methods:

Retrospective case series. Twenty consecutive children with CVI who presented to a pediatric ophthalmology practice over an 18-month period were included in the study. Horizontal and vertical VORs were assessed by a pediatric neuro-ophthalmologist using the standard doll's head maneuver. MRI studies were independently reviewed by a pediatric neuroradiologist in a masked fashion. The main outcome measures were the integrity of the VORs and the presence of brainstem abnormalities on MRI.

Results:

VORs were found to be absent or severely impaired in 13/20 (65%) children with CVI. More surprisingly, the doll's head maneuver failed to substantially overcome the deviated eye position in 8/13 (62%) children with conjugate gaze deviations. Reduced brainstem size and signal abnormalities were found in 4/7 children with normal VORs and in 9/13 children with abnormal VORs (P = 0.6), showing noncorrelation with the integrity of the VOR.

Conclusion:

VORs are commonly impaired in children with CVI. This ocular motor deficit reflects the diffuse cortical and subcortical injury that often accompanies perinatal injury to the developing brain. Consequently, these children may lack important visual compensatory mechanisms to stabilize gaze during head movements. This knowledge can help in planning visual rehabilitation.
Neuro-Ophthalmic Features of Autoimmune Encephalitides
Authors: Bohm Parker E. , Chen John J. , Bhatti Tariq M. , Eggenberger Eric R.
Published: June 2020

Background:

Over the past decade, there has been a remarkable advancement in the understanding of autoimmune etiologies of encephalitis. The first identified generation of paraneoplastic encephalitis tends to occur in older populations, responds poorly to immunotherapy, and is mediated by T-cell damage with antibodies directed toward intracellular antigens. A new generation of autoimmune encephalitides has been described, which are mediated by antibodies to cell-surface proteins, tend to occur in younger individuals, are less frequently associated with malignancy, and often respond better to treatment compared to their intracellular antigen-related paraneoplastic counterparts. This review will focus on several specific antibody-mediated autoimmune encephalitides with neuro-ophthalmic pertinence.

Evidence Acquisition:

Literature review and personal clinical experience.

Results:

Several of the antibody-mediated encephalitides, specifically N-methyl-D-aspartate receptor, dipeptidyl-peptidase-like protein 6, glial fibrillary acidic protein, metabotropic glutamate receptor 1 (mGluR1), gamma-aminobutyric acid receptor, glutamic acid decarboxylase 65 (GAD65), collapsing response mediator protein 5 (CRMP5), and kelch-like protein 11 (KLHL11), contain features of neuro-ophthalmic interest.

Conclusions:

The novel cell-surface protein-directed autoimmune encephalitis group can present with a wide range of afferent and efferent neuro-ophthalmic manifestations. Neuro-ophthalmologists should be familiar with these antibody-associated syndromes, which are treatable and often require a high index of suspicion for diagnosis.
The Radiologic Characteristics and Retinal Thickness Are Correlated With Visual Field Defect in Patients With a Pituitary Mass
Authors: Suh Hiebum , Choi Heeyoung , Jeon Hyeshin
Published: June 2020

Background:

Investigation of visual field defects (VFDs) is important to decide the treatment and to predict the prognosis in patients with a pituitary mass. The aim of this study was to evaluate the correlation among 2 diagnostic modalities—MRI and optical coherence tomography (OCT)—and VFDs.

Methods:

Consecutive patients who showed the presence of a pituitary mass on MRI and in whom ophthalmic examinations were performed were recruited. Height and volume of the mass, sagittal and coronal displacement of optic chiasm, and the direction of mass expansion were measured. Patients were divided into 2 groups according to the presence (VFD group) or absence of VFDs (no VFDs group [NVFD]). The correlation among MRI parameters, OCT parameters, and VFDs were examined, and the diagnostic values of MRI and OCT and the combined value of the 2 modalities were analyzed.

Results:

Forty-one patients were included. The greatest coefficients of determination were observed between the sagittal displacement and pattern standard deviation (PSD) (R2 = 0.3661, P < 0.001) and between the inferonasal ganglion cell–inner plexiform layer (GCIPL) and PSD (R2 = 0.4079, P < 0.001). The height and the size of the mass in the VFD group were significantly greater as 57% and 148%, respectively, and the VFD group had more severe chiasmal displacement both in the sagittal (165%) and in the coronal (178%) plane (large effect in all). All macular GCIPLs were thinner in the NVFD group (range 9%–26%, large effect), whereas only temporal (25%) and average (11%) values were among peripapillary retinal nerve fiber layers.

Conclusions:

The highest correlations with the degree of the VFD were seen in the sagittal displacement of optic chiasm and the inferonasal GCIPL, and these parameters were correlated concurrently. Both modalities showed a good diagnostic value for discriminating VFDs.
Considerations for the Treatment of Inflammatory Neuro-Ophthalmologic Disorders During the COVID-19 Pandemic
Authors: Martin Paez Yosbelkys , Bennett Jeffrey L. , Subramanian Prem S. , Pelak Victoria S.
Published: June 2020

The initiation and continuation of immune-based therapies to treat and prevent complications of inflammatory neuro-ophthalmologic disorders during the 2019 novel coronavirus (COVID-19) pandemic is the subject of considerable debate. In each case, a treatment decision must be reached based on best clinical practices for the disorder, patient comorbidities, the current state of knowledge about the pathogenesis and infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the utilization of hospital and community resources. Unfortunately, the evidence needed to standardize the decision-making process for each neuro-ophthalmologic disorder is currently absent and is likely to require months or years to develop based on the accrual of robust international data sets. In this article, we review the current understanding of SARS-CoV-2 and COVID-19 complications to provide a framework for approaching the treatment of inflammatory neuro-ophthalmic disorders during the COVID-19 viral pandemic.
TT01001 attenuates oxidative stress and neuronal apoptosis by preventing mitoNEET-mediated mitochondrial dysfunction after subarachnoid hemorrhage in rats
Authors: Shi Guangyao , Cui Lei , Chen Rui , Liang Shaodong , Wang Chunlei , Wu Pei
Published: June 2020

Oxidative stress and neuronal apoptosis are considered crucial therapeutic targets against early brain injury (EBI) after subarachnoid hemorrhage (SAH). Emerging evidence indicates that mitochondrial dysfunction is the main reason for oxidative stress and neuronal apoptosis. MitoNEET, an outer mitochondrial membrane protein, has been shown to regulate mitochondrial function. However, whether mitoNEET activation attenuates oxidative stress and neuronal apoptosis after SAH remains unknown. This study was therefore conducted to verify the neuroprotective role of mitoNEET in EBI after SAH in rats. A total of 93 rats were subjected to an endovascular perforation model of SAH. TT01001, a selective agonist of mitoNEET, was administered intraperitoneally 1 h after SAH induction. Neurological tests, immunofluorescence, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining, dihydroergotamine (DHE) staining, and western blot experiments were performed. The results showed that MitoNEET is expressed in neurons, but significantly decreased at 24 h after SAH induction. Activating mitoNEET with TT01001 significantly improved the neurological deficits, and reduced oxidative stress and neuronal apoptosis as measured by DHE and TUNEL staining, when compared with the SAH+vehicle group. Furthermore, TT01001 treatment decreased the expression of the proapoptotic marker, Bax, while increasing the expression of the antiapoptotic marker, Bcl-2. Together, our results suggested that mitoNEET activation with TT01001 reduced oxidative stress injury and neuronal apoptosis by improving mitochondrial dysfunction in EBI after SAH.
CORRELATION BETWEEN EARLY ANTIBIOTIC THERAPY AND IN-HOSPITAL MORTALITY IN PATIENTS WITH COMMUNITY ACQUIRED INFECTION
Authors: Araújo Beatriz , Reis Geovane Rossone , Araújo Isadora , Sales Marcella Soares Carreiro , Silveira Janne Marques
Published: June 2020

Sepsis is defined as the systemic response to an infectious disease, whether caused by bacteria, viruses, fungi or protozoa. Sepsis has several etiologies according to the worsening of the disease, those of bacterial origin with 70%, of which Gram-negative bacilli are the most frequent, especially in patients with the most severe disease. The most common community infections are respiratory infections, urinary tract infections and skin infections, with elderly individuals and children being more susceptible to complications of the immune system. The objective of this research is to analyze whether the time between hospitalization and the start of antibiotic treatment is directly related to the mortality rate and length of stay. This study was carried out in the form of documentary field research, where data collection was performed using data from the medical records of patients diagnosed with community infection or sepsis. Data collection was carried out from a form where patient identification, age, infectious focus, date and time of admission to the emergency room, date and time of the 1st dose of antibiotic, time interval between admission and antibiotic administration, ICU stay, days of mechanical ventilation and outcome. 34 patients were followed up in the emergency room and in the ICU, with an average age of these patients is 71.4 ± 30 years. This research showed a high mortality rate of the included patients who were diagnosed with community infection.
Opposing Wnt and JAK-STAT signaling gradients define a stem cell domain by regulating spatially patterned cell division and differentiation at two borders
Authors: Melamed David , Kalderon Daniel
Published: June 2020

Many adult stem cells are maintained as a community by population asymmetry, wherein stochastic actions of individual cells collectively result in a balance between stem cell division and differentiation. We have used Drosophila Follicle Stem Cells (FSCs) as a paradigm to explore the extracellular niche signals that define a stem cell domain and organize stem cell behavior. FSCs produce transit-amplifying Follicle Cells (FCs) from their posterior face and quiescent Escort Cells (ECs) to their anterior. Here we show that JAK-STAT pathway activity, which declines from posterior to anterior, dictates the pattern of divisions over the FSC and EC domains, promotes more posterior FSC locations and conversion to FCs, while opposing EC production. A Wnt pathway gradient of opposite polarity promotes more anterior FSC locations and EC production and opposes FC production. Promotion of both FSC division and conversion to FCs by JAK-STAT signaling buffers the effects of genetically altered pathway activity on FSC numbers and balances the four-fold higher rate of differentiation at the posterior face of the FSC domain with a higher rate of FSC division in the most posterior layer. However, genetic elimination of Wnt pathway activity exacerbated elevated FC production resulting from increased JAK-STAT pathway activity, leading to rapid FSC depletion despite high rates of division. The two pathways combine to define a stem cell domain through concerted effects on FSC differentiation to ECs (high Wnt, low JAK-STAT) and FCs (low Wnt, high JAK-STAT) at each end of opposing signaling gradients, further enforced by quiescence at the anterior border due to declining JAK-STAT pathway activity.
Coastal winds and larval fish abundance indicate a recruitment mechanism for southeast Australian estuarine fisheries
Authors: Schilling Hayden T. , Hinchliffe Charles , Gillson Jonathan P. , Miskiewicz Anthony , Suthers Iain M.
Published: June 2020

Coastal winds transport water masses and larval fish onshore or offshore which may influence estuarine recruitment, yet our understanding of the mechanism underlying this relationship is limited. Here, we combine datasets from a historical database of larval fish off southeast Australia with a high-resolution atmospheric reanalysis model to show that normalised abundance of coastally spawned larvae increased with weak to moderate upwelling favourable winds 14 days prior to sampling. The increase in abundance may reflect increased nutrient and plankton availability for larval fish. Normalised larval abundance decreased following strong upwelling favourable winds but increased after onshore (downwelling favourable) winds, due to wind-driven transport. By combining a commercial estuarine fisheries catch-rate dataset (4 species, 8 estuaries, 10 years) and the high-resolution atmospheric reanalysis model, we show that negative effects of upwelling favourable winds during the spawning period can be detected in lagged estuarine commercial fisheries catch rates (lagged by 2 – 8 years depending on species’ growth rates), potentially representing the same mechanism proposed for larval fish. Upwelling favourable winds in the southeast Australian region have increased since 1850 while onshore winds have decreased, which may reduce larval recruitment to estuaries. Coastal winds are likely an important factor for estuarine recruitment in the southeast Australian region and future research on the estuarine recruitment of fish should incorporate coastal winds.
Deep Learning for Virtual Screening: Five Reasons to Use ROC Cost Functions
Authors: Golkov Vladimir , Becker Alexander , Plop Daniel T. , Čuturilo Daniel , Davoudi Neda , Mendenhall Jeffrey , Moretti Rocco , Meiler Jens , Cremers Daniel
Published: June 2020

Computer-aided drug discovery is an essential component of modern drug development. Therein, deep learning has become an important tool for rapid screening of billions of moleculesin silicofor potential hits containing desired chemical features. Despite its importance, substantial challenges persist in training these models, such as severe class imbalance, high decision thresholds, and lack of ground truth labels in some datasets. In this work we argue in favor of directly optimizing the receiver operating characteristic (ROC) in such cases, due to its robustness to class imbalance, its ability to compromise over different decision thresholds, certain freedom to influence the relative weights in this compromise, fidelity to typical benchmarking measures, and equivalence to positive/unlabeled learning. We also propose new training schemes (coherent mini-batch arrangement, and usage of out-of-batch samples) for cost functions based on the ROC, as well as a cost function based on the logAUC metric that facilitates early enrichment (i.e. improves performance at high decision thresholds, as often desired when synthesizing predicted hit compounds). We demonstrate that these approaches outperform standard deep learning approaches on a series of PubChem high-throughput screening datasets that represent realistic and diverse drug discovery campaigns on major drug target families.
Neuroinvasion of SARS-CoV-2 in human and mouse brain
Authors: Song Eric , Zhang Ce , Israelow Benjamin , Lu-Culligan Alice , Prado Alba Vieites , Skriabine Sophie , Lu Peiwen , Weizman Orr-El , Liu Feimei , Dai Yile , Szigeti-Buck Klara , Yasumoto Yuki , Wang Guilin , Castaldi Christopher , Heltke Jaime , Ng Evelyn , Wheeler John , Alfajaro Mia Madel , Levavasseur Etienne , Fontes Benjamin , Ravindra Neal G. , Van Dijk David , Mane Shrikant , Gunel Murat , Ring Aaron , Jaffar Kazmi Syed A. , Zhang Kai , Wilen Craig B , Horvath Tamas L. , Plu Isabelle , Haik Stephane , Thomas Jean-Leon , Louvi Angeliki , Farhadian Shelli F. , Huttner Anita , Seilhean Danielle , Renier Nicolas , Bilguvar Kaya , Iwasaki Akiko
Published: June 2020

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstratein vivothat SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
Apple peel and flesh contain pro-neurogenic compounds
Authors: Ichwan Muhammad , Walker Tara L. , Nicola Zeina , Ludwig-Müller Jutta , Böttcher Christoph , Overall Rupert W. , Adusumilli Vijay S , Bulut Merve , Lugo-Hernández Enrique A. , Ramirez-Rodriguez Gerardo , Kempermann Gerd
Published: June 2020

As mammals evolved exposed to particular diets, naturally abundant compounds may have become part of the set of environmental co-determinants that shaped brain structure and function. Here we investigated whether bioactive factors found in apples directly affect hippocampal neural stem cells and promote neurogenesis in the adult mouse. Whereas the consumption of apple juiceper seneither altered adult hippocampal neurogenesis nor improved learning and memory, we did find specific direct effects of apple-derived factors on neural stem cell survival and differentiation. Our results revealed that quercetin, the most abundant flavanol in apple peel, was anti-proliferative at high concentrations but acted pro-neurogenically at low concentrations. This was confirmedin vivo, with intraperitoneally-delivered quercetin promoting survival and neuronal differentiation, without affecting proliferation, likely via the PI3 kinase-Akt and Nrf2-Keap1 pathways, respectively. Using a bio-assay-guided fractionation approach with high-resolution collision induced dissociation mass spectroscopy, we also identified additional pro-neurogenic compounds in apple flesh that were not related to flavonoids. In particular, we found that 3,5-dihydroxybenzoic acid, a weak agonist to the lactate receptor, significantly increased bothin vitroandin vivoneural precursor cell proliferation and neurogenesis. Altogether, this work shows that both flavonoids and 3,5-dihydroxybenzoic acid are pro-neurogenic, not only by activating precursor cell proliferation but also through promoting cell cycle exit, cellular survival, and neuronal differentiation.
rearrvisr: an R package to detect, classify, and visualize genome rearrangements
Authors: Lindtke Dorothea , Yeaman Sam
Published: June 2020

The identification of genome rearrangements is of direct relevance for understanding their potential impacts on evolution and disease. However, available methods that detect or visualize rearrangements from deviations in gene order do not map them onto a genome of interest, complicating downstream analysis. In this work, we presentrearrvisr, an R package that implements a novel algorithm for the identification and classification of rearrangements. In contrast to other software, it projects rearrangements onto a single genome, facilitating the localization of rearranged regions and estimation of their extent. We show that our tool achieves high precision and recall scores on simulated data, and illustrate the utility of our method by applying it to a data set generated from publicly availableDrosophilagenomes. The package is freely available from GitHub (https://github.com/dorolin/rearrvisr) and can be installed directly from R.
Distinct photooxidation-induced cell death pathways lead to selective killing of human breast cancer cells
Authors: dos Santos Ancély F. , Inague Alex , Arini Gabriel S. , Terra Letícia F. , Wailemann Rosangela A.M. , Pimentel André C. , Yoshinaga Marcos Y. , Silva Ricardo R. , Severino Divinomar , de Almeida Daria Raquel Q. , Gomes Vinícius M. , Bruni-Cardoso Alexandre , Terra Walter R. , Miyamoto Sayuri , Baptista Maurício S. , Labriola Leticia
Published: June 2020

Lack of effective treatments for aggressive breast cancer is still a major global health problem. We previously reported that Photodynamic Therapy using Methylene Blue as photosensitizer (MB-PDT) massively kills metastatic human breast cancer, marginally affecting healthy cells. In this study we aimed to unveil the molecular mechanisms behind MB-PDT effectiveness. Through lipidomic and biochemical approaches we demonstrated that MB-PDT efficiency and specificity relies on polyunsaturated fatty acids-enriched membranes and on the better capacity to deal with photooxidative damage displayed by non-tumorigenic cells. We found out that, in tumorigenic cells, lysosome membrane permeabilization is accompanied by ferroptosis and/or necroptosis. Our results broadened the understanding of MB-PDT-induced photooxidation mechanisms and specificity in breast cancer cells. Therefore, we demonstrated that efficient approaches could be designed on the basis of lipid composition and metabolic features for hard-to-treat cancers. The results further reinforce MB-PDT as a therapeutic strategy for highly aggressive human breast cancer cells.
Swarm Learning as a privacy-preserving machine learning approach for disease classification
Authors: Warnat-Herresthal Stefanie , Schultze Hartmut , Shastry Krishnaprasad Lingadahalli , Manamohan Sathyanarayanan , Mukherjee Saikat , Garg Vishesh , Sarveswara Ravi , Händler Kristian , Pickkers Peter , Aziz N. Ahmad , Ktena Sofia , Siever Christian , Kraut Michael , Desai Milind , Monnet Bruno , Saridaki Maria , Siegel Charles Martin , Drews Anna , Nuesch-Germano Melanie , Theis Heidi , Netea Mihai G. , Theis Fabian , Aschenbrenner Anna C. , Ulas Thomas , Breteler Monique M.B. , Giamarellos-Bourboulis Evangelos J. , Kox Matthijs , Becker Matthias , Cheran Sorin , Woodacre Michael S. , Goh Eng Lim , Schultze Joachim L. ,   German COVID-19 OMICS Initiative (DeCOI)
Published: June 2020

Identification of patients with life-threatening diseases including leukemias or infections such as tuberculosis and COVID-19 is an important goal of precision medicine. We recently illustrated that leukemia patients are identified by machine learning (ML) based on their blood transcriptomes. However, there is an increasing divide between what is technically possible and what is allowed because of privacy legislation. To facilitate integration of any omics data from any data owner world-wide without violating privacy laws, we here introduce Swarm Learning (SL), a decentralized machine learning approach uniting edge computing, blockchain-based peer-to-peer networking and coordination as well as privacy protection without the need for a central coordinator thereby going beyond federated learning. Using more than 14,000 blood transcriptomes derived from over 100 individual studies with non-uniform distribution of cases and controls and significant study biases, we illustrate the feasibility of SL to develop disease classifiers based on distributed data for COVID-19, tuberculosis or leukemias that outperform those developed at individual sites. Still, SL completely protects local privacy regulations by design. We propose this approach to noticeably accelerate the introduction of precision medicine.
Order and disorder – an integrative structure of the full-length human growth hormone receptor
Authors: Kassem Noah , Araya-Secchi Raul , Bugge Katrine , Barclay Abigail , Steinocher Helena , Khondker Adree , Lenard Aneta J. , Bürck Jochen , Ulrich Anne S. , Pedersen Martin Cramer , Wang Yong , Rheinstädter Maikel C. , Pedersen Per Amstrup , Lindorff-Larsen Kresten , Arleth Lise , Kragelund Birthe B.
Published: June 2020

Despite the many physiological and pathophysiological functions of the human growth hormone receptor (hGHR), a detailed understanding of itsmodus operandiis hindered by the lack of structural information of the entire receptor at the molecular level. Due to its relatively small size (70 kDa) and large content of structural disorder (>50%), this membrane protein falls between the cracks of conventional high-resolution structural biology methods. Here, we study the structure of the full-length hGHR in nanodiscs with small angle-X-ray scattering (SAXS) as the foundation. We developed an approach in which we combined SAXS, X-ray diffraction and NMR spectroscopy obtained on the individual domains and integrated the data through molecular dynamics simulations to interpret SAXS data on the full-length hGHR in nanodiscs. The structure of the hGHR was determined in its monomeric state and provides the first experimental model of any full-length cytokine receptor in a lipid membrane. Combined, our results highlight that the three domains of the hGHR are free to reorient relative to each other, resulting in a broad structural ensemble. Our work exemplifies how integrating experimental data from several techniques computationally, may enable the characterization of otherwise inaccessible structures of membrane proteins with long disordered regions, a widespread phenomenon in biology. To understand orchestration of cellular signaling by disordered chains, the hGHR is archetypal and its structure emphasizes that we need to take a much broader, ensemble view on signaling.