bluuebunny/crossref_metadata_2025 huggingface dataset:
The Importance of Making Assumptions in Bias Analysis
Authors: MacLehose Richard F. , Ahern Thomas P. , Lash Timothy L. , Poole Charles , Greenland Sander
Published: July 2021

Quantitative bias analyses allow researchers to adjust for uncontrolled confounding, given specification of certain bias parameters. When researchers are concerned about unknown confounders, plausible values for these bias parameters will be difficult to specify. Ding and VanderWeele developed bounding factor and E-value approaches that require the user to specify only some of the bias parameters. We describe the mathematical meaning of bounding factors and E-values and the plausibility of these methods in an applied context. We encourage researchers to pay particular attention to the assumption made, when using E-values, that the prevalence of the uncontrolled confounder among the exposed is 100% (or, equivalently, the prevalence of the exposure among those without the confounder is 0%). We contrast methods that attempt to bound biases or effects and alternative approaches such as quantitative bias analysis. We provide an example where failure to make this distinction led to erroneous statements. If the primary concern in an analysis is with known but unmeasured potential confounders, then E-values are not needed and may be misleading. In cases where the concern is with unknown confounders, the E-value assumption of an extreme possible prevalence of the confounder limits its practical utility.
Development and Validation of A Liquid Chromatography–Tandem Mass Spectrometry Method to Simultaneously Measure Tacrolimus and Everolimus Concentrations in Kidney Allograft Biopsies After Kidney Transplantation
Authors: Zhang Mengyu , Tajima Soichiro , Shigematsu Tomohiro , Noguchi Hiroshi , Kaku Keizo , Tsuchimoto Akihiro , Okabe Yasuhiro , Egashira Nobuaki , Ieiri Ichiro
Published: July 2021

Background:

Therapeutic drug monitoring is necessary for immunosuppressive therapy with tacrolimus and everolimus after kidney transplantation. Several studies have suggested that the concentrations of immunosuppressive agents in allografts may better reflect clinical outcomes than whole blood concentrations. This study aimed to develop a method for the simultaneous quantification of tacrolimus and everolimus concentrations in clinical biopsy samples and investigate their correlation with histopathological findings in kidney transplant recipients.

Methods:

Fourteen biopsy samples were obtained from kidney transplant recipients at 3 months after transplantation. Kidney allograft concentrations (Ctissue) of tacrolimus and everolimus were measured by liquid chromatography–tandem mass spectrometry, and the corresponding whole blood trough concentrations (C0) were obtained from clinical records.

Results:

The developed method was validated over a concentration range of 0.02–2.0 ng/mL for tacrolimus and 0.04–4.0 ng/mL for everolimus in kidney tissue homogenate. The Ctissue of tacrolimus and everolimus in kidney biopsies ranged from 21.0 to 86.7 pg/mg tissue and 33.5–105.0 pg/mg tissue, respectively. Dose-adjusted Ctissue of tacrolimus and everolimus was significantly correlated with the dose-adjusted C0 (P < 0.0001 and P = 0.0479, respectively). No significant association was observed between the Ctissue of tacrolimus and everolimus and the histopathologic outcomes at 3 months after transplantation.

Conclusions:

This method could support further investigation of the clinical relevance of tacrolimus and everolimus allograft concentrations after kidney transplantation.
Tear Film Surface Quality in Modern Daily Disposable Contact Lens Wear
Authors: Mousavi Maryam , Garaszczuk Izabela K. , De Jesus Danilo Andrade , Szczesna-Iskander Dorota H. , Armstrong Richard A. , Nichols Kelly K. , Iskander D. Robert
Published: July 2021

Objectives:

As reported previously, tear film surface quality (TFSQ) should be considered in contact lens (CL) fitting. This study followed noninvasive keratograph tear film break-up time (NIKBUT) in CL wearers for 12 months to validate its clinical utility in predicting CL performance.

Methods:

Fifty-five subjects (M/F=17/38) aged 26±4 years were prescribed silicone hydrogel or hydrogel CLs. The study included baseline measurements without CLs; 2 visits for CL fitting and control; follow-up after 3, 6, and 12 months of CL wear; and postwear visit without CLs. Ocular Surface Disease Index (OSDI), 8-Item Contact Lens Dry Eye Questionnaire (CLDEQ-8), first and mean NIKBUT (F/M-NIKBUT), fluorescein tear film break-up time (FBUT), and ocular surface staining were evaluated.

Results:

Post hoc analysis of each pair of visits showed differences between baseline and all CL visits for F-NIKBUT, M-NIKBUT, FBUT, and corneal staining. No difference was reported in symptoms. In addition, differences between baseline and postwear visits were noted in OSDI, M-NIKBUT, FBUT, and corneal staining, with three of the latter parameters showing a downward trend.

Conclusions:

No changes in TFSQ and symptoms were reported over 12 months. Introducing NIKBUT as part of routine CL fitting is advised to improve CL fit and predict success.
Distinct aberrations in cerebral pain processing differentiating patients with fibromyalgia from patients with rheumatoid arthritis
Authors: Sandström Angelica , Ellerbrock Isabel , Löfgren Monika , Altawil Reem , Bileviciute-Ljungar Indre , Lampa Jon , Kosek Eva
Published: July 2021

The current study used functional magnetic resonance imaging to directly compare disease-relevant cerebral pain processing in well-characterized patient cohorts of fibromyalgia (FM, nociplastic pain) and rheumatoid arthritis (RA, nociceptive pain). Secondary aims were to identify pain-related cerebral alterations related to the severity of clinical symptoms such as pain intensity, depression, and anxiety. Twenty-six patients with FM (without RA-comorbidity) and 31 patients with RA (without FM-comorbidity) underwent functional magnetic resonance imaging while stimulated with subjectively calibrated painful pressures corresponding to a pain sensation of 50 mm on a 100-mm visual analogue scale. Stimulation sites were at the most inflamed proximal interphalangeal joint in the left hand in patients with RA and the left thumbnail in patients with FM, 2 sites that have previously been shown to yield the same brain activation in healthy controls. The current results revealed disease-distinct differences during pain modulation in RA and FM. Specifically, in response to painful stimulation, patients with FM compared to patients with RA exhibited increased brain activation in bilateral inferior parietal lobe (IPL), left inferior frontal gyrus (IFG)/ventrolateral prefrontal cortex (vlPFC) encapsulating left dorsolateral prefrontal cortex, and right IFG/vlPFC. However, patients with RA compared to patients with FM exhibited increased functional connectivity (during painful stimulation) between right and left IPL and sensorimotor network and between left IPL and frontoparietal network. Within the FM group only, anxiety scores positively correlated with pain-related brain activation in left dorsolateral prefrontal cortex and right IFG/vlPFC, which further highlights the complex interaction between affective (ie, anxiety scores) and sensory (ie, cerebral pain processing) dimensions in this patient group.
Use of 3D Printing Technology for Cervical Thoracic Lumbosacral Orthosis Fabrication
Authors: Yelvington Miranda , Armstrong Gregory , Mallard Ellen , Shukla Ankita , Braden Eric
Published: July 2021

Introduction

This case report describes orthotic design using computed tomography and three-dimensional printing technology combined with traditional orthotic modalities in a newborn patient with chondrodysplasia punctata and cervical spinal stenosis. At day 5 of life, the infant was referred for fitting with a prefabricated cervical collar. Because of the infant's unique stature and small size, traditional prefabricated devices could not be used. The spinal instability and critical nature of the infant prevented traditional methods of orthosis fabrication. A multidisciplinary team used imaging, 3D printing technology, and traditional orthosis fabrication methods to construct a cervical thoracic lumbosacral orthosis (CTLSO).

Materials and Methods

Using computed tomography scans, data-segmenting software, and a 3D printer, a life-sized model of the patient's upper body was constructed. Traditional plaster molding and high-temperature orthoplastic techniques were used to fabricate a custom cervical thoracic lumbosacral orthosis for spinal stabilization, necessary for safe patient transport and handling.

Results

The custom orthosis demonstrated proper fit and stability, as evidenced by postfitting scans. With orthosis in place, needed care could be provided to the patient more safely and efficiently. In addition, the infant could be held by the caregivers, increasing parental/infant bonding.

Conclusions

Technological advances, including the ability to use computer tomography scans in combination with three-dimensional printers, can be a safe and effective option in situations of difficult orthosis fabrication for medically fragile patients.
Estimating the Pose of a Guinea-pig Cochlea Without Medical Imaging
Authors: Usevitch David E. , Park Albert H. , Scheper Verena , Abbott Jake J.
Published: July 2021

Hypothesis:

The pose (i.e., position and orientation) of a guinea-pig cochlea can be accurately estimated using externally observable features, without requiring computed-tomography (CT) scans.

Background:

Guinea pigs are frequently used in otologic research as animal models of cochlear-implant surgery. In robot-assisted surgical insertion of cochlear-implant electrode arrays, knowing the cochlea pose is required. A preoperative CT scan of the guinea-pig anatomy can be labeled and registered to the surgical system, however, this process can be expensive and time consuming.

Methods:

Anatomical features from both sides of 11 guinea-pig CT scans were labeled and registered, forming sets. Using a groupwise point-set registration algorithm, errors in cochlea position and modiolar-axis orientation were estimated for 11 iterations of registration where each feature set was used as a hold-out set containing a reduced number of features that could all be touched by a motion-tracking probe intraoperatively. The method was validated on 2000 simulated guinea-pig cochleae and six physical guinea-pig-skull cochleae.

Results:

Validation on simulated cochleae resulted in cochlea-position estimates with a maximum error of 0.43 mm and modiolar-axis orientation estimates with a maximum error of 8.1 degrees for 96.7% of cochleae. Physical validation resulted in cochlea-position estimates with a maximum error of 0.80 mm and modiolar-axis orientation estimates with a maximum error of 12.4 degrees.

Conclusions:

This work enables researchers conducting robot-assisted surgical insertions of cochlear-implant electrode arrays using a guinea-pig animal model to estimate the pose of a guinea-pig cochlea by locating six externally observable features on the guinea pig, without the need for CT scans.
Intratympanic Insulin-like Growth Factor-1 Administration Via the Otic Bulla in a Severe Facial Paralysis Model
Authors: Kimura Takuya , Yamada Hiroyuki , Teraoka Masato , Joko Tomonori , Iwata Shinji , Tabata Yasuhiro , Wakisaka Hiroyuki , Hato Naohito
Published: July 2021

Hypothesis:

We investigated the treatment effect of intratympanic insulin-like growth factor-1 (IGF-1) on severe facial paralysis in guinea pigs.

Background:

The use of regenerative medicine involving growth factors has been reported in the treatment of peripheral nerve diseases. IGF-1 plays a crucial role in nerve regeneration.

Methods:

We performed the following procedures on guinea pigs. In the normal group (n = 7), no procedure was performed. In the saline (n = 7) and IGF-1 (n = 7) groups, facial paralysis was induced by freezing of the facial canal. Subsequently, in the saline and IGF-1 groups, a gelatin hydrogel impregnated with 100 μL saline and 400 μg/100 μL IGF-1, respectively, was placed in the facial canal. Facial nerve functions were evaluated using three test batteries: facial movement observation, electrophysiological testing, and histological assessment.

Results:

At 10 weeks postoperatively, the facial movement scores for the IGF-1 group were improved compared to those in the saline group. The conductive velocity was significantly faster in the IGF-1 group than in the saline group. There was a significant between-group difference in the nerve fiber number and myelin thickness.

Conclusion:

Intratympanic IGF-1 administration improved facial nerve regeneration. This novel method could provide prompt ambulatory regenerative treatment and reduce the incidence of poor recovery in patients with severe facial paralysis.
Direct Oral Anticoagulants Versus Warfarin in Morbidly Obese Patients With Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-analysis
Authors: Mhanna Mohammed , Beran Azizullah , Al-Abdouh Ahmad , Sajdeya Omar , Abdulsattar Waleed , Srour Omar , Ayesh Hazem , Alom Modar , Khuder Sadik A. , Hamouda Danae , Assaly Ragheb
Published: July 2021

Background:

Direct oral anticoagulants (DOACs) have been increasingly preferred over warfarin; however, The International Society of Thrombosis and Hemostasis recommended avoiding the use of DOACs in morbidly obese patients (body mass index >40 or weight >120 kg) because of limited clinical data.

Study Question:

Are DOACs effective and safe in morbidly obese patients with nonvalvular atrial fibrillation (NVAF).

Data Sources:

We performed a comprehensive search for published studies indexed in PubMed/MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials that evaluated the efficacy and safety of DOACs in morbidly obese patients with NVAF.

Study Design:

Information on patient characteristics, comorbidities, primary anticoagulation indications, pharmacologic treatment, and outcomes were collected. The primary outcome of interest was stroke or systemic embolism (SSE) rate. The secondary outcome was major bleeding (MB).

Results:

A total of 10 studies including, 89,494 morbidly obese patients with NVAF on oral anticoagulation therapy (45,427 on DOACs vs. 44,067 on warfarin) were included in the final analysis. The SSE rate was significantly lower in DOACs group compared with warfarin group [odds ratio: 0.71; 95% confidence interval (CI): 0.62–0.81; P < 0.0001; I2 = 0%]. MB rate was also significantly lower in DOACs group compared with the warfarin group (odds ratio: 0.60; 95% CI: 0.46–0.78; P < 0.0001; I2 = 86%). On subgroup analysis, SSE and MB event rates were significantly lower in rivaroxaban and apixaban than warfarin; however, dabigatran showed noninferiority to warfarin in SSE rate but superiority in the safety outcome.

Conclusions:

Our meta-analysis demonstrated that DOACs are effective and safe with statistical superiority when compared with warfarin in morbidly obese patients. Large-scale randomized clinical trials are needed to further evaluate the efficacy and safety of DOACs in this cohort of patients.
Amyloidosis in a Patient With Congenital Neutropenia Because of G6PC3 Deficiency
Authors: Yildirmak Zeynep Yildiz , Ozcelik Gul , Ozagari Ayse Aysim , Genc Dildar Bahar , Onay Huseyin
Published: July 2021

Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency is a recently identified form of congenital neutropenia associated with developmental anomalies. The severity of neutropenia and the clinical spectrum are highly variable. Aside from infectious complications and extrahematologic features, inflammatory bowel disease and autoinflammatory complications are less frequently observed manifestations. However, amyloidosis has never been reported in G6PC3 deficiency. Here, we present a 12-year-old patient with incidentally discovered neutropenia because of the p.E65A (c.194A>C) variant of the G6PC3 gene. He had recurrent aphthae and abdominal pain episodes, and developed nephrotic-range proteinuria, amyloidosis, and end-stage renal failure during follow-up.
Pediatric Invasive Fungal Risk Score in Cancer and Hematopoietic Stem Cell Transplantation Patients With Febrile Neutropenia
Authors: Alali Muayad , Giurcanu Mihai , Elmuti Lena , Kumar Madan
Published: July 2021

Background:

Invasive fungal diseases (IFDs) are opportunistic infections that result in significant morbidity and mortality in pediatric oncology patients. Predictive risk tools for IFD in pediatric cancer are not available.

Methods:

We conducted a 7-year retrospective study of pediatric oncology patients with a diagnosis of febrile neutropenia at UCM Comer Children’s Hospitals. Fourteen clinical, laboratory, and treatment-related risk factors for IFD were analyzed. Stepwise variable selection for multiple logistic regression was used to develop a risk prediction model for IFD. Two comparative analyses have been conducted: (i) all suspected IFD cases and (ii) all proven and probable IFD cases.

Results:

A total of 667 febrile neutropenia episodes were identified in 265 patients. IFD was diagnosed in 62 episodes: 13 proven, 27 probable, and 22 possible. In the final multiple logistic regression models, 5 variables were independently significant for both analyses: fever days, neutropenia days, hypotension, and absolute lymphocyte count <250 at the time of diagnosis. The odds ratio and a relative weight for each factor were then calculated and summed to calculate a predictive score. A risk score of ≤4 and ≤5 (10/11 maximum) for each model signifies low risk, respectively (<1.2% incidence). Model discrimination was evaluated by the area under the receiver operator characteristics curve with an area under the curve of 0.95/0.94 for each model.

Conclusion:

Our prediction IFD risk models perform well, are easy–to-use, and are based on readily available clinical data. Profound lymphopenia absolute lymphocyte count <250 mm3 could serve as a new important prognostic marker for the development of IFD in pediatric cancer and hematopoietic stem cell transplant patients.
Pediatric EBV Positive Mucocutaneous Ulceration in Stomach a Rare Entity
Authors: Alakaya Mehmet , Gundogan Begumhan D. , Arslankoylu Ali E. , Karabulut Yasemin Y. , Akyurek Nalan , Karhan Asuman N. , Usta Yusuf , Citak Elvan C.
Published: July 2021

Epstein Barr virus (EBV) related lymphoproliferative diseases may occur in immunocompromised patients or patients with a history of drug use causing immunodeficiency. EBV positive mucocutaneous ulceration in the new classification of lymphoproliferative diseases in 2016 is very rare in children. Involvement occurs in the skin, oral mucosa, and gastrointestinal system. Gastric involvement is very rare in the literature. There is no case of gastric involvement in children. There are no specified modalities in the treatment of EBV positive mucocutaneous ulceration. We presented our pediatric patient with ataxia telangiectasia who presented with abdominal pain and difficulty swallowing and diagnosed with EBV positive mucocutaneous ulceration in the stomach. We started brentuximab vedotin during the treatment process, and complete remission was achieved after 6 cures of treatment. Our patient is the first case of EBV positive mucocutaneous ulceration in the pediatric case series.
Psychological Safety in Simulation-Based Prelicensure Nursing Education
Authors: Daniels Amy L. , Morse Catherine , Breman Rachel
Published: July 2021

Background

Psychological safety, essential in high-quality simulation-based education, positively influences learning behaviors and outcomes in corporate organizations. Current assessment of psychological safety is grounded in Edmondson's work team learning model. To understand applicability of this model in nursing education, a literature review was conducted. We reviewed literature on psychological safety in nursing education to assess support for this learning model constructs. Adapting existing models and assessment instruments in different contexts is an important contribution to the profession.

Methods

A structured narrative review examined psychological safety in nursing education simulation literature to identify support for Edmondson's work team learning model constructs.

Results

Included articles (n = 13) supported the Edmondson model constructs. When faculty practiced specific leader behaviors, learners experienced psychological safety and demonstrated specific learning-oriented behaviors.

Conclusion

Psychological safety literature in nursing education supports the work team learning model constructs. This link offers promise for transfer to an assessment instrument in nursing education.
Trends in Nationally Notifiable Sexually Transmitted Disease Case Reports During the US COVID-19 Pandemic, January to December 2020
Authors: Pagaoa Melissa , Grey Jeremy , Torrone Elizabeth , Kreisel Kristen , Stenger Mark , Weinstock Hillard
Published: July 2021

Background

To describe changes in reported sexually transmitted diseases (STDs) during the US coronavirus disease 2019 pandemic, we compared the weekly number of reported nationally notifiable STDs in 2020 to 2019.

Methods

We reviewed cases of chlamydia, gonorrhea, and primary and secondary (P&S) syphilis reported to the US National Notifiable Disease Surveillance System in 2020. For each STD, we compare the number of 2020 cases reported for a given Morbidity and Mortality Weekly Report (MMWR) week to the number of 2019 cases reported in the same week, expressing 2020 cases as a percentage of 2019 cases. We also calculated the percent difference between 2020 and 2019 cumulative case totals as of MMWR week 50 (week of December 9).

Results

During MMWR weeks 1 to 11 (week of December 29, 2019–March 11, 2020), the weekly number of cases of STDs reported in 2020 as a percentage of the cases in the same week in 2019 was similar. However, 2020 numbers were much lower than 2019 numbers in week 15 (week of April 8; chlamydia, 49.8%; gonorrhea, 71.2%; and P&S syphilis, 63.7%). As of week 50, the 2020 cumulative totals compared with 2019 were 14.0% lower for chlamydia, 7.1% higher for gonorrhea, and 0.9% lower for P&S syphilis.

Conclusions

During March–April 2020, national case reporting for STDs dramatically decreased compared with 2019. However, resurgence in reported gonorrhea and syphilis cases later in the year suggests STD reporting may have increased in 2020, underscoring the importance of continued STD prevention and care activities.
Pseudoaneurysm of the Maxillary Artery With Prebleeding Warning Signs After Le Fort I Osteotomy
Authors: Kashiyama Kazuya , Hirano Akiyoshi
Published: July 2021

Epistaxis after Le Fort I osteotomy is one of the relatively common postoperative complications. It can be controlled with conservative treatment, such as nasal packing, and will usually improve in a few days. However, if the epistaxis is repeated, the outcome can be life-threatening. A 22-year-old woman underwent Le Fort I osteotomy in order to correct her malocclusion. Postoperatively, pseudoaneurysm was formed in the descending palate artery, causing repeated epistaxis. Then, angiography and embolization were performed. Before the onset of epistaxis, there was discomfort around the nasal area. The patient remained asymptomatic during the 6-month follow-up. Some epistaxis after Le Fort I osteotomy is due to pseudoaneurysm formation in the maxillary artery. It is very rare. The epistaxis is delayed and recurrent. It can cause massive bleeding, and so, requires proper diagnosis and treatment. There may be signs of bleeding as in this case.
Consideration of Human Immunodeficiency Status in Patients Seeking Facial Feminization Surgery
Authors: Rodriguez Colon Ricardo , Chaya Bachar F. , Berman Zoe P. , Diep Gustave K. , Boczar Daniel , Trilles Jorge , Rodriguez Eduardo D.
Published: July 2021

Facial feminization surgery (FFS) with its proven safety and efficacy has become a mainstay surgical approach for those desiring gender-specific perceived feminine facial aesthetics. To date, specific characteristics of patients seeking FFS have been limited, with no studies investigating the role of the Human Immunodeficiency Virus (HIV) on FFS outcomes. The potential clinical implications of HIV and more specifically HIV-associated lipodystrophy, which can cause facial lipoatrophy, require further investigation. Given the importance of midface projection in feminizing the face, the authors aimed to investigate any associations HIV or Highly Active Antiretroviral Therapy may have on outcomes, including clinical consequences of facial lipoatrophy. The authors performed a retrospective chart review of all patients with a diagnosis of gender dysphoria referred to the senior author (EDR) for FFS between 2017 and 2020. Patients were grouped based on HIV status and demographics, history, and outcomes were assessed. Seventy-seven patients were included, with 28 patients (36.4%) having a diagnosis of HIV. A total of 25 (32.5%) and 23 (29.9%) patients underwent malar fat grafting and cheek implants, respectively. No significant difference was found between HIV-positive and HIV-negative patients when looking at the use of malar fat grafting, cheek implants, age, or complication rates. To the best of our knowledge, this study presents the largest cohort of HIV status assessment of FFS patients to date. Future studies, particularly on the long-term outcomes, are warranted, as is continued information sharing among providers and centers performing FFS, in order to continue advancing the literature and subsequently patient care.
Severity of Unilateral Coronal Synostosis Linked to Intracranial Volume
Authors: Kronig Sophia A.J. , Kronig Otto D.M. , Van Adrichem Léon N.A.
Published: July 2021

Severity of unilateral coronal synostosis (UCS) varies and can affect intracranial volume (ICV), and intracranial pressure. Correlation between ICV and severity according to Utrecht Cranial Shape Quantifier and presence of papilledema as sign of raised intracranial pressure is determined. The authors included patients with UCS (≤18 months). Intracranial volume was calculated on preoperative CT scans by manual segmentation (OsiriX [Fondation OsiriX, Geneva, Switzerland]). Calculated ICV was compared to Lichtenberg normative data for control patients. When present, papilledema was noted. Utrecht Cranial Shape Quantifier was used to quantify severity using the variables: asymmetry ratio of frontal peak and ratio of frontal peak gradient. Severity of UCS was correlated to ICV using Pearson correlation coefficient. Mean age at CT scan of patients with UCS was 7 months (1–18 months). Mean calculated ICV was 870.96 mL (617.31–1264.46 mL). All patients had ICV between ± 2 SD curves of Lichtenberg; 10 had an ICV between -1 SD and +1 SD. Majority of ICV in girls was at or larger than normative mean, in boys ICV was mostly lower than normative mean. Pearson correlation coefficient between severity of UCS and ICV was negligible (r = −0.28). Preoperative papilledema during fundoscopy was found in 4.5% (1/22; ICV 1003.88 mL; severe UCS). Therefore, severity of UCS does not correlate to ICV. Despite varying severity of UCS, ICV remains within normal ranges.
Cholesterol Granuloma of the Maxillary Sinus Misdiagnosed as Nasal Polyp or Mucocele: Four Cases
Authors: Kim Tae Hoon , Lim Eun Jung , Kim SungHee , Kim Aeri
Published: July 2021

Cholesterol granuloma is commonly found in the mastoid air cells but is rare in the paranasal sinuses. The most commonly affected sinuses are the frontal sinus, followed by the maxillary sinus. Cholesterol granuloma can be difficult to diagnose because clinical manifestations and radiologic findings are similar to those of other sinonasal disorders. The authors observed 4 cases of cholesterol granuloma that were preoperatively suspected to be nasal polyps or mucoceles. Here, the authors report on their clinical presentation and their successful treatment using the endoscopic sinus approach. These cases expand the current literature on cholesterol granuloma in the paranasal sinuses.
Endonasal Endoscopic and Hybrid Surgery Techniques for Blunt Trauma Fractures of the Skull Base With Cerebrospinal Fluid Leaks
Authors: Palma Díaz Marité , Martínez Anda Jaime Jesús , Guerrero Suarez Pablo David , de la Llata Segura Carolina , Galván Hernández Eduardo , Avendaño Pradel Rafael , Pineda Martínez Diego , Munguía López Jose Carlos , Díaz Espinoza Jorge Luis , Guerrero López David Antonio , Pane Pianese Carlo , Gómez Amador Juan Luis
Published: July 2021

Cerebrospinal fluid (CSF) leakage caused by skull base fracture represents high risks of bacterial meningitis, and a rate of mortality of 8.9%. Endoscopic endonasal repair of CSF leaks is quite safe and effective procedure with high rates of success. The aim of this study is to describe our technique for management of skull base CSF leaks secondary to craniofacial trauma based on the anatomic location of the leak. This is a retrospective case series of 17 patients with diagnosis of craniofacial trauma, surgically treated with sole endonasal endoscopic and combined endonasal/transcranial approaches with diagnosis of CSF leak secondary to skull base fractures. Seventeen patients met inclusion criteria for this study. Mean age was 46 years old. Most common etiology was motor vehicle. Early surgery was performed in 8 patients, and late surgery in 9 patients. The most common site of CSF leak was at ethmoid cells or at the fronto-ethmoid junction in 9 patients. Thirteen patients (76.4%) were treated only with endonasal endoscopic technique, and 4 (23.5%) with hybrid surgery, combining endonasal endoscopic and cranial bicoronal approaches with nasal and pericranial vascularized flaps, and nasal mucosal free flaps. Mean hospital stay was 23.7 days.

The mean follow-up time was 25.6 months. When surgical reconstruction is indicated for CSF leaks secondary to skull base fractures, endonasal endoscopic techniques should be part of the surgical management either as a sole procedure, or in combination with classical transcranial approaches with high rates of success and low morbidity.
Bruch Membrane Opening Minimum Rim Width in Neuromyelitis Optica
Authors: Bechet Lorane , Cabre Philippe , Merle Harold
Published: July 2021

Background:

Optical coherence tomography (OCT) analyzes the neurodegeneration in neuromyelitis optica (NMO) and multiple sclerosis (MS) and quantifies optical atrophy. The retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness are decreased, and this structural change is correlated with visual function of patients, including contrast vision and visual field deviation. The main objective of this study was to evaluate the Bruch membrane opening minimum rim width (BMO) of the patients with NMO.

Methods:

We studied the thickness of the BMO by OCT, in patients with NMO (n = 25; 34 eyes), MS (n = 50; 70 eyes), and a control group (n = 51; 100 eyes). The study evaluated the structure–function relationship with the correlation between OCT and visual function: Visual acuity, Pelli–Robson score, Sloan 2.5 and 1.25, color vision, standard automated perimetry (SAP), and frequency-doubling technology perimetry (FDT).

Results:

The average thickness of BMO was significantly reduced in NMO and MS with or without a history of optic neuritis (ON). Significant thinning of the average, nasal, and inferonasal BMO in the absence of ON in NMO was found compared with controls (P = 0.022, 0.006, and 0.026, respectively). BMO was strongly correlated with Pelli–Robson score (P < 0.001), Sloan 2.5 (P < 0.001), and mean deviation of SAP and FDT (P = 0.004). The sectorial study found a high correlation between the BMO and the corresponding sector of the visual field.

Conclusions:

The BMO thickness is decreased after ON in NMO and MS. This study showed an improved ability of BMO over RNFL and GCL to detect infraclinical impairment in patients with NMO without a history of optic neuropathy. Like the RNFL and GCL, BMO is well correlated with visual function, including contrast vision and visual field deviation.
Rv0802c is an acyltransferase that succinylates and acetylates Mycobacterium tuberculosis nucleoid-associated protein HU
Authors: Anand Chinmay , Santoshi Meghna , Singh Prakruti R , Nagaraja Valakunja
Published: July 2021

Among the nucleoid-associated proteins (NAPs), HU is the most conserved in eubacteria, engaged in overall chromosome organization and regulation of gene expression. Unlike other bacteria, HU from

Mycobacterium tuberculosis

(MtHU), has a long carboxyl terminal domain enriched in basic amino acids, resembling eukaryotic histone N-terminal tails. As with histones, MtHU undergoes post-translational modifications and we have previously identified interacting kinases, methyltransferases, an acetyltransferase and a deacetylase. Here we show that Rv0802c interacts and succinylates MtHU. Although categorized as a succinyltransferase, we show that this GNAT superfamily member can catalyse both succinylation and acetylation of MtHU with comparable kinetic parameters. Like acetylation of MtHU, succinylation of MtHU caused reduced interaction of the NAP with DNA, determined by electrophoretic mobility shift assay and surface plasmon resonance. However, in vivo expression of Rv0802c did not significantly alter the nucleoid architecture. Although such succinylation of NAPs is rare, these modifications of the archetypal NAP may provide avenues to the organism to compensate for the underrepresentation of NAPs in its genome to control the dynamics of nucleoid architecture and cellular functions.
Transmission event of SARS-CoV-2 Delta variant reveals multiple vaccine breakthrough infections
Authors: Farinholt Timothy , Doddapaneni Harsha , Qin Xiang , Menon Vipin , Meng Qingchang , Metcalf Ginger , Chao Hsu , Gingras Marie-Claude , Farinholt Paige , Agrawal Charu , Muzny Donna M. , Piedra Pedro A. , Gibbs Richard A. , Petrosino Joseph
Published: July 2021

Importance

Vaccine breakthrough by an emergent SARS-CoV-2 variant poses a great risk to global public health.

Objective

To determine the SARS-CoV-2 variant responsible for 6 cases of vaccine breakthrough.

Design

Nasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 by qPCR for Wuhan-Hu1 and Alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant.

Setting

Transmission event occurred at events surrounding a wedding outside of Houston, TX. Two patients from India, likely transmitted the Delta variant to other guests.

Participants

Following a positive SARS-CoV-2 qPCR test at a third-party site, six fully vaccinated patients were investigated. Three males and three females ranged from 53 to 69 years old. One patient suffered from diabetes while three others were classified as overweight. No significant other comorbidities were identified. None of the patients had a history of failed vaccination.

Key Points

Question

Which SARS-CoV-2 variant is responsible for 6 cases of vaccine breakthrough, one interventional monoclonal antibody treatment, and one death?

Findings

Viral sequencing revealed 6 vaccinated patients were infected with the Delta SARS-CoV-2 variant. With no histories of vaccine breakthrough, this suggests Delta variant may possess immune evasion in patients that received the Pfizer BNT162b2, Moderna mRNA-1273, and Covaxin BBV152.

Meaning

Delta variant may pose the highest risk out of any currently circulating SARS-CoV-2 variants, with increased transmissibility over Alpha variant and possible vaccine breakthrough.
A classification model to predict specialty drug use
Authors: Ni Xianglian , Fairless Andrew , McCammon Jasmine M. , Rahmanian Farbod , Lavoie Heather
Published: July 2021

Objective

Predicting who is likely to become utilizers of specialty drugs allows care managers to have an early intervention and payers to have financial preparation for the upcoming spending. Our administrative claims-based predictive model is to predict the members who might use specialty drugs.

Materials and Methods

A national database* and a commercial health plan claim data were used to select a total 6.5 million people who were not taking any specialty drugs before the Target Prediction Window. There were about 136,700 members who were older than 65 in the study. We extracted 81 features from past history of medical, pharmacy claims, and demographic data to predict the specialty drug use in the following year. Members having at least three-month continuous enrollment either under medical or pharmacy plan in the previous year immediately before the start of the target prediction window and with no specialty drug taking history were eligible for this study. We trained and tuned on 75% of the data using an extreme gradient boosting binary classifier. We used the remaining 25% of the data to predict the outcomes and evaluate the performance. We also recorded the performance for the age group older than 65 years old.

Results

There were 3% of members who used specialty drugs in the cohort under the current study. The important features for prediction included age, monthly pharmacy payment, monthly medical payment, diseases, procedure, or drug-related codes. On the test data with members of all ages, model performance for the area under the receiving operator characteristics curve (AUROC) was 78.6%. For the test set on members older than 65 (prevalence rate 3.6%), we had an AUROC of 79.3%.

Discussion

There is no similar machine learning model in the field to predict specialty drug use. Our model provides an unparalleled opportunity to allow early intervention for people who might develop diseases that require specialty drug use. It is also important for health plans and providers to know their covered population who might use specialty drugs and predict the increased cost in the next year.

Conclusion

A predictive model of specialty drug use can be helpful for both payers and providers to prepare for a spending spike or have an early intervention. In return, this helps to improve patients’ overall satisfaction.
Impact of regional heterogeneity on the severity of COVID-19
Authors: Tsuzuki Shinya , Asai Yusuke , Matsunaga Nobuaki , Ishioka Haruhiko , Akiyama Takayuki , Ohmagari Norio
Published: July 2021

Background

We aimed to assess the impact of regional heterogeneity on the severity of COVID-19 in Japan.

Methods

We included 27,865 cases registered between January 2020 and February 2021 in the COVID-19 Registry of Japan to examine the relationship between the National Early Warning Score (NEWS) of COVID-19 patients on the day of admission and the prefecture where the patients live. A hierarchical Bayesian model was used to examine the random effect of each prefecture in addition to the patients’ backgrounds. In addition, we compared the results of two models; one model included the number of beds secured for COVID-19 patients in each prefecture as one of the fixed effects, and the other model did not.

Results

The results indicated that the prefecture had a substantial impact on the severity of COVID-19 on admission. Even when considering the effect of the number of beds separately, the heterogeneity caused by the random effect of each prefecture affected the severity of the case on admission.

Conclusions

Our analysis revealed a possible association between regional heterogeneity and increased/decreased risk of severe COVID-19 infection on admission. This heterogeneity was derived not only from the number of beds secured in each prefecture but also from other factors.
COVID-19 vaccines dampen genomic diversity of SARS-CoV-2: Unvaccinated patients exhibit more antigenic mutational variance
Authors: Niesen Michiel J.M. , Anand Praveen , Silvert Eli , Suratekar Rohit , Pawlowski Colin , Ghosh Pritha , Lenehan Patrick , Hughes Travis , Zemmour David , O’Horo John C. , Yao Joseph D. , Pritt Bobbi S. , Norgan Andrew , Hurt Ryan T. , Badley Andrew D. , Venkatakrishnan AJ , Soundararajan Venky
Published: July 2021

Variants of SARS-CoV-2 are evolving under a combination of immune selective pressure in infected hosts and natural genetic drift, raising a global alarm regarding the durability of COVID-19 vaccines. Here, we conducted longitudinal analysis over 1.8 million SARS-CoV-2 genomes from 183 countries or territories to capture vaccination-associated viral evolutionary patterns. To augment this macroscale analysis, we performed viral genome sequencing in 23 vaccine breakthrough COVID-19 patients and 30 unvaccinated COVID-19 patients for whom we also conducted machine-augmented curation of the electronic health records (EHRs). Strikingly, we find the diversity of the SARS-CoV-2 lineages is declining at the country-level with increased rate of mass vaccination (n = 25 countries, mean correlation coefficient = −0.72, S.D. = 0.20). Given that the COVID-19 vaccines leverage B-cell and T-cell epitopes, analysis of mutation rates shows neutralizing B-cell epitopes to be particularly more mutated than comparable amino acid clusters (4.3-fold, p < 0.001). Prospective validation of these macroscale evolutionary patterns using clinically annotated SARS-CoV-2 whole genome sequences confirms that vaccine breakthrough patients indeed harbor viruses with significantly lower diversity in known B cell epitopes compared to unvaccinated COVID-19 patients (2.3-fold, 95% C.I. 1.4-3.7). Incidentally, in these study cohorts, vaccinated breakthrough patients also displayed fewer COVID-associated complications and pre-existing conditions relative to unvaccinated COVID-19 patients. This study presents the first known evidence that COVID-19 vaccines are fundamentally restricting the evolutionary and antigenic escape pathways accessible to SARS-CoV-2. The societal benefit of mass vaccination may consequently go far beyond the widely reported mitigation of SARS-CoV-2 infection risk and amelioration of community transmission, to include stemming of rampant viral evolution.
Megafaunal extinctions—not climate change—seem to explain Holocene genetic diversity declines inNumeniusshorebirds
Authors: Tan Hui Zhen , Jansen Justin J.F.J. , Allport Gary A. , Garg Kritika M. , Chattopadhyay Balaji , Irestedt Martin , Pang Sean E.H. , Chilton Glen , Gwee Chyi Yin , Rheindt Frank E.
Published: July 2021

Understanding the relative contributions of historical and anthropogenic factors to declines in genetic diversity is important for informing conservation action. Using genome-wide DNA of fresh and historic specimens, including that of two species widely thought to be extinct, we investigated fluctuations in genetic diversity and present the first complete phylogenomic tree for all nine species of the threatened shorebird genusNumenius, known as whimbrels and curlews. Most species faced sharp declines in effective population size, a proxy for genetic diversity, soon after the Last Glacial Maximum (around 20,000 years ago). These declines occurred prior to the Anthropocene and in spite of an increase in breeding area predicted by environmental niche modelling, suggesting that they were not caused by climatic or recent anthropogenic factors. Crucially, these genetic diversity declines coincide with mass extinctions of mammalian megafauna in the Northern Hemisphere. Demise of ecosystem-engineering megafauna which maintained open habitats would have been detrimental for grassland and tundra-breedingNumeniusshorebirds. Our work suggests that the impact of historical factors such as megafaunal extinction may have had wider repercussions on present-day population dynamics of open habitat biota than previously appreciated.
Efficacy and safety of cyclosporine in the management of coronavirus disease 2019: A protocol for systematic review and meta-analysis
Authors: Abdallah Ibtihal , Aabdien Mohamed , Danjuma Mohammed
Published: July 2021

Introduction

Cyclosporine may improve the clinical course and outcomes of Coronavirus disease 2019 (COVID-19) due to its antiviral and anti-cytokine effects as shown in vitro. A few ongoing trials are exploring the benefit of adding it to the standard of care (SOC) of COVID-19 patients.

Objectives

The primary objective is to evaluate the severity of COVID-19, determined by oxygen saturation, intensive care unit (ICU) admission, or the World Health Organization COVID-19 clinical severity scale in patients treated with oral or intravenous cyclosporine added to SOC compared SOC alone or placebo. Secondary objectives include mortality, length of hospitalization, length of ICU stay, and laboratory measurements as well as the safety outcomes of cyclosporine.

Methodology

A systematic review and meta-analysis of randomized clinical trials and observational studies that compared cyclosporine to placebo or SOC in COVID-19 patients will be conducted. PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, Google Scholar, and ClinicalTrials.gov will be explored for studies that satisfy pre-specified inclusion criteria. Quality assessment of all included studies will be performed. Meta-analyses will be done utilizing random effect models to estimate the effect of cyclosporine on the severity of COVID-19. Heterogeneity will be assessed utilizing Q statistics. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed.

Results

The result of this synthesis will inform potential changes in the management of COVID-19 patients, especially regarding the role of calcineurin inhibitors. Additionally, it will serve as hypothesis generating for potential future prospective studies.
Promoter architecture links gene duplication with transcriptional divergence
Authors: Fraimovitch Evgeny , Hagai Tzachi
Published: July 2021

Gene duplication is thought to be a central mechanism in evolution to gain new functions, but gene families vary greatly in their rates of gene duplication and long-term retention. Here, we discover a link between the promoter architecture of vertebrate genes and their rate of duplication: Genes that harbor CpG Islands in their promoters (CGI genes) – nearly 60% of our genes – have rarely duplicated in recent evolutionary times, and most CGI gene duplication events predate the emergence of CGI as a major regulatory element of vertebrate genes. In contrast, CGI-less genes predominate duplications that have occurred since the divergence of vertebrates. Furthermore, CGI-less paralogs are transcriptionally more divergent than CGI paralogs, even when comparing CGI and CGI-less paralogs that have duplicated at similar evolutionary times – suggesting greater capacity of CGI-less promoters to enable divergence in expression. This higher divergence between CGI-less paralogs is also reflected in lower similarity of transcription factors that bind to the promoters of CGI-less paralog pairs in comparison with CGI paralogs. Finally, CGI-less paralogs have a greater tendency to sub- and neo-functionalize, and they transcriptionally diversify faster following duplication. Our results highlight the links between promoter architecture, gene expression plasticity and their impact on gene expansion, and unravel an unappreciated role of CGI elements in shaping genome evolution.

Significance statement

Gene duplication generates extra gene copies, providing material for evolution of new functions. However, many duplicated genes are eliminated due to functional and regulatory constraints. The evolutionary processes that govern the elimination and persistence of duplicated genes are not well understood. Here, we focus on CpG Islands (CGIs) – important elements that occur in the majority of gene promoters. We show that genes with CGIs in their promoters have duplicated almost exclusively in ancient times, and nearly all recent duplications involve CGI-less genes. Furthermore, duplicated CGI-less genes diverge more in expression and display more distinctive transcription and cis-regulation compared to duplicated CGI-genes. Our results demonstrate how promoter structure influences transcriptional evolvability and, in turn, the retention of new genes.