bluuebunny/crossref_metadata_2025 huggingface dataset:
Wilson Disease Prevalence
Authors: Lorente‐Arencibia Pascual , García‐Villarreal Luis , González‐Montelongo Rafaela , Rubio‐Rodríguez Luis A. , Flores Carlos , Garay‐Sánchez Paloma , delaCruz Tanausú , Santana‐Verano Milagros , Rodríguez‐Esparragón Francisco , Benitez‐Reyes Juana N. , Fernández‐Fuertes Fernando , Tugores Antonio
Published: October 2021

Objectives:

Diagnosis of Wilson disease (WD) is difficult and, as early detection may prevent all symptoms, it is essential to know the exact prevalence to evaluate the cost‐efficacy of a screening program. As the number of WD patients was high in our population, we wished to estimate prevalence by determining the carrier frequency for clinically relevant ATP7B mutations.

Methods:

To estimate prevalence, screening for the most prevalent mutation was performed in 1661 individuals with ancestry in Gran Canaria, and the frequency of other mutations was estimated from patient records. Alternatively, ATP7B mutations were detected from exomes and genomes from 851 individuals with Canarian ancestry, 236 from Gran Canaria, and a public Spanish exome database.

Results:

Estimated carrier frequencies in Gran Canaria ranged from 1 in 20 to 28, depending on the method used, resulting in prevalences of 1 case per 1547 to 3140 inhabitants. Alternatively, the estimated affected frequencies were 1 in 5985 to 7980 and 1 in 6278 to 16,510 in the archipelago or mainland Spain respectively.

Conclusions:

The number of carriers predicts much higher prevalences than reported, suggesting that WD is underdiagnosed; specific mutations may remain unnoticed due to low penetrance or no signs of disease at all; regional prevalence rather than national prevalence should be considered in cost‐efficacy models to approach preventive screening in the asymptomatic population and genetic screening strategies will have to deal with the genetic heterogeneity of ATP7B in the general population and in patients.
Agreement and Repeatability of Corneal Thickness and Radius among Three Different Corneal Measurement Devices
Authors: Biswas Sayantan , Biswas Partha
Published: October 2021

SIGNIFICANCE

Corneal refractive surgery screening, orthokeratology, and contact lens fitting require accurate estimation of the corneal thickness and curvature. We found that any of the imaging devices used in this study can be used to image a healthy myopic cornea, which is essential to screen for corneal ectasia.

PURPOSE

This study aimed to compare agreement and repeatability of corneal thickness and radius measurements obtained using Scheimpflug imaging (Pentacam HR), swept-source optical coherence tomography (Casia SS-1000), and Placido-Scheimpflug tomography (Topographic Modeling System, version 5 [TMS-5]).

METHODS

Sixty eyes of 60 subjects with myopia were measured with Casia, TMS-5, and Pentacam for their central corneal thickness (CCT), thinnest corneal thickness, central corneal radius of the steep meridian (Ks), central corneal radius of the flat meridian (Kf), mean central corneal radius (Km), and anterior and posterior best-fit spheres. Two readings were obtained from each instrument. Central corneal thickness was also measured with ultrasound pachymetry. Intraclass correlation coefficient, repeatability coefficient, and coefficient of variation were calculated.

RESULTS

Repeatability coefficient, coefficient of variation, and intraclass correlation coefficient of CCT among the instruments ranged between 2.48 and 12.79, 0.17 and 0.86, and 0.98 and 1.00, respectively. Mean CCT measurements were similar between Casia, TMS-5, Pentacam, and ultrasound pachymetry (P = .13). Intraclass range of correlation for agreement was 0.95 to 0.99 for CCT among instruments. The range of 95% limits of agreement (LoAs) for ultrasound CCT was narrowest with Casia (31.94 μm). Casia–TMS-5 displayed a narrow range of 95% LoA for CCT (12.14 to −12.44), thinnest corneal thickness (12.31 to −11.31), and Ks (0.56 to −0.53), whereas Casia-Pentacam showed a narrow range of 95% LoA for Kf (0.56 to −0.42), Km (0.41 to −0.27), and anterior best-fit sphere (0.03 to −0.07). A significant difference in posterior best-fit sphere measurements was noted among all instruments (P = .01).

CONCLUSIONS

Casia, TMS-5, and Pentacam can be used interchangeably to measure corneal thickness and radius measurement in healthy eyes. Casia had the best agreement with ultrasound pachymeter CCT and exhibited the highest repeatability.
Case Report: Dry Eye Management Leads to Early Diagnosis of Seventh Nerve Schwannoma
Authors: Hyde Clark Benjamin
Published: October 2021

SIGNIFICANCE

Facial nerve schwannomas are rare tumors that are usually benign and relatively slow in their progression. Common symptoms include facial neuropathy, auditory deficiencies, and parotid masses. Because of slow progression, symptoms are often present for over a year before an appropriate diagnosis is made.

PURPOSE

The purpose of this study was to present a case in which comprehensive dry eye assessments and management led to diagnosis of facial nerve shwannoma in a patient who had no presenting symptoms of auditory deficiencies or facial weakness.

CASE REPORT

A 36-year-old woman presented for a contact lens examination with concerns of progressively worsening symptoms of irritation and dryness in her right eye that began 6 months earlier. Dry eye assessment visits and management strategies were implemented. Although this regimen was initially successful, symptoms returned after 7 months. At this visit, a new finding of incomplete blink in her right eye was manifested. Further in-office assessments revealed a weakened right orbicularis oculi and right frontalis muscle. These findings, combined with patient risk factors and no history of trauma, prompted MRI of the seventh nerve. Imaging revealed the presence of seventh nerve schwannoma, the location of which correlated with the geniculate ganglion and greater superficial petrosal nerve. This patient was later referred to a neurosurgeon, who assessed the risks and benefits of schwannoma removal. It was decided that the risks of the surgery outweighed the benefits, and regular MRI was scheduled for monitoring purposes. Appropriate management of the patient's chronic dry eye disease continues.

CONCLUSIONS

Facial nerve schwannomas can and do present with no presenting subjective facial neuropathy symptoms aside from mild unilateral dry eye and can be detected with comprehensive dry eye management. This case may contribute to future minor adjustments in clinical practice guidelines for asymmetric dry eye assessments.
Pattern-based Histologic Approach in Very Early Onset IBD: Main Features and Differential Diagnosis
Authors: Parente Paola , Mastracci Luca , Vanoli Alessandro , Fassan Matteo , Pastore Maria , Bossa Fabrizio , Francalanci Paola , Alaggio Rita , Graziano Paolo , Grillo Federica
Published: October 2021

Very early onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella classification composed of IBD-like diseases encompassing both classic IBD (Crohn’s disease and ulcerative colitis) and monogenic disorder, both arising before 6 years of age. VEO-IBD patients present significant clinical differences from IBD occurring in older children and in adults, including more severe disease, often unresponsive to conventional IBD therapy and a greater proportion of cases featuring an underlying genetic alteration. Histologic findings of gastrointestinal biopsies can show an IBD-like pattern (both Crohn’s disease-like and ulcerative colitis-like pattern), an apoptotic-like and enterocolitis-like pattern. Findings of specific morphologic alterations, such as villous blunting, apoptosis, dense eosinophilic infiltrates, lack of plasma cells and severe glandular atrophy, can suggest a monogenic disorder. Moreover, individuals with monogenic disorders may develop significant problems such as primary immunodeficiency, impacting treatment options. Finally, IBD histology in childhood can differ from that in older patients and adults. This complexity makes a differential diagnosis between IBD and other pediatric diseases involving the gastrointestinal tract difficult, especially considering that histologic features can be similar between different diseases. Without an appropriate diagnosis, the clinical course of VEO-IBD has greater potential for escalated treatment regimens involving extensive surgery and more intensive medical therapies rather than specific therapy directed toward the underlying defect. For these reasons, a pattern-based histologic approach correlated with clinical and laboratory findings with a multidisciplinary approach is fundamental to reach a correct diagnosis in an adequate clinical context.
Intraductal Adenocarcinoma of the Prostate With Cribriform or Papillary Ductal Morphology
Authors: Russell Daniel H. , Epstein Jonathan I.
Published: October 2021

Prostatic duct adenocarcinoma, characterized by pseudostratified columnar epithelium, has historically been considered invasive carcinoma, although it may commonly have an intraductal component. Usual (acinar) intraductal carcinoma of the prostate (IDC-P) is a noninvasive high-risk lesion typically associated with high-grade, high-stage prostate cancer. Whereas there have been rare biopsy studies of pure acinar IDC-P or IDC-P associated with only low-grade carcinoma, there have been no analogous series of IDC-P with cribriform or papillary ductal morphology on biopsy unassociated with invasive high-grade carcinoma. We identified 14 patients with biopsies showing IDC-P with ductal morphology, defined as prostatic duct adenocarcinoma confined to glands/ducts with immunohistochemically proven retention of basal cells. Our series includes 12 patients with pure IDC-P and 2 patients with concurrent low-volume Grade Group 1 invasive cancer in unassociated cores. Three patients underwent radical prostatectomy: 2/3 had high-grade cancer in their resection specimen (Grade Group 3, Grade Group 5), including 1 with advanced stage and nodal metastases; 1/3 had Grade Group 1 organ-confined carcinoma and spatially distinct IDC-P with ductal morphology. Five men had only follow-up biopsies: 2/5 had cancer (Grade Group 2, Grade Group 4); 1/5 had IDC-P (on 2 repeat biopsies); and 2/5 had benign transurethral resection of the prostate. In all 5 cases with invasive cancer, the invasive portion was comprised purely of acinar morphology; no invasive ductal component was identified. Five patients did not have follow-up biopsies and were treated with radiation therapy±androgen deprivation. One patient had no follow-up information. In an analogous situation to acinar IDC-P, we propose that rarely there is a precursor form of ductal adenocarcinoma that can exist without concurrent invasive high-grade carcinoma and propose the term “IDC-P with ductal morphology,” consistent with the terminology for acinar prostate adenocarcinoma. Until more evidence is accumulated, we recommend reporting and treating patients with IDC-P with ductal morphology in a manner analogous to those with acinar IDC-P. As with pure IDC-P with acinar morphology, we would also recommend not grading pure IDC-P with ductal morphology. Finally, we propose a new addition to the diagnostic criteria of IDC-P to include intraductal lesions with ductal morphology consisting of papillary fronds or cribriform lesions lined by cytologically atypical pseudostratified epithelium.
Psychological Symptom Trajectories and Non–Small Cell Lung Cancer Survival: A Joint Model Analysis
Authors: Andersen Barbara L. , McElroy Joseph P. , Carbone David P. , Presley Carolyn J. , Smith Rachel M. , Shields Peter G. , Brock Guy N.
Published: October 2021

Objective

Lung cancer remains the number one cause of cancer-related mortality worldwide, but less known is that lung cancer patients are among the most psychologically disabled of all cancer groups. Patients with stage IV non–small cell lung cancer (NSCLC) were studied to test the hypothesis that trajectories of depression and/or anxiety symptoms after diagnosis would show an adverse relationship with survival, beyond relevant controls.

Methods

Patients with stage IV NSCLC (n = 157) were enrolled (ClinicalTrials.gov Identifier: NCT03199651) at diagnosis and completed validated measures for depressive symptoms (Patient Health Questionnaire-9) and anxiety symptoms (Generalized Anxiety Disorder-7). Patients were reassessed every 1 to 2 months through 24 months (16 assessments; 80% average completion rate) and survival monitored. Joint statistical models provided simultaneous modeling of longitudinal (psychological) and time-to-event (survival) processes. Control variables were age, sex, marital status, education, smoking status, cancer type, and treatment received.

Results

Depression and anxiety symptoms significantly decreased with time since diagnosis. The 2-year trajectory of depressive symptoms was significantly associated with cancer survival after adjustment for covariates (hazard ratio = 1.09 per unit increase in the Patient Health Questionnaire-9, 95% confidence interval = 1.03–1.15, p = .002). Anxiety was marginally significant in the unadjusted (p = .053) but not the adjusted (p = .39) model.

Conclusions

For the first time, joint model analyses test the interaction of a longitudinal trajectory of psychological symptoms, assessed from diagnosis to 24 months, and cancer survival. New data show the continuation of depressive and anxiety symptoms through treatment and thereafter. Immunotherapy and targeted therapies have dramatically improved survival for patients with advanced NSCLC; however, novel data suggest their benefit may be constrained by depressive symptoms.
Solitary Isolated Dural Metastasis From Lung Adenocarcinoma Mimicking Meningioma
Authors: Zhang Jun , Dong Aisheng , Wang Yang
Published: October 2021

Solitary isolated dural metastasis is extremely rare. Distinguishing solitary dural metastasis from meningioma based on radiological findings can be challenging. We describe MRI and FDG PET/CT findings in 2 cases of histologically proved solitary isolated dural metastasis from lung adenocarcinoma. Enhanced brain MRI of the 2 cases showed parafalcine extra-axial, dural-based tumors with hypervascularity mimicking meningioma. Preoperative FDG PET/CT was performed in one case with a known history of lung adenocarcinoma showing intense FDG uptake of the parafalcine tumor. Postoperative FDG PET/CT was performed in the other case showing solitary lung tumor, suggestive of the primary tumor.
UAMC-3203 or/and Deferoxamine Improve Post-Resuscitation Myocardial Dysfunction Through Suppressing Ferroptosis in a Rat Model of Cardiac Arrest
Authors: Jin Tao , He Qing , Cheng Cheng , Li Hui , Liang Lian , Zhang Guozhen , Su Chenglei , Xiao Yan , Bradley Jennifer , Peberdy Mary Ann , Ornato Joseph P. , Tang Wanchun
Published: October 2021

Blocking ferroptosis reduces ischemia-reperfusion injury in some pathological contexts. However, there is no evidence that ferroptosis contributes to post-resuscitation myocardial dysfunction (PRMD). Here, we evaluated the therapeutic performance of ferroptosis inhibitors (UAMC-3203 or/and Deferoxamine) on the PRMD in a rat model of cardiac arrest and surveyed the changes of essential ferroptosis markers in the myocardium. Remarkably, all treatments reduce the severity of cardiac dysfunction and microcirculation hypoperfusion after resuscitation compared with control. Consistently, we observe that the ferroptosis marker Glutathione peroxidase 4, 4-hydroxynonenal and non-heme iron altered (1 ± 0.060 vs. 0.021 ± 0.016, 1 ± 0.145 vs. 3.338 ± 0.221, 52.010 ± 3.587 ug/g vs. 70.500 ± 3.158 ug/g, all P < 0.05) in the myocardium after resuscitation. These changes were significantly suppressed by UAMC-3203 [(0.187 ± 0.043, 2.848 ± 0.169, all P < 0.05), (72.43 ± 4.920 ug/g, P 
> 0.05)], or Deferoxamine (0.203 ± 0.025, 2.683 ± 0.273, 55.95 ± 2.497 ug/g, all P < 0.05). Briefly, UAMC-3203 or/and Deferoxamine improve post-resuscitation myocardial dysfunction and provide evidence of ferroptosis involvement, suggesting that ferroptosis inhibitors could potentially provide an innovative therapeutic approach for mitigating the myocardial damage caused by cardiopulmonary resuscitation.
Association of County-level Upward Economic Mobility with Stage at Diagnosis and Receipt of Treatment Among Patients Diagnosed with Pancreatic Adenocarcinoma
Authors: Dalmacy Djhenne , Paro Alessandro , Hyer J. Madison , Obeng-Gyasi Samilia , Pawlik Timothy M.
Published: October 2021

Objective:

Determining the impact of county-level upward economic mobility on stage at diagnosis and receipt of treatment among Medicare beneficiaries with pancreatic adenocarcinoma.

Summary background data:

The extent to which economic mobility contributes to socioeconomic disparities in health outcomes remains largely unknown.

Methods:

Pancreatic adenocarcinoma patients diagnosed in 2004–2015 were identified from the SEER-Medicare linked database. Information on countylevel upward economic mobility was obtained from the Opportunity Atlas. Its impact on early-stage diagnosis (stage I or II), as well as receipt of chemotherapy or surgery was analyzed, stratified by patient race/ethnicity.

Results:

Among 25,233 patients with pancreatic adenocarcinoma, 37.1% (n = 9349) were diagnosed at an early stage; only 16.7% (n = 4218) underwent resection, whereas 31.7% (n = 7996) received chemotherapy. In turn, 10,073 (39.9%) patients received any treatment. Individuals from counties with high upward economic mobility were more likely to be diagnosed at an earlier stage (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.07–1.25), as well as to receive surgery (OR 1.58, 95% CI 1.41–1.77) or chemotherapy (OR 1.51, 95% CI 1.39–1.63). White patients and patients who identified as neither White or Black had increased odds of being diagnosed at an early stage (OR 1.12, 95% CI 1.02–1.22 and OR 1.35, 95% CI 1.02–1.80, respectively) and of receiving treatment (OR 1.73, 95% CI 1.59–1.88 and OR 1.49, 95% CI 1.13–1.98, respectively) when they resided in a county of high vs low upward economic mobility. The impact of economic mobility on stage at diagnosis and receipt of treatment was much less pronounced among Black patients (high vs low, OR 1.28, 95% CI 0.96–1.71 and OR 1.30, 95% CI 0.99–1.72, respectively).

Conclusions:

Pancreatic adenocarcinoma patients from higher upward mobility areas were more likely to be diagnosed at an earlier stage, as well as to receive surgery or chemotherapy. The impact of county-level upward mobility was less pronounced among Black patients.
The Use of Learning Analytics to Enable Detection of Underperforming Trainees
Authors: Smith Brigitte K. , Yamazaki Kenji , Tekian Ara , Holmboe Eric , Hamstra Stanley J. , Mitchell Erica L. , Park Yoon Soo
Published: October 2021

Objective:

This study aims to investigate at-risk scores of semiannual Accreditation Council for Graduate Medical Education (ACGME) Milestone ratings for vascular surgical trainees' final achievement of competency targets.

Summary Background Data:

ACGME Milestones assessments have been collected since 2015 for Vascular Surgery. It is unclear whether milestone ratings throughout training predict achievement of recommended performance targets upon graduation.

Methods:

National ACGME Milestones data were utilized for analyses. All trainees completing 2-year vascular surgery fellowships in June 2018 and 5-year integrated vascular surgery residencies in June 2019 were included. A generalized estimating equations model was used to obtain at-risk scores for each of the 31 subcompetencies by semiannual review periods, to estimate the probability of trainees achieving the recommended graduation target based on their previous ratings.

Results:

A total of 122 vascular surgery fellows (VSFs) (95.3%) and 52 integrated vascular surgery residents (IVSRs) (100%) were included. VSFs and IVSRs did not achieve level 4.0 competency targets at a rate of 1.6% to 25.4% across subcompetencies, which was not significantly different between the 2 groups for any of the subcompetencies (P = 0.161–0.999). Trainees were found to be at greater risk of not achieving competency targets when lower milestone ratings were assigned, and at later time-points in training. At a milestone rating of 2.5, with 1 year remaining before graduation, the at-risk score for not achieving the target level 4.0 milestone ranged from 2.9% to 77.9% for VSFs and 33.3% to 75.0% for IVSRs.

Conclusion:

The ACGME Milestones provide early diagnostic and predictive information for vascular surgery trainees' achievement of competence at completion of training.
Spinal cord pathology revealed by MRI in traumatic spinal cord injury
Authors: Pfyffer Dario , Freund Patrick
Published: October 2021

Purpose of review

This review covers recent advances in identifying conventional and quantitative neuroimaging spinal cord biomarkers of lesion severity and remote spinal cord pathology following traumatic spinal cord injury (SCI). It discusses the potential of the most sensitive neuroimaging spinal cord biomarkers to complement clinical workup and improve prediction of recovery.

Recent findings

At the injury site, preserved midsagittal tissue bridges – based on conventional sagittal T2-weighted scans – can be identified in the majority of SCI patients; its width being predictive of recovery. Remote from the injury, diffusion indices, and myelin/iron-sensitive neuroimaging-based changes are sensitive to secondary disease processes; its magnitude of change being associated with neurological outcome.

Neuroimaging biomarkers reveal focal and remote cord pathology. These biomarkers show sensitivity to the underlying disease processes and are clinically eloquent. Thus, they improve injury characterization, enable spatiotemporal tracking of cord pathology, and predict recovery of function following traumatic SCI. Neuroimaging biomarkers, therefore, hold potential to complement the clinical diagnostic workup, improve patient stratification, and can serve as potential endpoints in clinical trials.
Induced Pluripotent Stem Cells for Inherited Optic Neuropathies—Disease Modeling and Therapeutic Development
Authors: Harvey Joshua Paul , Sladen Paul Edward , Yu-Wai-Man Patrick , Cheetham Michael E.
Published: October 2021

Background:

Inherited optic neuropathies (IONs) cause progressive irreversible visual loss in children and young adults. There are limited disease-modifying treatments, and most patients progress to become severely visually impaired, fulfilling the legal criteria for blind registration. The seminal discovery of the technique for reprogramming somatic nondividing cells into induced pluripotent stem cells (iPSCs) has opened several exciting opportunities in the field of ION research and treatment.

Evidence Acquisition:

A systematic review of the literature was conducted with PubMed using the following search terms: autosomal dominant optic atrophy, ADOA, dominant optic atrophy, DOA, Leber hereditary optic neuropathy, LHON, optic atrophy, induced pluripotent stem cell, iPSC, iPSC derived, iPS, stem cell, retinal ganglion cell, and RGC. Clinical trials were identified on the ClinicalTrials.gov website.

Results:

This review article is focused on disease modeling and the therapeutic strategies being explored with iPSC technologies for the 2 most common IONs, namely, dominant optic atrophy and Leber hereditary optic neuropathy. The rationale and translational advances for cell-based and gene-based therapies are explored, as well as opportunities for neuroprotection and drug screening.

Conclusions:

iPSCs offer an elegant, patient-focused solution to the investigation of the genetic defects and disease mechanisms underpinning IONs. Furthermore, this group of disorders is uniquely amenable to both the disease modeling capability and the therapeutic potential that iPSCs offer. This fast-moving area will remain at the forefront of both basic and translational ION research in the coming years, with the potential to accelerate the development of effective therapies for patients affected with these blinding diseases.
Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico
Authors: Dunkle Lisa M. , Kotloff Karen L. , Gay Cynthia L. , Áñez Germán , Adelglass Jeffrey M. , Barrat Hernández Alejandro Q. , Harper Wayne L. , Duncanson Daniel M. , McArthur Monica A. , Florescu Diana F. , McClelland R. Scott , Garcia-Fragoso Veronica , Riesenberg Robert A. , Musante David B. , Fried David L. , Safirstein Beth E. , McKenzie Mark , Jeanfreau Robert J. , Kingsley Jeffrey K. , Henderson Jeffrey A. , Lane Dakotah C. , Ruíz-Palacios Guillermo M. , Corey Lawrence , Neuzil Kathleen M. , Coombs Robert W. , Greninger Alex L. , Hutter Julia , Ake Julie A. , Smith Katherine , Woo Wayne , Cho Iksung , Glenn Gregory M. , Dubovsky Filip ,   for the 2019nCoV-301 Study Group
Published: October 2021

BACKGROUND

Vaccination using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein antigen has been effective in the prevention of coronavirus disease 2019 (Covid-19). NVX-CoV2373 is an adjuvanted, recombinant S protein nanoparticle vaccine that demonstrated clinical efficacy for prevention of Covid-19 in phase 2b/3 trials in the United Kingdom and South Africa.

METHODS

This phase 3, randomized, observer-blinded, placebo-controlled trial evaluated the efficacy and safety of NVX-CoV2373 in adults ≥18 years of age in the United States and Mexico during the first quarter of 2021. Participants were randomized in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary end point was vaccine efficacy (VE) against reverse transcriptase-polymerase chain reaction-confirmed Covid-19 in SARS-CoV-2-naïve participants ≥7 days after the second dose administration.

RESULTS

Of the 29,949 participants randomized between December 27, 2020, and February 18, 2021, 29,582 (median age: 47 years, 12.6% ≥65 years) received ≥1 dose: 19,714 received vaccine and 9868 placebo. In the per-protocol population, there were 77 Covid-19 cases; 14 among vaccine and 63 among placebo recipients (VE: 90.4%, 95% confidence interval [CI] 82.9 to 94.6, P<0.001). All moderate-to-severe cases occurred in placebo recipients, yielding VE of 100% (95% CI 87.0 to 100). Most sequenced viral genomes (48/61, 78.7%) were variants of concern (VOC) or interest (VOI), mainly represented by variant alpha/B.1.1.7 (31/35, 88.6% VOC identified). VE against any VOC/VOI was 92.6% (95% CI 83.6 to 96.7). Reactogenicity was mostly mild-to-moderate and transient, but more frequent in NVX-CoV2373 recipients and after the second dose. Serious adverse events were rare and evenly distributed between treatments.

CONCLUSIONS

NVX-CoV2373 was well tolerated and demonstrated a high overall VE (>90%) for prevention of Covid-19, with most cases due to variant strains.

(Funded by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; PREVENT-19 ClinicalTrials.gov number, NCT04611802.)
SARS-CoV-2 DNA Vaccine INO-4800 Induces Durable Immune Responses Capable of Being Boosted in a Phase 1 Open-Label Trial
Authors: Kraynyak Kimberly A , Blackwood Elliott , Agnes Joseph , Tebas Pablo , Giffear Mary , Amante Dinah , Reuschel Emma L , Purwar Mansi , Christensen-Quick Aaron , Liu Neiman , Andrade Viviane , Diehl Malissa , Wani Snehal , Lupicka Martyna , Sylvester Albert , Morrow Matthew P , Pezzoli Patrick , McMullan Trevor , Kulkarni Abhijeet J , Zaidi Faraz I , Frase Drew , Liaw Kevin , Smith Trevor R.F. , Ramos Stephanie J , Ervin John , Adams Mark , Lee Jessica , Dallas Michael , Shah Brown Ami , Shea Jacqueline E , Kim J Joseph , Weiner David B , Broderick Kate E , Humeau Laurent M , Boyer Jean D , Mammen Mammen P
Published: October 2021

Background: Additional SARS-CoV-2 vaccines that are safe and effective as primary vaccines and boosters remain urgently needed to combat the COVID-19 pandemic. We describe the safety and durability of the immune responses following two primary doses and a homologous booster dose of an investigational DNA vaccine (INO-4800) targeting the full-length spike antigen.
Methods: Three dosage strengths of INO-4800 (0.5 mg, 1.0 mg, and 2.0 mg) were evaluated in 120 age-stratified healthy adults. Intradermal injection of INO-4800 followed by electroporation at 0 and 4 weeks preceded an optional booster 6-10.5 months after the second dose.
Results: INO-4800 appeared well tolerated, with no treatment-related serious adverse events. Most adverse events were mild and did not increase in frequency with age and subsequent dosing. A durable antibody response was observed 6 months following the second dose; a homologous booster dose significantly increased immune responses. Cytokine producing T cells and activated CD8+ T cells with lytic potential were significantly increased in the 2.0 mg dose group.
Conclusion: INO-4800 was well tolerated in a 2-dose primary series and as a homologous booster in all adults, including the elderly. These results support further development of INO-4800 for use as a primary vaccine and as a booster.

Keywords: SARS-CoV-2; Clinical trial; DNA Vaccine; INO-4800; COVID-19; Safety; Immunogenicity; Booster
The influence of reproductive stage on cerebellar network connectivity across adulthood
Authors: Ballard Hannah K. , Jackson T. Bryan , Hicks Tracey H. , Bernard Jessica A.
Published: October 2021

Sex-specific differences in the aging cerebellum may be related to hormone changes with menopause. We evaluated the influence of reproductive stage on lobular cerebellar network connectivity using data from the Cambridge Centre for Ageing and Neuroscience repository. We used raw structural and resting state neuroimaging data and information regarding age, sex, and menopause-related variables. Crus I and II and Lobules V and VI were our cerebellar seeds of interest. We characterized reproductive stage using the Stages of Reproductive Aging Workshop criteria. Results show that postmenopausal females have lower cerebello-striatal and cerebello-cortical connectivity, particularly in frontal regions, along with lower connectivity within the cerebellum, compared to reproductive females. Postmenopausal females also exhibit greater connectivity in some brain areas as well. Differences begin to emerge across transitional stages of menopause. Further, results reveal sex-specific differences in connectivity between female reproductive groups and age-matched male control groups. This suggests that menopause may influence cerebellar network connectivity in aging females, and sex differences in the aging brain may be related to this biological process.

Highlights

Lobular analysis of cerebellar network connectivity across reproductive stages

Postmenopausal females show lower cerebellar connectivity, compared to reproductive

Connectivity differences begin to emerge in transitional stages of menopause

Age-matched male control groups show distinct patterns of cerebellar connectivity

Reproductive stage influences cerebellar network connectivity in aging females
Use of a graph neural network to the weighted gene co-expression network analysis of Korean native cattle
Authors: Lee Hyo-Jun , Chung Yoonji , Chung Ki Yong , Kim Young-Kuk , Lee Jun Heon , Koh Yeong Jun , Lee Seung Hwan
Published: October 2021

In the general framework of the weighted gene co-expression network analysis (WGCNA), a hierarchical clustering algorithm is commonly used to module definition. However, hierarchical clustering depends strongly on the topological overlap measure. In other words, this algorithm may assign two genes with low topological overlap to different modules even though their expression patterns are similar. Here, a novel gene module clustering algorithm for WGCNA is proposed. We develop a gene module clustering network (gmcNet), which simultaneously addresses single-level expression and topological overlap measure. The proposed gmcNet includes a “co-expression pattern recognizer” (CEPR) and “module classifier”. The CEPR incorporates expression features of single genes into the topological features of co-expressed ones. Given this CEPR-embedded feature, the module classifier computes module assignment probabilities. We validated gmcNet performance using 4,976 genes from 20 native Korean cattle. We observed that the CEPR generates more robust features than single-level expression or topological overlap measure. Given the CEPR-embedded feature, gmcNet achieved the best performance in terms of modularity (0.261) and the differentially expressed signal (27.739) compared with other clustering methods tested. Furthermore, gmcNet detected some interesting biological functionalities for carcass weight, backfat thickness, intramuscular fat, and beef tenderness of Korean native cattle. Therefore, gmcNet is a useful framework for WGCNA module clustering.

Author summary

A graph neural network is a good alternative algorithm for WGCNA module clustering. Even though the graph-based learning methods have been widely applied in bioinformatics, most studies on WGCNA did not use graph neural network for module clustering. In addition, existing methods depend on topological overlap measure of gene pairs. This can degrade similarity of expression not only between modules, but also within module. On the other hand, the proposed gmcNet, which works similar to message-passing operation of graph neural network, simultaneously addresses single-level expression and topological overlap measure. We observed the higher performance of gmcNet comparing to existing methods for WGCNA module clustering. To adopt gmcNet as clustering algorithm of WGCNA, it remains future research issues to add noise filtering and optimal k search on gmcNet. This further research will extend our proposed method to be a useful module clustering algorithm in WGCNA. Furthermore, our findings will be of interest to computational biologists since the studies using graph neural networks to WGCNA are still rare.
Reservoir host immunology and life history shape virulence evolution in zoonotic viruses
Authors: Brook Cara E. , Rozins Carly , Guth Sarah , Boots Mike
Published: October 2021

The management of future pandemic risk requires a better understanding of the mechanisms that determine the virulence of emerging zoonotic viruses. Meta-analyses suggest that the virulence of emerging zoonoses is correlated with but not completely predictable from reservoir host phylogeny, indicating that specific characteristics of reservoir host immunology and life history may drive the evolution of viral traits responsible for cross-species virulence. In particular, bats host viruses that cause higher case fatality rates upon spillover to humans than those derived from any other mammal, a phenomenon that cannot be explained by phylogenetic distance alone. In order to disentangle the fundamental drivers of these patterns, we develop a nested modeling framework that highlights mechanisms which underpin the evolution of viral traits in reservoir hosts that cause virulence following cross-species emergence. We apply this framework to generate virulence predictions for viral zoonoses derived from diverse mammalian reservoirs, successfully recapturing corresponding virus-induced human mortality rates reported in the literature. Notably, our work offers a mechanistic explanation for the extreme virulence of bat-borne zoonoses and, more generally, demonstrates how key differences in reservoir host longevity, viral tolerance, and constitutive immunity impact the evolution of viral traits that cause virulence following spillover to humans. Our theoretical framework offers a series of testable questions and hypotheses designed to stimulate future work comparing cross-species virulence evolution in zoonotic viruses derived from diverse mammalian hosts.
No difference in retinal fluorescence after oral curcumin intake in amyloid proven AD cases compared to controls
Authors: den Haan Jurre , Hart de Ruyter Frederique J. , Lochocki Benjamin , Kroon Maurice A.G.M. , Kemper E. Marleen , Teunissen Charlotte E. , van Berckel Bart , Scheltens Philip , Hoozemans Jeroen J. , van de Kreeke Aleid , Verbraak Frank D. , de Boer Johannes F. , Bouwman Femke H.
Published: October 2021

INTRODUCTION

Previous work showed thein-vivopresence of retinal amyloid in AD patients using curcumin. We aimed to replicate these findings in an amyloid biomarker confirmed cohort.

METHODS

Twenty-six AD patients (age 66 (+9), MMSE≥17) and 14 controls (age 71(+12)) used one of three curcumin formulations: Longvida®, Theracurmin®and Novasol®.

Plasma levels were determined and pre- and post-curcumin retinal fluorescence scans were visually assessed in all cases and quantitatively assessed in a subset.

RESULTS

Visual assessment showed no difference between AD patients and controls for pre- and post-curcumin images. This was confirmed by quantitative analyses on a subset. Mean conjugated plasma curcumin levels were 198.7 nM (Longvida®), 576.6 nM (Theracurmin®) and 1605.8 nM (Novasol®).

DISCUSSION

We found no difference in retinal fluorescence betweenamyloid confirmed AD cases and control participants, using Longvida®and two additional curcumin formulations. Additional replication studies in amyloid confirmed cohorts are needed to assess the diagnostic value of retinal fluorescence as an AD biomarker.
Using brain cell-type-specific protein interactomes to interpret genetic data in schizophrenia
Authors: Hsu Yu-Han H. , Nacu Eugeniu , Liu Ruize , Pintacuda Greta , Kim April , Tsafou Kalliopi , Petrossian Natalie , Crotty William , Suh Jung Min , Riseman Jackson , Martin Jacqueline M. , Biagini Julia C. , Ching Joshua K.T. , Malolepsza Edyta , Li Taibo , Singh Tarjinder , Ge Tian , Egri Shawn B. , Tanenbaum Benjamin , Stanclift Caroline R. , Apffel Annie M. ,   Schizophrenia Working Group of the Psychiatric Genomics Consortium,   Stanley Global Asia Initiatives, Carr Steven A. , Schenone Monica , Jaffe Jake , Fornelos Nadine , Huang Hailiang , Eggan Kevin C. , Lage Kasper
Published: October 2021

Genetics have nominated many schizophrenia risk genes that lack functional interpretation. To empower such interpretation, we executed interaction proteomics for six risk genes in human induced neurons and found the resulting protein network to be enriched for common variant risk of schizophrenia in Europeans and East Asians. The network is down-regulated in layer 5/6 cortical neurons of patients and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and also contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in patients with schizophrenia and bipolar disease. Our findings establish brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and psychiatric diseases.

One Sentence Summary

Neuronal protein interactomes is an organizing framework for integrating genetic and transcriptomic data in schizophrenia.
Identification of a novel modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast
Authors: Sing Cierra N. , Garcia Enrique J. , Lipkin Thomas G. , Huckaba Thomas M. , Tsang Catherine A. , Coughlin Arielle C. , Yang Emily J. , Boldogh Istvan R. , Higuchi-Sanabria Ryo , Pon Liza A.
Published: October 2021

In yeast, actin cables are F-actin bundles that are essential for cell division through their function as tracks for cargo movement from mother to daughter cell. Actin cables also affect yeast lifespan by promoting transport and inheritance of higher-functioning mitochondria to daughter cells. Here, we report that actin cable stability declines with age. Our genome-wide screen for genes that affect actin cable stability identified the open reading frame YKL075C. Deletion of YKL075C results in increases in actin cable stability and abundance, mitochondrial fitness, and replicative lifespan. Transcriptome analysis revealed a role for YKL075C in regulating branched-chain amino acid (BCAA) metabolism. Consistent with this, modulation of BCAA metabolism or decreasing leucine levels promotes actin cable stability and function in mitochondrial quality control. Our studies support a role for actin stability in yeast lifespan, and demonstrate that this process is controlled by BCAA and a previously uncharacterized ORF YKL075C, which we refer to as actin, aging and nutrient modulator protein 1 (AAN1).
Large-scale discovery of candidate type VI secretion effectors with antibacterial activity
Authors: Geller Alexander Martin , Zlotkin David , Levy Asaf
Published: October 2021

Type VI secretion systems (T6SS) are common bacterial contractile injection systems that inject toxic “effector” proteins into neighboring cells. Effector discovery is generally done manually, and computational approaches used for effector discovery depend on genetic linkage to T6SS genes and/or sequence similarity to known effectors. We bioinformatically investigated T6SS in more than 11,832 genomes of Gram negative bacteria. We found that T6SS encoding bacteria are host-associated and pathogenic, enriched in specific human and plant tissues, while depleted in marine, soil, and engineered environments. Analysis of T6SS cores with C-terminal domains (“evolved” cores) showed “evolved” HCP are rare, overwhelmingly encoded in orphan operons, and are largely restricted toEscherichia. Using the wealth of data generated from our bioinformatic analysis, we developed two algorithms for large-scale discovery of T6SS effector proteins (T6Es). We experimentally validated ten putative antibacterial T6SS effector proteins and one cognate immunity gene from a diverse species. This study provides a systematic genomic perspective of the role of the T6SS in nature, a thorough analysis of T6E evolution and genomic properties, and discovery of a large number of candidate T6Es using new approaches.
A bacteria-based assay to study SARS-CoV-2 protein-protein interactions
Authors: Springstein Benjamin L. , Deighan Padraig , Grabe Grzegorz , Hochschild Ann
Published: October 2021

Methods for detecting and dissecting the interactions of virally encoded proteins are essential for probing basic viral biology and providing a foundation for therapeutic advances. The dearth of targeted therapeutics for the treatment of COVID-19, an ongoing global health crisis, underscores the importance of gaining a deeper understanding of the interactions of SARS-CoV-2-encoded proteins. Here we describe the use of a convenient bacteria-based two-hybrid (B2H) system to analyze the SARS-CoV-2 proteome. We identify sixteen distinct intraviral protein-protein interactions (PPIs), involving sixteen proteins. We find that many of the identified proteins interact with more than one partner. We further show how our system facilitates the genetic dissection of these interactions, enabling the identification of selectively disruptive mutations. We also describe a modified B2H system that permits the detection of disulfide bond-dependent PPIs in the normally reducing Escherichia coli cytoplasm and we use this system to detect the interaction of the SARS-CoV-2 spike protein receptor-binding domain (RBD) with its cognate cell surface receptor ACE2. We then examine how the RBD-ACE2 interaction is perturbed by several RBD amino acid substitutions found in currently circulating SARS-CoV-2 variants. Our findings illustrate the utility of a genetically tractable bacterial system for probing the interactions of viral proteins and investigating the effects of emerging mutations. In principle, the system could also facilitate the identification of potential therapeutics that disrupt specific interactions of virally encoded proteins. More generally, our findings establish the feasibility of using a B2H system to detect and dissect disulfide bond-dependent interactions of eukaryotic proteins.

Importance

Understanding how virally encoded proteins interact with one another is essential in elucidating basic viral biology, providing a foundation for therapeutic discovery. Here we describe the use of a versatile bacteria-based system to investigate the interactions of the protein set encoded by SARS-CoV-2, the virus responsible for the current pandemic. We identify sixteen distinct intraviral protein-protein interactions, involving sixteen proteins, many of which interact with more than one partner. Our system facilitates the genetic dissection of these interactions, enabling the identification of selectively disruptive mutations. We also describe a modified version of our bacteria-based system that permits detection of the interaction between the SARS-CoV-2 spike protein (specifically its receptor binding domain) and its cognate human cell surface receptor ACE2 and we investigate the effects of spike mutations found in currently circulating SARS-CoV-2 variants. Our findings illustrate the general utility of our system for probing the interactions of virally encoded proteins.
Novel Investigation of SARS-CoV-2 in COVID-19 Survivors’ Semen in Surabaya, Indonesia
Authors: Supardi Supardi , Nidom Reviany V. , Sisca Eni M. , Tribowo Jefry A. , Kandar Patricia S. , Budiharto Joice M. , Siswidiyanto Eko , Wen Maitra Djiang , Kirana Tiara , Nidom Astria N. , Ansori Arif N. M. , Normalina Irine , Indrasari Setyarina , I’tishom Reny
Published: October 2021

The emergence and the widespread of Coronavirus disease 2019 (COVID-19) demands an accurate detection method to establish a diagnosis. Real-time polymerase chain reaction (real-time PCR) is accounted for the perfect point of reference in detecting this virus. The notion that this virus also invades the male reproductive tract requires further investigation to prove the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in the semen. This investigation was designed to detect SARS-CoV-2 in COVID-19 survivors’ semen. This study design was a cross-sectional examination and conducted between November 2020 and March 2021 in the Andrology Unit of Dr. Soetomo General Hospital and Professor Nidom Foundation, both located in the City of Surabaya, Indonesia. The sample was 34 male participants aged above 18 years old and had been confirmed COVID-19 by nasopharyngeal swab PCR test. Part of the semen was taken for real-time PCR testing with the QuantStudio 5 Applied Biosystem (AB) PCR machine and the kits utilized were the STANDARD M nCOV Real-Time Detection Kit and mBioCov-19 RT-PCR Kit. Furthermore, the mean of participants’ ages was 35.74 years old with 25% of them had had a history of primary infertility and 21.8% of secondary infertility. From the real-time PCR COVID-19 of the semen examination, this investigation found that 27 participants had been negatives (74.4%), six inconclusive (17.6%), and one positive (3%) of SARS CoV-2. In summary, SARS-CoV-2 could be found in the semen of COVID-19 survivors. This should be a concern for the potential impact of COVID-19 in male fertility and the possibility of transmission reproductively.