bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered visual entrainment in patients with Alzheimer’s disease: magnetoencephalography evidence
Authors: Springer Seth D , Wiesman Alex I , May Pamela E , Schantell Mikki , Johnson Hallie J , Willett Madelyn P , Castelblanco Camilo A , Eastman Jacob A , Christopher-Hayes Nicholas J , Wolfson Sara L , Johnson Craig M , Murman Daniel L , Wilson Tony W
Published: August 2022

Recent research has indicated that rhythmic visual entrainment may be useful in clearing pathological protein deposits in the central nervous system of mouse models of Alzheimer’s disease. However, visual entrainment studies in human patients with Alzheimer’s disease are rare, and as such the degree to which these patients exhibit aberrations in the neural tracking of rhythmic visual stimuli is unknown. To fill this gap, we recorded magnetoencephalography during a 15 Hz visual entrainment paradigm in amyloid-positive patients on the Alzheimer’s disease spectrum and compared their neural responses to a demographically matched group of biomarker-negative healthy controls. Magnetoencephalography data were imaged using a beamformer and virtual sensor data were extracted from the peak visual entrainment responses. Our results indicated that, relative to healthy controls, participants on the Alzheimer’s disease spectrum exhibited significantly stronger 15 Hz entrainment in primary visual cortices relative to a pre-stimulus baseline period. However, the two groups exhibited comparable absolute levels of neural entrainment, and higher absolute levels of entertainment predicted greater Mini-mental Status Examination scores, such that those patients whose absolute entrainment amplitude was closer to the level seen in controls had better cognitive function. In addition, 15 Hz periodic activity, but not aperiodic activity, during the pre-stimulus baseline period was significantly decreased in patients on the Alzheimer’s disease spectrum. This pattern of results indicates that patients on the Alzheimer’s disease spectrum exhibited increased visual entrainment to rhythmic stimuli and that this increase is likely compensatory in nature. More broadly, these results show that visual entrainment is altered in patients with Alzheimer’s disease and should be further examined in future studies, as changes in the capacity to entrain visual stimuli may prove useful as a marker of Alzheimer’s disease progression.
LINC02418 upregulates EPHA2 by competitively sponging miR-372-3p to promote 5-Fu/DDP chemoresistance in colorectal cancer
Authors: Yao Fei , Huang Xiaoying , Xie Zhufu , Chen Jie , Zhang Ling , Wang Qiang , Long Hui , Jiang Jue , Wu Qingming
Published: August 2022

Chemoresistance is a huge clinical challenge in the treatment of advanced colorectal cancer (CRC). Non-coding RNAs (ncRNAs) and messenger RNA (mRNA) are involved in CRC chemoresistance. However, the profiles of long ncRNAs (lncRNAs), microRNAs (miRNAs), mRNAs and competing endogenous RNA (ceRNA) networks in CRC chemoresistance are still largely unknown. Here, we compared the gene expression profiles in chemosensitive (HCT8) and chemoresistant [HCT8/5-fluorouracil (5-Fu) and HCT8/cisplatin (DDP)] cell lines by whole-transcriptome sequencing. The common differentially expressed RNAs in two drug-resistant cells were selected to construct lncRNA–miRNA–mRNA networks. The ceRNA network closely related to chemoresistance was further established based on the widely accepted drug resistance-associated genes enriched in three signaling pathways involved in chemoresistance. In total 52 lncRNA–miRNA–mRNA pathways were screened out, among which EPHA2 and LINC02418 were identified as hub genes; thus, LINC02418/miR-372-3p/EPHA2 were further selected and proved to affect the 5-Fu and DDP resistance of CRC. Mechanistically, LINC02418 upregulated EPHA2 by functioning as a ‘sponge’ of miR-372-3p to modulate the chemoresistance of CRC. Collectively, our study uncovered the underlying mechanism of LINC02418/miR-372-3p/EPHA2 in 5-Fu and DDP resistance of CRC, which may provide potential therapeutic targets for improving the chemosensitivity of CRC.
First Demonstration Project of Long-Acting Injectable Antiretroviral Therapy for Persons With and Without Detectable Human Immunodeficiency Virus (HIV) Viremia in an Urban HIV Clinic
Authors: Christopoulos Katerina A , Grochowski Janet , Mayorga-Munoz Francis , Hickey Matthew D , Imbert Elizabeth , Szumowski John D , Dilworth Samantha , Oskarsson Jon , Shiels Mary , Havlir Diane , Gandhi Monica
Published: August 2022

Background

Long-acting injectable antiretroviral therapy (LAI-ART) is approved for treatment-naive or experienced people with human immunodeficiency virus (HIV; PWH) based on trials that only included participants with viral suppression. We performed the first LAI-ART demonstration project to include PWH unable to achieve or maintain viral suppression due to challenges adhering to oral ART.

Methods

Ward 86 is a large HIV clinic in San Francisco that serves publicly insured and underinsured patients. We started patients on LAI-ART via a structured process of provider referral, multidisciplinary review (MD, RN, pharmacist), and monitoring for on-time injections. Inclusion criteria were willingness to receive monthly injections and a reliable contact method.

Results

Between June 2021 and April 2022, 51 patients initiated LAI-ART, with 39 receiving at least 2 follow-up injections by database closure (median age, 46 years; 90% cisgender men, 61% non-White, 41% marginally housed, 54% currently using stimulants). Of 24 patients who initiated injections with viral suppression (median CD4 cell count, 706 cells/mm3), 100% (95% confidence interval [CI], 86%–100%) maintained viral suppression. Of 15 patients who initiated injections with detectable viremia (median CD4 cell count, 99 cells/mm3; mean log10 viral load, 4.67; standard deviation, 1.16), 12 (80%; 95% CI, 55%–93%) achieved viral suppression, and the other 3 had a 2-log viral load decline by a median of 22 days.

Conclusions

This small demonstration project of LAI-ART in a diverse group of patients with high levels of substance use and marginal housing demonstrated promising early treatment outcomes, including in those with detectable viremia due to adherence challenges. More data on LAI-ART in hard-to-reach populations are needed.
Precocious Sperm Exchange in the Simultaneously Hermaphroditic Nudibranch,Berghia stephanieae
Authors: Taraporevala Neville F , Lesoway Maryna P , Goodheart Jessica A , Lyons Deirdre C
Published: August 2022

Synopsis

Sexual systems vary greatly across molluscs. This diversity includes simultaneous hermaphroditism, with both sexes functional at the same time. Most nudibranch molluscs are thought to be simultaneous hermaphrodites, but detailed studies of reproductive development and timing remain rare as most species cannot be cultured in the lab. The aeolid nudibranch, Berghia stephanieae, is one such species that can be cultured through multiple generations on the benchtop. We studied B. stephanieae reproductive timing to establish when animals first exchange sperm and how long sperm can be stored. We isolated age- and size-matched individuals at sequential timepoints to learn how early individuals can exchange sperm. Individuals isolated at 10 weeks post initial feeding (wpf; ∼13 weeks postlaying [wpl]) can produce fertilized eggs. This is 6 weeks before animals first lay egg masses, indicating that sperm exchange occurs well before individuals are capable of laying eggs. Our results indicate that male gonads become functional for animals between 6 mm (∼6 wpf, ∼9 wpl) and 9 mm (∼12 wpf, ∼15 wpl) in length. That is much smaller (and sooner) than the size (and age) of individuals at first laying (12–19 mm; ∼16 wpf, ∼19 wpl), indicating that male and female functions do not develop simultaneously. We also tracked the number of fertilized eggs in each egg mass, which remained steady for the first 10–15 egg masses, followed by a decline to near-to-no fertilization. This dataset provides insights into the precise timing of the onset of functionality of the male and female reproductive systems in B. stephanieae. These data contribute to a broader understanding of reproductive development and the potential for understanding the evolution of diverse sexual systems in molluscs.
A case of solitary neurofibroma in the maxillary gingiva
Authors: Komatsu Yuko , Takeda Yasunori , Kawai Tadashi , Sasou Shunichi , Takahashi Kazuaki , Yamada Hiroyuki , Ishibashi Shu
Published: August 2022

Neurofibromas are benign tumors. They are known to be a manifestation of von Recklinghausen’s disease (neurofibromatosis type 1) and tend to be generalized and rarely solitary. In this report, we present a case of solitary neurofibroma in the maxillary gingiva. A 39-year-old woman presented with a chief complaint of swollen gingiva. There were no special findings in her medical or family history. After a biopsy was performed under local anesthesia and a diagnosis of neurofibroma was made, tumor resection was performed under general anesthesia. The patient’s progress was good, with no recurrence.
Intraoperative selective arterial calcium injection test to confirm complete resection of a proinsulinoma
Authors: Sakamoto Akimasa , Ogawa Kohei , Iwata Miku , Ito Chihiro , Shine Mikiya , Matsui Takashi , Nishi Yusuke , Uraoka Mio , Utsunomiya Takeshi , Nagaoka Tomoyuki , Tamura Kei , Funamizu Naotake , Inoue Hitoshi , Sakamoto Katsunori , Kurata Mie , Takada Yasutsugu
Published: August 2022

Proinsulinoma is a subtype of insulinoma that is surgically curable, but localization can be difficult as these tumors are typically too small to be visualized by imaging. We report the case of a 53-year-old woman referred to our hospital with dizziness and headache. Her blood glucose level was 46 mg/dl and Whipple’s triad was present. Although her immunoreactive insulin level during hypoglycemia was in the normal range (5.0 μU/ml), the proinsulin level was elevated (408 pmol/l). Imaging examinations showed no evidence of pancreatic tumor. A preoperative selective arterial calcium injection (SACI) test showed excessive insulin secretion in the splenic artery region, which localized the proinsulinoma to the body or tail of the pancreas, and laparoscopic spleen-preserving distal pancreatectomy was performed. Intraoperative SACI test performed after tumor removal did not show excessive insulin secretion. The intraoperative SACI test appears to be useful for localization and for confirming complete resection of proinsulinoma.
Direct innominate artery access for transcatheter aortic valve replacement
Authors: de Biasi Andreas R , Raval Amish , Tester Gregory , Osaki Satoru
Published: August 2022

Hostile vascular disease can pose a challenge for transcatheter aortic valve replacement, for which the preferred access is via a common femoral artery. However, extensive peripheral arterial disease may also preclude traditional points of alternative access in some patients. Herein, we describe two patients in whom successful transcatheter aortic valve replacement was performed via direct innominate artery access.
The carotid diaphragm, an often overlooked cause of stroke by cardiologists
Authors: El Mesnaoui Rim , Nikiema Soumaila , Massimbo Desire , El Mesnaoui Abbes
Published: August 2022

Carotid diaphragm is a rare cause of stroke. Because of its rarity, it remains often undiagnosed. We report the case of four patients who presented a stroke due to carotid diaphragm. The diagnosis was made either by ultrasound Doppler, computed tomography-angiography or angiography. Two of the four patients were managed by carotid stenting and the other two by surgery. The follow-up was normal. Carotid diaphragm stroke is associated with a high risk of recurrence if not well managed. Therefore, the knowledge of this rare entity is necessary.
Neurologic Music Therapy with a Habilitative Approach for Older Adults with Dementia: A Feasibility Study
Authors: Prieto Álvarez Leticia
Published: August 2022

The incidence of dementia continues to increase in our aging population. Numerous cognitive, behavioral, and psychological symptoms accompany this diagnosis, and the need for non-pharmacological interventions that may alleviate them is of paramount importance. This feasibility study presents the results of a crossover randomized control trial that evaluated the effects of neurologic music therapy with a habilitative approach on the treatment acceptability, cognition, mood, and behavior of older adults with moderate to severe dementia. Twenty-nine residents living in an assisted living community rotated between 50-minute group sessions of Neurologic Music Therapy (NMT) techniques implemented with a habilitative approach, an Enrichment Program (EP) that combined physical and cognitive exercises, and a non-facilitated television program (TV). Data were collected before and after each crossover period using attendance, the Neuropsychiatric Inventory-Nursing Home (NPI-NH) version, the Dementia Mood Picture Test (DMPT), and the Montreal Cognitive Assessment (MoCA). NMT had the highest level of treatment acceptability, as measured by attendance and adherence. NPI-NH scores were the lowest after TV viewings, and DMPT results were the highest after NMT, followed by EP and TV. The positive effect of NMT on general cognitive functioning for residents with moderately severe cognitive decline was remarkable. These results suggest that NMT with a habilitative approach is a viable tool to engage older adults with dementia. The promising results on cognition and its high treatment acceptability make a powerful case to increase NMT use with this population and continue studying its effectiveness.
The effects of kefir consumption on human health: a systematic review of randomized controlled trials
Authors: Kairey Lana , Leech Bradley , El-Assaad Fatima , Bugarcic Andrea , Dawson Drew , Lauche Romy
Published: August 2022

Context

Kefir, a traditional, fermented-milk beverage, has increasingly been promoted for various health benefits. The evidence from systematic reviews, however, is limited.

Objective

Evidence from randomized controlled trials testing oral consumption of fermented-milk kefir on any outcome of human health or disease.

Data Sources

A systematic search of 4 electronic databases (PubMed, Scopus, Allied and Complementary Medicine Database, and Cochrane Trials) from inception to July 31, 2021, was conducted.

Data Extraction

Data extraction and risk-of-bias assessments were conducted by 2 reviewers independently.

Data Analysis

A total of 18 publications reporting the results of 16 studies were included. Per the narrative analysis, fermented-milk kefir may have potential as a complementary therapy in reducing oral Streptococcus mutans, thereby reducing dental caries risk, and in Helicobacter pylori eradication therapy. Kefir may further aid treatment of adult dyslipidemia and hypertension, although evidence was very limited. Safety was only assessed in 5 of the 18 included publications, and 12 of the studies had an overall high risk for bias.

Conclusion

Kefir is a dairy product with a unique microbiological profile that appears to be a safe for generally healthy populations to consume. However, efficacy and safety data from high-quality human trials are essential before any recommendations may be made for conditions of the oral and gastric microbiota and metabolic health.

Systematic review registration

PROSPERO registration no. CRD42020211494.
Physical, Psychological, and Cognitive Profile of Post-COVID Conditions in Healthcare Workers, Quebec, Canada
Authors: Carazo Sara , Skowronski Danuta M , Laforce Robert , Talbot Denis , Falcone Emilia L , Laliberté Denis , Denis Geoffroy , Deshaies Pierre , Hegg-Deloye Sandrine , De Serres Gaston
Published: August 2022

Background

The prevalence of post-COVID conditions (PCC) and associated physical, psychological, and cognitive symptoms was assessed among Quebec healthcare workers (HCWs) with coronavirus disease 2019 (COVID-19).

Methods

This case-control study compared 6061 symptomatic HCWs with polymerase chain reaction–confirmed COVID-19 between July 2020 and May 2021 with a random sample of 4390 symptomatic HCWs who were test-negative controls. The prevalence of physical symptoms lasting ≥4 weeks (PCC4w) or ≥12 weeks (PCC12w) was estimated among hospitalized and nonhospitalized cases. In multivariate models, sociodemographic and clinical characteristics, as well as vaccine history, were evaluated as potential risk factors. Prevalence ratios compared 4 aspects of self-reported cognitive dysfunction among PCC cases to controls, adjusting for psychological distress and fatigue.

Results

PCC4w and PCC12w prevalences of 46% (2746/5943) and 40% (653/1746), respectively, were observed among nonhospitalized cases and 76% (90/118) and 68% (27/37), respectively, among hospitalized cases. Hospitalization, female sex, and age were associated with higher PCC risk. A substantial proportion of nonhospitalized PCC4w cases often or very often reported cognitive dysfunction, including concentration (33%) or organizing (23%) difficulties, forgetfulness (20%), and loss of necessary items (10%). All 4 aspects of cognitive dysfunction were associated with PCC4w symptoms, psychological distress, and fatigue.

Conclusions

PCC may be a frequent sequela of ambulatory COVID-19 in working-age adults, with important effects on cognition. With so many HCWs infected, the implications for quality healthcare delivery could be profound if cognitive dysfunction and other severe PCC symptoms persist in a professionally disabling way. Further evaluation of PCC prevalence and prognosis is warranted.
Geographic Influence Upon Noninfectious Diseases Accounting for Fever of Unknown Origin: A Systematic Review and Meta-Analysis
Authors: Wright William F , Yenokyan Gayane , Auwaerter Paul G
Published: August 2022

Background

Diagnostic outcomes for fever of unknown origin (FUO) remain with notable numbers of undiagnosed cases. A recent systemic review and meta-analysis of studies reported geographic variation in FUO-related infectious diseases. Whether geography influences types of FUO noninfectious diagnoses deserves examination.

Methods

We systematically searched Medline (PubMed), Embase, Scopus, and Web of Science databases using medical subject headings published from January 1, 1997 to March 31, 2021. Prospective clinical studies investigating participants meeting adult FUO defining criteria were selected if they assessed final diagnoses. Meta-analyses were based on the random-effects model according to World Health Organization (WHO) geographical regions.

Results

Nineteen studies with significant heterogeneity were analyzed, totaling 2667 participants. Noninfectious inflammatory disorders had a pooled estimate at 20.0% (95% confidence interval [CI], 17.0%–23.0%). Undiagnosed illness had a pooled estimate of 20.0% (95% CI, 14.0%–26.0%). The pooled estimate for cancer was 15.0% (95% CI, 12.0%–18.0%). Miscellaneous conditions had a pooled estimate of 6.0% (95% CI, 4.0%–8.0%). Noninfectious inflammatory disorders and miscellaneous conditions were most prevalent in the Western Pacific region with a 27.0% pooled estimate (95% CI, 20.0%–34.0%) and 9.0% (95% CI, 7.0%–11.0%), respectively. The highest pooled estimated for cancer was in the Eastern Mediterranean region at 25.0% (95% CI, 18.0%–32.0%). Adult-onset Still’s disease (114 [58.5%]), systemic lupus (52 [26.7%]), and giant-cell arteritis (40 [68.9%]) predominated among the noninfectious inflammatory group. Lymphoma (164 [70.1%]) was the most common diagnosis in the cancer group.

Conclusions

In this systematic review and meta-analysis, noninfectious disease diagnostic outcomes varied among WHO-defined geographies. Evaluations for FUO should include local variations in disease prevalence.
Single-centre experience of refractory rheumatoid arthritis
Authors: Fitton John , Melville Andrew , Naraghi Kamran , Nam Jacqueline , Dass Shouvik , Emery Paul , Buch Maya H
Published: August 2022

Objectives

The aim was to evaluate the proportion of RA patients who are refractory to multiple targeted therapies (TTs) in a real-world cohort of patients in a tertiary rheumatology referral centre, to describe patterns of drug sequencing associated with the development of refractory RA (RefRA) and to identify whether there is a subgroup of RefRA patients in whom successive drugs have shown primary lack of efficacy.

Methods

Patients at a single centre were defined as refractory if they had failed two or more classes of TT and were identified from a dedicated TT clinic database. Reasons for drug failure were recorded, and patients were categorized pragmatically as having mild [failure of two biologic DMARD (bDMARD) classes], moderate [failure of at least three bDMARD classes] or severe [failure of at least two bDMARD classes and JAK inhibitor] refractory disease.

Results

One hundred and seventy-two patients were identified as RefRA (>10% of our TT-exposed cohort); median [interquartile range (IQR)] TT exposures of four (two), 81.5% female, 82% seropositive, mean (s.d.) age of 63 (12.3) years. Detailed analysis of 60 patients showed a median (IQR) disease duration of 22 (10.75) years, median (IQR) time from diagnosis to initiation of first TT of 5 (10) years, and mean (s.d.) baseline DAS28CRP before starting first-line TT of 5.91 (0.84). Among RefRA patients, 15% were severely refractory, and 6% had demonstrated no clinical response to any TT.

Conclusion

A small proportion of patients have true RefRA. Most patients fail multiple therapies owing to a combination of inefficacy and adverse events.
Bile acid restrained T cell activation explains cholestasis aggravated hepatitis B virus infection
Authors: Ding Chujie , Hong Yu , Che Yuan , He Tianyu , Wang Yun , Zhang Shule , Wu Jiawei , Xu Wanfeng , Hou Jingyi , Hao Haiping , Cao Lijuan
Published: August 2022

Cholestasis is a common complication of hepatitis B virus (HBV) infection, characterized by increased intrahepatic and plasma bile acid levels. Cholestasis was found negatively associated with hepatitis outcome, however, the exact mechanism by which cholestasis impacts anti‐viral immunity and impedes HBV clearance remains elusive. Here, we found that cholestatic mice are featured with dysfunctional T cells response, as indicated by decreased sub‐population of CD25+/CD69+ CD4+ and CD8+ cells, while CTLA‐4+ CD4+ and CD8+ subsets were increased. Mechanistically, bile acids disrupt intracellular calcium homeostasis via inhibiting mitochondria calcium uptake and elevating cytoplasmic Ca2+ concentration, leading to STIM1 and ORAI1 decoupling and impaired store‐operated Ca2+ entry which is essential for NFAT signaling and T cells activation. Moreover, in a transgenic mouse model of HBV infection, we confirmed that cholestasis compromised both CD4+ and CD8+ T cells activation resulting in poor viral clearance. Collectively, our results suggest that bile acids play pivotal roles in anti‐HBV infection via controlling T cells activation and metabolism and that targeting the regulation of bile acids may be a therapeutic strategy for host‐virus defense.
Artificial intelligence and its applications in digital hematopathology
Authors: Hu Yongfei , Luo Yinglun , Tang Guangjue , Huang Yan , Kang Juanjuan , Wang Dong
Published: August 2022

The advent of whole-slide imaging, faster image data generation, and cheaper forms of data storage have made it easier for pathologists to manipulate digital slide images and interpret more detailed biological processes in conjunction with clinical samples. In parallel, with continuous breakthroughs in object detection, image feature extraction, image classification and image segmentation, artificial intelligence (AI) is becoming the most beneficial technology for high-throughput analysis of image data in various biomedical imaging disciplines. Integrating digital images into biological workflows, advanced algorithms, and computer vision techniques expands the biologist’s horizons beyond the microscope slide. Here, we introduce recent developments in AI applied to microscopy in hematopathology. We give an overview of its concepts and present its applications in normal or abnormal hematopoietic cells identification. We discuss how AI shows great potential to push the limits of microscopy and enhance the resolution, signal and information content of acquired data. Its shortcomings are discussed, as well as future directions for the field.
Nivolumab-associated Nasal Polyposis and Eosinophilic Asthma Responsive to Benralizumab, An Anti-IL5R Biologic
Authors: Rembalski Steven , Steinberg Joshua A.
Published: August 2022

We present a case report of nivolumab-aggravated treatment-resistant chronic rhinosinusitis with nasal polyposis with asthma, suggestive of aspirin-exacerbated respiratory disease, normalized with the IL-5R antagonist benralizumab. For patients experiencing symptomatic complications of immunotherapy-associated eosinophilia, this case suggests anti-IL-5(R) biologics may durably resolve nasal polyposis and asthma symptoms, permitting continuity of checkpoint inhibitor therapy and sparing of systemic corticosteroids. Postulated mechanisms of checkpoint inhibition favoring eosinophilia and polyposis, and the uncertain effect of eosinophil reduction upon malignancy progression, are reviewed.
Coronavirus disease 2019, hypertension, and renin–angiotensin–aldosterone system inhibitors
Authors: Rizk John G. , Sanchis-Gomar Fabian , Henry Brandon M. , Lippi Giuseppe , Lavie Carl J.
Published: August 2022

Purpose of review

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mostly uses the angiotensin-converting enzyme 2 (ACE-2) as cellular receptor for entering the host cells. Some, but not all, animal studies have shown that renin–angiotensin–aldosterone system (RAAS) inhibitors can increase ACE-2 expression. On that premise, it was hypothesized that these agents could make it more likely to develop coronavirus disease 2019 (COVID-19). On the other hand, there was also evidence that being on these agents could lessen the severity of the lung injury in patients with severe SARS-CoV-2 infection. Herein, we review the available evidence on the role of RAAS inhibitors on SARS-CoV-2 and COVID-19 development.

Recent findings

Recent randomized controlled trials demonstrate that RAAS blockade or withdrawal does not influence the severity of COVID-19 in patients who are already on these medications. Currently, there is no evidence to support stopping RAAS inhibitors in patients hospitalized for COVID-19. Several questions still need to be addressed. Ongoing studies are currently evaluating the de novo use of RAAS inhibitors in patients with COVID-19. Another area that needs to be investigated is whether or not using these medications increase the risk of infection.

The wealth of evidence indicates that ACE inhibitors and angiotensin-receptor blocker administration has no harmful effects on hospitalizations and severity of COVID-19 in patients already on these medications and might even reduce mortality among hypertensive patients diagnosed with COVID-19. More evidence and data need to be collected, and at this time, these agents should not be discontinued.
Comparing 2D-shear wave to transient elastography for the evaluation of liver fibrosis in nonalcoholic fatty liver disease
Authors: Karagiannakis Dimitrios S , Markakis George , Lakiotaki Dimitra , Cholongitas Evangelos , Vlachogiannakos Jiannis , Papatheodoridis George
Published: August 2022

Background and aim

The aim of this study is to evaluate the performance of 2D-shear wave elastography (2D-SWE) in patients with nonalcoholic fatty liver disease (NAFLD) and compare it to transient elastography.

Methods

Over 6 months, 552 patients with NAFLD underwent liver stiffness measurement (LSM) by both 2D-SWE and transient elastography with controlled attenuation parameter (CAP) at the same visit.

Results

LSM was not feasible by transient elastography (M/XL probe) in 18 (3.3%) and by 2D-SWE in 26 (4.7%) patients. The median LSM of transient elastography was 5.5 (2.8–75) kPa and of 2D-SWE 6.2 (3.7–46.2) kPa. LSMs by transient elastography and 2D-SWE were correlated regardless of the obesity status (r, 0.774; P < 0.001; r, 0.774; P < 0.001; r, 0.75; P < 0.001 in BMI <25, 25–30 and ≥30 kg/m2 respectively), or the degree of liver steatosis (r = 0.63; P < 0.001 and r = 0.743; P < 0.001 in mild and moderate/severe steatosis, respectively). According to transient elastography, 88 (15.9%) patients were classified with at least severe fibrosis (≥F3) and 55 (10%) with cirrhosis. By using the 2D-SWE, 85 (15.4%) patients had at least severe fibrosis and 52 (9.4%) cirrhosis. The correlation between the two methods was strong in patients with at least severe fibrosis (r, 0.84; P < 0.001) or cirrhosis (r, 0.658; P < 0.001). When transient elastography was used as reference, 2D-SWE showed an excellent accuracy of 98.8 and 99.8% in diagnosing severe fibrosis and cirrhosis, respectively.

Conclusions

In NAFLD, 2D-SWE and transient elastography have comparable feasibility and clinical applicability providing LSMs with strong correlation, even in overweight/obese patients, independently of the severity of liver steatosis and fibrosis. Thus, either of the two methods can be effectively used for the assessment of fibrosis in this setting.
Preoperative Cognitive Impairment and Postoperative Delirium in Elderly Surgical Patients
Authors: Weiss Yotam , Zac Lilach , Refaeli Einat , Ben-Yishai Shimon , Zegerman Alexander , Cohen Barak , Matot Idit
Published: August 2022

Objective:

To test the hypothesis that in surgical patients ≥70 years, preoperative cognitive impairment is independently associated with postoperative delirium.

Background:

Postoperative delirium is common among elderly surgical patients and is associated with longer hospitalization and significant morbidity. Some evidence suggest that baseline cognitive impairment is an important risk factor. Routine screening for both preoperative cognitive impairment and postoperative delirium is recommended for older surgical patients. As of 2019, we implemented such routine perioperative screening in all elective surgical patients ≥70 years.

Methods:

Retrospective single-center analysis of prospectively collected data between January and December 2020. All elective noncardiac surgical patients ≥70 years without pre-existing dementia were included. Postoperative delirium, defined as 4A’s test score ≥4, was evaluated in the postanesthesia care unit and during the initial 2 postoperative days. Patients’ electronic records were also reviewed for delirium symptoms and other adverse outcomes.

Results:

Of 1518 eligible patients, 1338 (88%) were screened preoperatively [mean (SD) age 77 (6) years], of whom 21% (n=279) had cognitive impairment (Mini-Cog score ≤2). Postoperative delirium occurred in 15% (199/1338). Patients with cognitive impairment had more postoperative delirium [30% vs. 11%, adjusted odds ratio (95% confidence interval) 3.3 (2.3–4.7)]. They also had a higher incidence of a composite of postoperative complications [20% vs. 12%, adjusted odds ratio: 1.8 (1.2–2.5)], and median 1-day longer hospital stay [median (interquartile range): 6 (3,12) vs. 5 (3,9) days].

Conclusions:

One-fifth of elective surgical patients ≥70 years present to surgery with preoperative cognitive impairment. These patients are at increased risk of postoperative delirium and major adverse outcomes.
Ultraliser: a framework for creating multiscale, high-fidelity and geometrically realistic 3D models for in silico neuroscience
Authors: Abdellah Marwan , García Cantero Juan José , Román Guerrero Nadir , Foni Alessandro , Coggan Jay S. , Calì Corrado , Agus Marco , Zisis Eleftherios , Keller Daniel , Hadwiger Markus , Magistretti Pierre J. , Markram Henry , Schürmann Felix
Published: August 2022

Ultraliser is a neuroscience-specific software framework capable of creating accurate and biologically realistic 3D models of complex neuroscientific structures at intracellular (e.g. mitochondria and endoplasmic reticula), cellular (e.g. neurons and glia) and even multicellular scales of resolution (e.g. cerebral vasculature and minicolumns). Resulting models are exported as triangulated surface meshes and annotated volumes for multiple applications in in silico neuroscience, allowing scalable supercomputer simulations that can unravel intricate cellular structure-function relationships. Ultraliser implements a high performance and unconditionally robust voxelization engine adapted to create optimized watertight surface meshes and annotated voxel grids from arbitrary non-watertight triangular soups, digitized morphological skeletons or binary volumetric masks. The framework represents a major leap forward in simulation-based neuroscience, making it possible to employ high-resolution 3D structural models for quantification of surface areas and volumes, which are of the utmost importance for cellular and system simulations. The power of Ultraliser is demonstrated with several use cases in which hundreds of models are created for potential application in diverse types of simulations. Ultraliser is publicly released under the GNU GPL3 license on GitHub (BlueBrain/Ultraliser).

Significance

There is crystal clear evidence on the impact of cell shape on its signaling mechanisms. Structural models can therefore be insightful to realize the function; the more realistic the structure can be, the further we get insights into the function. Creating realistic structural models from existing ones is challenging, particularly when needed for detailed subcellular simulations. We present Ultraliser, a neuroscience-dedicated framework capable of building these structural models with realistic and detailed cellular geometries that can be used for simulations.

Key points

Ultraliser creates spatial models of neuro-glia-vascular (NGV) structures with realistic geometries.

Ultraliser creates high fidelity watertight manifolds and large scale volumes from centerline descriptions, non-watertight surfaces, and binary masks.

Resulting models enable scalable in silico experiments that can probe intricate structure-function relationships.

The framework is unrivalled both in ease-of-use and in the accuracy of resulting geometry representing a major leap forward in simulation-based neuroscience.
Specialized Tfh cell subsets driving type-1 and type-2 humoral responses in lymphoid tissue
Authors: Kumar Saumya , Basto Afonso P. , Ribeiro Filipa , Almeida Silvia C. P. , Campos Patricia , Peres Carina , Al-Khalidi Sarwah , Kilbey Anna , Tosello Jimena , Piaggio Eliane , Russo Momtchilo , Gama-Carvalho Margarida , Coffelt Seth B. , Roberts Ed W. , Florindo Helena , Graca Luis
Published: August 2022

Effective antibody responses are essential to generate protective humoral immunity. Different inflammatory signals polarize T cells towards an appropriate effector phenotype during an infection or immunization. Th1 and Th2 cells have been associated with the polarization of humoral responses for several decades. However, it is now established that T follicular helper cells (Tfh) have a unique ability to access the B cell follicle and support the Germinal Centre (GCs) responses by providing help to B cells. We investigated the specialization of Tfh cells induced under type-1 and type-2 conditions. We first studied homogenous Tfh cell populations generated by adoptively transferred TCR-transgenic T cells in mice immunized with type-1 and type-2 adjuvants. Using a machine learning approach, we established a gene expression signature that discriminates Tfh cells polarized towards type-1 and type-2 response, defined as Tfh1 and Tfh2 cells. The Tfh1 and Tfh2 distinct signature was validated against datasets of Tfh cells induced following LCMV or helminth infection. Using single-cell transcriptomics, we also dissected the heterogeneity of Tfh cells from the two immunizing conditions. Our results show that Tfh cells acquire a specialized function under distinct types of immune responses, but with the coexistence of a small population of Tfh cells of the alternative type. Furthermore, the specific molecular hallmarks of Tfh1 and Tfh2 cells identified herein offer putative new targets for tuning humoral responses.
Assessment of mosquito longevity, fecundity, and dengue virus titer following exposure to plasma from a host with Type 2 diabetes mellitus – a pilot study
Authors: Smartt Chelsea T. , Kendziorski Natalie , Chen Tse-Yu , Farless Sara
Published: August 2022

The mosquito Aedes aegypti (Linnaeus) prefers feeding on humans and will encounter many blood components that might influence mosquito physiology and vectorial capacity. The effects of dengue virus infection in patients with type-2 diabetes mellitus revealed an influence on platelet numbers in blood and diabetic persons are more likely to develop severe dengue. Infection with dengue virus (DENV) is known to impact diabetic patients but the impact of diabetic blood on mosquito vectorial capacity is not known. This pilot study investigated the effects of ingesting blood plasma from a patient with diabetes on mosquito fecundity, longevity, and vector competence for DENV-2 in the mosquito, Ae. aegypti. Female mosquitoes fed on plasma from a diabetic individual laid significantly more eggs. Diabetic plasma shortened overall mosquito life span. Vector competence was significantly different between extrinsic incubation periods at 7 (3.44±2.5 log PFUe DENV) and 14 days post-infection (4.28±2.4 log PFUe DENV) in mosquitoes fed DENV-2 in plasma from a diabetic individual. As this study is an initial investigation into the influence of diabetes plasma on mosquito life history traits, a more comprehensive study with more samples of diabetes plasma is underway and should yield more details about the impact of diabetes on mosquito biology.
Optogenetic Targeting of AII Amacrine Cells restores Retinal Computations performed by the Inner Retina
Authors: Khabou Hanen , Orendorff Elaine , Trapani Francesco , Rucli Marco , Desrosiers Melissa , Yger Pierre , Dalkara Deniz , Marre Olivier
Published: August 2022

Most inherited retinal dystrophies display progressive photoreceptor cell degeneration leading to severe visual impairment. Optogenetic reactivation of inner retinal neurons is a promising avenue to restore vision in retinas having lost their photoreceptors. Expression of optogenetic proteins in surviving ganglion cells, the retinal output, allows them to take on the lost photoreceptive function. Nonetheless, this creates an exclusively ON retina by expression of depolarizing optogenetic proteins in all classes of ganglion cells, whereas a normal retina extracts several features from the visual scene, with different ganglion cells detecting light increase (ON) and light decrease (OFF). Refinement of this therapeutic strategy should thus aim at restoring these computations. In an attempt to do so, we used a promoter that targets gene expression to a specific interneuron of the retina called the AII amacrine cell. The AII amacrine cell simultaneously activates the ON pathway and inhibits the OFF pathway. We show that the optogenetic stimulation of AII amacrine cells allows restoration of both ON and OFF responses in the retina, but also mediates other types of retinal processing such as sustained and transient responses. Targeting amacrine cells with optogenetics is thus a promising avenue to restore better retinal function and visual perception in patients suffering from retinal degeneration.
Deep Generative Models of Protein Structure Uncover Distant Relationships Across a Continuous Fold Space
Authors: Draizen Eli J. , Veretnik Stella , Mura Cameron , Bourne Philip E.
Published: August 2022

Our views of fold space implicitly rest upon many assumptions that impact how we analyze, interpret and understand biological systems—from protein structure comparison and classification to function prediction and evolutionary analyses. For instance, is there an optimal granularity at which to view protein structural similarities (e.g., architecture, topology or some other level)? If so, how does it vary with the type of question being asked? Similarly, the discrete/continuous dichotomy of fold space is central in structural bioinformatics, but remains unresolved. Discrete views of fold space bin 'similar' folds into distinct, non-overlapping groups; unfortunately, such binning may inherently miss many remote relationships. While hierarchical systems like CATH, SCOP and ECOD represent major steps forward in protein classification, a scalable, objective and conceptually flexible method, with less reliance on assumptions and heuristics, could enable a more systematic and nuanced exploration of fold space, particularly as regards evolutionarily-distant relationships. Building upon a recent 'Urfold' model of protein structure, we have developed a new approach to analyze protein interrelationships. This framework, termed 'DeepUrfold', is rooted in deep generative modeling via variational Bayesian inference, and we find it to be useful for comparative analysis across the protein universe. Critically, DeepUrfold leverages its deep generative model's learned embeddings, which occupy high-dimensional latent spaces and can be distilled for a given protein in terms of an amalgamated representation that unites sequence, structure, biophysical and phylogenetic properties. Notably, DeepUrfold is structure-guided, versus being purely structure-based, and its architecture allows each trained model to learn protein features (structural and otherwise) that, in a sense, 'define' different superfamilies. Deploying DeepUrfold with CATH suggests a new, mostly-continuous view of fold space—a view that extends beyond simple 3D structural/geometric similarity, towards the realm ofintegratedsequence ↔ structure ↔ function properties. We find that such an approach can quantitatively represent and detect evolutionarily-remote relationships that evade existing methods.
Evolution to increased positive charge on the viral spike protein may be part of the adaptation of SARS-CoV-2 to human transmission
Authors: Cotten Matthew , Phan My V.T.
Published: August 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, continues to evolve and infect individuals. The exterior surface of the SARS-CoV-2 virion is dominated by the spike protein and the current work examined spike protein biochemical features that have changed during the 2 years that SARS-CoV-2 has infected humans. These biochemical properties may influence virion survival and promote movement through the environment and within the human airway to reach target cells to bind, enter and establish the next round of infection. In addition to selective pressure to avoid immune recognition of viral proteins, we hypothesised that SARS-CoV-2 emerged from an animal reservoir capable of human infection and transmission but in a sub-optimum state and a second level of selective pressure is acting on these biochemical features. Our analysis identified a striking change in spike protein charge, from −8.3 in the original Lineage A and B viruses to −1.26 in the current Omicron viruses. In summary, we conclude that in addition to immune selection pressure, the evolution of SARS-CoV-2 has also altered viral spike protein biochemical properties. Future vaccine and therapeutic development should also exploit and target these biochemical properties.
Light-dependent Control of Bacterial Expression at the mRNA Level
Authors: Ranzani Américo T. , Wehrmann Markus , Kaiser Jennifer , Juraschitz Marc , Weber Anna M. , Pietruschka Georg , Mayer Günter , Möglich Andreas
Published: August 2022

Sensory photoreceptors mediate numerous light-dependent adaptations across organisms. In optogenetics, photoreceptors achieve the reversible, non-invasive, and spatiotemporally precise control by light of gene expression and other cellular processes. The light-oxygen-voltage receptor PAL binds to small RNA aptamers with sequence specificity upon blue-light illumination. By embedding the responsive aptamer in the ribosome-binding sequence of genes of interest, their expression can be downregulated by light. We developed the pCrepusculo and pAurora optogenetic systems that are based on PAL and allow to down- and upregulate, respectively, bacterial gene expression using blue light. Both systems are realized as compact, single plasmids that exhibit stringent blue-light responses with low basal activity and up to several ten-fold dynamic range. As PAL exerts light-dependent control at the RNA level, it can be combined with other optogenetic circuits that generally control transcription initiation. By integrating regulatory mechanisms operating at the DNA and mRNA levels, optogenetic circuits with emergent properties can thus be devised. As a case in point, the pEnumbra setup permits to upregulate gene expression under moderate blue light whereas strong blue light shuts off expression again. Beyond providing novel signal-responsive expression systems for diverse applications in biotechnology and synthetic biology, our work also illustrates how the light-dependent PAL-aptamer interaction can be harnessed for the control and interrogation of RNA-based processes.
ROP16-mediated activation of STAT6 facilitates encystment of type IIIToxoplasma gondiiin neurons
Authors: Kochanowsky Joshua A. , Chandrasekaran Sambamurthy , Sanchez Jacqueline R. , Thomas Kaitlin K. , Koshy Anita A.
Published: August 2022

Toxoplasma gondiiestablishes a long-lived latent infection in the central nervous system (CNS) of its hosts. Reactivation in immunocompromised individuals can lead to life threatening disease. Latent infection is driven by the ability of the parasite to convert from the acute-stage tachyzoite to the latent-stage bradyzoite which resides in long-lived intracellular cysts. While much work has focused on the parasitic factors that drive cyst development, the host factors that influence encystment are not well defined. Here we show that a polymorphic secreted parasite kinase (ROP16), that phosphorylates host cell proteins, mediates efficient encystment ofT. gondiiin stress-induced models of encystment and primary neuronal cell cultures (PNCs) in a strain-specific manner. Using short-hairpin RNA (shRNA) knockdowns in human foreskin fibroblasts (HFFs) and PNCs from transgenic mice, we determined that ROP16’s cyst enhancing abilities are mediated by phosphorylation of the host cell transcription factor STAT6. To test the role of STAT6in vivo, we infected STAT6KO mice, finding that, compared to infected wild-type mice, infected STAT6KO mice have a decrease in cyst burden, but not overall parasite burden or dissemination to the CNS. Finally, we found a similar ROP16-dependent encystment defect in human pluripotent stem cell-derived neurons. Together, these findings identify a host cell factor (STAT6) thatT. gondiimanipulates in a strain-specific manner to generate a favorable encystment environment.