bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-prostate cancer activity of a nanoformulation of the spleen tyrosine kinase (SYK) inhibitor C61
Authors: Sahin Taha Koray , Aktepe Oktay Halit , Uckun Fatih Mehmet , Yalcin Suayib
Published: February 2020

Patients with advanced or metastatic castration-resistant prostate cancer have a dismal prognosis and are therefore in urgent need for therapeutic innovations. Spleen tyrosine kinase has emerged as a new molecular target for castration-resistant prostate cancer. This study was done to test the cytotoxicity of the lead nanoformulation of a potent spleen tyrosine kinase inhibitor, C61-LNP, against the human prostatic carcinoma cell line, PC-3. PC-3 cells were treated with various concentrations of C61-LNP either alone or in combination with cisplatin (CDDP) for 24, 48 and 72 hours. The cell viability was evaluated by MTS assay. Cellular expression levels of various regulatory proteins in treated PC-3 cells were evaluated by Western blot analyses. C61-LNP exhibited dose-dependent cytotoxicity against PC-3 cells. C61-LNP, as well as C61-LNP + CDDP treatments, caused pro-apoptotic proteomic changes including an increase in cleaved fragments of caspases-3 and -9 consistent with caspase activation as well as an improvement in the anti-apoptotic Bcl2 and Bax levels. The combination of C61-LNP and CDDP changed in alterations of the cell cycle regulatory proteins p53, p21, p27, cyclin D1 and cyclin E levels. C61-LNP exhibited cytotoxicity against the castration-resistant prostate cancer cell line PC3. It also caused alterations in expression levels of regulatory proteins involved in apoptosis and cell cycle regulation and these effects were not abrogated by the standard chemotherapy drug CDDP. We are planning to further develop C61-LNP as a selective spleen tyrosine kinase inhibitor as part of a multi-modality treatment strategy for advanced/metastatic castration-resistant prostate cancer.
Sepsis Among Medicare Beneficiaries: 1. The Burdens of Sepsis, 2012–2018*
Authors: Buchman Timothy G. , Simpson Steven Q. , Sciarretta Kimberly L. , Finne Kristen P. , Sowers Nicole , Collier Michael , Chavan Saurabh , Oke Ibijoke , Pennini Meghan E. , Santhosh Aathira , Wax Marie , Woodbury Robyn , Chu Steve , Merkeley Tyler G. , Disbrow Gary L. , Bright Rick A. , MaCurdy Thomas E. , Kelman Jeffrey A.
Published: February 2020

Objectives:

To provide contemporary estimates of the burdens (costs and mortality) associated with acute inpatient Medicare beneficiary admissions for sepsis.

Design:

Analysis of paid Medicare claims via the Centers for Medicare & Medicaid Services DataLink Project.

Setting:

All U.S. acute care hospitals, excluding federally operated hospitals (Veterans Administration and Defense Health Agency).

Patients:

All Medicare beneficiaries, 2012–2018, with an inpatient admission including one or more explicit sepsis codes.

Interventions:

None.

Measurements and Main Results:

Total inpatient hospital and skilled nursing facility admission counts, costs, and mortality over time. From calendar year (CY)2012–CY2018, the total number of Medicare Part A/B (fee-for-service) beneficiaries with an inpatient hospital admission associated with an explicit sepsis code rose from 811,644 to 1,136,889. The total cost of inpatient hospital admission including an explicit sepsis code for those beneficiaries in those calendar years rose from $17,792,657,303 to $22,439,794,212. The total cost of skilled nursing facility care in the 90 days subsequent to an inpatient hospital discharge that included an explicit sepsis code for Medicare Part A/B rose from $3,931,616,160 to $5,623,862,486 over that same interval. Precise costs are not available for Medicare Part C (Medicare Advantage) patients. Using available federal data sources, we estimated the aggregate cost of inpatient admissions and skilled nursing facility admissions for Medicare Advantage patients to have risen from $6.0 to $13.4 billion over the CY2012–CY2018 interval. Combining data for fee-for-service beneficiaries and estimates for Medicare Advantage beneficiaries, we estimate the total inpatient admission sepsis cost and any subsequent skilled nursing facility admission for all (fee-for-service and Medicare Advantage) Medicare patients to have risen from $27.7 to $41.5 billion. Contemporary 6-month mortality rates for Medicare fee-for-service beneficiaries with a sepsis inpatient admission remain high: for septic shock, approximately 60%; for severe sepsis, approximately 36%; for sepsis attributed to a specific organism, approximately 31%; and for unspecified sepsis, approximately 27%.

Conclusion:

Sepsis remains common, costly to treat, and presages significant mortality for Medicare beneficiaries.
Detecting Patient Deterioration Using Artificial Intelligence in a Rapid Response System
Authors: Cho Kyung-Jae , Kwon Oyeon , Kwon Joon-myoung , Lee Yeha , Park Hyunho , Jeon Ki-Hyun , Kim Kyung-Hee , Park Jinsik , Oh Byung-Hee
Published: February 2020

Objectives:

As the performance of a conventional track and trigger system in a rapid response system has been unsatisfactory, we developed and implemented an artificial intelligence for predicting in-hospital cardiac arrest, denoted the deep learning-based early warning system. The purpose of this study was to compare the performance of an artificial intelligence-based early warning system with that of conventional methods in a real hospital situation.

Design:

Retrospective cohort study.

Setting:

This study was conducted at a hospital in which deep learning-based early warning system was implemented.

Patients:

We reviewed the records of adult patients who were admitted to the general ward of our hospital from April 2018 to March 2019.

Interventions:

The study population included 8,039 adult patients. A total 83 events of deterioration occurred during the study period. The outcome was events of deterioration, defined as cardiac arrest and unexpected ICU admission. We defined a true alarm as an alarm occurring within 0.5–24 hours before a deteriorating event.

Measurements and Main Results:

We used the area under the receiver operating characteristic curve, area under the precision-recall curve, number needed to examine, and mean alarm count per day as comparative measures. The deep learning-based early warning system (area under the receiver operating characteristic curve, 0.865; area under the precision-recall curve, 0.066) outperformed the modified early warning score (area under the receiver operating characteristic curve, 0.682; area under the precision-recall curve, 0.010) and reduced the number needed to examine and mean alarm count per day by 69.2% and 59.6%, respectively. At the same specificity, deep learning-based early warning system had up to 257% higher sensitivity than conventional methods.

Conclusions:

The developed artificial intelligence based on deep-learning, deep learning-based early warning system, accurately predicted deterioration of patients in a general ward and outperformed conventional methods. This study showed the potential and effectiveness of artificial intelligence in an rapid response system, which can be applied together with electronic health records. This will be a useful method to identify patients with deterioration and help with precise decision-making in daily practice.
EPIDERMAL GROWTH FACTOR RECEPTOR EXPRESSION IN A CASE OF FOCAL NODULAR GLIOSIS OF THE RETINA
Authors: Tagami Mizuki , Misawa Norihiko , Noma-Ishikura Saki , Honda Satoshi , Kase Satoru , Honda Shigeru
Published: February 2020

Purpose:

To describe the immunohistochemical profile in a case with focal nodular gliosis (FNG) of the retina.

Methods:

A 56-year-old female patient presented with vitreoretinal tractional syndrome with FNG of the retina. After resection of the retinal tumor tissue during the 25-G pars plana vitrectomy, immunohistochemistry using anti–epidermal growth factor receptor (EGFR), p-53, Ki67, glial fibrillary acid protein (GFAP), CD34, and vascular endothelial growth factor antibodies was performed in the excised tissue of the FNG of the retina.

Results:

Histopathological analysis of the tumor led to a diagnosis of FNG of the retina. Spindle cells of the tumor exhibited strong positive staining for glial fibrillary acid protein, and there was local staining for CD34 in the endothelial cells in the blood vessels. The epidermal growth factor receptor and vascular endothelial growth factor immunoreactivity were strongly observed in the endothelial cells.

Conclusion:

This study demonstrated epidermal growth factor receptor expression in eyes with FNG of the retina. Oncogenic epidermal growth factor receptor might trigger and amplify the expression and function of endothelial vascular endothelial growth factor.
Empyema Necessitans Due to Methicillin-Sensitive Staphylococcus aureus
Authors: DeSuza Kayla , Bush Larry M.
Published: February 2020

Empyema refers to a collection of pus in the pleural cavity. Empyema necessitans is a rare complication of an empyema that refers to an insidious extension of the pus through the parietal pleura into the neighboring subcutaneous tissue of the chest wall or, less often, other thoracic structures. Left untreated, the purulent material may penetrate the chest wall forming a fistula or subcutaneous abscess. Drainage and empiric antimicrobial therapy should be started when the diagnosis is made and adjusted once the infecting organism is identified. Mycobacterium tuberculosis and Actinomyces species, both generally slow-growing microbes, remain the most common pathogens associated with the development of empyema necessitans. Although rarely encountered in the postantibiotic era, acute infections involving pyogenic organisms including Staphylococcus aureus may serve as the etiologic agents associated with this problematic subset of pleural effusion. The majority of reported cases of empyema necessitans due to S. aureus have occurred with strains that are methicillin resistant. This case describes a 70-year-old man who, after a month long of symptoms, presented with empyema necessitans due to methicillin-sensitive S. aureus. This case underscores the importance of diagnosing an empyema and treating early with antibiotics in order to avoid subsequent surgical intervention if and when empyema necessitans should develop.
Clostridioides difficile Infections in Adult and Pediatric Intestinal and Multivisceral Transplant Patients
Authors: Modi Anita , Gonzalez Blanca E. , Brizendine Kyle D.
Published: February 2020

Background

Solid organ transplant (SOT) recipients are at increased risk of Clostridioides difficile infection (CDI). Studies addressing the epidemiology of CDI in intestinal and multivisceral transplant are limited. Since 2013, our center greatly expanded its intestinal and multivisceral transplant program, providing the consummate opportunity to examine CDI in this vulnerable population.

Methods

We conducted a retrospective study of all intestinal and multivisceral transplant recipients between 2009 and 2018.

Results

We identified 86 patients who underwent a total of 94 transplants. There were 60 isolated intestinal transplants (64%), 21 intestine/pancreas/liver (22%), 10 intestine/pancreas (11%), 2 intestine/pancreas/liver/kidney (2%), and 1 intestine/kidney transplant (1%). All but 3 patients received perioperative metronidazole. Four patients (5%) had CDI before transplant, but none experienced recurrence in the first 6 months posttransplant. Five patients suffered 7 mild-moderate episodes of early CDI (attack rate, 5.9%). Three patients (60%) with early CDI developed rejection, similar to the observed incidence (70%) in patients without CDI. Two patients with early CDI developed recurrent infection; both of these patients underwent intestinal retransplant. Overall, 1-year mortality was similar (20% among patients with early CDI vs. 23% among those without early CDI).

Conclusions

For certain solid organ transplant recipients, an association between CDI and allograft loss, rejection, and mortality has been shown. Although limited by sample size, we observed that early CDI was not associated with those outcomes in the present investigation. Multicenter studies are merited to explore risk factors for CDI and associations with transplant-related outcomes in intestinal and multivisceral transplant recipients.
Five-year outcomes of small-incision lenticule extraction vs femtosecond laser–assisted laser in situ keratomileusis: a contralateral eye study
Authors: Aygün Beril Tülü , Çankaya Kadir İlker , Ağca Alper , Yıldırım Yusuf , Yıldız Burçin Kepez , Sucu Mehmet Emin , Kandemir Beşek Nilay , Demirok Ahmet
Published: February 2020

Purpose:

To compare the long-term refractive and visual outcomes and the corneal higher-order aberrations of contralateral eyes of patients who received small-incision lenticule extraction (SMILE) in one eye and femtosecond laser–assisted laser in situ keratomileusis (FS-LASIK) in the other eye.

Setting:

Refractive Surgery Clinic of the University of Health Sciences Beyoğlu Eye Training and Research Hospital, Istanbul, Turkey.

Design:

Retrospective case series.

Methods:

The medical files of patients who received SMILE in one eye and FS-LASIK in the contralateral eye for myopia and myopic astigmatism were reviewed. Postoperative examinations at 1 year, 3 years, and 5 years were evaluated. The main outcome measures were the comparison of the refractive and visual outcomes and the effect on corneal higher-order aberrations between the procedures.

Results:

This study included 44 eyes from 22 patients. At the 5-year follow-up, the mean uncorrected distance visual acuity improved to 0.03 ± 0.06 and 0.02 ± 0.05 logarithm of the minimum angle of resolution (range 0.15 to −0.08 and 0.10 to −0.08) for SMILE and FS-LASIK groups, respectively. There was no statistically significant difference between the groups (P = .572). At 5 years, all eyes in both groups were within ±1.00 diopter of attempted spherical equivalent refraction, and no statistically significant difference was found between the intended and achieved correction comparing the groups at any time points. None of the aberrations showed a difference between the groups at any time.

Conclusions:

Both SMILE and FS-LASIK were safe and similar in terms of efficacy and predictability at long-term follow-up for the correction of myopia and myopic astigmatism.
A refractive optical device potentially masking an intraocular tumor
Authors: Edington Magdalena , Connolly Julie , Lockington David , Cauchi Paul , Chadha Vikas
Published: February 2020

A 62-year-old woman was referred with reduced vision in her left eye and suspected retinal detachment. Bilateral laser in situ keratomileusis with KAMRA corneal inlay insertion was performed in the left eye 2 years earlier. On examination, a shadow from the corneal inlay limited posterior segment examination even with dilated fundoscopy, but a temporal raised lesion extending over the macula was noted. Ocular ultrasound confirmed a large tumor consistent with malignant melanoma, requiring enucleation. It is unclear whether the patient had baseline dilated fundoscopy before corneal inlay implantation; however, a pinhole effect for the patient will cause a pinhole effect for the clinician, potentially limiting the fundal view. The authors emphasize the importance of appropriate informed consent patients, including discussion of rare risks and complications, which can have profound implications. In this case, the elective refractive procedure potentially masked an intraocular tumor. Enucleation may have been avoided if the lesion had been identified at an earlier stage.
Diagonal haptic capture of a plate intraocular lens with 4 haptics
Authors: Jin Haiying , Zhang Hongyang
Published: February 2020

A technique of diagonal haptic capture of a plate intraocular lens (IOL) with 4 haptics for cases with insufficient posterior capsular support is presented. The diagonal haptics were captured through the capsulorhexis by sequentially depressing each side of the haptic beneath the rim of the capsulorhexis with a gentle pressure. The IOL is fixated by pure IOL–capsule capture without sulcus fixation of haptics. The technique was used in 12 eyes (12 patients). The IOLs were well centered within the follow-up period. No IOL malposition, pseudophacodonesis, pupil capture, pigmental dispersion, or high intraocular tension was observed postoperatively. Ultrasound biomicroscopy revealed that there was no chafing of the IOL with the posterior iris. The technique provided an instant and definitive fixation with high adaptability to different sizes of capsulorhexis, and thereby could reduce the risk for complications related to haptic–sulcus fixation.
To Be or Not to Be (A Morton's/Interdigital Neuroma): That Is the Question—A Case Series of Lateral Forefoot Pain Localized to the Proper Digital Nerve of the Fifth Toe
Authors: Reisner Jacob H. , Boettcher Brennan J. , Johnson Adam C. , Cummings Nancy M. , Jelsing Elena J.
Published: February 2020

We present 2 cases where the initial history and examination were similar to a Morton's/interdigital neuroma. In both cases, however, diagnostic ultrasound revealed symptomatic snapping of the proper digital nerve of the fifth toe. The anatomy of the proper digital nerve of the fifth toe may predispose it to a snapping phenomenon. Clinical awareness of this atypical cause of forefoot pain can help guide the diagnosis and treatment in those patients with persistent and refractory lateral forefoot pain and paresthesias.
Attention-Deficit/Hyperactivity Disorder Status and Sex Moderate Mild Traumatic Brain Injury Symptom Severity in Children and Adolescents: Implications for Clinical Management
Authors: Orban Sarah A. , Epstein Jeffery N. , Carr Devon , Logan Kelsey , Gubanich Paul J. , Sidol Craig , Myer Gregory D.
Published: February 2020

Objective:

To investigate the impact of pediatric mild traumatic brain injury (mTBI), using a broad parent-reported measure, and to determine whether parent-ratings of mTBI symptoms are higher among those with premorbid attention-deficit/hyperactivity disorder (ADHD) and females.

Design:

Retrospective case–control.

Setting:

Hospital-based sports medicine clinic.

Participants:

The retrospective chart review included 1346 (age: M = 13.11 years, SD = 2.6; 61.7% male) pediatric patients with (n = 209) and without (n = 1137) ADHD.

Independent Variables:

Group membership (ADHD vs non-ADHD) and sex (male vs female).

Main Outcome Measures:

Baseline and current Post-Concussion Symptom Inventory–Parent Report Form (PCSI-P) Physical, Emotional, Cognitive, and Fatigue subscale scores. This study used a retrospective chart review; therefore, the hypotheses reported for the current study were formed after data were collected.

Results:

Controlling for patient age and days from mTBI, patients with ADHD had significantly higher retrospective parent-reported pre-mTBI ratings of physical, emotional, and cognitive symptoms (ds = 0.17-0.62) and higher post-mTBI ratings across all 4 symptom domains (ds = 0.18-0.57) than those without ADHD. There was no group × time interaction for any of the PCSI-P subscales. Females overall had higher retrospective parent-reported pre-injury Fatigue and Emotional symptoms (ds = 0.13-0.19) and higher post-mTBI symptoms in all 4 PCSI-P symptom domains (ds = 0.23-0.35), relative to males.

Conclusions:

Attention-deficit/hyperactivity disorder-related postinjury exacerbations in parent-reported symptoms can be explained, in part, by elevated retrospective parent-reported ADHD-related pre-mTBI ratings. These results highlight the importance of assessing a patient's baseline symptoms post-mTBI. These data also indicate that ADHD status and sex should be considered when interpreting mTBI symptom severity during clinical evaluation of concussion.
Impact of Viral Seasonal Outbreaks on Crowding and Health Care Quality in Pediatric Emergency Departments
Authors: Noel Guilhem , Maghoo Ajmal , Piarroux Josephine , Viudes Gilles , Minodier Philippe , Gentile Stéphanie
Published: February 2020

In pediatric emergency departments (PEDs), seasonal viral outbreaks are believed to be associated with an increase of workload, but no quantification of this impact has been published. A retrospective cross-sectional study aimed to measure this impact on crowding and health care quality in PED. The study was performed in 1 PED for 3 years. Visits related to bronchiolitis, influenza, and gastroenteritis were defined using discharge diagnoses. The daily epidemic load (DEL) was the proportion of visits related to one of these diagnoses. The daily mean of 8 crowding indicators (selected in a published Delphi study) was used. A total of 93,976 children were admitted (bronchiolitis, 2253; influenza, 1277; gastroenteritis, 7678). The mean DEL was 10.4% (maximum, 33.6%). The correlation between the DEL and each indicator was significant. The correlation was stronger for bronchiolitis (Pearson R from 0.171 for number of hospitalization to 0.358 for length of stay). Between the first and fourth quartiles of the DEL, a significant increase, between 50% (patients left without being seen) and 8% (patient physician ratio), of all the indicators was observed. In conclusion, seasonal viral outbreaks have a strong impact on crowding and quality of care. The evolution of “patients left without being seen” between the first and fourth quartiles of DEL could be used as an indicator reflecting the capacity of adaptation of an emergency department to outbreaks.
Screening With Reticulocyte Hemoglobin Increased Iron Sufficiency Among NICU Patients
Authors: Morton Sarah U. , Yuen Jenny Chan , Feldman Henry A. , Hashim Emily , Rudie Coral , Lindamood Kristen E. , Caughey Daniel , Moline Mark , Sims Jessica K. , Sola-Visner Martha C. , Leeman Kristen T.
Published: February 2020

Introduction:

To increase the rate of iron sufficiency among neonatal intensive care unit (NICU) patients from 16% to >35% within 12 months of implementing standardized assessment of reticulocyte hemoglobin (retHE).

Methods:

We implemented a quality improvement (QI) study to improve iron sufficiency in our out-born level III/IV NICU. We screened 2,062 admissions, of which 622 were eligible based on feeding status at discharge. QI interventions included educational efforts and guideline implementation. Our primary outcome measure was the percentage of patients with their discharge retHE measure within the normal range. We also tracked the process measure of the number of retHE tests performed and a balancing measure of the incidence of elevated retHE among patients receiving iron supplementation. Statistical process control (SPC) charts assessed for special cause variation.

Results:

The percentage of patients with a retHe within the normal range was significantly increased from a mean of 20% to 39% on SPC chart analysis. We measured significantly more retHE values after guideline implementation (11/mo to 24/mo) and found no cases of elevated retHE among patients receiving iron supplementation.

Conclusions:

After the implementation of a standardized guideline, a higher rate of iron sufficiency was found in NICU patients at discharge. This work is generalizable to neonatal populations with the potential for a significant impact on clinical practice.
Anxiety Disorders in Patients With Somatic Diseases
Authors: Henning Michaela , Subic-Wrana Claudia , Wiltink Jörg , Beutel Manfred
Published: February 2020

Objective

Anxiety disorders are among the most frequent mental disorders and are associated with a range of short- and long-term impairments and disabilities. Relatively little is known about anxiety disorders in patients with somatic diseases, and the present literature review highlights the current research in this field, data about prevalences of anxiety disorders in patients with somatic diseases, and the effectiveness of interventions. This article also introduces a comprehensive model of inpatient treatment and summarizes the evidence pertinent to this approach.

Methods

A narrative review is presented with regard to prevalence and treatment of anxiety disorders in patients with somatic diseases. The effects of inpatient treatment are illustrated based on a case report.

Results

This review indicates that anxiety disorders are more common in patients with somatic diseases, with prevalence estimates ranging from 2.5% to 55%, than in the general population. Several outpatient treatment options exist, with substantial support for the effectiveness of cognitive behavioral therapy, psychodynamic therapy, and pharmacotherapy. We also provide evidence in support of psychosomatic inpatient treatment for patients with anxiety disorders that are comorbid with somatic diseases.

Conclusions

Anxiety disorders are common in patients with somatic diseases, and several effective treatment options exist, including cognitive behavioral therapy and pharmacological interventions. We also provide support for the effectiveness of inpatient treatment with unique opportunities for multidisciplinary psychosomatic treatment of anxiety disorders with comorbid somatic diseases.
Brief Report: Recent HIV Infection Surveillance in Routine HIV Testing in Nairobi, Kenya: A Feasibility Study
Authors: Welty Susie , Motoku John , Muriithi Chris , Rice Brian , de Wit Mariken , Ashanda Brenda , Waruiru Wanjiru , Mirjahangir Joy , Kingwara Leonard , Bauer Richard , Njoroge David , Karimi Jesse , Njoroge Alice , Rutherford George W.
Published: February 2020

Background:

Serological tests can distinguish recent (in the prior 12 months) from long-term HIV infection. Integrating recency testing into routine HIV testing services (HTS) can provide important information on transmission clusters and prioritize clients for partner testing. This study assessed the feasibility and use of integrating HIV recency into routine testing.

Methods:

We conducted a multi-method study at 14 facilities in Kenya, and key informant interviews with health care providers. We abstracted clinical record data, collected specimens, tested specimens for recent infection, returned results to participants, and conducted a follow-up survey for those recently infected.

Results:

From March to October 2018, we enrolled 532 clients who were diagnosed HIV-positive for the first time. Of these, 46 (8.6%) were recently infected. Women aged 15–24 years had 2.9 (95% confidence interval: 1.46 to 5.78) times higher adjusted odds of recent infection compared with 15–24-year-old men and those tested within the past 12 months having 2.55 (95% confidence interval: 0.38 to 4.70) times higher adjusted odds compared with those tested ≥12 months previously. Fourteen of 17 providers interviewed found the integration of recency testing into routine HTS services acceptable and feasible. Among clients who completed the follow-up interview, most (92%) felt that the recency results were useful.

Conclusions:

Integrating recent infection testing into routine HTS services in Kenya is feasible and largely acceptable to clients and providers. More studies should be done on possible physical and social harms related to returning results, and the best uses of the recent infection data at an individual and population level.
Identification of Normal Pressure Hydrocephalus by Disease-Specific Patterns of Brain Stiffness and Damping Ratio
Authors: Murphy Matthew C. , Cogswell Petrice M. , Trzasko Joshua D. , Manduca Armando , Senjem Matthew L. , Meyer Fredric B. , Ehman Richard L. , Huston John
Published: February 2020

Objectives

The aim of this study was to perform a whole-brain analysis of alterations in brain mechanical properties due to normal pressure hydrocephalus (NPH).

Materials and Methods

Magnetic resonance elastography (MRE) examinations were performed on 85 participants, including 44 cognitively unimpaired controls, 33 with NPH, and 8 who were amyloid-positive with Alzheimer clinical syndrome. A custom neural network inversion was used to estimate stiffness and damping ratio from patches of displacement data, accounting for edges by training the network to estimate the mechanical properties in the presence of missing data. This learned inversion was first compared with a standard analytical approach in simulation experiments and then applied to the in vivo MRE measurements. The effect of NPH on the mechanical properties was then assessed by voxel-wise modeling of the stiffness and damping ratio maps. Finally, a pattern analysis was performed on each individual's mechanical property maps by computing the correlation between each person's maps with the expected NPH effect. These features were used to fit a classifier and assess diagnostic accuracy.

Results

The voxel-wise analysis of the in vivo mechanical property maps revealed a unique pattern in participants with NPH, including a concentric pattern of stiffening near the dural surface and softening near the ventricles, as well as decreased damping ratio predominantly in superior regions of the white matter (family-wise error correctedP< 0.05 at cluster level). The pattern of viscoelastic changes in each participant predicted NPH status in this cohort, separating participants with NPH from the control and the amyloid-positive with Alzheimer clinical syndrome groups, with areas under the receiver operating characteristic curve of 0.999 and 1, respectively.

Conclusions

This study provides motivation for further development of the neural network inversion framework and demonstrates the potential of MRE as a novel tool to diagnose NPH and provide a window into its pathogenesis.
Stereological study on the numerical plasticity of myelinated fibers and oligodendrocytes in the rat spinal cord with painful diabetic neuropathy
Authors: Lin Jing-yan , Zhu Na , He Yi-na , Xu Bo-lin , Peng Bin
Published: February 2020

Painful diabetic neuropathy may associate with nerve morphological plasticity in both peripheral and central nervous system. The aim of this study was to determine numerical changes of myelinated fibers in the spinothalamic tract region and oligodendrocytes in the spinal dorsal horn of rats with painful diabetic neuropathy and the effects of metformin on the above changes. Male Sprague–Dawley rats were randomly allocated into the control group (n = 7), the painful diabetic neuropathy group (n = 6) and the painful diabetic neuropathy treated with metformin group (the PDN + M group, n = 7), respectively. Twenty-eight days after medication, numbers of myelinated fibers in the spinothalamic tract and oligodendrocytes in the spinal dorsal horn were estimated by the optical disector (a stereological technique). Compared to the control group, number of myelinated fibers in the spinothalamic tract increased significantly in the painful diabetic neuropathy and PDN + M group, compared to the painful diabetic neuropathy group, number of myelinated fibers decreased in the PDN + M group (P < 0.05). As the oligodendrocyte in the spinal dorsal horn was considered, its number increased significantly in the painful diabetic neuropathy group compared to the control and the PDN + M group (P < 0.05), there was no significant difference between the control and the PDN + M group (P > 0.05). Our results indicate that painful diabetic neuropathy is associated with a serial of morphometric plasticity in the rat spinal cord including the numerical increase of the myelinated fibers in the spinothalamic tract and the oligodendrocytes in the spinal dorsal horn. The analgesic effect of metformin against painful diabetic neuropathy might be related to its adverse effects on the above morphometric plasticity.
Evidence of both brainstem and auditory cortex involvement in categorical perception for Chinese lexical tones
Authors: Li Xiaolin , Zhang Xiaochen , Gong Qin
Published: February 2020

The categorical perception of lexical tones is important to understand tonal languages. Recent studies have provided electrophysiological evidence for the categorical perception of lexical tones at the cortical level; however, whether neural correlates exist at subcortical levels remain unknown. In this study, by using across-category and within-category lexical tone contrasts with the equivalent physical interval, we recorded deviance detection activities at both the brainstem (reflected by frequency following response) and cortical levels (reflected by mismatch negativity) simultaneously. We found that significantly enhanced intertrial phase-locking of frequency following response s was observed only during the across-category deviance detection, which indicates that phonological differences could be detected at the level of brainstem. In addition, the across-category deviants induced stronger mismatch negativity than within-category deviants. For the first time, our results demonstrate that neural correlates of categorical perception of lexical tones exist even in the brainstem, and suggests that both cortical and subcortical processes are involved in the coding and categorization of tonal information.
Evaluation of cariprazine in the treatment of bipolar I and II depression: a randomized, double-blind, placebo-controlled, phase 2 trial
Authors: Yatham Lakshmi N. , Vieta Eduard , Earley Willie
Published: February 2020

This double-blind placebo-controlled, fixed/flexible-dose phase 2 trial assessed the efficacy, safety, and tolerability of cariprazine vs. placebo for depressive episodes associated with bipolar I or II disorder. Primary endpoint was change in Montgomery–Åsberg Depression Rating Scale (MADRS) total scores (baseline to week 8), and secondary endpoint was mean Clinical Global Impressions-Improvement score (week 8). Patients were randomized (N = 233) 1:1:1 to placebo, ‘low-dose’ 0.25–0.5 mg/day or ‘high-dose’ 1.5–3.0 mg/day cariprazine. Adverse events, laboratory results, vital signs, extrapyramidal symptoms, and suicide risk were monitored. Neither cariprazine group significantly separated from placebo in primary (mixed-effect model repeated measures MADRS least-squares mean differences: low-dose = −0.7, P = 0.7408; high-dose = 0.0, P = 0.9961) or secondary efficacy measures. No new safety signals with cariprazine were observed and common treatment-emergent adverse events (≥5% of cariprazine patients and twice the rate of placebo) included insomnia, akathisia, dry mouth, nausea, weight increased, diarrhea, restlessness, vomiting, musculoskeletal stiffness, migraine, and cough. Metabolic and weight changes were generally similar for cariprazine and placebo. Factors that may have affected the outcome of the trial were identified, which helped to inform the design and conduct of subsequent phase 2b/3 clinical trials of cariprazine in bipolar depression.
Long-Term Persistence of IgG Antibodies in SARS-CoV Infected Healthcare Workers
Authors: Guo Xiaoqin , Guo Zhongmin , Duan Chaohui , Chen Zeliang , Wang Guoling , Lu Yi , Li Mengfeng , Lu Jiahai
Published: February 2020

BACKGROUND

The ongoing worldwide outbreak of the 2019-nCoV is markedly similar to the severe acute respiratory syndrome (SARS) outbreak 17 years ago. During the 2002-2003 SARS outbreak, healthcare workers formed a special population of patients. Although virus-specific IgG play important roles in virus neutralization and prevention against future infection, limited information is available regarding the long term persistence of IgG after infection with SARS-like coronavirus.

METHODS

A long-term prospective cohort study followed 34 SARS-CoV-infected healthcare workers from a hospital with clustered infected cases during the 2002-2003 SARS outbreak in Guangzhou, China, with a 13-year follow-up. Serum samples were collected annually from 2003-2015. Twenty SARS-CoV-infected and 40 non-infected healthcare workers were enrolled in 2015, and their serum samples were collected. All sera were tested for IgG antibodies with ELISA using whole virus and a recombinant nucleocapsid protein of SARS-CoV, as a diagnostic antigen.

RESULTS

Anti SARS-CoV IgG was found to persist for up to 12 years. IgG titers typically peaked in 2004, declining rapidly from 2004-2006, and then continued to decline at a slower rate. IgG titers in SARS-CoV-infected healthcare workers remained at a significantly high level until 2015. Patients treated with corticosteroids at the time of infection were found to have lower IgG titers than those without.

CONCLUSIONS

IgG antibodies against SARS-CoV can persist for at least 12 years. The presence of SARS-CoV IgG might provide protection against SARS-CoV and other betacoronavirus. This study provides valuable information regarding humoral immune responses against SARS-CoV and the 2019-nCoV.
Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain
Authors: van der Vlist Michiel , Raoof Ramin , Willemen Hanneke L.D.M. , Prado Judith , Versteeg Sabine , Gil Christian Martin , Vos Martijn , Lokhorst Roeland E. , Pasterkamp R. Jeroen , Kojima Toshiyuki , Karasuyama Hajime , Khoury-Hanold William , Meyaard Linde , Eijkelkamp Niels
Published: February 2020

The current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight how inflammatory pain is resolved is lacking. Here we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. The resolution of pain and the transfer of mitochondria requires expression of CD200 Receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain.

Graphical Abstract
Towards understanding the structure of the capsid of Banana Bunchy Top Virus
Authors: Sairam Sundaram , Selvarajan Ramasamy , Handanahalli Savithri S , Venkataraman Sangita
Published: February 2020

Banana is the major staple food crop for approximately 400 million people. Bunchy Top disease of Banana is one of the most devastating diseases caused by Banana Bunchy Top Virus (BBTV) that results in a significant loss of yield, stunting and bunchy appearance of leaves. While many isolates of BBTV from various regions of India have been characterized by different groups, no structural study exists for this important virus. To pursue structural studies, the pET28a clone of coat protein (CP) gene from BBTV isolate of Hill Banana grown in lower Pulney Hills (Virupakshi) of Tamilnadu was expressed in BL21 (DE3) pLysS. Purification of the CP was done using Ni-NTA affinity chromatography. In vitro capsid assembly studied using sucrose density gradient centrifugation suggested that the CP did not assemble as virus like particle (VLPs) but remained as smaller oligomers. Studies using dynamic light scattering (DLS) indicates that the purified protein is poly-dispersed represented majorly as pentamers. Studies using both homology modelling andab initiostructure determination gave useful insights into the probable fold of the CP suggesting it is a β-sandwich fold similar to that seen in majority of plant viruses.In silicocapsid reconstruction aided understanding of the quaternary organization of subunits in the capsid and molecular interactions present between the subunits. The location of aphid binding EAG motif was identified on the surface loops close to the pentameric axis indicating their role in vector mediated transmission.
A Front-Back Confusion Metric in Horizontal Sound Localization: The FBC Score
Authors: Fischer Tim , Caversaccio Marco , Wimmer Wilhelm
Published: February 2020

In sound localization experiments, currently used metrics for front-back confusion (FBC) analysis weight the occurring FBCs equally, regardless of their deviation from the cone of confusion. To overcome this limitation, we introduce the FBC Score. A sound localization experiment in the horizontal plane with 12 bilaterally implanted cochlear implants (CI) users and 12 normal hearing subjects was performed to validate the method with real clinical data. The overall FBC Rate of the CI users was twice as high as the FBC Score. For the control group, the FBC Rate was 4 times higher than the FBC Score. The results indicate that the FBC Rate is inflated by FBCs that show a considerable deviation from the corresponding value on the cone of confusion.
The major subunit of widespread competence pili exhibits a novel and conserved type IV pilin fold
Authors: Sheppard Devon , Berry Jamie-Lee , Denise Rémi , Rocha Eduardo P. C. , Matthews Steve , Pelicic Vladimir
Published: February 2020

Type IV filaments (T4F), which are helical assemblies of type IV pilins, constitute a superfamily of filamentous nanomachines virtually ubiquitous in prokaryotes that mediate a wide variety of functions. The competence (Com) pilus is a widespread T4F, mediating DNA uptake (the first step in natural transformation) in bacteria with one membrane (monoderms), an important mechanism of horizontal gene transfer. Here, we report the results of genomic, phylogenetic, and structural analyses of ComGC, the major pilin subunit of Com pili. By performing a global comparative analysis, we show that Com pili genes are virtually ubiquitous in Bacilli, a major monoderm class of Firmicutes. This also revealed that ComGC displays extensive sequence conservation, defining a monophyletic group among type IV pilins. We further report ComGC solution structures from two naturally competent human pathogens,Streptococcus sanguinis(ComGCSS) andStreptococcus pneumoniae(ComGCSP), revealing that this pilin displays extensive structural conservation. Strikingly, ComGCSSand ComGCSPexhibit a novel type IV pilin fold that is purely helical. Results from homology modelling analyses suggest that ComGC unusual structure is compatible with helical filament assembly. Because ComGC displays such a widespread distribution, these results have implications for hundreds of monoderm species.
OTX2 non-cell autonomous activity regulates inner retinal function
Authors: Torero-Ibad Raoul , Mazhar Bilal , Vincent Clémentine , Bernard Clémence , Dégardin Julie , Simonutti Manuel , Lamonerie Thomas , Di Nardo Ariel , Prochiantz Alain , Moya Kenneth L.
Published: February 2020

OTX2 is a homeoprotein transcription factor expressed in photoreceptors and bipolar cells in the retina. OTX2, like many other homeoproteins, transfers between cells and exerts non-cell autonomous effects such as promoting survival of retinal ganglion cells that do not express the protein. Here we used a genetic approach to target extracellular OTX2 in the retina by conditional expression of a secreted single chain anti-OTX2 antibody. Compared to control mice, the expression of this antibody by Parvalbumin-expressing neurons in the retina is followed by a reduction in visual acuity in one-month-old mice with no alteration of the retinal structure or cell type number or aspect. A- and b-waves measured by electroretinogram were also indistinguishable from control mice, suggesting no functional deficit of photoreceptors and bipolar cells. Mice expressing the OTX2-neutralizing antibody did show a significant doubling in the flicker amplitude, consistent with a change in inner retinal function. Our results show that interferingin vivowith OTX2 non-cell autonomous activity in the postnatal retina leads to an alteration in inner retinal cell functions and causes a deficit in visual acuity.

Significance statement

OTX2 is a homeoprotein transcription factor expressed in retinal photoreceptors and bipolar cells. Although theOtx2locus is silent in the inner retina, the protein is detected in cells of the ganglion cell layer consistent with the ability of this class of proteins to transfer between cells. We expressed a secreted single chain antibody (scFv) against OTX2 in the retina to neutralize extracellular OTX2. Antibody expression leads to reduced visual acuity with no change in retinal structure, or photoreceptor or bipolar physiology; however, activity in the inner retina was altered. Thus, interfering with OTX2 non-cell autonomous activity in postnatal retina alters inner retinal function and causes vision loss, highlighting the physiological value of homeoprotein direct non-cell autonomous signaling.
Modulation of spatial cue processing across the lifespan: a geometric polarization of space restores allocentric navigation strategies in children and older adults
Authors: Bécu Marcia , Sheynikhovich Denis , Ramanoël Stephen , Tatur Guillaume , Ozier-Lafontaine Anthony , Sahel José-Alain , Arleo Angelo
Published: February 2020

The impact of development and healthy aging on spatial cognition has been traditionally attributed to a difficulty in using allocentric strategies and a preference for egocentric ones. An alternative possibility, suggested by our previous works, is that this preference is actually conditioned by the spatial cues (e.g. geometric of landmark cues) present in the environment rather than a strategic choice per se. We tested this prediction by having 79 subjects (children, young and older adults) navigating a Y-maze composed either of landmarks or geometric cues, with an immersive head-mounted display that allows us to record both head and eye movements. Our results show that when the performance is based on landmarks solely, children and older adults exhibit a deficit in using allocentric strategies when compared to young adults. Hence, an inverted U-profile of allocentric strategies was observed across the lifespan. This was not due to a default of attention to the landmarks, as evidenced by analysis of gaze dynamics. When geometric were provided, however, older adults and children used allocentric strategies in the same proportion as young adults. They were, in addition, as efficient and quick to implement the strategy. We thus propose a reinterpretation of the previous data in the literature, whereby reference to geometric cues is the default mode for spatial representations, which is immune to age, whereas spatial representations fail to be anchored on landmarks early in development and later in aging. This new interpretation has the potential to reunify several data from the literature, ranging from spatial cues processing to strategy preference, and including other spatial skills like path integration and route learning.