bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural mechanisms of reward and loss processing in a low-income sample of at-risk adolescents
Authors: Murray Laura , Lopez-Duran Nestor L , Mitchell Colter , Monk Christopher S , Hyde Luke W
Published: November 2020

Adolescence is a time of engagement in risky, reward-driven behaviors, with concurrent developmental changes within reward-related neural systems. As previous research has recruited mostly higher socioeconomic, European and European American participants, therefore limiting generalizability to the US population, especially for populations of color or low-income populations. The current study provided one of the first opportunities to examine the neural correlates of reward and loss functioning in a population-based sample of adolescents at increased risk for poverty-related adversities. The study investigated neural reward and loss processing and whether age, pubertal status and the social constructs of gender and race predicted individual differences in reward- and loss-related brain function. One hundred and twenty-eight primarily low-income adolescents (mean age: 15.9 years, 75% African American) from urban environments completed a modified monetary incentive delay task during functional magnetic resonance imaging (fMRI). Consistent with the previous research, reward and loss anticipation recruited similar motivational circuitry including striatal, insular, thalamic and supplementary motor areas. Race and gender were not associated with reward- or loss-related neural reactivity. Age and pubertal development were associated with differences in neural reactivity to reward and loss, suggesting that older and more mature adolescents had increased activity in sensory and motivational circuits, but decreased activity in regions responsible for error detection and behavior modification.
The emergence of systemic risk: The Federal Reserve, bailouts, and monetary government at the limits
Authors: Özgöde Onur
Published: November 2020

Why does the Federal Reserve bail banks out in violation of a core principle of free-market capitalism: private gain–private loss? This article argues the Fed rescues banks not because it is captured by financial interests, but because it is captured by the paradigm of ‘systemic risk’. Systemic risk emerged in the 1960s out of a jurisdictional struggle over the Fed between two expert groups, ‘monetary substantivists’ and ‘monetary formalists’. The latter’s triumph transformed the Fed into a macroeconomic institution, responsible for managing growth. It also led to the institutionalization of ‘systemic risk’—a conception of the financial system as a vital and yet vulnerable economic system and of the Fed’s responsibility for protecting it. In this process, policymakers grew to fear bank failures as they began to see financial disasters through the lens of systemic risk.
Rapid Diagnosis of IPA Relied on Calcofluor White Fluorescence Staining: Two Cases Report
Authors: Shi Buyun , Xia Zhi , Tang Wen , Qin Chenguang , Cheng Ying , Huang Tao , Li Yong , Xu Hui
Published: November 2020

Invasive pulmonary aspergillosis (IPA) is a serious infectious disease with high mortality. However, the rapid diagnosis of IPA remains difficult since the microbiological evidence is difficult to obtain or time-consuming. Thus, we attempted to rapidly diagnose two pediatric cases with respiratory failure due to IPA via bronchoalveolar lavage fluid with Calcofluor White fluorescence staining, which has rarely been used before.
Multinational Appraisal of the Chronic Otitis Media Questionnaire 12 (COMQ-12)
Authors: Phillips John S. , Yung Matthew W. , Nunney Ian , Doruk Can , Kara Hakan , Kong Taehoon , Quaranta Nicola , Peñaranda Augusto , Bernardeschi Danièle , Dai Chunfu , Kania Romain , Denoyelle Françoise , Tono Tetsuya
Published: November 2020

Objectives:

The Chronic Otitis Media Questionnaire-12 (COMQ-12) assesses patient-reported health-related quality of life. A multinational collaborative project was performed to translate and appraise the psychometric properties of the COMQ-12 across Europe, Asia, and South America.

Methods:

Eight otology units from seven countries (China, Colombia, France, Italy, Japan, Korea, Turkey) created native versions of the COMQ-12 by the process of translation and back-translation. Questionnaire reliability was assessed on the basis of internal consistency by calculating Cronbach's coefficient alpha. Exploratory factor analysis was performed to identify underlying correlations between individual questionnaire items.

Results:

This study included 478 participants from 8 countries. Calculated values for Cronbach's coefficient alpha were between 0.71 and 0.90. Exploratory factor analysis allowed the identification of three dominant factors, the primary factor (related to hearing problems) explaining 42% of the total variance, the secondary factor (related to daily activities) explaining 30% of the variance, and the third factor (related to acute disease activity) explaining 28% of the variance.

Conclusions:

This is a large study of patients with chronic otitis media, from centers from within many different countries spanning Europe, Asia, and South America. This study supports the use of the COMQ-12 within the individual countries where it was tested.
Comparison of Ossiculoplasty Outcomes Using Different Materials in the Treatment of Chronic Otitis Media
Authors: Jung Da Jung , Yoo Myung Hoon , Lee Kyu-Yup
Published: November 2020

Objective:

This study aimed to evaluate success rates after ossicular chain reconstruction using different materials.

Study Design:

Retrospective cohort study.

Setting:

Tertiary referral center.

Patients:

Four hundred forty-three participants who underwent ossiculoplasty at a tertiary medical center were included.

Intervention:

Ossicular chain reconstruction using five materials: autologous malleus, incus, and cortical bone, as well as Hydroxyapatite (HA) and titanium.

Main Outcome Measures:

Hearing data were measured 1 day preoperatively and 6 months postoperatively. Successful hearing outcomes were defined by the fulfillment of more than one of the following criteria: postoperative air–bone gap of 20 dB or less, hearing air conduction (AC) gain of 15 dB or more, or postoperative AC hearing less than 30 dB.

Results:

Preoperative median AC values (95% confidence interval) among participants with malleus, incus, cortical bone, HA, and titanium transplants or prostheses were 50 (39.6–54.6) dB, 51.3 (48.1–51.8) dB, 50 (45.2–52.2) dB, 56.3 (50.9–57.6) dB, and 54.3 (48.5–56.0) dB, respectively (p = 0.092). The success rates in malleus, incus, cortical bone, HA, and titanium were 53.3%, 60.3%, 51.7%, 61.6%, and 69.7%, respectively. Titanium had the highest success rate among the five materials, but the differences between the materials were not statistically significant (p = 0.283). Titanium had highest success rate among the participants with erosive stapes suprastructure or obstructed Eustachian tubes (p = 0.042 for erosive stapes suprastructure and p = 0.010 for obstructed Eustachian tubes).

Conclusion:

Our study demonstrated that titanium prostheses would be a good alternative for ossiculoplasty in cases wherein autologous material is unavailable, especially in association with unfavorable conditions, such as with the presence of cholesteatoma, erosive stapes suprastructure, edematous middle ear mucosa, and obstructed Eustachian tube.
JAK/STAT Dysregulation With SOCS1 Overexpression in Acquired Cholesteatoma-Adjacent Mucosa
Authors: Westerberg Johanna , Tideholm Ellen , Piersiala Krzysztof , Drakskog Cecilia , Kumlien Georén Susanna , Mäki-Torkko Elina , Cardell Lars Olaf
Published: November 2020

Importance:

Surgery remains the gold standard in cholesteatoma treatment. However, the rate of recurrence is significant and the development of new nonsurgical treatment alternatives is warranted. One of the possible molecular pathways to target is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway.

Objective:

To investigate the JAK/STAT pathway in the middle ear mucosa in patients with acquired cholesteatoma compared with middle ear mucosa from healthy controls.

Design:

Case-control study.

Setting:

Linköping University Hospital, Sweden, and Karolinska Institutet, Stockholm, Sweden. Sampling period: February 2011 to December 2016.

Participants:

Middle ear mucosa from 26 patients with acquired cholesteatoma undergoing tympanoplasty and mastoidectomy, and 27 healthy controls undergoing translabyrinthine surgery for vestibular schwannoma or cochlear implantation was investigated.

Main Outcomes/Measures:

The expression of Interleukin-7 receptor alpha, JAK1, JAK2, JAK3, STAT5A, STAT5B, and suppressor of cytokine signaling-1 (SOCS1) were quantified using quantitative polymerase chain reaction. In addition, expression level of cyclin D2, transforming growth factor beta 1, thymic stromal lymphopoietin, CD3, and CD19 was evaluated.

Results:

In cholesteatoma-adjacent mucosa, SOCS1 was significantly upregulated (p= 0.0003) compared with healthy controls, whereas STAT5B was significantly downregulated (p = 0.0006). The expression of JAK1, JAK2, JAK3, and STAT5A did not differ significantly between groups.

Conclusions and Relevance:

To the best of our knowledge, this is the first article reporting dysregulation of the JAK/STAT pathway in cholesteatoma-adjacent mucosa. The main finding is that important players of the aforementioned pathway are significantly altered, namely SOCS1 is upregulated and STAT5B is downregulated compared with healthy controls.
Survival and recurrence rates of hepatocellular carcinoma after treatment of chronic hepatitis C using direct acting antivirals
Authors: Lithy Rania M. , Elbaz Tamer , H. Abdelmaksoud Ahmed , M. Nabil Mohamed , Rashed Noha , Omran Dalia , Kaseb Ahmed O. , O. Abdelaziz Ashraf , I. Shousha Hend
Published: November 2020

Background

Conflicting studies were proposed either suggested or denied the relationship between early hepatocellular carcinoma (HCC) recurrence and the use of direct-acting antivirals (DAAs) for chronic hepatitis C management

Aim of the study

To evaluate HCC recurrence rate post-DAAs and potential predictive factors.

Study This prospective cohort study included all HCC patients achieved complete response attending our multidisciplinary HCC clinic, Cairo University, from November 2013 to February 2018. Group I (60 patients) who received DAAs after HCC ablation and group II (273 patients) who were DAAs-untreated. We studied factors that could play a role in HCC recurrence.

Results

The sustained virological response rate was 88.3% among DAA-treated patients. HCC recurrence rate was 45% in the post-DAA group vs. 19% in the non-DAAs group; P < 0.001. Mean survival was significantly higher in the post-DAA group (34.23 ± 16.16 vs. 23.92 ± 13.99 months respectively; P value <0.001). There was a significant correlation between HCC recurrence rate and age, male gender, mean size of tumors and time interval between complete HCC ablation and occurrence of HCC recurrence.

Conclusion

Our study reports high rate of HCC recurrence post-DAA therapy in patients treated with transarterial chemoembolization but not in those treated with curative measures. DAA therapy after curative treatment for HCC led to significantly earlier HCC recurrence, which correlated with specific clinic-pathologic features in our prospective single-institution study. However, future independent prospective randomized studies are warranted to evaluate this correlation which may lead to a change in the current standard-of-care approach to patients with hepatitis C virus-related HCC.
Is Doppler/Dopplex ultrasonography reliable in the assessment of percutaneous ablative therapies of hepatocellular carcinoma: a prospective cross-sectional study
Authors: Darweesh Samar Kamal , El-Kady Nabeel M. , Abdel-Haleem Hanan , Amer Ayman R. , Maher Rabab M.
Published: November 2020

Introduction

After hepatocellular carcinoma (HCC) interventional therapies, noninvasive vascular diagnostic imaging [duplex, Color/power Doppler ultrasonography, and triphasic computed tomography (CT)] determines the lesion complete/incomplete ablation. The aim was to analyze the usefulness of duplex, color/power Doppler ultrasonography in HCC ablation after percutaneous ablative therapies (PATs).

Methods

We included 30 patients with 33 HCCs subjected to duplex/Doppler ultrasonography, ultrasound-guided fine-needle aspiration cytology (FNAC), and triphasic CT, all these before and after PATs.

Results

One week after treatment ended, out of 21 lesions with pretreatment positive color-Doppler, signals disappeared in 19 (90.5%) lesions. Out of 29 lesions with pretreatment positive power-Doppler, signals disappeared in 24 (82.8%). Out of 13 lesions with pretreatment intralesional power/duplex arterial signals, signals disappeared in eight (61.5%). There was a significant correlation (P < 0.05) between power-Doppler arterial signals and FNAC. Before HCC ablation, power-Doppler demonstrated a sensitivity 40% and specificity 96% in HCC detection in relation to FNAC, it had a sensitivity 60% and specificity 85% in HCC detection compared to triphasic CT. After HCC ablation, power-Doppler had a sensitivity and specificity of 100% in viable malignancy detection in relation to FNAC. Power-Doppler had a sensitivity 89% and specificity 93% in residual malignancy detection in relation to triphasic CT.

Conclusion

Power-Doppler is a good positive test as intralesional arterial signals in a cirrhotic liver lesion is highly suggestive of HCC. Power-Doppler was sensitive in HCC ablation assessment in pretreatment positive cases only. Both triphasic CT and duplex/Doppler are complementary and the use of different diagnostic modalities after ablation is mandatory.
Real-world efficacy and safety of direct-acting antiviral drugs in patients with chronic hepatitis C and inherited blood disorders
Authors: Ruiz Isaac , Fourati Slim , Ahmed-Belkacem Abdelhakim , Rodriguez Christophe , Scoazec Giovanna , Donati Flora , Soulier Alexandre , Demontant Vanessa , Poiteau Lila , N’Debi Mélissa , François Murielle , Chevaliez Stéphane , Pawlotsky Jean-Michel
Published: November 2020

Background

Patients with inherited blood disorders (IBLD) have a high risk of hepatitis C virus (HCV) infection. The aim of this work was to assess the efficacy and safety of HCV direct-acting antiviral (DAA)-based treatment in patients with IBLD and chronic HCV infection.

Methods

Twenty-seven patients (25 with sickle cell disease, 1 with β-thalassemia and 1 with hemoglobin D-Punjab), including 3 with compensated cirrhosis, were included. They were treated with sofosbuvir in combination with ribavirin, daclatasvir, ledipasvir, or velpatasvir or with grazoprevir/elbasvir for 8 or 12 weeks. In the case of treatment failure, in-vitro assessment of resistance-associated substitutions (RASs) and full-length genome sequence analysis by means of deep sequencing were performed.

Results:

Treatment was safe and well-tolerated and there were no drug discontinuations due to DAA-related adverse events. Twenty-five out of the 27 patients (93%) achieved sustained virological response 12 weeks post-treatment. One patient discontinued after 18 days due to adverse events unrelated to the antiviral treatment. One patient infected with ‘unusual’ genotype 2 subtype 2m relapsed. Subtype 2m naturally carries the NS5A L31M RAS. In a genotype 2a subgenomic replicon model, L31M increased daclatasvir effective concentration 50% (EC50) by 97-fold, but velpatasvir EC50 by only 3-fold, without altering the replication capacity. This patient was successfully retreated with sofosbuvir/velpatasvir for 12 weeks.

Conclusion

DAA-based regimens are well tolerated and highly efficacious in patients with chronic hepatitis C and IBLD in the real-world setting. Thus, DAA-based antiviral treatment should be prioritized in this thus far neglected population of HCV-infected patients.
Individual and Area-level Factors Contributing to the Geographic Variation in Ambulatory Care Sensitive Conditions in Finland
Authors: Satokangas Markku , Arffman Martti , Antikainen Harri , Leyland Alastair H. , Keskimäki Ilmo
Published: November 2020

Background:

Measuring primary health care (PHC) performance through hospitalizations for ambulatory care sensitive conditions (ACSCs) remains controversial—recent cross-sectional research claims that its geographic variation associates more with individual socioeconomic position (SEP) and health status than PHC supply.

Objectives:

To clarify the usage of ACSCs as a PHC performance indicator by quantifying how disease burden, both PHC and hospital supply and spatial access contribute over time to geographic variation in Finland when individual SEP and comorbidities were adjusted for.

Methods:

The Finnish Care Register for Health Care provided hospitalizations for ACSCs (divided further into subgroups of acute, chronic, and vaccine-preventable causes) in 2011–2017. With 3-level nested multilevel Poisson models—individuals, PHC authorities, and hospital authorities—we estimated the proportion of the variance in ACSCs explained by selected factors at 3 time periods.

Results:

In age-adjusted and sex-adjusted analysis of total ACSCs the variances between hospital authorities was nearly twice that between PHC authorities. Individual SEP and comorbidities explained 19%–30% of the variance between PHC authorities and 25%–36% between hospital authorities; and area-level disease burden and arrangement and usage of hospital care a further 14%–16% and 32%–33%—evening out the unexplained variances between PHC and hospital authorities.

Conclusions:

Alongside individual factors, areas’ disease burden and factors related to hospital care explained the excess variances in ACSCs captured by hospital authorities. Our consistent findings over time suggest that the local strain on health care and the regional arrangement of hospital services affect ACSCs—necessitating caution when comparing areas’ PHC performance through ACSCs.
Can Regionalization of Care Reduce Socioeconomic Disparities in Breast Cancer Survival?
Authors: Nattinger Ann B. , Rademacher Nicole , McGinley Emily L. , Bickell Nina A. , Pezzin Liliana E.
Published: November 2020

Background:

Breast cancer patients of low socioeconomic status (SES) have worse survival than more affluent women and are also more likely to undergo surgery in low-volume facilities. Since breast cancer patients treated in high-volume facilities have better survival, regionalizing the care of low SES patients toward high-volume facilities might reduce SES disparities in survival.

Objective:

We leverage a natural experiment in New York state to examine whether a policy precluding payment for breast cancer surgery for New York Medicaid beneficiaries undergoing surgery in low-volume facilities led to reduced SES disparities in mortality.

Research Design:

A multivariable difference-in-differences regression analysis compared mortality of low SES (dual enrollees, Medicare-Medicaid) breast cancer patients to that of wealthier patients exempt from the policy (Medicare only) for time periods before and after the policy implementation.

Subjects:

A total of 14,183 Medicare beneficiaries with breast cancer in 2006–2008 or 2014–2015.

Measures:

All-cause mortality at 3 years after diagnosis and Medicaid status, determined by Medicare administrative data.

Results:

Both low SES and Medicare-only patients had better 3-year survival after the policy implementation. However, the decline in mortality was larger in magnitude among the low SES women than others, resulting in a 53% smaller SES survival disparity after the policy after adjustment for age, race, and comorbid illness.

Conclusion:

Regionalization of early breast cancer care away from low-volume centers may improve outcomes and reduce SES disparities in survival.
Orabase Promotes Oral Epithelization in a Wound Healing Rat Model: An Immunohistochemical Study
Authors: Chaushu Liat , Rahmanov Gavrielov Marina , Chaushu Gavriel , Zar Keidar , Vered Marilena
Published: November 2020

Background:

Recent evidence suggests that bone marrow–derived stem cells may have an important role in the natural process of wound healing. The aim of the present study was to examine the effect of orabase paste application on primary wound healing in a palatal rat model.

Materials and Methods:

A total of 48 six-month-old male Wistar rats weighting 427 to 650 g were included. A mid-crestal incision was made on the maxillary alveolar ridge. A full-thickness flap was raised on either side of the incision and was then repositioned and sutured. Three experimental groups were used: O—study group—orabase, N—negative control group, and I—intact control group. Half of the animals were killed on 7 days and the remaining on 14 days postoperatively. Outcome parameters included epithelial gap; inflammatory infiltration; expression of stem cell markers within the oral epithelium and stromal cells; and physical properties of stromal collagen fibers and myofibroblasts. Investigations were performed at 2 time points (7 and 14 d) during the wound healing process.

Results:

The epithelial gap closed completely after 7 days in the O group versus 14 days or more in the N group. The inflammatory reaction was relatively low and not significantly different between groups O and N. Orabase upregulated the expression of CK14, CK15, and epithelial SOX2. Connective tissue SOX2, CD34, and α-smooth muscle actin and physical properties of stromal collagen fibers were not influenced by the application of orabase.

Conclusions:

Orabase promotes epithelial gap closure in a primary wound healing model in rats. The effect is exerted through promotion of epithelial differentiation from stem cells.
Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix
Authors: Cimic Adela , Vranic Semir , Arguello David , Contreras Elma , Gatalica Zoran , Swensen Jeffrey
Published: November 2020

Neuroendocrine carcinoma of the cervix (NEC) is a rare and highly aggressive cervical malignancy. Given that no targeted therapy has been approved specifically to NEC, we investigated the presence of novel, potentially targetable biomarkers in a large cohort of NEC. Sixty-two NEC were molecularly profiled for biomarkers of targeted therapies including antibody-drug conjugates [delta-like canonical notch ligand 3 (DLL3), a trophoblast cell surface antigen 2 (TROP-2), and folate receptor 1 (FOLR1)], NTRK1-3 gene fusions, and immune checkpoint inhibitors [programmed death-ligand 1 (PD-L1), tumor mutational burden, and microsatellite instability] using immunohistochemistry and DNA/RNA next-generation sequencing assays. A cohort of squamous cell carcinomas of the cervix (n=599) was used for comparison for immune-oncology biomarkers. DLL3 expression was observed in 81% of the cases. DLL3 expression was inversely correlated with commonly observed pathogenic mutations in PIK3CA (17%) (P=0.018) and PTEN (10%) (P=0.006). Other more frequently seen pathogenic mutations (TP53 17%, KRAS 11%, and CTNNB1 5%) were not associated with DLL3 expression. TROP-2 expression was detected in only 1 case and no case expressed FOLR1. Although NTRK protein expression was observed in 21% of the cases, none of these had an NTRK gene fusion. PD-L1 expression (10%) and high tumor mutational burden (3%) were significantly less frequent in NEC compared with the squamous cell carcinoma cohort (79% and 11%, respectively). None of the NEC exhibited high microsatellite instability status. Despite frequent DLL3 expression in NEC, a potential therapeutic benefit of DLL3-targeted drugs remains uncertain given the recent failure of the Rova-T therapeutic trial in small cell lung carcinomas. Small cohorts of NEC enriched in PIK3CA/PTEN/AKT and programmed cell death protein 1/PD-L1 alterations indicate therapeutic roles for their respective inhibitors.
IDO1 Expression in Melanoma Metastases Is Low and Associated With Improved Overall Survival
Authors: Lynch Kevin T. , Gradecki Sarah E. , Kwak Minyoung , Meneveau Max O. , Wages Nolan A. , Gru Alejandro A. , Slingluff Craig L.
Published: November 2020

Indoleamine 2-3 dioxygenase 1 (IDO1) expression may contribute to immunologic escape by melanoma metastases. However, a recent clinical trial failed to identify any clinical benefits of IDO1 inhibition in patients with unresectable metastatic melanoma, and prior characterizations of IDO1 expression have predominately studied primary lesions and local metastases, generating uncertainty regarding IDO1 expression in distant metastases. We hypothesized that IDO1 expression in such lesions would be low and correlated with decreased overall survival (OS). Metastases from patients (n=96) with stage IIIb to IV melanoma underwent tissue microarray construction and immunohistochemical staining for IDO1. Th1-related gene expression was determined quantitatively. Associations between OS and IDO1 expression were assessed with multivariate models. Of 96 metastatic lesions, 28% were IDOpos, and 85% exhibited IDO1 expression in <10% of tumor cells. IDOpos lesions were associated with improved OS (28.9 vs. 10.5 mo, P=0.02) and expression of Th1-related genes. OS was not associated with IDO1 expression in a multivariate analysis of all patients; however, IDO1 expression (hazard ratio=0.25, P=0.01) and intratumoral CD8+ T-cell density (hazard ratio=0.99, P<0.01) were correlated with OS in patients who underwent metastasectomy with curative-intent. IDOpos metastases were less likely to recur after metastasectomy (54% vs. 16%, P=0.01). IDO1 expression was low in melanoma metastases and correlated with OS after metastasectomy with curative-intent. Intratumoral CD8+ T cells and Th1-related genes were correlated with IDO1 expression, as was tumor recurrence. These suggest that IDO1 expression may be a marker of immunologic tumor control, and may inform participant selection in future trials of IDO1 inhibitors.
An Analysis of How Characteristics of Local Health Department Jurisdictions Influence Involvement in PHAB Accreditation: Implications for Health Equity
Authors: Kovach Kevin A. , Lipnicky Ashlyn
Published: November 2020

Objective:

To explore how characteristics of local health department (LHD) jurisdictions impact involvement in Public Health Accreditation Board (PHAB) accreditation and to characterize the implications for health equity.

Methods:

Data from the 2016 National Profile of LHDs survey were linked with data from the American Community Survey, National Center for Health Statistics, Behavioral Risk Factor Surveillance System, and the 2016 presidential election. Outcome measures included LHDs that were formally engaged in PHAB accreditation and LHDs that planned to apply for PHAB accreditation but were not formally engaged. Logistic regression was used to assess for the impact LHD jurisdictions' socioeconomic position, demographics, population health status, political ideology, and LHD organizational characteristics have on PHAB accreditation.

Results:

Approximately 37% of the participants were formally engaged (n = 297) and planned to apply (n = 337) for PHAB accreditation. Involvement in PHAB accreditation was equal among LHDs based on poverty and income inequality, but median household income was negatively associated. Diverse jurisdictions were more likely to be involved in PHAB accreditation but less likely to be involved after controlling for covariates. Jurisdictions with worse population health status were either as likely or more likely to be involved in PHAB accreditation. Jurisdictions with a greater conservative political ideology were less likely to be involved.

Conclusion:

LHD involvement in PHAB accreditation varies by their jurisdiction's characteristics. This has implications for health equity based on socioeconomic, racial, and population health status. Policies and practices are needed to improve the uptake of PHAB accreditation in LHD jurisdictions impacted most by health inequities.
Pharmacologic modulation of brain metabolism by valproic acid can induce a neuroprotective environment
Authors: Bhatti Umar F. , Karnovsky Alla , Dennahy Isabel S. , Kachman Maureen , Williams Aaron M. , Nikolian Vahagn C. , Biesterveld Ben E. , Siddiqui Ali , O’Connell Rachel L. , Liu Baoling , Li Yongqing , Alam Hasan B.
Published: November 2020

OBJECTIVE

Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality. Valproic acid (VPA) has been shown to attenuate brain lesion size and swelling within the first few hours following TBI. Because injured neurons are sensitive to metabolic changes, we hypothesized that VPA treatment would alter the metabolic profile in the perilesional brain tissues to create a neuroprotective environment.

METHODS

We subjected swine to combined TBI (12-mm cortical impact) and hemorrhagic shock (40% blood volume loss and 2 hours of hypotension) and randomized them to two groups (n = 5/group): (1) normal saline (NS; 3× hemorrhage volume) and (2) NS-VPA (NS, 3× hemorrhage volume; VPA, 150 mg/kg). After 6 hours, brains were harvested, and 100 mg of the perilesional tissue was used for metabolite extraction. Samples were analyzed using reversed-phase liquid chromatography–mass spectrometry in positive and negative ion modes, and data were analyzed using MetaboAnalyst software (McGill University, Quebec, Canada).

RESULTS

In untargeted reversed-phase liquid chromatography–mass spectrometry analysis, we detected 3,750 and 1,955 metabolites in positive and negative ion modes, respectively. There were no significantly different metabolites in positive ion mode; however, 167 metabolite features were significantly different (p < 0.05) in the negative ion mode, which included VPA derivates. Pathway analysis showed that several pathways were affected in the treatment group, including the biosynthesis of unsaturated fatty acids (p = 0.001). Targeted amino acid analysis on glycolysis/tricarboxylic acid (TCA) cycle revealed that VPA treatment significantly decreased the levels of the excitotoxic amino acid serine (p = 0.001).

CONCLUSION

Valproic acid can be detected in perilesional tissues in its metabolized form. It also induces metabolic changes in the brains within the first few hours following TBI to create a neuroprotective environment.
Combined Assessment of Functional and Metabolic Performance of Human Donor Hearts: Possible Application in Donation After Circulatory Death
Authors: Bhaskaran Prasanna , Ou Ruchong , Marasco Silvana , Perera Shanaka , Brookes John , Rosenfeldt Franklin
Published: November 2020

Background.

Donation after circulatory death (DCD) represents an increasing source of organs. However, evaluating the suitability of DCD hearts for transplantation represents a challenge. Contractile function is the ultimate determinant of recovery. We developed a novel technique in an ex vivo rig for the measurement of contractility using intraventricular balloons. We compared this technique with the measurement of lactate metabolism, the current gold standard.

Methods.

Human DCD (n = 6) and donation after brain death (n = 6) hearts were preserved by perfusion with a cold oxygenated crystalloid solution for 4 h, transferred to a blood perfusion rig at 37 °C where balloons were inserted into the left (LV) and right (RV) ventricles to measure developed pressure (DP = systolic minus diastolic). Perfusate lactate levels were measured for metabolic assessment. Concordance between LVDP and lactate was assessed during 4 h using cutoffs for LVDP of 70 mm Hg and for lactate of 10 mmol/L.

Results.

Measurements of contractile function (LVDP) and metabolism (lactate levels) were deemed concordant in 7 hearts with either a high LVDP (mean 100 mm Hg) with low lactate (mean 6.7 mmol/L)) or a low LVDP (15 mm Hg) with high lactate (mean 17.3 mmol/). In the remaining 5 hearts, measurements were deemed discordant: 4 hearts had high LVDP (mean 124 mm Hg), despite high lactate levels 17.3 mmol/L) and 1 had low LVDP (54 mm Hg) but low lactate (6.9 mmol/L).

Conclusions.

The intraventricular balloon technique provides useful information regarding contractile recovery of donor hearts that if combined with lactate metabolism has potential application for the evaluation of DCD and marginal donation after brain death hearts before transplant.
Longitudinal Analysis of the T-cell Receptor Repertoire in Graft-infiltrating Lymphocytes Following Hand Transplantation
Authors: Kim Joseph Y. , Lei Zhengdeng , Maienschein-Cline Mark , Chlipala George E. , Balamurugan Arumugam , McDiarmid Sue V. , Azari Kodi , Yang Otto O.
Published: November 2020

Background.

T lymphocyte–mediated acute rejection is a significant complication following solid organ transplantation. Standard methods of monitoring for acute rejection rely on assessing histological tissue damage but do not define the immunopathogenesis. Additionally, current therapies for rejection broadly blunt cellular immunity, creating a high risk for opportunistic infections. There is, therefore, a need to better understand the process of acute cellular rejection to help develop improved prognostic tests and narrowly targeted therapies.

Methods.

Through next-generation sequencing, we characterized and compared the clonal T-cell receptor (TCR) repertoires of graft-infiltrating lymphocytes (GILs) and blood-derived lymphocytes from a hand transplant recipient over 420 days following transplantation. We also tracked the TCR clonal persistence and V beta (BV) gene usage, evaluating overlap between these 2 compartments.

Results.

TCR repertoires of blood and GIL populations remained distinct throughout the sampling period, and differential BV usage was consistently seen between these compartments. GIL TCR clones persisted over time and were seen in only limited frequency in the blood T-lymphocyte populations.

Conclusions.

We demonstrate that blood monitoring of TCR clones does not reveal the pathogenic process of acute cellular rejection in transplanted tissue. GILs show clonal persistence with biased BV usage, suggesting that tissue TCR clonal monitoring could be useful, although a deeper understanding is necessary to prognosticate rejection based on TCR clonal repertoires. Finally, the distinct TCR BV usage bias in GILs raises the possibility for prevention and therapy of acute cellular rejection based on targeting of specific TCR clones.
The Problem of Subclinical Antibody-mediated Rejection in Kidney Transplantation
Authors: Filippone Edward John , Farber John L.
Published: November 2020

Defined as histologic evidence of rejection on a protocol biopsy in the absence of kidney dysfunction, subclinical rejection has garnered attention since the 1990s. The major focus of much of this research, however, has been subclinical T cell–mediated rejection (TCMR). Herein, we review the literature on subclinical antibody-mediated rejection (AMR), which may occur with either preexisting donor-specific antibodies (DSA) or upon the development of de novo DSA (dnDSA). In both situations, subsequent kidney function and graft survival are compromised. Thus, we recommend protocol biopsy routinely within the first year with preexisting DSA and at the initial detection of dnDSA. In those with positive biopsies, baseline immunosuppression should be maximized, any associated TCMR treated, and adherence stressed, but it remains uncertain if antibody-reduction treatment should be initiated. Less invasive testing of blood for donor DNA or gene profiling may have a role in follow-up of those with negative initial biopsies. If a protocol biopsy is positive in the absence of detectable HLA-DSA, it also remains to be determined whether non-HLA-DSA should be screened for either in particular or on a genome-wide basis and how these patients should be treated. Randomized controlled trials are clearly needed.
The effect of body image dissatisfaction on goal-directed decision making in a population marked by negative appearance beliefs and disordered eating
Authors: Onysk Jakub , Seriès Peggy
Published: November 2020

Eating disorders are associated with one of the highest mortality rates among all mental disorders, yet there is very little research about them within the newly emerging and promising field of computational psychiatry. As such, we focus on investigating a previously unexplored, yet a core aspect of eating disorders – body image dissatisfaction. We continue a freshly opened debate about model-based learning and its trade-off against model-free learning – a proxy for goal-directed and habitual behaviour. We perform a behavioural study that utilises a two-step decision-making task and a reinforcement learning model to understand the effect of body image dissatisfaction on model-based learning in a population characterised by high scores of disordered eating and negative appearance beliefs, as recruited using Prolific. We find a significantly reduced model-based contribution in the body image dissatisfaction task condition in the population of interest as compared to a healthy control.
Multisensory integration-attention trade-off in cochlear-implanted deaf individuals
Authors: van de Rijt Luuk P.H. , van Opstal A. John , van Wanrooij Marc M.
Published: November 2020

Abstract

The cochlear implant (CI) allows profoundly deaf individuals to partially recover hearing. Still, due to the coarse acoustic information provided by the implant, CI users have considerable difficulties in recognizing speech, especially in noisy environments. CI users therefore rely heavily on visual cues to augment speech comprehension, more so than normal-hearing individuals. However, it is unknown how attention to one (focused) or both (divided) modalities plays a role in multisensory speech recognition. Here we show that unisensory speech listening and reading were negatively impacted in divided-attention tasks for CI users - but not for normal-hearing individuals. Our psychophysical experiments revealed that, as expected, listening thresholds were consistently better for the normal-hearing, while lipreading thresholds were largely similar for the two groups. Moreover, audiovisual speech recognition for normal-hearing individuals could be described well by probabilistic summation of auditory and visual speech recognition, while CI users were better integrators than expected from statistical facilitation alone. Our results suggest that this benefit in integration comes at a cost. Unisensory speech recognition is degraded for CI users when attention needs to be divided across modalities. We conjecture that CI users exhibit an integration-attention trade-off. They focus solely on a single modality during focused-attention tasks, but need to divide their limited attentional resources in situations with uncertainty about the upcoming stimulus modality. We argue that in order to determine the benefit of a CI for speech comprehension, situational factors need to be discounted by presenting speech in realistic or complex audiovisual environments.

Significance statement

Deaf individuals using a cochlear implant require significant amounts of effort to listen in noisy environments due to their impoverished hearing. Lipreading can benefit them and reduce the burden of listening by providing an additional source of information. Here we show that the improved speech recognition for audiovisual stimulation comes at a cost, however, as the cochlear-implant users now need to listen and speech-read simultaneously, paying attention to both modalities. The data suggests that cochlear-implant users run into the limits of their attentional resources, and we argue that they, unlike normal-hearing individuals, always need to consider whether a multisensory benefit outweighs the unisensory cost in everyday environments.
Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration
Authors: Arango-Gonzalez Blanca , Sen Merve , Guarascio Rosellina , Ziaka Kalliopi , del Amo Eva M. , Hau Kwan , Poultney Hannah , Asfahani Rowan , Urtti Arto , Chou Tsui-Fen , Bolz Sylvia , Deshaies Raymond J. , Haq Wadood , Cheetham Michael E. , Ueffing Marius
Published: November 2020

Due to continuously high production rates of rhodopsin (RHO) and high metabolic activity, photoreceptor neurons are especially vulnerable to defects in proteostasis. A proline to histidine substitution at position 23 (P23H) leads to production of structurally misfolded RHO, causing the most common form of autosomal dominant Retinitis Pigmentosa (adRP) in North America. The AAA-ATPase valosin-containing protein (VCP) extracts misfolded proteins from the ER membrane for cytosolic degradation. Here, we provide the first evidence that inhibition of VCP activity rescues degenerating P23H rod cells and improves their functional properties in P23H transgenic rat and P23H knock-in mouse retinae, bothin vitroandin vivo. This improvement correlates with the restoration of the physiological RHO localization to rod outer segments (OS) and properly-assembled OS disks. As a single intravitreal injection suffices to deliver a long-lasting benefitin vivo, we suggest VCP inhibition as a potential therapeutic strategy for adRP patients carrying mutations in theRHOgene.
The Mutational Signature Comprehensive Analysis Toolkit (musicatk) for the discovery, prediction, and exploration of mutational signatures
Authors: Chevalier Aaron , Yang Shiyi , Khurshid Zainab , Sahelijo Nathan , Tong Tong , Huggins Jonathan , Yajima Masanao , Campbell Joshua D.
Published: November 2020

Mutational signatures are patterns of somatic alterations in the genome caused by carcinogenic exposures or aberrant cellular processes. To provide a comprehensive workflow for preprocessing, analysis, and visualization of mutational signatures we created the Mutational Signature Comprehensive Analysis Toolkit (musicatk) package.musicatkenables users to select different schemas for counting mutation types and easily combine count tables from different schemas. Multiple distinct methods are available to deconvolute signatures and exposures or to predict exposures in individual samples given a pre-existing set of signatures. Additional exploratory features include the ability to compare signatures to the COSMIC database, embed tumors in two dimensions with UMAP, cluster tumors into subgroups based on exposure frequencies, identify differentially active exposures between tumor subgroups and plot exposure distributions across user-defined annotations such as tumor type. Overall,musicatkwill enable users to gain novel insights into the patterns of mutational signature observed in cancer cohorts.
Selective vulnerability of supragranular layer neurons in schizophrenia
Authors: Batiuk Mykhailo Y. , Tyler Teadora , Mei Shenglin , Rydbirk Rasmus , Petukhov Viktor , Sedmak Dora , Frank Erzsebet , Feher Virginia , Habek Nikola , Hu Qiwen , Igolkina Anna , Roszik Lilla , Pfisterer Ulrich , Petanjek Zdravko , Adorjan Istvan , Kharchenko Peter V. , Khodosevich Konstantin
Published: November 2020

Schizophrenia is one of the most wide-spread mental brain disorders with complex and largely unknown etiology. To characterize the impact of schizophrenia at a cellular level, we performed single nucleus RNA sequencing of >190,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls (7 vs 11, respectively). In addition, to correlate data with cortical anatomy, >100,000 neurons were analyzed topographically by immunohistochemistry in an extended cohort of cases with schizophrenia and controls (10 vs 10). Compositional analysis of RNA sequencing data revealed reduction in relative abundance across all families of GABAergic neurons and a concomitant increase in principal neurons, which was most pronounced for supragranular subtypes (layers 2-3). Moreover, supragranular subtypes of GABAergic interneurons showed most dramatic transcriptomic changes. These results were substantiated by histological analysis, which revealed a reduction in the density of calretinin, calbindin and parvalbumin GABAergic interneurons particularly in layer 2. Common effect of schizophrenia on supragranular neuronal networks was underlined by downregulation of protein processing genes and upregulation of neuronal development/plasticity genes across supragranular subtypes of principal neurons and GABAergic interneurons.In situhybridization and spatial transcriptomics further confirmed supragranular layer neuron vulnerability, revealing complexity of schizophrenia-affected cortical circuits. These point towards general network impairment within supragranular layers being a core substrate associated with schizophrenia symptomatology.
Hundreds of nuclear and plastid loci yield insights into orchid relationships
Authors: Pérez-Escobar Oscar Alejandro , Dodsworth Steven , Bogarín Diego , Bellot Sidonie , Balbuena Juan A. , Schley Rowan , Kikuchi Izai , Morris Sarah K. , Epitawalage Niroshini , Cowan Robyn , Maurin Olivier , Zuntini Alexandre , Arias Tatiana , Serna Alejandra , Gravendeel Barbara , Torres Maria Fernanda , Nargar Katharina , Chomicki Guillaume , Chase Mark W. , Leitch Ilia J. , Forest Félix , Baker William J.
Published: November 2020

Premise of the study

Evolutionary relationships in the species-rich Orchidaceae have historically relied on organellar DNA sequences and limited taxon sampling. Previous studies provided a robust plastid-maternal phylogenetic framework, from which multiple hypotheses on the drivers of orchid diversification have been derived. However, the extent to which the maternal evolutionary history of orchids is congruent with that of the nuclear genome has remained uninvestigated.

Methods

We inferred phylogenetic relationships from 294 low-copy nuclear genes sequenced/obtained using the Angiosperms353 universal probe set from 75 species representing 69 genera, 16 tribes and 24 subtribes. To test for topological incongruence between nuclear and plastid genomes, we constructed a tree from 78 plastid genes, representing 117 genera, 18 tribes and 28 subtribes and compared them using a co-phylogenetic approach. The phylogenetic informativeness and support of the Angiosperms353 loci were compared with those of the 78 plastid genes.

Key Results

Phylogenetic inferences of nuclear datasets produced highly congruent and robustly supported orchid relationships. Comparisons of nuclear gene trees and plastid gene trees using the latest co-phylogenetic tools revealed strongly supported phylogenetic incongruence in both shallow and deep time. Phylogenetic informativeness analyses showed that the Angiosperms353 genes were in general more informative than most plastid genes.

Conclusions

Our study provides the first robust nuclear phylogenomic framework for Orchidaceae plus an assessment of intragenomic nuclear discordance, plastid-nuclear tree incongruence, and phylogenetic informativeness across the family. Our results also demonstrate what has long been known but rarely documented: nuclear and plastid phylogenetic trees are not fully congruent and therefore should not be considered interchangeable.