bluuebunny/crossref_metadata_2025 huggingface dataset:
Interpretation of network-based integration from multi-omics longitudinal data
Authors: Bodein Antoine , Scott-Boyer Marie-Pier , Perin Olivier , Lê Cao Kim-Anh , Droit Arnaud
Published: November 2021

Multi-omics integration is key to fully understand complex biological processes in an holistic manner. Furthermore, multi-omics combined with new longitudinal experimental design can unreveal dynamic relationships between omics layers and identify key players or interactions in system development or complex phenotypes. However, integration methods have to address various experimental designs and do not guarantee interpretable biological results. The new challenge of multi-omics integration is to solve interpretation and unlock the hidden knowledge within the multi-omics data. In this paper, we go beyond integration and propose a generic approach to face the interpretation problem. From multi-omics longitudinal data, this approach builds and explores hybrid multi-omics networks composed of both inferred and known relationships within and between omics layers. With smart node labelling and propagation analysis, this approach predicts regulation mechanisms and multi-omics functional modules. We applied the method on 3 case studies with various multi-omics designs and identified new multi-layer interactions involved in key biological functions that could not be revealed with single omics analysis. Moreover, we highlighted interplay in the kinetics that could help identify novel biological mechanisms. This method is available as an R package netOmics to readily suit any application.
Rational design ofStriga hermonthica-specific seed germination inhibitors
Authors: Zarban Randa A , Hameed Umar F Shahul , Jamil Muhammad , Ota Tsuyoshi , Wang Jian You , Arold Stefan T , Asami Tadao , Al-Babili Salim
Published: November 2021

The obligate hemiparasitic weed Striga hermonthica grows on cereal roots and presents a severe threat to global food security by causing enormous yield losses, particularly in sub-Saharan Africa. The rapidly increasing Striga seed bank in infested soils provides a major obstacle in controlling this weed. Striga seeds require host-derived strigolactones (SLs) for germination, and corresponding antagonists could be used as germination inhibitors. Recently, we demonstrated that the common detergent Triton X-100 is a specific inhibitor of Striga seed germination by binding noncovalently to its receptor, S. hermonthica HYPO-SENSITIVE TO LIGHT 7 (ShHTL7), without blocking the rice (Oryza sativa) SL receptor DWARF14 (OsD14). Moreover, triazole ureas, the potent covalently binding antagonists of rice SL perception with much higher activity toward OsD14, showed inhibition of Striga but were less specific. Considering that Triton X-100 is not suitable for field application and by combining structural elements of Triton and triazole urea, we developed two hybrid compounds, KK023-N1 and KK023-N2, as potential Striga-specific germination inhibitors. Both compounds blocked the hydrolysis activity of ShHTL7 but did not affect that of OsD14. Binding of KK023-N1 diminished ShHTL7 interaction with S. hermonthica MORE AXILLARY BRANCHING 2, a major component in SL signal transduction, and increased ShHTL7 thermal specificity. Docking studies indicate that KK023-N1 binding is not covalent but is caused by hydrophobic interactions. Finally, in vitro and greenhouse tests revealed specific inhibition of Striga seed germination, which led to a 38% reduction in Striga infestation in pot experiments. These findings reveal that KK023-N1 is a potential candidate for combating Striga and a promising basis for rational design and development of further Striga-specific herbicides.
The Lived Experience of Patients with an Ostomy: A Pilot Study on the Effect of Ostomy Pouch Opacity
Authors: Heerschap Corey , Duff Victoria
Published: November 2021

OBJECTIVE

To explore the effects of ostomy pouch opacity on the lived experience of patients with ostomies in the postoperative period.

METHODS

This qualitative, descriptive phenomenology study used purposive sampling to recruit seven participants who were inpatients in an acute care facility in Central Ontario, Canada, after their first ostomy surgery. Face-to-face, audio-recorded, semistructured interviews were used to collect data regarding patient experience with either a transparent or opaque ostomy pouch. Data were collected between August and November 2019. Audio tapes were transcribed verbatim and analyzed using a thematic analysis technique focused on describing patient lived experience.

RESULTS

Five themes were discovered: “undercover,” “fiscal consideration,” “past medical experience,” “self-esteem,” and “functionality.” Most participants focused on appliance functionality over pouch opacity in the immediate postoperative period. However, participants did describe difficulties adjusting to their new stoma and noted that an opaque pouch can improve postoperative comfort. Past exposure to medical devices, particularly in terms of their cost, may impact the decision to use a transparent or opaque pouching system.

CONCLUSIONS

Pouching systems that are opaque while still allowing for assessment of the pouching contents and stoma are ideal. When this is not available, providers should consider the patient’s wishes to alleviate any psychosocial effects the opacity of the pouching system may have.
Pulmonary function testing for the primary care nurse practitioner
Authors: Smith Whitney , Chinnis Simone , Durham Catherine , Fowler Terri
Published: November 2021

Knowledge of which pulmonary function tests are commonly performed in primary care and interpretation of their results is integral for the diagnosis, care, and management of those with pulmonary symptoms. This article provides an overview of the most common pulmonary function tests and interpretation of their results.
Antiretroviral therapies and corticosteroids
Authors: Cadet Myriam Jean
Published: November 2021

Antiretroviral therapies for HIV may cause systemic toxicities when coadministered with corticosteroids. Potential drug-drug interactions may occur, leading to iatrogenic Cushing syndrome or adrenal insufficiency. This article highlights the drug-drug interactions of antiretroviral therapies with corticosteroids. Practice implications are discussed.
Navigating Ethical Challenges for Pediatric Sickle Cell Pain Management in the Context of the Opioid Epidemic
Authors: Mulchan Siddika S. , Wakefield Emily O. , Martin Sarah R. , Ayr-Volta Lauren , Krenicki Kayla , Zempsky William T.
Published: November 2021

Objectives:

The aim was to describe the impact of the opioid epidemic on pain management practices in pediatric sickle cell disease (SCD) and propose a conceptual framework for navigating ethical decision-making in pediatric sickle cell pain management.

Methods:

A review of the literature on ethical challenges in the management of sickle cell pain was conducted and considered in the context of the opioid epidemic and psychosocial factors affecting youth with SCD. The Integrated Ethical Framework for Pain Management (IEFPM) was applied to pediatric sickle cell pain management using a clinical case example.

Results:

Implicit bias, health-related stigma, and potential neurocognitive impairment all present unique challenges in ethical decision-making for youth with SCD. National guidelines for prescribing opioid medication may complicate providers’ clinical decision-making and affect their sickle cell pain management practices. The IEFPM was found to be applicable to ethical decision-making for pediatric sickle cell pain and captures both patient-related and provider-related aspects of clinical pain management.

Discussion:

The opioid epidemic has exacerbated existing ethical challenges for pain management among youth with SCD. The IEFPM provides a conceptual model that can be integrated into health care settings to facilitate ethical decision-making and promote greater health equity in the clinical management of pediatric sickle cell pain.
Atypical Clinical and Neuroradiological Findings in a Child With Bifacial Weakness With Paresthesias
Authors: Rubino Alfonso , della Corte Marida , Bruno Giorgia , Tucci Celeste , Fasolino Alessandra , de Liso Maria , Varone Antonio
Published: November 2021

Background:

Guillain–Barré syndrome (GBS) is the broad term used to describe a number of related acute autoimmune neuropathies, which together form a continuous spectrum of variable and overlapping syndromes. Bifacial weakness with paresthesias (BFP) is a rare variant of GBS, characterized by isolated facial diplegia in the absence of ophthalmoplegia, ataxia, or limb weakness, and it is usually associated with distal limb paresthesias.

Case Description:

An 8-year-old boy was brought to our attention; because 5 days before coming to the hospital, he noticed he could no longer smile. Bilateral facial droop and inability to close both eyes were evident along with slight paresthesias at the hands and feet and gait disturbances. He progressively developed hypophonia, dysarthria, dysphagia associated with dysmetria, and limb ataxia. Nerve conduction studies showed a demyelinating polyneuropathy. Brain and spine magnetic resonance imaging (MRI) revealed contrast enhancement of both facial nerves and cauda equina nerve roots along with a hyperintense signal of the periaqueductal gray matter, superior cerebellar peduncles, and pontine tegmentum. Because BFP is not typically associated with other cranial neuropathies or ataxia, these clinical features along with peculiar MRI findings supported the diagnosis of “BFP plus.” Finally, it can be speculated that this case configures a rare overlap between BFP and the other GBS variants, such as Bickerstaff encephalitis.

Conclusions:

This atypical case underlines the potential role of MRI in contributing to refining the nosological classification of GBS spectrum and optimizing individual treatment, especially in children where unusual manifestations are not infrequent and neurological examination is more challenging.
LncRNA NEAT1 Accelerates the Proliferation, Oxidative Stress, Inflammation, and Fibrosis and Suppresses the Apoptosis Through the miR-423-5p/GLIPR2 Axis in Diabetic Nephropathy
Authors: Wu Xu , Fan Deyong , Chen Bo
Published: November 2021

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. The aim of our study was to investigate the potential mechanism in DN progression. SV40 mesangial cells (MES)13 cells were exposed to high concentration of glucose (HG: 30 mmol/L) for 48 hours to establish a DN cell model in vitro. Bioinformatic software StarBase was adopted to establish the long noncoding RNA (lncRNA)-microRNA–messenger RNA axis. Dual-luciferase reporter assay, RNA immunoprecipitation assay, and RNA pull-down assay were performed to verify intermolecular interaction. LncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) was overexpressed in the serum of patients with DN. HG time-dependently upregulated NEAT1 levels, and HG promotes cell proliferation, oxidative stress, inflammation, and fibrosis and suppressed cell apoptosis in SV40 MES13 cells partly through upregulating NEAT1. NEAT1 functioned as a molecular sponge of miR-423-5p, and NEAT1 silencing-mediated effects were partly overturned by miR-423-5p interference in HG-induced SV40 MES13 cells. Glioma pathogenesis related-2 (GLIPR2) was a target of miR-423-5p. GLIPR2 overexpression in normal concentration of glucose (NG)-induced SV40 MES13 cells partly simulated HG-induced effects. GLIPR2 overexpression partly reversed NEAT1 interference–induced effects in HG-induced SV40 MES13 cells. LncRNA NEAT1 contributed to HG-induced DN progression through the miR-423-5p/GLIPR2 axis in vitro. NEAT1/miR-423-5p/GLIPR2 axis might be a potential target for DN treatment.
Bridging Care Transition After Hospitalization for Atrial Fibrillation and Coronary Interventions
Authors: Hijazi Yosef , Karkabi Basheer , Feldman Marina , Malca Bruria , Lavi Idit , Jaffe Ronen , Schliamser Jorge E. , Shiran Avinoam , Flugelman Moshe Y.
Published: November 2021

Treatment fragmentation between hospitals and the community can result in catastrophic outcomes; uninterrupted treatment with anticoagulant and platelet aggregation inhibitors is particularly important. We assessed the proportion and characteristics of patients who did not visit their primary community-based physician within 1 week of discharge from our department of cardiovascular medicine and the proportion that failed to procure essential drugs at the community pharmacy. We prospectively studied 423 patients who were discharged from our department. They were provided detailed explanations, tablets for 7 days, prescriptions, and a printed drug plan. We traced the time from discharge until a visit with a primary community-based physician, and the time until the procurement of medications, using our computerized community–hospital–integrated system. Complete data were available for 313 patients, of whom 220 were treated with anticoagulants or platelet aggregation inhibitors. For 175 patients, these drugs were initiated during index hospitalizations. Only 1 patient did not receive platelet aggregation inhibitors despite recommendations. Seventy-nine patients (25%) first visited their primary care physicians more than 1 week after discharge. Predictors for delayed visits were living alone (hazard ratio 1.91) and having an in-house caregiver (hazard ratio 2.01). In conclusion, all but 1 patient continued drug therapy after discharge from the hospital. The simple predischarge steps included patient education and provision of a 1-week supply of tablets and prescriptions. Treatment continuation was independent of visits to the community-based primary physician. Patients living alone or with an in-house caregiver more often delayed visits to primary physicians yet continued relevant drug therapy.
A Myocutaneous Latissimus Dorsi Propeller Flap Based on a Single Dorsal Intercostal Perforator
Authors: Geierlehner Alexander , Ludolph Ingo , Arkudas Andreas , Horch Raymund E.
Published: November 2021

This study presents a novel surgical technique for the reconstruction of highly challenging large lower back defects. In this case, a 72-year-old man initially diagnosed with renal cell carcinoma received nephrectomy followed by the dissection of an iliac crest metastasis and repeated high-dose irradiation therapy. Several years later, an osteocutaneous fistula at the right caudal posterior trunk made the reconstruction of the lower back defect necessary. High-dose irradiation of the lower back and poor vascular conditions at the pelvic region disqualified the patient for previously published local or free flap options. The initial strategy of an arteriovenous loop anastomosed to the femoral vessels and a free latissimus dorsi flap transfer had to be withdrawn due to repeated intraoperative loop thrombosis. For that reason, the entire latissimus dorsi muscle was used as a myocutaneous propeller flap receiving its blood supply solely through a single dorsal intercostal artery perforator. The flap survived completely and no fistulous formation occurred postoperatively. The time to complete wound healing was 4 months. This new technique is considered a valuable addition for the reconstruction of challenging posterior caudal trunk defects.
Simultaneous Central Slip and Volar Plate Injuries at PIP Joint: A Novel Therapeutic Approach
Authors: Alotaibi Ahmed S. , AlMarshad Felwa A. , Alzahrani Abdullah M. , Hossein Mohanad O. , Ijaz Attiya , Ifthikar Zainab , Jarman Abdulaziz T.
Published: November 2021

Background:

Central slip and volar plate injuries rarely occur in the same finger, with only two cases previously reported in published literature. In these two patients, both teenagers, two highly distinct protocols were used. Here, we report a third case involving a 51-year-old gentleman who closed a door on his left third finger.

Methods:

Because the fractures were noncomminuted and only minimally displaced, he was treated nonsurgically using a multi-step process of splinting to prevent impairment of either proximal interphalangeal joint extension or flexion, combined with active range of motion exercises. This included five weeks of splinting in neutral, 24-hour daily use of a proximal interphalangeal dorsal block, followed by active range of motion exercises combined with nocturnal splinting using a PIP volar block over the next 7 weeks, with relative motion and Joint Jack splints added over the final 4 of these 7 weeks.

Results:

Twelve weeks after initial splinting, the patient’s finger was pain free, with swelling largely resolved, normal extension (−10 degrees) and near-normal flexion (95 degrees) achieved, and full function restored. The patient was very satisfied with the result.

Conclusions:

Ours is just the third case of concomitant central slip and volar plate injuries reported in the literature. Other surgeons are strongly encouraged to publish similar cases, approaches, and results, as clinical wisdom can sometimes be gleaned from even a small number of well-documented clinical cases.
Artifacts on Magnetic Resonance Imaging from Electronic Identification Enablement in Silicone Gel Implants Are Not Negligible
Authors: Kurz Kathinka D. , Kallevåg Øystein , Austrått Kenneth , Styr Bodil , Leiknes Jon Bjarne , Krøger Pål
Published: November 2021

Breast implants filled with silicone gel are used worldwide for cosmetic reasons, or breast reconstruction following risk-reducing or therapeutic mastectomy. The importance of identifiable implants is undeniable. A recent development has been the labeling of the implants with a radio-frequency device micro responder chip (RFID). We examined a patient with silicone implants containing RFID chips with magnetic resonance imaging and were surprised by the artifacts caused by the RFID chip. We raise the question if the benefits of RFID-labeled silicone implants outweigh the drawbacks of magnetic resonance artifacts caused by the RFID chip itself.
Simultaneous Breast and Nipple–Areolar Reconstruction Using Musculo-derma-glandular, Axio-perforator, Bipedicled Flap
Authors: Kalender Vagif , Guliyeva Gunel , Güven Erdem , Galandarova Aysune
Published: November 2021

Although breast reconstruction has been performed for centuries, there is a constant search for new approaches to achieve an aesthetically pleasing appearance while causing minimal patient morbidity. In our previous article, we have described our experience with the bipedicled musculo-derma-glandular, axio-perforator flap. The main advantage of this well-vascularized flap is the ability to restore the shape after mastectomy while removing the excess tissue from the hypertrophic and ptotic healthy breast. Based on our promising results with this technique in the previous two patients, we combined the breast reconstruction using bipedicled musculo-derma-glandular, axio-perforator flap with simultaneous nipple–areolar complex reconstruction. The surgery was successful, and the patient did not experience any complications. We believe this technique can be applied for patients with breast hypertrophy and ptosis to achieve reliable and aesthetically acceptable results in a one-stage operation.
RADIATION MACULOPATHY IS ANTICIPATED BY OCT HYPERREFLECTIVE RETINAL FOCI
Authors: Parrozzani Raffaele , Midena Giulia , Frizziero Luisa , Marchione Giulia , Midena Edoardo
Published: November 2021

Purpose:

To investigate, by means of spectral domain optical coherence tomography, retinal reflectivity changes as an early biomarker anticipating radiation-induced macular edema (ME) in patients treated by iodine-125 (I-125) brachytherapy.

Methods:

Thirty patients planned for I-125 brachytherapy because of uveal melanoma were prospectively included and followed every 4 months for five years. Reflectivity alterations, namely hyperreflective retinal foci, were characterized and counted by two independent masked examiners by means of spectral domain optical coherence tomography imaging. Hyperreflective retinal foci were defined as discrete intraretinal reflectivity changes ≤30 µm, with reflectivity similar to nerve fiber layer and without back shadowing.

Results:

Macular edema occurred in 17 patients (24.2 ±15.1 months) (group 1) after irradiation. Thirteen patients showed no signs of ME at the 5-year follow-up (group 2). The number of hyperreflective retinal foci was statistically higher in sequential visits until the evidence of ME in group 1 vs group 2 (P < 0.0001). In group 1, hyperreflective retinal foci at the follow-up before the evidence of ME were significantly related to the OCT central subfield thickness at ME appearance (P = 0.0002, r2=0.6129). The intergrader agreement was almost perfect (intraclass correlation coefficient = 0.80).

Conclusion:

Hyperreflective retinal foci may be considered as an early in vivo imaging biomarker of retinal inflammatory response to ocular irradiation, anticipating the development of radiation maculopathy.
Quantifying Ambulatory Care Use Preceding Emergency Department Visits and Hospitalizations for Ambulatory Care Sensitive Conditions
Authors: Dev Sharmistha , Goldstick Jason , Peterson Timothy , Brenner Jeffrey , Abir Mahshid
Published: November 2021

Ambulatory Care Sensitive Conditions (ACSC) represent a significant source of health care spending in the United States. Existing literature is largely descriptive and there is limited information about how an emergency department (ED) visit or hospitalization for ACSCs is related to prior ambulatory care visits. A retrospective, observational study was conducted using health records from a large midwestern health system during a 20-month period between 2012 and 2014. Our primary variables were (1) type of care setting (i.e., ED visit or hospitalization) and (2) whether the patient received ambulatory care services in the 14, 30, and 60 days before the ED visit or hospital admission. Of patients seen in the ED for ACSCs, 11.9%, 16.3%, and 21.67% were seen in ambulatory care in the 14, 30, and 60 days prior, respectively. Of those hospitalized for ACSCs, 29.1%, 39.9%, and 53% were seen in ambulatory care in the 14, 30, and 60 days prior, respectively. These results highlight a potential lost opportunity to address ACSCs in the ambulatory care setting. Such knowledge can inform interventions to reduce avoidable ACSC-related acute care use and health care costs, and improve patient outcomes.
Avoiding Retained Surgical Items at an Academic Medical Center: Sustainability of a Surgical Quality Improvement Project
Authors: Cima Robert R. , Bearden Brenda A. , Kollengode Anantha , Nienow Joseph M. , . Weisbrod Cheryl A , Dowdy Sean C. , Amstutz Gwendolyn J. , Narr Bradly J.
Published: November 2021

Unintentionally retained surgical items (RSIs) are a serious complication representing a surgical “Never” event. The authors previously reported the process and significant improvement over a 3-year multiphased quality improvement RSI reduction effort that included sponge-counting technology. Herein, they report the sustainability of that effort over the decade following the formal quality improvement project conclusion. This retrospective analysis includes descriptive and qualitative data collected during RSI event root cause analysis. Between January 2009 and December 2019, 640 889 operations were performed with 24 RSIs reported. The resulting RSI rate of 1 per 26 704 operations represent a 486% performance improvement compared to the preintervention rate of 1 per 5500 operations. The interval, in days, between RSI events increased to 160 from 26 during the preintervention phase. Cotton sponges were the most retained RSI despite the use of sponge-counting technology. A significant and sustained reduction in RSI is possible after designing a sustainable comprehensive multidisciplinary effort.
Technical Note on Three- and Four-Wall Orbital Reconstructions With Patient-Specific Implants
Authors: Sabelis Juliana F. , Youssef Stephen A.L.Y. , Hoefnagels Friso W.A. , Becking Alfred G. , Schreurs Ruud , Dubois Leander
Published: November 2021

Orbital reconstruction is one of the most complex procedures in maxillofacial surgery. It becomes even more complex when all references to the original anatomy are lost. The purpose of this article is to provide an overview of techniques for complex three- and four-wall orbital reconstructions. Preoperative virtual surgical planning is essential when considering different reconstruction possibilities. The considerations that may lead to different approaches are described, and the advantages and drawbacks of each technique are evaluated. It is recommended to reconstruct solitary three-wall or four-wall orbital defects with multiple patientspecific implants. Optimizations of this treatment protocol are suggested, and their effects on predictability are demonstrated in a case presentation of a four-wall defect reconstruction with multiple patient-specific implants.
Assessment of the Pelvic Floor and Associated Musculoskeletal System: Guide for Medical Practitioners
Authors: Harm-Ernandes Ingrid , Boyle Valerie , Hartmann Dee , Fitzgerald Colleen M. , Lowder Jerry L. , Kotarinos Rhonda , Whitcomb Emily
Published: November 2021

Objectives

This study aimed to assist practitioners in performing an accurate assessment of the external and internal pelvic musculoskeletal (MSK) systems to improve appropriate diagnosis and referral of patients with pelvic floor disorders or pelvic pain and to improve understanding of physical therapy (PT) treatment principles, thereby improving communication between practitioners and encouraging a multidisciplinary approach.

Methods

A referenced review of the anatomy of the pelvic floor muscles, pelvis, and surrounding structures, followed by a detailed assessment of anatomy, posture, and gait, is presented. A thorough description of PT assessment and treatment is included with clinical relevance.

Results

When proper assessments are routinely performed, MSK conditions can be recognized, allowing for prompt and appropriate referrals to PT. Assessment and treatment by qualified physical therapists are integral to pelvic health care. After efficient medical assessment, MSK dysfunction can be addressed expeditiously, thereby avoiding further decline. Left unaddressed, pelvic dysfunction may become chronic.

Conclusions

We propose a guide for MSK assessment of the pelvis and associated structures that can be used for both clinical and research purposes. This guide is designed for health care providers caring for women with pelvic floor disorders, including physicians, advanced practice providers, and nurses. This guide serves to improve communication among multidisciplinary practitioners to refine MSK assessment and treatment approaches and thereby advance clinical care and research.
Increase in Pediatric Pseudotumor Cerebri Syndrome Emergency Department Visits, Inpatient Admissions, and Surgeries During the COVID-19 Pandemic
Authors: Chang Melinda Y. , Yim Cindi K. , Borchert Mark S.
Published: November 2021

Background:

Pediatric pseudotumor cerebri syndrome (PTCS) is a vision-threatening condition that is associated with female sex and obesity in pubertal and postpubertal children. It is unknown whether the increase in childhood obesity during the COVID-19 pandemic has affected the rates and characteristics of pediatric PTCS.

Methods:

We conducted a retrospective study of children evaluated for PTCS (inpatient or emergency department) at our children's hospital before (March 19, 2015 to March 19, 2020) and during (March 20, 2020 to February 20, 2021) the pandemic. We compared the monthly number of inpatient and emergency department encounters for pediatric PTCS before and during the pandemic. In addition, anthropometric and ophthalmologic characteristics of children evaluated for pediatric PTCS before and during the pandemic were compared.

Results:

A total of 36 encounters in the 5 years before the pandemic and 26 encounters in the 11 months during the pandemic were identified. The median monthly number of encounters for pediatric PTCS was significantly higher during the pandemic compared with the 5 years before the pandemic (2 vs 0, P = 0.0021). Compared with prepandemic patients, children evaluated during the pandemic were older (median age 16 vs 14 years, P = 0.02), with higher rates of obesity (85% vs 66%, P = 0.05) and lower likelihood of reporting Caucasian race (4% vs 31%, P = 0.02). Pandemic patients had worse presenting visual acuity (median logMAR 0.14 vs 0.05, P = 0.05) and were more likely to have fulminant presentation (23% vs 6%, P = 0.04) and require surgical intervention (23% vs 6%, P = 0.04).

Conclusions:

At our children's hospital, the rate of inpatient admissions and emergency department visits for pediatric PTCS increased during the pandemic. The severity of disease and frequency of surgical treatment also increased. Racial and ethnic minorities seem to be disproportionately affected. These changes may be related to increasing rates of childhood obesity during the pandemic.
Behavioural response to heterogeneous severity of COVID-19 explains temporal variation of cases among different age groups
Authors: Steinegger Benjamin , Arola-Fernández Lluís , Granell Clara , Gómez-Gardeñes Jesús , Arenas Alex
Published: November 2021

Together with seasonal effects inducing outdoor or indoor activities, the gradual easing of prophylaxis caused second and third waves of SARS-CoV-2 to emerge in various countries. Interestingly, data indicate that the proportion of infections belonging to the elderly is particularly small during periods of low prevalence and continuously increases as case numbers increase. This effect leads to additional stress on the health care system during periods of high prevalence. Furthermore, infections peak with a slight delay of about a week among the elderly compared to the younger age groups. Here, we provide a mechanistic explanation for this phenomenology attributable to a heterogeneous prophylaxis induced by the age-specific severity of the disease. We model the dynamical adoption of prophylaxis through a two-strategy game and couple it with an SIR spreading model. Our results also indicate that the mixing of contacts among the age groups strongly determines the delay between their peaks in prevalence and the temporal variation in the distribution of cases.

This article is part of the theme issue ‘Data science approaches to infectious disease surveillance’.
Calibrating COVID-19 susceptible-exposed-infected-removed models with time-varying effective contact rates
Authors: Gleeson James P. , Brendan Murphy Thomas , O’Brien Joseph D. , Friel Nial , Bargary Norma , O'Sullivan David J. P.
Published: November 2021

We describe the population-based susceptible-exposed-infected-removed (SEIR) model developed by the Irish Epidemiological Modelling Advisory Group (IEMAG), which advises the Irish government on COVID-19 responses. The model assumes a time-varying effective contact rate (equivalently, a time-varying reproduction number) to model the effect of non-pharmaceutical interventions. A crucial technical challenge in applying such models is their accurate calibration to observed data, e.g. to the daily number of confirmed new cases, as the history of the disease strongly affects predictions of future scenarios. We demonstrate an approach based on inversion of the SEIR equations in conjunction with statistical modelling and spline-fitting of the data to produce a robust methodology for calibration of a wide class of models of this type.

This article is part of the theme issue ‘Data science approaches to infectious disease surveillance’.
Unequal impact and spatial aggregation distort COVID-19 growth rates
Authors: Burghardt Keith , Guo Siyi , Lerman Kristina
Published: November 2021

The COVID-19 pandemic has posed unprecedented challenges to public health world-wide. To make decisions about mitigation strategies and to understand the disease dynamics, policy makers and epidemiologists must know how the disease is spreading in their communities. Here we analyse confirmed infections and deaths over multiple geographic scales to show that COVID-19’s impact is highly unequal: many regions have nearly zero infections, while others are hot spots. We attribute the effect to a Reed–Hughes-like mechanism in which the disease arrives to regions at different times and grows exponentially at different rates. Faster growing regions correspond to hot spots that dominate spatially aggregated statistics, thereby skewing growth rates at larger spatial scales. Finally, we use these analyses to show that, across multiple spatial scales, the growth rate of COVID-19 has slowed down with each surge. These results demonstrate a trade-off when estimating growth rates: while spatial aggregation lowers noise, it can increase bias. Public policy and epidemic modelling should be aware of, and aim to address, this distortion.

This article is part of the theme issue ‘Data science approaches to infectious disease surveillance’.
Microbacterium paulum sp. nov., isolated from microfiltered milk
Authors: Bellassi Paolo , Fontana Alessandra , Callegari Maria Luisa , Cappa Fabrizio , Morelli Lorenzo
Published: November 2021

A novel Gram-stain-positive, strictly aerobic, short rod-shaped bacterium, designated 2CT, was isolated from freshly packaged microfiltered milk. This strain was able to grow within the NaCl concentration range of 0–5 % (w/v), temperature range of 8–37 °C (optimally at 30 °C) and at pH 6.0–10.0. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 2CT was closely related to species of the genus

Microbacterium

, with the highest sequence similarity (99.2 %) to

Microbacterium lacticum

DSM 20427T as well as

Microbacterium flavum

DSM 18909T (=YM18-098T). The phylogenetic tree based on 16S rRNA genes showed that strain 2CT clustered with

M. flavum

DSM 18909T. However, the phylogenetic tree based on concatenated 16S rRNA and four housekeeping genes showed that strain 2CT clustered with

M. lacticum

DSM 20427T. Furthermore, the phylogenomic tree showed that strain 2CT clustered with

M. lacticum

DSM 20427T and

M. flavum

DSM 18909T. The major respiratory quinones were MK-10, MK-11 and MK-12. The predominant cellular fatty acids were anteiso-C15 : 0, iso-C16 : 0 and anteiso-C17 : 0. The polar lipid composition of strain 2CT consisted of diphosphatidylglycerol, phosphatidylglycerol, three unidentified glycolipids and two unidentified lipids. The cell-wall peptidoglycan type was a variant of B1α {Gly} [l-Lys] d-Glu-l-Lys, with the amino acids lysine, glycine, alanine and glutamic acid. The whole-cell sugars consisted of galactose, glucose, ribose and minor amounts of rhamnose. In addition, strain 2CT showed a glycolyl-type cell wall. The genomic DNA G+C content was 69.8mol%, while the average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values with the closely related

Microbacterium

species were below the recognized thresholds of 95–96 % ANI and 70 % DDH for species definition. Based on the phenotypic and genotypic data, strain 2CT (=LMG 32277T=CECT 30329T) is considered to represent a new species, for which the name Microbacterium paulum sp. nov. is proposed.
ROLE OF BODY MASS AND PHYSICAL ACTIVITY IN AUTONOMIC FUNCTION MODULATION ON POST-COVID-19 CONDITION: AN OBSERVATIONAL SUBANALYSIS OF FIT-COVID STUDY
Authors: Figueira Freire Ana Paula Coelho , de Lira Fabio Santos , von Ah Morano Ana Elisa , Pereira Telmo , Silva Manuel-João Coelho , Caseiro Armando , Destro Christofaro Diego Giulliano , Júnior Osmar Marchioto , Dorneles Gilson Pires , Pinho Ricardo Aurino , de Alencar Silva Bruna Spolador
Published: November 2021

The harmful effects of coronavirus disease 2019 (COVID-19) can reach the autonomic nervous system (ANS) and endothelial function. Therefore, the detrimental multiorgan effects of COVID-19 could be induced by deregulations in ANS that may persist after the acute SARS-CoV-2 infection. Additionally, investigating the differences in ANS response in overweight/obese, and physically inactive participants who had COVID-19 compared to those who did not have the disease is necessary. The aim of the study was to analyze the autonomic function of young adults after mild-to-moderate infection with COVID-19 and to assess whether body mass index (BMI) and levels of physical activity modulates autonomic function in participants with and without COVID-19. Patients previously infected with COVID-19 and healthy controls were recruited for this cross-sectional observational study. A general anamnesis was taken and BMI and physical activity levels were assessed. The ANS was evaluated through heart rate variability. A total of 57 subjects were evaluated. Sympathetic nervous system activity in post-COVID-19 group was increased (stress index; p=0.0273). They also presented lower values of parasympathetic activity (p<0.05). Overweight/obese subjects in the post-COVID-19 group presented significantly lower parasympathetic activity and reduced global variability compared to non-obese in control group (p<0.05). Physically inactive subjects in post-COVID-19 group presented significantly higher sympathetic activity than active subjects in control group. Parasympathetic activity was significantly increased in physically active subjects in control group compared to the physically inactive post-COVID-19 group (p<0.05). COVID-19 promotes changes in the ANS of young adults, and these changes are modulated by Overweight/obesity and physical activity levels.

Key Points

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Our main finding is that even in mild and moderate infections, young adults who had COVID-19 had greater sympathetic activity, less parasympathetic activity, and global variability when compared to uninfected individuals.

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In participants who were overweight and obese and/or physically inactive, cardiac autonomic modulation showed worse indices.

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Our study provides new insights regarding the role of body mass index and physical activity status on post-COVID-19 infection autonomic deregulation that may contribute to the understand of pathophysiology and treatment of of post-acute sequelae SARS-CoV-2 infection.
SARS-CoV-2 papain-like protease PLpro in complex with natural compounds reveal allosteric sites for antiviral drug design
Authors: Srinivasan Vasundara , Brognaro Hévila , Prabhu Prince R. , de Souza Edmarcia Elisa , Günther Sebastian , Reinke Patrick Y. A. , Lane Thomas J. , Ginn Helen , Han Huijong , Ewert Wiebke , Sprenger Janina , Koua Faisal H. M. , Falke Sven , Werner Nadine , Andaleeb Hina , Ullah Najeeb , Franca Bruno Alves , Wang Mengying , Barra Angélica Luana C , Perbandt Markus , Schwinzer Martin , Schmidt Christina , Brings Lea , Lorenzen Kristina , Schubert Robin , Guaragna Machado Rafael Rahal , Candido Erika Donizette , Leal Oliveira Danielle Bruna , Durigon Edison Luiz , Yefanov Oleksandr , Lieske Julia , Gelisio Luca , Domaracky Martin , Middendorf Philipp , Groessler Michael , Trost Fabian , Galchenkova Marina , Saouane Sofiane , Hakanpää Johanna , Wolf Markus , Turk Dusan , Pearson Arwen R. , Chapman Henry N. , Hinrichs Winfried , Wrenger Carsten , Meents Alke , Betzel Christian
Published: November 2021

SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to aid coronaviruses in evading the host’s innate immune responses. We established a high-throughput X-ray screening to identify inhibitors by elucidating the native PLpro structure refined to 1.42 Å and performing co-crystallization utilizing a diverse library of selected natural compounds. We identified three phenolic compounds as potential inhibitors. Crystal structures of PLpro inhibitor complexes, obtained to resolutions between 1.7-1.9 Å, show that all three compounds bind at the ISG15/Ub-S2 allosteric binding site, preventing the essential ISG15-PLpro molecular interactions. All compounds demonstrate clear inhibition in a deISGylation assay, two exhibit distinct antiviral activity and one inhibited a cytopathic effect in a non-cytotoxic concentration range. These results highlight the druggability of the rarely explored ISG15/Ub-S2 PLpro allosteric binding site to identify new and effective antiviral compounds. Importantly, in the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections.
The Effect of COVID-19 on the Postdoctoral Experience: a comparison of pre-pandemic and pandemic surveys
Authors: Morin Andréanne. , Helling Britney A. , Krishnan Seetha. , Risner Laurie E. , Walker Nykia D. , Schwartz Nancy B.
Published: November 2021

In the interest of advocating for the postdoctoral community in the United States, we present results from survey data collected before and during the COVID-19 pandemic on the same population of postdocs. In 2019, 5,929 postdocs in the US completed a comprehensive survey, and in 2020, a subset completed a follow-up survey several months into the pandemic. The results show that the pandemic has substantially impacted postdocs’ mental health and wellness irrespective of gender, race, citizenship, or other identities. Postdocs also reported a significant impact on their career trajectories and progression, reduced confidence in achieving career goals, and negative perceptions of the job market compared to pre-COVID-19. International postdocs also reported experiencing distinct stressors due to the changes in immigration policy. Notably, having access to Postdoctoral Associations and Postdoctoral Offices positively impacted postdocs’ overall well-being and helped mitigate the personal and professional stresses and career uncertainties caused by the pandemic.

Graphical Abstract

Graphical Abstract of survey responses to: Why or how has your research been disrupted or not disrupted due to the pandemic? Overall, postdocs responded with feelings of loss of control as the pandemic was acting upon them and taking away their ability to complete their work.
Characterization of SARS-CoV-2 public CD4+ αβ T cell clonotypes through reverse epitope discovery
Authors: Rosati Elisa , Pogorelyy Mikhail V. , Minervina Anastasia A. , Scheffold Alexander , Franke Andre , Bacher Petra , Thomas Paul G.
Published: November 2021

The amount of scientific data and level of public sharing produced as a consequence of the COVID-19 pandemic, as well as the speed at which these data were produced, far exceeds any previous effort against a specific disease condition. This unprecedented situation allows for development and application of new research approaches. One of the major technical hurdles in immunology is the characterization of HLA-antigen-T cell receptor (TCR) specificities. Most approaches aim to identify reactive T cells starting from known antigens using functional assays. However, the need for a reverse approach identifying the antigen specificity of orphan TCRs is increasing.

Utilizing large public single-cell gene expression and TCR datasets, we identified highly public CD4+ T cell responses to SARS-CoV-2, covering >75% of the analysed population. We performed an integrative meta-analysis to deeply characterize these clonotypes by TCR sequence, gene expression, HLA-restriction, and antigen-specificity, identifying strong and public CD4+ immunodominant responses with confirmed specificity. CD4+ COVID-enriched clonotypes show T follicular helper functional features, while clonotypes depleted in SARS-CoV-2 individuals preferentially had a central memory phenotype. In total we identify more than 1200 highly public CD4+ T cell clonotypes reactive to SARS-CoV-2. TCR similarity analysis showed six prominent TCR clusters, for which we predicted both HLA-restriction and cognate SARS-CoV-2 immunodominant epitopes. To validate our predictions we used an independent cohort of TCR repertoires before and after vaccination with ChAdOx1, a replication-deficient simian adenovirus-vectored vaccine, encoding the SARS-CoV-2 spike protein. We find statistically significant enrichment of the predicted spike-reactive TCRs after vaccination with ChAdOx1, while the frequency of TCRs specific to other SARS-CoV-2 proteins remains stable. Thus, the CD4-associated TCR repertoire differentiates vaccination from natural infection.

In conclusion, our study presents a novel reverse epitope discovery approach that can be used to infer HLA- and antigen-specificity of orphan TCRs in any context, such as viral infections, antitumor immune responses, or autoimmune disease.

Highlights

Identification of highly public CD4+ T cell responses to SARS-CoV-2

Systematic prediction of exact immunogenic HLA class II epitopes for CD4+ T cell response

Methodological framework for reverse epitope discovery, which can be applied to other disease contexts and may provide essential insights for future studies and clinical applications
CAMO: A molecular congruence analysis framework for evaluating model organisms
Authors: Zong Wei , Rahman Tanbin , Zhu Li , Zeng Xiangrui , Zhang Yingjin , Zou Jian , Liu Song , Ren Zhao , Li Jingyi Jessica , Osterreich Steffi , Ma Tianzhou , Tseng George C.
Published: November 2021

CAMO provides a rigorous and user-friendly solution for quantification and mechanistic exploration of omics congruence in model organisms and humans. It performs threshold-free differential analysis, quantitative concordance/discordance scoring, pathway-centric investigation, and topological subnetwork detection. Instead of dichotomous claims of “poorly” or “greatly” mimicking humans, CAMO facilitates discovery and visualization of specific molecular mechanisms that are best or least mimicked, providing foundations for hypothesis generation and subsequent translational investigations.
The “Alu-ome” shapes the epigenetic environment of regulatory elements controlling cellular defense
Authors: Costallat Mickael , Batsché Eric , Rachez Christophe , Muchardt Christian
Published: November 2021

Promoters and enhancers are sites of transcription initiation (TSSs) and carry active histone modifications, including H3K4me1, H3K4me3, and H3K27ac. Yet, the principles governing the boundaries of such regulatory elements are still poorly characterized. Alu elements are good candidates for a boundary function, being highly abundant in gene-rich regions, while essentially excluded from regulatory elements. Here, we show that the interval from the TSS to the first upstream Alu accommodates all H3K4me3 and most H3K27ac marks, while excluding DNA methylation. Remarkably, the average length of this intervals greatly varies in-between tissues, being longer in stem-and shorter in immune-cells. The very shortest TSS-to-Alu intervals were observed at promoters active in T cells, particularly at immune genes, correlating with RNA polymerase II transcription through the first Alu and accumulation of H3K4me1 signal on this first Alu. Finally, DNA methylation at first-Alus was found to evolved with age, regressing from young to middle-aged, then recovering later in life. Thus, the first Alus upstream of TSSs appear as dynamic boundaries marking the transition from DNA methylation to active histone modifications at regulatory elements, while also participating in the recording of immune gene transcriptional events by positioning H3K4me1-modified nucleosomes.