bluuebunny/crossref_metadata_2025 huggingface dataset:
Revisiting glomerular hyperfiltration and examining the concept of high dietary protein-related nephropathy in athletes and bodybuilders
Authors: Cho Eunjung , Choi Soo Jeong , Kang Duk-Hee , Kalantar-Zadeh Kamyar , Ko Gang-Jee
Published: November 2021

Purpose of review

High-protein diets (HPDs) are popular but their consequences for kidney health, especially among athletes and bodybuilders who typically maintain a high protein intake for a long time, have not been investigated. This review focused on recent studies of the association of HPD with long-term kidney health and the concept of high dietary protein-related nephropathy.

Recent findings

Several long-term observational studies including large populations have reinforced the notion that HPDs are associated with a rapid decline of kidney function. An increase in renal blood flow and glomerular hyperfiltration caused by vasodilation, and increased levels of endocrine and paracrine factors (glucagon, IGF-1, prostanoids, and nitric oxide), facilitates the excretion of protein-derived nitrogenous waste. Inhibition of tubule-glomerular feedback and increased proximal tubular Na+ reabsorption after a HPD augment glomerular hyperfiltration and may trigger synthesis of proinflammatory cytokines and receptor for advanced glycation end-products (RAGE). Focal segmental glomerulosclerosis reported in association with anabolic steroid may indeed be a HPD nephropathy given that HPD results in progressive glomerulosclerosis, especially in remnant glomeruli or in diabetic kidney disease but can happen in any high-risk situation, such as solitary kidney and polycystic kidneys.

HPD among athletes and bodybuilders in an extreme way across a long-term period may pose a risk to renal health including high incidence of HPD nephropathy.
Innovative systemic therapies for penile cancer
Authors: Chahoud Jad , Pham Rachel , Sonpavde Guru
Published: November 2021

Purpose of review

The purpose of this review is to look at recent advancements and treatment options of systemic therapies to treat penile squamous cell carcinoma (PSCC). PSCC is a rare cancer that remains with limited funding for research and systemic therapy development. This review aims to discuss the most recent advancements in systemic treatments and our understanding of PSCC.

Recent findings

Neoadjuvant chemotherapy (NAC) and adjuvant therapy remain integral parts of treatment in locally advanced PSCC. New potential drug regimens are being studied to expand on the availability of first-line regimen options. There has been a large development in discoveries of cellular pathways and immune system targets as potential treatment options but these therapies as of today have limited trial evidence and currently have no support to be used in a clinical setting.

PSCC is a rare genitourinary cancer with limited treatment options for patients with advanced disease that is refractory to chemotherapy. Although many new therapies targeting the immune system and cellular pathways are being developed for other studies, clinical and translational research for PSCC are still understudied and underfunded.
Preliminary Data on Gastrointestinal Deficiencies Incidence and the Prevalence of Anxiety During the COVID-19 Pandemic Among the Medical Workers
Authors: Ilie Ovidiu-Dumitru , Bolos Alexandra , Nita Ilinca-Bianca , Cojocariu Roxana-Oana , Balmus Ioana-Miruna , Ciobica Alin , Trus Constantin , Doroftei Bogdan
Published: November 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious new β-coronavirus that primarily affects the lungs. Because of its unprecedented spread, in a relatively short interval, it is declared a global pandemic. Binding to the angiotensin-converting enzyme 2 receptors, SARS-CoV-2 is easily disseminated through air. Apart from the established clinical panel, individuals exposed to prolonged chronic stress also manifest gastrointestinal (GI) symptoms similar to those exhibited by SARS-CoV-2–infected patients.

The present study aims to assess the incidence of GI deficiencies and prevalence of anxiety among healthy medical staff by applying the Visual Analog Scale for Irritable Bowel Syndrome (VAS-IBS) and Hamilton Anxiety Rating Scale (HAM-A) during this global crisis.

We found significant differences on several items of the VAS-IBS: regarding the incidence of diarrhea (p = 0.04), bloating/gases (p = 0.02), and nausea/vomiting (p = 0.01) from the physical spectrum. After stratification based on age of the participants and after we applied Kruskal-Wallis test because of heterogeneity between groups, we noted two situations in which the null hypothesis is rejected: nausea/vomiting in women between 20 and 30 years, and between 30 and 40, and between 40 and 50 years, respectively (p = 0.026/0.029). Anxiety was prevalent among young and middle-class people after the centralization of HAM-A data, where 40.4% of the participants had various forms of anxiety: mild (n = 13; 13.82%), severe (n = 13; 13.82%), and moderate (n = 12; 12.76%).

This study demonstrates that VAS-IBS is a reliable tool for assessing the incidence of GI deficiencies, as well as HAM-A for anxiety.
The Use of Checklists Among New Graduate Nurses in a Surgical Intensive Care Unit to Improve Patient Safety and Outcomes
Authors: Dippel Kathryn S. , Duli Lorraine , Keckeisen Maureen
Published: November 2021

New graduate nurses (NGNs) in the intensive care unit have trouble learning standards of care essential to patient safety and outcomes. Two checklists were developed to help NGNs learn to consistently practice to the unit standards of care during orientation. NGNs were more consistently able to practice to the standards of care compared to a control group that had not utilized the checklists. Preceptors noticed modest improvements in the abilities of NGNs to practice to the standards of care.
Evaluating the Impact of a School of Nursing Civility Team
Authors: Bernard R. Oscar , Sanford Ashley , Duffy Allyson , Rechenberg Kaitlyn , Lopez Maikelyn , Brown Kimberly
Published: November 2021

Background:

Promoting civility in nursing education can be accomplished with civility teams, assessing perceptions of civility and developing initiatives to address areas needing improvement.

Problem:

There is a lack of information about the effectiveness of civility teams in nursing education, leading to uncertainty on how to develop and assess civility teams.

Approach:

This article discusses how 1 school of nursing implemented a civility team and used the Clark Healthy Work Environment Inventory to assess the impact of the team.

Outcomes:

The civility team used the inventory responses from 110 team members to establish civility action items. One year later, the inventory was repeated, and the responses from 122 team members were used to evaluate the impact of the civility action items.

Conclusion:

This program evaluation indicates an effective way for nursing programs to develop civility initiatives using a validated assessment tool to create and evaluate civility action items.
Evaluation of the Performance of OraQuick Rapid HIV-1/2 Test Among Decedents in Kisumu, Kenya
Authors: Opollo Valarie , Nyakeriga Emmanuel , Kingwara Leonard , Sila Alex , Oguta Macxine , Oyaro Boaz , Onyango Dickens , Mboya Frankline O. , Waruru Anthony , Musingila Paul , Mwangome Mary , Nyagah Lilly M. , Ngugi Catherine , Sava Solomon , Waruiru Wanjiru , Young Peter W. , Junghae Muthoni
Published: November 2021

Background:

Estimating cause-related mortality among the dead is not common, yet for clinical and public health purposes, a lot can be learnt from the dead. HIV/AIDS accounted for the third most frequent cause of deaths in Kenya; 39.7 deaths per 100,000 population in 2019. OraQuick Rapid HIV-1/2 has previously been validated on oral fluid and implemented as a screening assay for HIV self-testing in Kenya among living subjects. We assessed the feasibility and diagnostic accuracy of OraQuick Rapid HIV-1/2 for HIV screening among decedents.

Methods:

Trained morticians collected oral fluid from 132 preembalmed and postembalmed decedents aged >18 months at Jaramogi Oginga Odinga Teaching and Referral Hospital mortuary in western Kenya and tested for HIV using OraQuick Rapid HIV-1/2. Test results were compared with those obtained using the national HIV Testing Services algorithm on matched preembalming whole blood specimens as a gold standard (Determine HIV and First Response HIV 1-2-O). We calculated positive predictive values, negative predictive values, area under the curve, and sensitivity and specificity of OraQuick Rapid HIV-1/2 compared with the national HTS algorithm.

Results:

OraQuick Rapid HIV-1/2 had similar sensitivity of 92.6% [95% confidence interval (CI): 75.7 to 99.1] on preembalmed and postembalmed samples compared with the gold standard. Specificity was 97.1% (95% CI: 91.9 to 99.4) and 95.2% (95% CI: 89.2 to 98.4) preembalming and postembalming, respectively. Preembalming and postembalming positive predictive value was 89.3% (95% CI: 71.8 to 97.7) and 83.3% (95% CI: 65.3 to 94.4), respectively. The area under the curve preembalming and postembalming was 94.9% (95% CI: 89.6 to 100) and 93.9% (95% CI: 88.5 to 99.4), respectively.

Conclusions:

The study showed a relatively high-performance sensitivity and specificity of OraQuick Rapid HIV-1/2 test among decedents, similar to those observed among living subjects. OraQuick Rapid HIV-1/2 presents a convenient and less invasive screening test for surveillance of HIV among decedents within a mortuary setting.
Lumbosacral Plexus Neurolymphomatosis
Authors: Bordeau Karl , Eberlé Marie-Claude , Fabbro Michel , Fersing Cyril , Deshayes Emmanuel
Published: November 2021

A 79-year-old man anteriorly treated for primary central nervous system diffuse large B-cell lymphoma with MRI complete response after immunochemotherapy was referred 1 year later for 18FDG PET/CT because of right persistent lombosciatic radicular pain for 6 months with negative medullary and spine MRI and negative cerebrospinal fluid cytology. Linearly intense uptake was observed in several roots of lumbosacral plexus, highly suggestive of peripheral neurolymphomatosis relapse. No specific treatment was engaged because of rapid decrease of performance status leading to death.
An Unusual False-Positive Uptake of Radioiodine Caused by Posttraumatic Superficial Scab
Authors: Xiao Liu , Jiang Lisha , Huang Rui , Tian Rong , Liu Bin
Published: November 2021

A 22-year-old man with a history of recurrent papillary thyroid cancer underwent 131I therapy. Posttherapeutic whole-body scintigraphy was performed 5 days after administration of 5.5 GBq of 131I. The scintigraphy revealed increased activity in the left elbow. On physical examination, the patient had posttraumatic superficial scab at the site of the abnormal activity.
Clearing the Congestion
Authors: Berman Jesse , Lee Lynden , Monga Rahul , Ye Kenny , Sprayregen Seymour , Haramati Linda B.
Published: November 2021

Purpose:

Ruling out congestive heart failure (CHF) is clinically important in Emergency Department (ED) patients. Normal serum brain natriuretic peptide (BNP) represents an important reference standard for excluding CHF. Results of chest radiographs (CXR) are also considered and, when discordant with BNP levels, may result in a clinical dilemma. The present study was designed to elucidate factors associated with CHF on CXR in an ED cohort with normal BNP.

Materials and Methods:

All adults at our urban health system’s EDs who underwent CXR within 24 hours and had a normal BNP (<300 pg/mL) within 24 hours of CXR were retrospectively identified. Of these, 0.9% (8/862) had equivocal CXRs and was excluded. Demographics, comorbidities, CXR report results for CHF, and portable technique were noted. Logistic regression was used to assess factors that are associated with the presence of CHF on CXR.

Results:

The study cohort comprised 854 patients (433 men, mean age 60.99±15.30) with normal BNP; 91.5% (781/854) had no CHF on CXR and 8.5% (73/854) had CHF. Patients with CHF on CXR had a higher body mass index (32.9 vs. 29.8 kg/m2, P=0.0205) were more likely to have a history of CHF or diabetes with complications (OR: 2.72 and 2.53, respectively), had higher serum BNP levels (median 164 vs. 98 pg/mL, P=4.91×10−5), and underwent portable examination more frequently (86.3% vs. 57.5%, OR: 4.65).

Conclusions:

Normal serum BNP was concordant with CXR results, adding diagnostic confidence in ruling out CHF in a large majority of ED patients. A higher body mass index, history of CHF, and diabetes with complications and portable CXR technique were associated with CHF on CXR among the minority with normal BNP.
Treatment of Dentofacial Deformity Associated with Temporomandibular Joint Ankylosis Through Vertical and Sagittal Osteotomies of the Mandibular Ramus
Authors: Filho Antônio Mont’Alverne Lopes , Junior George Matos Ferreira Gomes , Santos Eliardo Silveira , JUnior Moises Joao Bortoluzzi , Neto Jose Valdir Pessoa , Santos Juliana Mara Oliveira
Published: November 2021

Ankylosis of the temporomandibular joint is a disorder resulting from fibrous, osseous, or fibro-osseous adhesion that directly affects the quality of life of the individual. The authors present a case of unilateral temporomandibular joint ankylosis treated by condilectomy and ipsilateral sliding vertical ramus osteotomy associated with contralateral sagittal osteotomy aiming to restore function and to correct dentofacial deformity class II. A 31-year-old female patient presented with a history of facial trauma and major complaint of oral opening limitation. Physical examination revealed hypoplasia of the lower third of the face, facial pattern type II, anterior open bite, and maximum mouth opening of 22.5 mm. Computed tomography showed an ankylotic mass in the right mandibular condyle with deformity of the condylar structure and fusion to the right zygomatic arch and a contralateral condylar fracture sequel. It was proposed to perform a condilectomy of the right mandibular condyle for the removal of the bone mass concomitant to the sliding vertical ramus osteotomy of the mandibular ramus for condylar reconstruction by rhytidectomy approach and the sagittal osteotomy of the left mandibular aiming the reestablishment of occlusion and the correction of dentofacial deformity. The condylar fracture was not operated because the condyle was remodeled. The patient is in her fourth year postoperative presenting satisfactory esthetic-functional re-stabilization, without clinical signs of recurrence. In conclusion, the authors believe that combined sliding vertical ramus osteotomy and sagittal osteotomy can bring satisfactory results in complex cases.
Using the Helical Free Flap Based on the Retrograde Flow From Frontal Branch of Superficial Temporal Vessels in Lower Third Nasal Reconstruction
Authors: Pham Thi Viet Dung , Tran Thiet Son , Thai Duy Quang , Ta Thi Hong Thuy
Published: November 2021

Although the helical free flap is 1 of the most effective option for the lower third nasal reconstruction, the main limitation is still related to having a short pedicle length. In this report, the authors presented our experience in using the long pedicle helical free flap based on the frontal branch of the superficial temporal vessels in nasal reconstruction. Five patients, 3 alar full-thickness defects, 1 columellar defect, and 1 multiple subunit defect, underwent reconstruction using this technique. The pedicle length ranged from 4 to 6 cm. All the flaps were survived completely. However, vein congestion was seen post-operation in 1 case. This flap was saved by using medical leech. No vascular graft was needed. The helical free flap based on the retrograde flow of the frontal branch of the superficial temporal artery offers an option to overcome the limitation of short pedicle length. This composite flap is valuable for nasal alar and columellar reconstruction or even the larger defects, which involve multiple subunits.
Assessment of Protection Offered By the NRF2 Pathway Against Hyperoxia-Induced Acute Lung Injury in NRF2 Knockout Rats
Authors: Audi Said H. , Jacobs Elizabeth R. , Taheri Pardis , Ganesh Swetha , Clough Anne V.
Published: November 2021

Nuclear factor erythroid 2-related factor (Nrf2) is a redox-sensitive transcription factor that responds to oxidative stress by activating expressions of key antioxidant and cytoprotective enzymes via the Nrf2-antioxidant response element (ARE) signaling pathway. Our objective was to characterize hyperoxia-induced acute lung injury (HALI) in Nrf2 knock-out (KO) rats to elucidate the role of this pathway in HALI. Adult Nrf2 wildtype (WT), and KO rats were exposed to room air (normoxia) or >95% O2 (hyperoxia) for 48 h, after which selected injury and functional endpoints were measured in vivo and ex vivo. Results demonstrate that the Nrf2-ARE signaling pathway provides some protection against HALI, as reflected by greater hyperoxia-induced histological injury and higher pulmonary endothelial filtration coefficient in KO versus WT rats. We observed larger hyperoxia-induced increases in lung expression of glutathione (GSH) synthetase, 3-nitrotyrosine (index of oxidative stress), and interleukin-1β, and in vivo lung uptake of the GSH-sensitive SPECT biomarker 99mTc-HMPAO in WT compared to KO rats. Hyperoxia also induced increases in lung expression of myeloperoxidase in both WT and KO rats, but with no difference between WT and KO. Hyperoxia had no effect on expression of Bcl-2 (anti-apoptotic protein) or peroxiredoxin-1. These results suggest that the protection offered by the Nrf2-ARE pathway against HALI is in part via its regulation of the GSH redox pathway. To the best of our knowledge, this is the first study to assess the role of the Nrf2-ARE signaling pathway in protection against HALI using a rat Nrf2 knockout model.
Factors Associated With Postictal Agitation After Electroconvulsive Therapy
Authors: Allen Nicholas D. , Allison Clayton L. , Golebiowski Raphael , Janowski John Patrick B. , LeMahieu Allison M. , Geske Jennifer R. , Rasmussen Keith G.
Published: November 2021

Objective

This study investigated the occurrence of postictal agitation (PA) in patients undergoing an acute series of electroconvulsive therapy (ECT) and further explored patient and treatment variables associated with PA.

Methods

Charts were retrospectively searched for patients undergoing an acute series of ECT. Postictal agitation was identified by the administration of a sedative after ECT. Demographic, diagnostic, medication, and ECT variables that could also be associated with PA were collected and accounted for in statistical analysis.

Results

In this population, 22 of 156 patients experienced PA. Associations that reached statistical significance included sex, weight, active substance use disorder, seizure duration (as observed by motor movements), and waking time. Only seizure duration and waking time maintained significance after multivariable analysis.

Conclusions

These data identify clinical factors that could help predict PA. Patients with greater weight, male sex, or an active substance use disorder ought to be carefully monitored for PA, and staff in the recovery suite should be especially vigilant about such patients with longer seizures and waking times.
Ultrabrief Right Unilateral Electroconvulsive Therapy for the Treatment of the Neuropsychiatric Symptoms of Dementia with Lewy Bodies
Authors: Hermida Adriana P. , Sterina Evelina , Schwab P. Parker , Browning Cody Michael , Chapman Hannah M. , Marques Pinheiro Ana P. , Mori Neil
Published: November 2021

Objectives

Dementia with Lewy bodies (DLB) is a debilitating disorder associated with a number of distressing neuropsychiatric symptoms. There is currently limited guidance regarding the most effective strategies of managing these symptoms, and both pharmacologic and nonpharmacologic strategies are often used. Electroconvulsive therapy (ECT) has been reported as a potential nonpharmacologic method to alleviate some of these debilitating neuropsychiatric symptoms. However, there remains a paucity of evidence in current literature. This report aims to add to existing literature regarding ECT in DLB by highlighting successful treatment in seven cases.

Methods

Our study is a retrospective case series of 7 patients with DLB who received treatment with ultrabrief (UB) right unilateral (RUL) ECT for the treatment of agitation and depressive symptoms. Participants included patients with a diagnosis of DLB who were admitted to Emory University Hospital at Wesley Woods from 2011 to 2020 presenting with agitation and/or depressive symptoms after failing pharmacologic intervention. Patients underwent UB RUL ECT administered by a board-certified psychiatrist. After treatment, Pittsburg Agitation Scale and Clinical Global Impression—Improvement scales were recorded as measures of agitation and clinical improvement, respectively.

Results

All 7 patients responded to UB RUL ECT with marked improvement in their presenting symptoms of agitation and/or depression without significant adverse effects from treatment.

Conclusions

Ultrabrief RUL ECT seems to be a safe and effective treatment of the agitative and depressive features of DLB.
Flagellatimonas centrodinii gen. nov., sp. nov., a novel member of the family Nevskiaceae isolated from toxin-producing dinoflagellate Centrodinium punctatum
Authors: Jiang Yue , Jiang Lingmin , Peng Yuxin , Kim Ki-Hyun , Shin Hyeon Ho , Kim Young-Min , Lee Jiyoung , Li Zhun
Published: November 2021

A Gram-stain-negative, aerobic, rod-shaped strain (R2A-3T) was isolated from the toxin-producing dinoflagellate Centrodinium punctatum and identified as a novel genus and new species based on a polyphasic taxonomic approach. The optimum conditions for growth of the strain were at 25 °C, pH 8.0 and in the presence of 3 % (w/v) NaCl. Phylogenetic analyses based on 16S rRNA genes and 92 core genes sets revealed that strain R2A-3T belongs to the family

Nevskiaceae

in the class

Gammaproteobacteria

and represented an independent taxon separated from other genera. The 16S rRNA gene of strain R2A-3T showed the highest sequence similarity to

Polycyclovorans algicola

TG408T (95.2%),

Fontimonas thermophila

HA-01T (94.1%) and

Sinimarinibacterium flocculans

NH6-24T (93.2%), and less than 92.8 % similarity to other genera in the family

Nevskiaceae

. The genome length of strain R2A-3T was 3608892 bp with 65.2 mol% G+C content. Summed feature 8 (comprising C18 : 1
 ω7c and/or C18 : 1
 ω6c) was the major fatty acid (>10 %). Diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine were detected as the major polar lipids. The major respiratory quinone was ubiquinone-8. According to its phylogenetic, phenotypic, chemotaxonomic and genomic features, strain R2A-3T represents a new species in the new genus of the family

Nevskiaceae

. It is recommended to name it Flagellatimonas centrodinii gen. nov., sp. nov. The type strain is R2A-3T (=KCTC 82469T=GDMCC 1.2523T).
DEVELOPMENT AND TEST OF A CHATBOT TO IDENTIFY DEPRESSION
Authors: Hyun Choi Stefano Neto Jai , Lopes Moreira Rita Simone , de Azevedo Costa Ana Luiza Fontes , Saito Regatieri Caio Vinicius , dos Santos Vagner Rogério
Published: November 2021

Purpose

to develop and test a prototype of Chatbot with the purpose of applying a questionnaire to assess depression in visually impaired individuals.

Methods

This project was carried out in the Federal University of São Paulo. The Chatbot was developed using the platform BLiP®. The social-demography questionnaire and the Center for Epidemiological Scale – Depression (CES-D) were selected to collect the essential data and to identify the presence of depression, respectively. After the development, validation tests were applied to verify the functionality and structure of the chatbot.

Results

The Chatbot prototype presented an excellent flow of conversation in the tests conducted. The questionnaires were applied in a satisfactory manner during the tests. Software validation tests approved the prototype’s function.

Conclusions

The Chatbot prototype is an affordable and easy way to apply questionnaires that can be used to identify health conditions, such as the likelihood of being depressed.
A clustering of missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder
Authors: Blok Lot Snijders , Verseput Jolijn , Rots Dmitrijs , Venselaar Hanka , Innes A. Micheil , Stumpel Connie , Ounap Katrin , Reinson Karit , Seaby Eleanor G. , McKee Shane , Burton Barbara , Kim Katherine , van Hagen Johanna M. , Waisfisz Quinten , Joset Pascal , Steindl Katharina , Rauch Anita , Li Dong , Zackai Elaine , Sheppard Sarah , Keena Beth , Hakonarson Hakon , Roos Andreas , Kohlschmidt Nicolai , Cereda Anna , Iascone Maria , Rebessi Erika , Kernohan Kristin D. , Campeau Philippe M. , Millan Francisca , Taylor Jesse A. , Lochmüller Hanns , Higgs Martin R. , Goula Amalia , Bernhard Birgitta , Fisher Simon E. , Brunner Han G. , Kleefstra Tjitske
Published: November 2021

WDR5 is a broadly studied, highly conserved protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. Here, we present data from ten unrelated individuals with six different rare de novo missense variants in WDR5; one identical variant was found in four individuals, and another variant in two individuals. All ten individuals had neurodevelopmental disorders including speech/language delays (N=10), intellectual disability (N=8), epilepsy (N=6) and autism spectrum disorder (N=4). Additional phenotypic features included abnormal growth parameters (N=6), heart anomalies (N=2) and hearing loss (N=2). All six missense variants occurred in regions of the WDR5 locus that are known to be extremely intolerant for variation. Three-dimensional structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino-acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS family complexes. Thus, we define a new neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of associated features including intellectual disability, speech/language impairments, epilepsy and autism spectrum disorders. This finding highlights the important role of COMPASS family proteins in neurodevelopmental disorders.
Dysfunction of exocytosis causes catecholamine hypersecretion in patient with pheochromocytoma
Authors: Houy Sébastien , Streit Laura , Drissa Ines , Rame Marion , Decraene Charles , Moog Sophie , Brunaud Laurent , Lanoix Joël , Chelbi Rabie , Bihain Florence , Lacomme Stéphanie , Lomazzi Sandra , Vix Michel , Mutter Didier , Paramithiotis Eustache , Dubessy Christophe , Vitale Nicolas , Ory Stéphane , Gasman Stéphane
Published: November 2021

Pheochromocytoma (Pheo) is a neuroendocrine tumor that develops from chromaffin cells of the adrenal medulla, and is responsible of an excess of catecholamines secretion leading to severe clinical symptoms such as hypertension, elevated stroke risk and various cardiovascular complications. Surprisingly, hypersecretory activity of Pheo has never been explored at the cellular and molecular levels from individual tumor cells. In the present study, we have combined catecholamine secretion measurement by carbon fiber amperometry on human tumor cells directly cultured from freshly resected Pheo, with the analysis by mass spectrometry of the exocytotic proteins differentially expressed between the tumor and the matched adjacent non-tumor tissue. Catecholamine secretion recordings from individual Pheo cells obtained from most patients reveal a higher number of exocytic events per cell associated with faster kinetic parameters. Accordingly, we unravel significant tumor-associated modifications in the expression of key proteins involved in different steps of the calcium-regulated exocytic pathway. Altogether, our findings indicate that dysfunction of the calcium-regulated exocytosis at the level of individual Pheo cell is a cause of the tumor-associated hypersecretion of catecholamines.
Somatic activating BRAF variants cause isolated lymphatic malformations
Authors: Zenner Kaitlyn , Jensen Dana M. , Dmyterko Victoria , Shivaram Giridhar M. , Myers Candace T. , Paschal Cate R. , Rudzinski Erin R. , Pham Minh-Hang M. , Cheng V. Chi , Manning Scott C. , Bly Randall A. , Ganti Sheila , Perkins Jonathan A. , Bennett James T.
Published: November 2021

Somatic activating variants in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, have been previously detected in ∼80% of lymphatic malformations (LM).1; 2 We report the presence of somatic activating variants in BRAF in individuals with PIK3CA-negative LM. The BRAF substitution p.Val600Glu (c.1799T>A), one of the most common driver mutations in cancer, was detected in multiple individuals with LM. Histology revealed abnormal lymphatic channels with immunopositivity for BRAFV600E in endothelial cells that was otherwise indistinguishable from PIK3CA positive LM. The finding that BRAF variants contribute to low-flow LMs increases the complexity of prior models associating low flow vascular malformations (LM and venous malformations) with mutations in the PI3K-AKT-MTOR and high flow vascular malformations (arteriovenous malformations) with mutations in the RAS-MAPK pathway.3 Additionally, this work highlights the importance of genetic diagnosis prior to initiating medical therapy as more studies examine therapeutics for individuals with vascular malformations.
Longitudinal intronic RNA-Seq analysis of Parkinson’s Disease patients reveals disease-specific nascent transcription
Authors: Kõks Sulev , Pfaff Abigail L. , Bubb Vivien J. , Quinn John P.
Published: November 2021

Transcriptomic studies usually focus on either gene or exon-based annotations, and only limited experiments have reported changes in reads mapping to introns. The analysis of intronic reads allows the detection of nascent transcription that is not influenced by steady - state RNA levels and provides information on actively transcribed genes. Here we describe substantial intronic transcriptional changes in Parkinson’s Disease (PD) patients compared to healthy controls (CO) at two different timepoints; at the time of diagnosis (BL) and three years later (V08). We used blood RNA-Seq data from the Parkinson’s Progression Markers Initiative (PPMI) cohort and identified significantly changed transcription of intronic reads only in PD patients during this follow up period. In CO subjects, only nine transcripts demonstrated differentially expressed introns between visits. However, in PD patients 4,873 transcripts had differentially expressed introns at visit V08 compared to BL, many of them in genes previously associated with neurodegenerative diseases, such as LRRK2, C9orf72, LGALS3, KANSL1AS1 and ALS2. In addition, at the time of diagnosis (BL visit) we identified 836 transcripts (e.g. SNCA, DNAJC19, PRRG4) and at visit V08 2,184 transcripts (e.g. PINK1, GBA, ALS2, PLEKHM1) with differential intronic expression specific to PD patients. In contrast, reads mapping to exonic regions demonstrated little variation indicating highly specific changes only in intronic transcription. Our study demonstrated that Parkinson’s disease is characterized by substantial changes in the nascent transcription and description of these changes could help to understand the molecular pathology underpinning this disease.

Impact statement

Transcriptomic studies in most cases describe the steady state changes of the cellular RNA combined with signals from newly synthesised RNA or nascent RNA. Nascent RNA reflects dynamic alterations in the cellular transcriptome and improves the resolution of RNA-Seq analysis. In the present study, we describe the changes in nascent RNA transcription in Parkinson’s disease by using intronic RNA-Seq analysis. We compared transcriptome changes at the time of diagnosis and 3 years after the initial diagnosis. As a result, we were able to describe disease-specific time-dependent alterations in the nascent transcription in the blood of Parkinson’s patients illustrating another layer of the blood-based biomarkers that could be diagnostic of both risk and progression of Parkinson’s disease.
Reappraising Treatment Effect Heterogeneity in Schizophrenia: A Meta-analysis
Authors: McCutcheon Robert A , Pillinger Toby , Efthimiou Orestis , Maslej Marta , Mulsant Benoit H , Young Allan H , Cipriani Andrea , Howes Oliver D
Published: November 2021

Objective

Determining whether individual patients differ in response to treatment (‘treatment effect heterogeneity’) is important as it is a prerequisite to developing personalised treatment approaches. Previous variability meta-analyses of response to antipsychotics in schizophrenia found no evidence for treatment effect heterogeneity. Conversely, individual patient data meta-analyses suggest treatment effect heterogeneity does exist. In the current paper we combine individual patient data with study level data to resolve this apparent contradiction and quantitively characterise antipsychotic treatment effect heterogeneity in schizophrenia.

Method

Individual patient data (IPD) was obtained from the Yale University Open Data Access (YODA) project. Clinical trials were identified in EMBASE, PsycInfo, and PubMed. Treatment effect heterogeneity was estimated from variability ratios derived from study-level data from 66 RCTs of antipsychotics in schizophrenia (N=17,202). This estimation required a correlation coefficient (ρ) between placebo response and treatment effects to be estimated. We estimated this from both study level estimates of the 66 trials, and individual patient data (N=560).

Results

Both individual patient (ρ=-0.32, p=0.002) and study level (ρ=-0.38, p<0.001) analyses yielded a negative correlation between placebo response and treatment effect. Using these estimates we found evidence of clinically significant treatment effect heterogeneity for total symptoms (our most conservative estimate was SD = 13.5 Positive and Negative Syndrome Scale (PANSS) points). Mean treatment effects were 8.6 points which, given the estimated SD, suggests the top quartile of patients experienced beneficial treatment effects of at least 17.7 PANSS points, while the bottom quartile received no benefit as compared to placebo.

Conclusions

We found evidence of clinically meaningful treatment effect heterogeneity for antipsychotic treatment of schizophrenia. This suggests efforts to personalise treatment have potential for success, and demonstrates that variability meta-analyses of RCTs need to account for relationships between placebo response and treatment effects.
Analyzing Surgical Volumes, Rates, and Need in Rural India
Authors: Zadey Siddhesh , Nickenig Vissoci Joao Ricardo
Published: November 2021

Background

Globally, 5 billion people lack timely access to safe and affordable surgical care, with over a fifth of them living in India. Solving India’s surgical access issues can have high returns on investment. While healthcare access and unaffordability problems are well-known in India particularly among its rural people, research on surgical volumes and need is scant. This study attempts to fill the research gap through high-resolution nationwide estimates that have direct implications for India’s national surgical plan.

Methods

Secondary data analysis with a diverse geospatial and statistical toolbox was used to create the national, state, and district-level estimates for surgical rates and c- section proportions and their corresponding met need w.r.t. to the globally prescribed thresholds – 5000 major surgeries (those requiring anesthesia) per 100,000 (Lancet Commission on Global Surgery) and 10-15% of all institutional deliveries (World Health Organization).

Results

Nationally, only 6.81% of need for major surgical operations was met for rural India. 13.6% of the institutional deliveries were c-sections falling within the WHO- prescribed range of 10-15%. There were marked variations at state and district-levels and significant rural-urban differences for surgical rates and c-section proportions. We validate our estimates based on data from Health Management and Information System against existing sources that are commonly used in academic and policy research.

Conclusions

Our methodological workflow has high translational value for global surgery research in low-and-middle-income countries. For India, these are the first such nationwide findings that can direct the development of a National Surgical, Obstetric, and Anesthesia Plan (NSOAP).
Sex-Related Neurocircuitry Supporting Camouflaging in Adults with Autism: Female Protection Insights
Authors: Walsh Melissa J. M. , Pagni Broc , Monahan Leanna , Delaney Shanna , Smith Christopher J. , Baxter Leslie , Braden B. Blair
Published: November 2021

The male preponderance in autism led to the hypothesis that aspects of female biology are protective against autism. Females with autism report engaging in more compensatory behaviors (i.e., “camouflaging”) to overcome autism-related social differences, which may be a downstream result of protective pathways. No studies have examined sex-related brain pathways supporting camouflaging in females with autism, despite its potential to inform mechanisms underlying the sex bias in autism.

This case-control design included 45 non-intellectually-disabled adults with autism (male/female: 21/24) and 40 neurotypical adults (male/female: 19/21) ages 18-71. We used group multivariate voxel pattern analysis to conduct a data-driven, connectome-wide characterization of “sex-atypical” (sex-by-diagnosis) and “sex-typical” (sex) brain functional connectivity features linked to camouflaging, and validated findings in females with autism multi-modally via structural connectometry. Exploratory associations with cognitive control, memory, emotion recognition, and depression/anxiety examined the adaptive nature of functional connectivity patterns supporting camouflaging in females with autism.

We found 1) “sex-atypical” functional connectivity patterns predicting camouflaging in the hypothalamus and precuneus and 2) “sex-typical” patterns in the anterior cingulate and right anterior parahippocampus. Higher hypothalamic functional connectivity with a limbic reward cluster was the strongest predictor of camouflaging in females with autism (a “sex-atypical” pattern), and also predicted better cognitive control/emotion recognition. Structural connectometry validated functional connectivity results with consistent brain pathways/effect patterns implicated across multi-modal findings in females with autism.

This data-driven, connectome-wide characterization of “sex-atypical” and “sex-typical” brain connectivity features supporting compensatory social behavior in autism suggests hormones may play a role in the autism sex bias. Furthermore, both “male-typical” and “female-typical” brain connectivity patterns are implicated in camouflaging in females with autism in circuits associated with reward, emotion, and memory processing. “Sex-atypical” results are consistent with the fetal steroidogenic hypothesis, which would result in masculinized brain features in females with autism. However, female genetics/biology may contribute to “female-typical” patterns implicated in camouflaging.
Clinically observed deletions in SARS-CoV-2 Nsp1 affect protein stability and its ability to inhibit translation
Authors: Kumar Pravin , Schexnaydre Erin , Rafie Karim , Terenin Ilya , Hauryliuk Vasili , Carlson Lars-Anders
Published: November 2021

Nonstructural protein 1 (Nsp1) is a major pathogenicity factor of SARS-CoV-2. It inhibits host-cell translation, primarily through a direct interaction between its C-terminal domain and the mRNA entry channel of the 40S small ribosomal subunit, with an N-terminal β-barrel domain fine-tuning the inhibition and promoting selective translation of viral mRNA. SARS-CoV-2 nsp1 is a target of recurring deletions, some of which are associated with altered COVID-19 disease progression. To provide the biochemical basis for this, it is essential to characterize the efficiency of translational inhibition by the said protein variants. Here, we use an in vitro translation system to investigate the translation inhibition capacity of a series of clinically observed Nsp1 deletion variants. We find that a frequently observed deletion of residues 79-89 destabilized the N-terminal domain (NTD) and severely reduced the capacity of Nsp1 to inhibit translation. Interestingly, shorter deletions in the same region have been reported to effect the type I interferon response but did not affect translation inhibition, indicating a possible translation-independent role of the Nsp1 NTD in interferon response modulation. Taken together, our data provide a mechanistic basis for understanding how deletions in Nsp1 influence SARS-CoV-2 induction of interferon response and COVID-19 progression.
Hybridization and introgression are prevalent in Southern European Erysimum (Brassicaceae) species
Authors: Osuna-Mascaró Carolina , de Casas Rafael Rubio , Gómez José M. , Loureiro João , Castro Silvia , Landis Jacob B. , Hopkins Robin , Perfectti Francisco
Published: November 2021

Background and Aims

Hybridization is a common and important force in plant evolution. One of its outcomes is introgression - the transfer of small genomic regions from one taxon to another by hybridization and repeated backcrossing. This process is believed to be common in glacial refugia, where range expansions and contractions can lead to cycles of sympatry and isolation, creating conditions for extensive hybridization and introgression. Polyploidization is another genome-wide process with a major influence on plant evolution. Both hybridization and polyploidization can have complex effects on plant evolution. However, these effects are often difficult to understand in recently evolved species complexes.

Methods

We combined flow cytometry, transcriptomic and genomic analyses, and pollen-tube growth assays to investigate the consequences of polyploidization, hybridization, and introgression on the recent evolution of several Erysimum (Brassicaceae) species from the South of the Iberian Peninsula, a well-known glacial refugium. This species complex differentiated in the last 2Myr, and its evolution has been hypothesized to be determined mainly by polyploidization, interspecific hybridization, and introgression.

Key Results

Our results support a scenario of widespread hybridization involving both extant and “ghost” taxa. Several taxa studied here, most notably those with purple corollas, are polyploids, likely of allopolyploid origin. Moreover, hybridization in this group might be an ongoing phenomenon, as prezygotic barriers appeared weak in many cases.

Conclusions

The evolution of Erysimum spp. has been determined by hybridization to a large extent. The adaptive value of such genomic exchanges remains unclear, but our results indicate the importance of hybridization for plant diversification across evolutionary scales.
A novel and highly divergent Canine Distemper Virus lineage causing distemper in ferrets in Australia
Authors: George Ankita M. , Wille Michelle , Wang Jianning , Anderson Keith , Cohen Shari , Moselen Jean , Lee Leo Yi Yang , Suen Willy W. , Bingham John , Dalziel Antonia E , Hurt Aeron C. , Williams David T. , Deng Yi-Mo , Barr Ian G.
Published: November 2021

Canine distemper virus (CDV) is a highly contagious systemic viral disease of dogs, that regularly spills-over into other animal species. Despite widespread vaccination, CDV remains endemic in many parts of the world. In this study we report an outbreak of distemper in ferrets in two independent research facilities in Australia. We found that disease severity varied, although most animals had mild to moderate disease signs. Histopathology results of animals with severe disease presented the typical profile of distemper pathology with multi-system virus replication. Through the development of a discriminatory PCR paired with full genome sequencing we revealed that the outbreak at both facilities was caused by a single, novel lineage of CDV. This lineage was highly divergent across the H gene, F signal peptide and full genome and had less than 93% similarity across the H gene to other described lineages, including the vaccine strain. Molecular analysis indicates that this strain belongs to a distinct lineage that diverged from other clades approximately 140 to 400 years ago, and appears to be unique to Australia. Given the differences in key viral proteins of this novel CDV strain, a review of the efficacy of the CDV vaccines currently in use in Australia is warranted to ensure maximum protection of dogs and other vulnerable species. In addition, enhanced surveillance to determine the prevalence of CDV in ferrets, dogs and other at-risk species in Australia would be useful to better understand the diversity of CDV in Australia.

Importance

Canine distemper virus (CDV) is highly contagious and while dogs are the main reservoir, it may spill over into a number of other animal species. In this study we report an outbreak of distemper in ferrets in two research facilities in Australia. Outcomes of pathology and histopathology suggest ferrets have widespread multi-systemic infection, consistent with previously reported distemper infections in ferrets and dogs. Critically, through sequencing and phylogenetic analysis, we revealed that the outbreak at both facilities was caused by a single, novel and highly divergent lineage of CDV. This virus had less than 93% nucleotide similarity to other described lineages and the vaccine strain. This manuscript adds considerably to the epidemiology, ecology and evolution of this virus, and is one of few reports of distemper in Australia in the literature.
Safety and immunogenicity of heterologous and homologous inactivated and adenoviral-vectored COVID-19 vaccines in healthy adults
Authors: Wanlapakorn Nasamon , Suntronwong Nungruthai , Phowatthanasathian Harit , Yorsaeng Ritthideach , Vichaiwattana Preeyaporn , Thongmee Thanunrat , Auphimai Chompoonut , Srimuan Donchida , Thatsanatorn Thaksaporn , Assawakosri Suvichada , Kanokudom Sitthichai , Sudhinaraset Natthinee , Poovorawan Yong
Published: November 2021

In light of intermittent supply shortages of individual vaccines and evidence of rare but serious adverse events after vaccination, heterologous regimens for COVID-19 vaccines have gained significant interest. This study aims to assess the reactogenicity and immunogenicity of the heterologous adenoviral vector vaccine regimen (ChAdOx1-S, AstraZeneca; hereafter referred to as AZ) and the inactivated vaccine regimen (CoronaVac; hereafter referred to as CV) regimen in healthy Thai adults immunized between June and September 2021. Our study showed that adverse events following homologous CV-CV and AZ-AZ, and heterologous CV-AZ and AZ-CV combinations, were mild and well tolerated overall. Receptor-binding domain (RBD)-specific antibody responses and neutralizing activities against wild-type and variants of concern after two-dose vaccination were higher in the heterologous CV-AZ and homologous AZ-AZ groups compared to the CV-CV and AZ-CV groups. Conversely, the spike-specific IgA response was detected only in the CV-AZ group after two doses of vaccination. The total interferon gamma response was detected in both the CV-AZ and AZ-CV groups after the two-dose vaccination. Given the shorter completion time of two doses, heterologous CoronaVac followed by ChAdOx1-S can be considered as an alternative regimen to homologous efficacy-proven ChAdOx1-S in countries with circulating variants. Additional studies on the efficacy and durability of immune responses induced by heterologous vaccine regimens are warranted.