bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical impacts of cerebral microbleeds in patients with established coronary artery disease
Authors: Uemura Yusuke , Shibata Rei , Imai Ryo , Ishikawa Shinji , Takemoto Kenji , Watarai Masato , Murohara Toyoaki
Published: October 2020

Objective:

Although cerebral microbleeds predict the occurrence and recurrence of cerebrovascular events in stroke patients, their clinical impacts are unclear in coronary artery disease patients. We aimed to investigate the clinical effect of the presence of cerebral microbleeds in patients with coronary artery disease receiving antithrombotic treatment.

Methods:

We included 447 coronary artery disease patients taking at least one thrombotic agent who underwent brain MRI. The association between the presence of cerebral microbleeds and incidence of major adverse cardiac and cerebrovascular events was investigated.

Results:

Cerebral microbleeds were identified in 18.7% of patients. Median follow-up duration was 1055 (interquartile range, 781–1172) days. Kaplan–Meier survival analysis demonstrated that patients with cerebral microbleeds had a higher incidence of major adverse cardiac and cerebrovascular events than those without (log-rank P = 0.003). A multivariate Cox regression analysis revealed that the presence of cerebral microbleeds was independently correlated with the occurrence of major adverse cardiac and cerebrovascular events after adjusting for other classical risk factors of coronary artery disease (hazard ratio 1.965, 95% confidence interval 1.086–3.556, P = 0.026). Hypertension was associated with the presence of cerebral microbleeds. The cut-off values to maximize the predictive power of SBP and DBP were 132 and 74 mmHg, respectively (P < 0.001).

Conclusion:

The presence of cerebral microbleeds predicts major adverse cardiac and cerebrovascular events in coronary artery disease patients receiving antithrombotic treatment. Evaluation of cerebral microbleeds and hypertension treatment complying with the established guidelines may be beneficial in the management of coronary artery disease patients.
Additive effect of hypertension on left ventricular structure and function in patients with asymptomatic type 2 diabetes mellitus
Authors: Jiang Li , Ren Yan , Yu Hong , Guo Ying-kun , Liu Xi , Deng Ming-yan , Xie Lin-jun , Gao Yue , Shen Meng-ting , Han Pei-lun , Yang Zhi-gang
Published: October 2020

Objective:

We aimed to comprehensively determine the effects of hypertension on left ventricular (LV) structure, microcirculation, tissue characteristics, and deformation in type 2 diabetes mellitus (T2DM) using multiparametric cardiac magnetic resonance (CMR) imaging.

Methods:

We prospectively enrolled 138 asymptomatic patients with T2DM (80 normotensive and 58 hypertensive individuals) and 42 normal glucose-tolerant and normotensive controls and performed multiparametric CMR examination to assess cardiac geometry, microvascular perfusion, extracellular volume (ECV), and strain. Univariable and multivariable linear analysis was performed to analyze the effect of hypertension on LV deformation in patients with T2DM.

Results:

Compared with controls, patients with T2DM exhibited decreased strain, decreased microvascular perfusion, increased LV remodeling index, and increased ECV. Hypertension lead to greater deterioration of LV strain (peak strain-radial, P = 0.002; peak strain-longitudinal, P = 0.006) and LV remodeling index (P = 0.005) in patients with T2DM after adjustment for covariates; however, it did not affect microvascular perfusion (perfusion index, P = 0.469) and ECV (P = 0.375). In multivariable analysis, hypertension and diabetes were independent predictors of reduced LV strain, whereas hypertension is associated with greater impairment of diastolic function (P = 0.009) but not systolic function (P = 0.125) in the context of diabetes, independent of clinical factors and myocardial disorder.

Conclusion:

Hypertension in the context of diabetes is significantly associated with LV diastolic function and concentric remodeling; however, it has little effect on systolic function, myocardial microcirculation, or fibrosis independent of covariates, which provide clinical evidence for understanding the pathogenesis of comorbidities and explaining the development of distinct heart failure phenotypes.
Knowledge, perception and practice of health professionals regarding blood pressure measurement methods: a scoping review
Authors: Todkar Shweta , Padwal Raj , Michaud André , Cloutier Lyne
Published: October 2020

Objective:

Guideline-concordant performance of accurate blood pressure measurement (BPM), whether the modality is home (HBPM), ambulatory (ABPM), automated (AOBP) or office (OBPM), is dependent on proper technique. Knowledge, perception and practice of health professionals for BPM is crucial and has been partly studied, but a thorough review has never been reported. A scoping review of global studies was conducted to synthesize published data on this topic.

Methods:

An Arksey and O‘Malley methodological framework was used. Keywords were identified and extraction was completed to April 2019 using CINAHL and MEDLINE. Studies were classified as positive for knowledge, perception and practice if the majority (>50%) of reported responses were favourable, and negative otherwise. If specific results were not reported, the author's conclusions were used to classified.

Results:

Seventy-two studies were identified: 25 HBPM, 14 ABPM, two AOBP, 40 OBPM. For knowledge, the percentage of negative studies were higher for HBPM (40%) and OBPM (68%) and lower for ABPM (14%) regarding BPM techniques. For perception, the number of negative studies were lower for HBPM (20%) and ABPM (7%) regarding usefulness of BPM methods in hypertension management. For practice, the number of negative studies were higher for HBPM (48%), ABPM (71%), OBPM (73%) and AOBP (50%) regarding implementation of hypertension guidelines.

Conclusion:

The results of this scoping review demonstrate adequate perception of BPM but suboptimal knowledge and practice. Education is still needed to improve knowledge and practice. Future efforts should focus on improving what we know and what we do when measuring BP.
Angiotensin II Administration in Patients With COVID-19 Shock
Authors: Ofosu-Barko Kwadwo , Liu Yi , Alkhatib Tamimi Faisal , Al Husami Wael , Ganatra Sarju , Resnic Frederic , Shah Sachin P.
Published: October 2020

Purpose:

To understand the hemodynamic effect of angiotensin II as a vasopressor in patients with shock secondary to COVID-19 infection.

Methods:

A retrospective analysis was performed on all patients at a single center with COVID-19 infection and shock who were treated with angiotensin II. The hemodynamic response to angiotensin II was estimated by recording the mean arterial pressure, norepinephrine equivalent dose (NED) and urine output.

Results:

Ten patients with COVID-19 related shock were treated with angiotensin II. Over the initial 6 hours, the average the NED decreased by 30.4% (from 64.6 to 44 µg/min) without a significant change in the mean arterial pressure (0.7% decrease). Six patients experienced at least a 25% reduction in NED by 6 hours, and 2 experienced at least a 50% reduction.

Conclusions:

On average, the hemodynamic response to angiotensin II in COVID-19 related shock was favorable. Two patients had a marked rapid improvement. Given the relationship of SARS-CoV-2 with the renin-angiotensin-aldosterone system, further evaluation of angiotensin II for the treatment of COVID-19 related shock is warranted.
ACUTE EXUDATIVE POLYMORPHOUS VITELLIFORM MACULOPATHY ASSOCIATED WITH PRIMARY EPSTEIN–BARR VIRUS INFECTION
Authors: Lentzsch Anna M. , Dooling Vivienne , Wegner Ina , Di Cristanziano Veronica , Sadda Srinivas R. , Freund K. Bailey , Liakopoulos Sandra
Published: October 2020

Purpose:

To report a case of acute exudative polymorphous vitelliform maculopathy associated with primary Epstein–Barr virus infection.

Methods:

Multimodal imaging including color fundus photography, spectral-domain optical coherence tomography, blue-light fundus autofluorescence, fluorescein angiography, and indocyanine green angiography.

Results:

A 24-year-old otherwise healthy woman presented with an acute bilateral visual disturbance associated with cervical lymphadenopathy. Spectral-domain optical coherence tomography showed bilateral foveal serous retinal detachment (SRD) with thickening of the ellipsoid zone throughout the posterior pole corresponding to hyperautofluorescence on fundus autofluorescence, faint diffuse hyperfluorescence on fluorescein angiography without leakage, and mild late hyperfluorescence on indocyanine green angiography. Systemic workup revealed an acute Epstein–Barr virus infection. Within several weeks, multifocal SRDs developed in the macula and paramacula. The SRDs then became increasingly hyperautofluorescent with spectral-domain optical coherence tomography showing subretinal hyperreflective material. This vitelliform material then slowly resolved while the thickness of the surrounding ellipsoid zone normalized. The fluorescein angiography and indocyanine green angiography appeared normal at Month 8. Visual acuity was 20/20 in both eyes at all times. No treatment was initiated.

Conclusion:

Acute exudative polymorphous vitelliform maculopathy may be associated with an acute Epstein–Barr virus infection. Acutely, multimodal imaging revealed findings consistent with RPE dysfunction and reduced photopigment density. Subsequent accumulation of vitelliform material gradually resolved over an 8-month follow-up.
The Effect of Continuity of Care and Provider Volume on Late Presentation of Glaucoma: A Nested Case-Control Study
Authors: Lu Yu-Chin , Pu Christy , Hou Chiun-Ho
Published: October 2020

Précis:

Glaucoma late presentation is not associated with continuity of care. However, it is associated with frequency of physician visits and physician volume.

Purpose:

Late presentation of glaucoma often causes blindness. Continuity of care (COC) has been the central element in primary care. We investigated whether COC, frequency of visits to ophthalmology departments, and provider experience can reduce late presentation.

Methods:

We conducted a nested case-control study on patients aged above 20 years with confirmed glaucoma diagnosis. Claims data from the Taiwan’s National Health Insurance Research Database during 2007 to 2016 were linked to the Disability Registry (n=231,330) to identify patients with glaucoma late presentation. Physician experience was proxied using service volume. Logistic regression was estimated using matched samples.

Results:

A total of 111 patients satisfied the definition of late presentation. Patients with a low frequency of visits had lower odds of being in the late-presentation group (odds ratio=0.39, 95% confidence interval=0.18-0.81). COC index did not statistically affect late presentation. Old age and lower socioeconomic status were significantly associated with higher odds of late presentation. A statistically significant negative association was observed between physician volume and odds of late presentation.

Conclusion:

Late presentation for glaucoma can be reduced by promoting more frequent physician visits. However, enhancement from the provider-side, such as spreading awareness and offering routine tests, also play essential role in reducing late presentation.
Comparison of Gonioscopy-assisted Transluminal Trabeculotomy Versus Trabeculectomy With Mitomycin C in Patients With Open-angle Glaucoma
Authors: Fontana Luigi , De Maria Michele , Caristia Alice , Mastrofilippo Valentina , Braglia Luca , Iannetta Danilo , Scarale Giuliano Pio
Published: October 2020

Précis:

Trabeculectomy (TRAB) lowers the intraocular pressure (IOP) more than gonioscopy-assisted transluminal trabeculotomy (GATT) at 18 months, with a reduction in IOP of 30% or more and a significant reduction in the number of glaucoma medications compared with baseline.

Purpose:

To compare the IOP-lowering efficacy of GATT with mitomycin-C augmented TRAB in patients with uncontrolled open-angle glaucoma.

Methods:

Single-center, retrospective, comparative cohort study. One hundred ten consecutive patients (110 eyes) underwent GATT (n=61) or TRAB (n=49). The primary outcome measure was IOP reduction, defined as a percentage decrease ≥30% and absolute IOP≤18 mm Hg at 18 months with (qualified) or without (complete) medications. Secondary outcomes were visual field change, number of glaucoma medications, complications, and reintervention.

Results:

The mean±SD baseline IOP was 30.04±7.5 and 27.59±4.70 (P=0.072) with the mean number of medications of 3.08±0.73 and 2.92±0.91 (P=0.310) in TRAB and GATT, respectively. At 18 months, the mean±SD IOP was 15.26±3.47 mm Hg and 12.48±4.58 mm Hg after GATT and TRAB, respectively (P=0.002). The percentage of IOP lowering from baseline was 56.05±17.72 after TRAB and 42.04±15.56 after GATT (P<0.001). Percentages of complete and qualified success were 59% and 27% after TRAB and 46% and 31% after GATT (P=0.353). No change in visual field loss was observed in both groups. The mean reduction in medications was 2.3±1.4 and 2.1±1.5 in TRAB and GATT, respectively (P=0.493). The most frequent complication after TRAB was hypotony and after GATT hyphema. Reintervention occurred in 8.2% of cases after TRAB and in 14.8% after GATT (P=0.341).

Conclusions:

IOP lowering was greater after TRAB than after GATT at 18 months with a significant reduction in the number of medications after both procedures. Complications and reintervention occurred equally in both groups but differed in type.
The Direct and Indirect Impact of SARS-CoV-2 Infections on Neonates
Authors: Saha Senjuti , Ahmed ASM Nawshad Uddin , Sarkar Probir Kumar , Bipul Mohammed Rizwanul Ahsan , Ghosh Kinkar , Rahman Sheikh Wasik , Rahman Hafizur , Hooda Yogesh , Ahsan Nafiz , Malaker Roly , Sajib Mohammad Saiful Islam , Islam Mohammad Shahidul , Anik Ataul Mustufa , Saha Sudipta , Kanon Naito , Islam Maksuda , Hamer Davidson H. , Amin Ruhul , Shahidullah Mohammod , Saha Samir K.
Published: October 2020

Background:

The impact of SARS-CoV-2 on neonates remains largely unknown in low- and middle-income countries (LMICs). We provide an epidemiologic and clinical report of SARS-CoV-2 infections in neonates hospitalized in Bangladesh.

Methods:

Outborn neonates admitted to Dhaka Shishu Hospital, a tertiary-care referral hospital, between 29 March and 1 July were screened for SARS-CoV-2. We reviewed clinical data, including chest radiograph and laboratory reports, and conducted SARS-CoV-2 genome sequencing. Patients were followed-up for 27–75 days. A subset of caregivers was also tested.

Results:

Of 83 neonates tested, 26 were positive (median age 8 days). Most neonates were admitted with diagnosis unrelated to SARS-CoV-2: 11 presented with serious non-communicable diseases, 7 with early-onset sepsis, 5 with late-onset sepsis and 2 with pneumonia. In 3 of 5 chest radiograph, infiltrates and ground-glass or patchy opacities were noted. Two neonates developed metabolic acidosis, one developed disseminated intravascular coagulation. Most SARS-CoV-2 positive neonates were referred to government-designated COVID-19 hospitals, leading to gaps in treatment. Twenty-three neonates could be followed-up: 12 were healthy, 8 died and 3 were still seeking medical care. Of 9 caregivers tested, 8 were positive.

Conclusions:

SARS-CoV-2 may have serious adverse effects on children born in LMICs. The virus likely contributed directly to two deaths, but the remaining 6 neonates who died had serious comorbidities. Positive SARS-CoV-2 test results led to gaps in immediate clinical care for other morbidities, which likely contributed to adverse outcomes. This case series emphasizes the need to understand COVID-19 in neonates in LMICs and its indirect impacts.
Intensive Insulin Therapy (Basal-Bolus)
Authors: Chico Ana , Corcoy Rosa
Published: October 2020

Background:

Intensive insulin therapy (IIT) aims at achieving near-normal glycemic control and usually uses a basal-bolus (BB) schema to mimic physiologic insulin secretion.

Areas of Uncertainty:

The treatment burden of IIT should be outweighed by improved glycemic control and reduction of chronic complications, but reviews summarizing the effects of IIT in subjects with T1DM and T2DM in glycated hemoglobin, hypoglycemia, insulin doses, and weight are limited.

Data Sources:

We performed a PubMed search to identify relevant randomized control trials (RCTs) comparing IIT and conventional insulin treatment in T1DM and T2DM subjects and addressing glycated hemoglobin, hypoglycemia, insulin requirements, and weight.

Therapeutic Advances:

We have identified 11 RCTs in T1DM subjects, published years ago and very heterogenous in design. Throughout the studies there was a consistent superiority of IIT in glycated hemoglobin reduction, a higher rate of severe hypoglycemia and more weight gain in the IIT group without a clear effect on insulin doses. We have identified 2 RCTs in T2DM subjects, only one of them using a definite BB schema in the IIT group. IIT induced more hypoglycemia and better HbA1c, but not more weight gain.

Conclusions:

IIT is the best option for treatment of subjects with T1DM in HbA1c reduction with a cost in the rate of hypoglycemia and weight gain. In subjects with T2DM, IIT also yields improvement in HbA1c versus conventional treatment, also at the cost of more hypoglycemic episodes, but not of higher weight gain. RCT treatment arms did not only differ in the insulin schema, but also in treatment goals, therapeutic education, and frequency of clinical visits among other characteristics. However, most evidence was gained using a BB insulin schema in the intensive arm and it is likely that the insulin schema had a relevant contribution in the results.
The Use of Umbilical Cord-derived Mesenchymal Stem Cells Seeded Fibrin Matrix in the Treatment of Stage IV Acute Graft-Versus-Host Disease Skin Lesions in Pediatric Hematopoietic Stem Cell Transplant Patients
Authors: Akçay Arzu , Atay Didem , Yilanci Muhammet , Kongur Merve , Eyüboğlu Fatma , Öztürk Gülyüz , Ovali Ercüment
Published: October 2020

Mesenchymal stem cells (MSCs) have been used systemically or locally in many chronic and nonhealing skin lesions in recent years. In this study, umbilical cord-derived MSCs (UC-MSCs)-seeded fibrin matrix was used as a wound dressing in pediatric patients with stage 4 acute graft-versus-host disease (aGVHD)-induced desquamated skin lesions. This is the first study in which the UC-MSCs-seeded fibrin matrix was used as a wound dressing in aGVHD. A total of 14 times the MSCs-seeded fibrin matrix were applied to 9 patients as a wound dressing. On the seventh day, epithelialization and clinical response were evaluated. According to the size of the skin defect min: 1, max: 6 pieces were applied at a time. After 48 to 72 hours, it was observed that all of the MSCs-seeded fibrin matrixes adhered to the skin and the crustation started in 6 (43%) applications, whereas liquefaction was detected under all of them in 7 (50%) applications. Complete response was obtained in 6 applications (43%), partial response in 1 (7%), and no response in 7 applications (50%). This study showed that the MSCs-seeded fibrin matrix can be used effectively and safely in the matrix in the local treatment of aGVHD-induced skin wounds in pediatric patients.
Sedation With Midazolam After Cardiac Surgery in Children With and Without Down Syndrome: A Pharmacokinetic-Pharmacodynamic Study
Authors: Valkenburg Abraham J. , Goulooze Sebastiaan C. , Breatnach Cormac V. , Mathôt Ron A. A. , Tibboel Dick , van Dijk Monique , Knibbe Catherijne A. J. , Peeters Mariska Y. M.
Published: October 2020

Objectives:

To compare the pharmacokinetics and pharmacodynamics of IV midazolam after cardiac surgery between children with and without Down syndrome.

Design:

Prospective, single-center observational trial.

Setting:

PICU in a university-affiliated pediatric teaching hospital.

Patients:

Twenty-one children with Down syndrome and 17 without, 3–36 months, scheduled for cardiac surgery with cardiopulmonary bypass.

Interventions:

Postoperatively, nurses regularly assessed the children’s pain and discomfort with the validated COMFORT-Behavioral scale and Numeric Rating Scale for pain. A loading dose of morphine (100 µg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 µg/kg/hr. Midazolam was started if COMFORT-Behavioral scale score of greater than 16 and Numeric Rating Scale score of less than 4 (suggestive of undersedation). Plasma midazolam and metabolite concentrations were measured for population pharmacokinetic- and pharmacodynamic analysis using nonlinear mixed effects modeling (NONMEM) (Version VI; GloboMax LLC, Hanover, MD) software.

Measurements and Main Results:

Twenty-six children (72%) required midazolam postoperatively (15 with Down syndrome and 11 without; p = 1.00). Neither the cumulative midazolam dose (p = 0.61) nor the time elapsed before additional sedation was initiated (p = 0.71), statistically significantly differed between children with and without Down syndrome. Population pharmacokinetic and pharmacodynamics analysis revealed no statistically significant differences between the children with and without Down syndrome. Bodyweight was a significant covariate for the clearance of 1-OH-midazolam to 1-OH-glucuronide (p = 0.003). Pharmacodynamic analysis revealed a marginal effect of the midazolam concentration on the COMFORT-Behavioral score.

Conclusions:

The majority of children with and without Down syndrome required additional sedation after cardiac surgery. This pharmacokinetic and pharmacodynamic analysis does not provide evidence for different dosing of midazolam in children with Down syndrome after cardiac surgery.
Gamma Probe–Guided Surgery in Postoperative Recurrent Osteoid Osteoma of Left Index Finger
Authors: Subramanyam Padma , Palaniswamy Shanmuga Sundaram
Published: October 2020

Osteoid osteomas are painful benign osteoblastic tumors that usually affect the metaphysis or diaphysis of long bones. Hands are rarely involved. Identification of recurrent lesion by anatomical imaging modalities is a challenge especially in postoperative setting. Diagnosis of osteoid osteoma is based on typical clinical signs, radiographs, bone scintigraphy, thin-slice computed tomography, or magnetic resonance imaging. Atypical locations, multicentricity of nidus, or incomplete excision of the nidus result in a high rate of recurrence. Here we present a case of recurrent osteoid osteoma at an unusual site in left index finger and was operated under gamma probe guidance.
99mTc-Mebrofenin SPECT/CT in Hepatic Infarction
Authors: Mattay Govind S. , O’Leary Cathal , Dubroff Jacob G. , R. Pantel Austin
Published: October 2020

A 68-year-old man with hereditary hypercoagulability was referred to nuclear medicine for elevated aminotransferases after a recent living-donor liver transplant. A hepatic infarction was suspected. A 99mTc-mebrofenin SPECT/CT was performed and showed decreased radiotracer uptake in a wedge-shaped distribution in the anterior liver suggestive of a hepatic infarction. Subsequently, an enhanced MRI corroborated the diagnosis. Oral anticoagulation therapy was then initiated, and aminotransferases soon normalized.
Gallbladder Perforation Into the Peritoneal Cavity
Authors: Wang Bing F. , Yi Steven , Keshavamurthy Jayanth , Williams Hadyn , Pucar Darko
Published: October 2020

Gallbladder perforation is an uncommon but morbid complication of acute cholecystitis with mural ischemia and necrosis. The most common site of perforation is the fundus because of limited blood supply in this region. The Niemeier classification proposed in 1934 remains the criterion standard in grading gallbladder perforation; type 1 is acute with free perforation into the peritoneal cavity, type 2 is subacute with pericholecystic abscess, and type 3 is chronic with cholecystoenteric fistula. We report a challenging case of type 1 gallbladder perforation due to acute acalculous cholecystitis.
Relapsing Mitral Involvement in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Briane Aurélie , Jamet Bastien , Mugniot Antoine , Néel Antoine , Agard Christian
Published: October 2020

Cardiac valvular involvement in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is very rare. We report the case of a patient seen in 2019, followed for ANCA-associated vasculitis for 15 years, who had a first relapse with cardiac valvular involvement in 2012, and who underwent a second histologically proven vasculitis relapse involving mitral periprosthetic endocardium. PET/CT imaging showed an intense and focal FDG activity of paramitral bioprosthesis leak site. Mitral bioprosthesis was replaced, and the patient improved with steroids and rituximab. Through this exceptional case, we suggest that FDG PET/CT could be of interest in the follow-up of ANCA-associated vasculitis with cardiac valvular involvement.
Normothermic Ex Situ Liver Perfusion Enhances Mitochondrial Function of DCD Grafts as Evidenced by High-throughput Metabolomics
Authors: Bhat Mamatha , Linares-Cervantes Ivan , Pasini Elisa , Patel Preya , Goto Toru , Noguchi Yuki , Mazilescu Laura , Urbanellis Peter , Selzner Markus , Selzner Nazia
Published: October 2020

Background.

Normothermic ex situ liver perfusion (NEsLP) reduces reperfusion injury of donation after circulatory death (DCD) grafts and optimizes graft function. The goal of our study was to elucidate how NEsLP impacts global metabolism in DCD grafts using high-throughput metabolomics.

Methods.

Pig livers were preserved by 2 different techniques: static cold storage and NEsLP. Grafts obtained from heart-beating donors were compared with donation after circulatory death (DCD) grafts with either 30 minutes (DCD30) or 60 minutes (DCD60) ischemia time. Liver tissues were collected at the end of preservation period (T0) with either cold storage or NEsLP (n = 5 per group). Grafts were transplanted into recipient pigs and a second liver biopsy was collected 2 hours following liver transplantation (T1). Snap-frozen tissue was processed and analyzed by Sciex 6600 Q-TOF high-resolution mass spectrometer. Data analysis was performed using MetaboAnalyst 4.0 software.

Results.

Prolonged ischemia resulted in 38 out of 81 metabolites being differentially abundant over time. Mitochondrial metabolism was significantly affected, with disruption in oxidative phosphorylation capacity i.e the Warburg effect (P = 3.62E-03) and urea cycle (P = 7.95E-0.4). NEsLP resulted in improved mitochondrial metabolism and glycolysis (4.20E-02) oxidation of branched chain fatty acids (P = 4.07E-02).

Conclusions.

This unbiased, high-throughput metabolomics study reveals that mitochondrial function is globally rescued with NEsLP, associated with improvement in DCD graft function. NEsLP is able to rescue DCD grafts, improving their metabolic function to that of livers not exposed to DCD procurement.
FOXP3 mRNA Profile Prognostic of Acute T Cell–mediated Rejection and Human Kidney Allograft Survival
Authors: Luan Danny , Dadhania Darshana M. , Ding Ruchuang , Muthukumar Thangamani , Lubetzky Michelle , Lee John R. , Sharma Vijay K. , August Phyllis , Mueller Franco B. , Schwartz Joseph E. , Suthanthiran Manikkam
Published: October 2020

Background.

T cell–mediated rejection (TCMR) is the most frequent type of acute rejection and is associated with kidney allograft failure. Almost 40% of TCMR episodes are nonresponsive to therapy, and molecular mechanisms for the nonresponsiveness are unknown. Our single-center study identified that urinary cell FOXP3 mRNA abundance predicts TCMR reversibility and allograft survival.

Methods.

We developed PCR assays and measured absolute copy numbers of transcripts for FOXP3, CD25, CD3E, perforin, and 18S rRNA in 3559 urines from 480 kidney allograft recipients prospectively enrolled in the multicenter Clinical Trials in Organ Transplantation-04. In this replication study, we investigated the association between mRNA profile and TCMR diagnosis, TCMR reversibility, and allograft survival.

Results.

18S rRNA normalized levels of mRNA for FOXP3 (P = 0.01, Kruskal-Wallis test), CD25 (P = 0.01), CD3E (P < 0.0001), and perforin (P < 0.0001) were diagnostic of TCMR, but only FOXP3 mRNA level predicted TCMR reversibility (ROC AUC = 0.764; 95% confidence interval, 0.611-0.917; P = 0.008). Multivariable logistic regression analyses showed that urinary cell FOXP3 mRNA level predicted reversal, independent of clinical variables. A composite model of clinical variables and FOXP3 mRNA (AUC = 0.889; 95% CI, 0.781-0.997; P < 0.001) outperformed FOXP3 mRNA or clinical variables in predicting TCMR reversibility (P = 0.01, likelihood ratio test). Multivariable Cox proportional hazards regression analyses showed that FOXP3 mRNA level predicts kidney allograft survival (P = 0.047) but not after controlling for TCMR reversal (P = 0.477).

Conclusions.

Urinary cell level of FOXP3 mRNA is diagnostic of TCMR, predicts TCMR reversibility, and is prognostic of kidney allograft survival via a mechanism involving TCMR reversal.
Comparative genomics of Clostridioides difficile toxinotypes identifies module-based toxin gene evolution
Authors: Janezic Sandra , Dingle Kate , Alvin Joseph , Accetto Tomaž , Didelot Xavier , Crook Derrick W. , Lacy D. Borden , Rupnik Maja
Published: October 2020

Clostridioides difficile

is a common cause of nosocomial diarrhoea. Toxins TcdA and TcdB are considered to be the main virulence factors and are encoded by the PaLoc region, while the binary toxin encoded in the CdtLoc region also contributes to pathogenicity. Variant toxinotypes reflect the genetic diversity of a key toxin-encoding 19 kb genetic element (the PaLoc). Here, we present analysis of a comprehensive collection of all known major

C. difficile

toxinotypes to address the evolutionary relationships of the toxin gene variants, the mechanisms underlying the origin and development of variability in toxin genes and the PaLoc, and the relationship between structure and function in TcdB variants. The structure of both toxin genes is modular, composed of interspersed blocks of sequences corresponding to functional domains and having different evolutionary histories, as shown by the distribution of mutations along the toxin genes and by incongruences of domain phylogenies compared to overall

C. difficile

cluster organization. In TcdB protein, four mutation patterns could be differentiated, which correlated very well with the type of TcdB cytopathic effect (CPE) on cultured cells. Mapping these mutations to the three-dimensional structure of the TcdB showed that the majority of the variation occurs in surface residues and that point mutation at residue 449 in alpha helix 16 differentiated strains with different types of CPE. In contrast to the PaLoc, phylogenetic trees of the CdtLoc were more consistent with the core genome phylogenies, but there were clues that CdtLoc can also be exchanged between strains.
Nutritional status and its associated factors among HIV positive adolescents on Atazanavir-based regimen attending an urban clinic in Uganda
Authors: Darshit Dave , Provia Ainembabazi , Nakiddu Nana , Sodawasser Erin , Harper Katrina , Ssenkusu John M. , Bakeera-Kitaka Sabrina , Nicol Melanie , Musaazi Joseph , Sekaggya-Wiltshire Christine
Published: October 2020

Background

Adolescents between the ages of 10-19 represent a growing portion of people living with HIV worldwide. A large proportion of adolescents living with HIV suffer from severe malnutrition because of the chronic ill health and this has been associated with increased morbidity and mortality particularly in Sub-Saharan Africa. Little is known about the nutrition status of adolescents living with HIV who are on second line treatment particularly Atazanavir. Therefore, we assessed the nutrition status and associated factors among HIV positive adolescents on Atazanavir-based regimen attending an urban clinic in Uganda.

Method

This was a cross-sectional study carried out between December 2017 and July 2018. Using convenience sampling, adolescents aged 10-19 years attending an urban clinic in Kampala on Atazanavir-based regimen were enrolled into the study. Nutritional status was assessed using BMI-for-Age and Height-for-age as measures of thinness and stunting respectively. Standard deviation scores (Z scores) were applied to determine the nutritional status. WHO and CDC Z-score cut offs were used to categorize the nutrition status. Data was entered into an electronic database using REDCap. Statistical analysis was done using STATA version 15.1 (Texas, USA).

Results

Data from 132 adolescents were included. We found that 28% were malnourished (composite outcome of stunting and thinness). The prevalence malnutrition of thinness was 7.6% with 2.3% being severely thin. The prevalence of stunting was 23.7% with 1.5% being severely stunted. Adolescents with no parent were more likely to be malnourished than adolescents who had either one or both parents (Adjusted Odds Ratio [AOR]: 3.70 95% Confidence Interval [CI]: 1.20-11.37, p=0.023). In addition, adolescents who had attained at least secondary education were less likely to be malnourished (AOR: 0.40, CI:0.17-0.95, P-value=0.037).

Conclusion

There is a high proportion of adolescents with HIV who are malnourished. Low level of education (No education and elementary) and having no parent are important risk factors to malnutrition in this population. There is need for optimizing nutrition care for adolescents on HIV treatment.
MultiPhATE2: Code for Functional Annotation and Comparison of Bacteriophage Genomes
Authors: Ecale Zhou Carol L. , Kimbrel Jeffrey , Edwards Robert , McNair Katlyn , Souza Brian A. , Malfatti Stephanie
Published: October 2020

To address the need for improved tools for annotation and comparative genomics of bacteriophage genomes, we developed multiPhATE2. As an extension of the multiPhATE code, multiPhATE2 performs gene finding and functional sequence annotation of predicted gene and protein sequences, and additional search algorithms and databases extend the search space of the original functional annotation subsystem. MultiPhATE2 includes comparative genomics codes for gene matching among sets of input bacteriophage genomes, and scales well to large input data sets with the incorporation of multiprocessing in the functional annotation and comparative genomics subsystems. MultiPhATE2 was implemented in Python 3.7 and runs as a command-line code under Linux or MAC-OS. MultiPhATE2 is freely available under an open-source GPL-3 license at https://github.com/carolzhou/multiPhATE2. Instructions for acquiring the databases and third party codes used by multiPhATE2 are found in the README file included with the distribution. Users may report bugs by submitting issues to the project GitHub repository webpage. Contact: zhou4@llnl.gov or multiphate@gmail.com. Supplementary materials, which demonstrate the outputs of multiPhATE2, are available in a GitHub repository, at https://github.com/carolzhou/multiPhATE2_supplementaryData/.
Higher Order AMMI (HO-AMMI) analysis: A novel stability model to study genotype-location interactions
Authors: Ajay BC , Abdul Fiyaz R , Bera SK , kumar Narendra , Gangadhar K , kona Praveen , Rani Kirti , Radhakrishnan T
Published: October 2020

Additive main effects and multiplicative interaction (AMMI) model is most widely used to analyse genotype*environment interactions (GEI) wherein interaction effects of location is masked by year effect. Hence, presently available models are not able to estimate interaction effects of genotype*location (GLI) and genotype*year (GYI) separately. Moreover, genotype ranking differs as number of years of evaluation vary making selection of genotype for target location difficult. In the present study we propose a novel stability model i.e Higher-order-AMMI (HO-AMMI) analysis which is capable of calculating GLI without the confounding effect of GYI and GLYI. GEI of AMMI model and all 2-way interactions of HO-AMMI model follow χ2distribution, whereas 3-way interaction (GLYI) of HO-AMMI follow noncentral χ2distribution. With increase in number of years of evaluation contribution of GLI towards total variation increased whereas in AMMI model contribution of GEI towards total variation decreased. Variation explained by multiplicative components is higher in HO-AMMI compared to AMMI model. Genotypes were ranked using GL, GY and GL+GY+GLY interactions of HO-AMMI and GEI of AMMI for stability and yield and compared their ranks with field ranking. Correlation and linear regression analysis have indicated high association of GLI (HO-AMMI) with field ranking with high R2values. Further, HO-AMMI model was able to remove the confounding effect of GYI and GLYI on GLI for accurate identification of genotype for target location irrespective of number of years of evaluation. Hence, HO-AMMI model can be used under multi-environment trials (MET) for selecting genotypes efficiently.

Availability and Information

Source code implemented in R is available from corresponding author.
BayesSMILES: Bayesian Segmentation Modeling for Longitudinal Epidemiological Studies
Authors: Jiang Shuang , Zhou Quan , Zhan Xiaowei , Li Qiwei
Published: October 2020

The coronavirus disease of 2019 (COVID-19) is a pandemic. To characterize its disease transmissibility, we propose a Bayesian change point detection model using daily actively infectious cases. Our model builds on a Bayesian Poisson segmented regression model that can 1) capture the epidemiological dynamics under the changing conditions caused by external or internal factors; 2) provide uncertainty estimates of both the number and locations of change points; and 3) adjust any explanatory time-varying covariates. Our model can be used to evaluate public health interventions, identify latent events associated with spreading rates, and yield better short-term forecasts.
Nudging the N170 forward with prior stimulation – Bridging the gap between N170 and recognition potential
Authors: Luo Canhuang , Chen Wei , VanRullen Rufin , Gaspar Carl Michael , Zhang Ye
Published: October 2020

Some neural responses are classified by the stimulus conditions leading up to that response while other neural responses are also classified by the morphology of the responses themselves. However, morphology-based classification may not be appropriate if one can nudge a neural response into looking like another neural response. Morphology-based classification occurs with the N170 and RP (Recognition Potential), ERP components that are studied in separate literatures and yet share much in common in terms of functionality. In this study, we demonstrate a gradual transformation in the morphology of the N170 to the RP using a simple parametric manipulation of forward masks that is unlikely to cause a change in the underlying processing. Both the N170 and RP are N1 components, meaning that they are the first negative deflection of the evoked response. However, the RP is often measured with a forward mask that ends at stimulus onset whereas the N170 is often measured with no masking at all. This study investigates how ISI may delay and distort the N170 into an RP by manipulating the temporal gap (ISI) between forward mask and target. The results revealed reverse relationships between the ISI on the one hand, and the N170 latency, single-trial N1 jitter (an approximation of N1 width) and reaction time on the other hand. Importantly, we find that scalp topographies have a unique signature at the N1 peak across all conditions, from the longest gap (N170) to the shortest (RP). These findings prove that the mask-delayed N1 is still the same N170, even under conditions that are normally associated with a different component like the RP. In general, our results suggest that greater caution should be taken to interpret the time course of a measured effect when forward masks are employed.
Genetic and metabolite biomarkers reveal actinobacteria-mediated estrogen biodegradation in urban estuarine sediment
Authors: Hsiao Tsun-Hsien , Chen Yi-Lung , Meng Menghsiao , Chuang Meng-Rong , Horinouchi Masae , Hayashi Toshiaki , Wang Po-Hsiang , Chiang Yin-Ru
Published: October 2020

Steroidal estrogens are often accumulated in urban estuarine sediments worldwide at microgram per gram levels. These aromatic steroids have been classified as endocrine disruptors with an EC50 at sub-nanomolar concentrations and classified as Group 1 carcinogens by the World Health Organization. Microbial degradation is a naturally occurring mechanism that mineralizes estrogens in the biosphere; however, the corresponding genes in estrogen-degrading actinobacteria remain unidentified. In this study, we identified a gene cluster encoding several putative estrogen-degrading genes in actinobacteriumRhodococcussp. strain B50. Among them, theoecBandoecCgenes involved in estrogenic A-ring cleavage were identified through gene-disruption experiments. We also detected the accumulation of two extracellular estrogenic metabolites, including pyridinestrone acid (PEA) and 3aα-H-4α(3’-propanoate)-7aβ-methylhexahydro-1,5-indanedione (HIP), in the estrone-fed strain B50 cultures. Since actinobacterialoecCand proteobacterialoecCshared less than 40% sequence identity,oecCcould serve as a specific biomarker to differentiate the contribution of actinobacteria and proteobacteria in environmental estrogen degradation. Therefore,oecCand the extracellular metabolites PEA and HIP were used as biomarkers to investigate estrogen biodegradation in an urban estuarine sediment. Interestingly, our data suggested that actinobacteria, rather than alpha-proteobacteria function in sewage treatment plants, are actively degrading estrogens in the urban estuarine sediment.

Graphical Abstract

Highlights

Isolation of an estrogen-degrading actinobacteriumRhodococcussp. strain B50 and establishment of a strain B50 genetic manipulation system.

Strain B50 exhibits a two-fold estrogen degradation rate of that of estrogen-degrading alpha-proteobacteria under the same cultivation conditions.

Functional characterization of two oxygenase genes,oecBandoecC, involved in estrogenic A-ring cleavage in actinobacteria.

Identification of two extracellular estrogenic metabolites, PEA and HIP, in the estrone-fed strain B50 cultures.

Detection of actinobacterialoecCsequences as well as PEA and HIP in the estrone-spiked urban estuarine sediments.
Evidence of hippocampal learning in human infants
Authors: Ellis C. T. , Skalaban L. J. , Yates T. S. , Bejjanki V. R. , Córdova N. I. , Turk-Browne N. B.
Published: October 2020

The hippocampus is essential for human memory. Thus, memory deficiencies in infants are often attributed to hippocampal immaturity. However, the functionality of the infant hippocampus has never been tested directly. Here we report that the human hippocampus is indeed active in infancy. We recorded hippocampal activity using fMRI while awake infants aged 3-24 months viewed sequences of objects. Greater activity was observed when the order of the sequence contained regularities that could be learned compared to when the order was random. The involvement of the hippocampus in such statistical learning, with additional recruitment of the medial prefrontal cortex, is consistent with findings from adults. These results suggest that the hippocampus supports the important ability of infants to extract the structure of their environment through experience.
Mass spectrometric based detection of protein nucleotidylation in the RNA polymerase of SARS-CoV-2
Authors: Conti Brian J. , Kirchdoerfer Robert N. , Sussman Michael R.
Published: October 2020

Coronaviruses, like SARS-CoV-2, encode a nucleotidyl transferase in the N-terminal NiRAN domain of thenon-structuralprotein (nsp) 12 protein within theRNA dependentRNApolymerase (RdRP)1-3. Though the substrate targets of the viral nucleotidyl transferase are unknown, NiRAN active sites are highly conserved and essential for viral replication3. We show, for the first time, the detection and sequence location of GMP-modified amino acids in nidovirus RdRP-associated proteins using heavy isotope-assisted MS and MS/MS peptide sequencing. We identified lys-143 in the equine arteritis virus (EAV) protein, nsp7, as a primary site of nucleotidylation in vitro that uses a phosphoramide bond to covalently attach with GMP. In SARS-CoV-2 replicase proteins, we demonstrate a unique O-linked GMP attachment on nsp7 ser-1, whose formation required the presence of nsp12. It is clear that additional nucleotidylation sites remain undiscovered, which includes the possibility that nsp12 itself may form a transient GMP adduct in the NiRAN active site that has eluted detection in these initial studies due to instability of the covalent attachment. Our results demonstrate new strategies for detecting GMP-peptide linkages that can be adapted for higher throughput screening using mass spectrometric technologies. These data are expected to be important for a rapid and timely characterization of a new enzymatic activity in SARS-CoV-2 that may be an attractive drug target aimed at limiting viral replication in infected patients.
A small UTX stabilization domain of Trr is conserved within mammalian MLL3-4/COMPASS and is sufficient to rescue loss of viability in null animals
Authors: Rickels Ryan , Wang Lu , Iwanaszko Marta , Ozark Patrick A. , Morgan Marc A. , Piunti Andrea , Khalatyan Natalia , Soliman Shimaa H.A. , Rendleman Emily J. , Savas Jeffrey N. , Smith Edwin R. , Shilatifard Ali
Published: October 2020

Catalytic-inactivating mutations within the Drosophila enhancer H3K4 mono-methyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared with whole-gene deletions for these COMPASS members. To identify essential histone methyltransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality and demonstrate that this domain binds and stabilizes Utx in vivo. Using the homologous MLL3/MLL4 human sequences, we mapped a short ∼80-amino-acid UTX stabilization domain (USD) that promotes UTX stability in the absence of the rest of MLL3/4. Nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. Thus, COMPASS-dependent UTX stabilization is an essential noncatalytic function of Trr/MLL3/MLL4, suggesting that stabilizing UTX could be a therapeutic strategy for cancers with MLL3/4 loss-of-function mutations.
DICER1-associated metastatic abdominopelvic primitive neuroectodermal tumor with an EWSR1 rearrangement in a 16-yr-old female
Authors: Pancaldi Alessia , Peng Lei , Rhee Daniel S. , Dunn Emily , Forcucci Jessica A. , Belchis Deborah , Pratilas Christine A.
Published: October 2020

We report a case of a DICER1-associated EWSR1-rearranged malignant primitive neuroectodermal tumor (PNET) arising in a patient with DICER1 tumor predisposition syndrome. A 16-yr-old female with a history of multinodular goiter presented with a widely metastatic abdominal small round blue cell tumor with neuroectodermal differentiation. EWSR1 gene rearrangement was identified in the tumor by fluorescence in situ hybridization (FISH). Genetic analysis revealed biallelic pathogenic DICER1 variation. The patient was treated with an aggressive course of chemotherapy, surgery, and radiation with complete pathologic response. We believe this case to represent a new expression of the DICER1 tumor predisposition syndrome, an entity caused by deleterious germline mutations in the DICER1 gene, encoding a ribonuclease active in the processing of miRNA. Patients with germline mutations in DICER1 develop a diverse group of benign and malignant tumors. Some of these tumors have been noted to have immature neuroepithelium as a component, including the ciliary body medulloepithelioma and the recently described DICER1-associated presacral malignant teratoid neoplasm. To our knowledge, abdominal sarcomas that resemble PNET histology with an EWSR1 rearrangement have not previously been described as a classical expression of the DICER1 syndrome phenotype.