bluuebunny/crossref_metadata_2025 huggingface dataset:
Febrile Neutropenia Syndromes in Children: Risk Factors and Outcomes of Primary, Prolonged, and Recurrent Fever
Authors: Alali Muayad , David Michael Z. , Ham Sandra A. , Danziger-Isakov Lara , Pisano Jennifer
Published: June 2021

Background:

The approach to recurrent febrile neutropenia (FN) in children with cancer has not been sufficiently addressed and was cited as a research gap in the International Pediatric Fever and Neutropenia (IPFNP) Guideline 2017.

Methods:

Retrospective medical record review for all pediatric cancer patients with a diagnosis of FN was performed. Variables were collected at 2 different time sets (at day 1 and day 4 of presentation). Three FN syndromes have been defined based on the duration and time course of the fever: (1) primary: fever resolved before 96 hours and did not follow with recurrent fever; (2) prolonged fever: episodes failing to defervesce after at least 96 hours of antibacterial therapy; (3) recurrent fever: a new episode of fever >72 hours after resolution of the initial fever when a patient remained neutropenic and on antibiotics or if a fever developed within 1 week after antibiotic discontinuation. These entities were compared with define risk factors and adverse outcomes associated with recurrent fever.

Results:

A total of 633 FN episodes (FNEs) were identified in 268 patients. Each FNE was classified as primary (n=453, 71.5%), prolonged (n=119, 18.7%), or recurrent (n=61, 9.7%). In multivariable analysis, acute myelogenous leukemia (odds ratio [OR]=4.6, 95% confidence interval [CI]: 2.95-7.24), allogeneic stem cell transplant (SCT) (OR=4.9, 95% CI: 2.61-7.35), absolute lymphocyte count <300/mm3 (OR=3.8, 95% CI: 1.30-5.02), prior neutropenia of ≥10 days, (OR=3.95, 95% CI: 1.70-5.93) and hypotension (OR=3.65, 95% CI: 1.30-5.86) on day 1 of presentation were all associated with an increased risk of recurrent fever when compared with primary fever. In subset analysis for only the high-risk FN group, hypotension (OR=3.2, 95% CI: 1.80-4.96), prior neutropenia ≥10 days (OR=2.55, 95% CI: 1.40-6.22), and absolute lymphocyte count <300/mm3 at presentation (OR=2.6, P=0.03, 95% CI: 2.65-7.12) were associated with an increased risk of recurrent fever when compared with high-risk FN not developing recurrent fever. Allogeneic SCT (OR=5.9, 95% CI: 2.65-7.12) and prior neutropenia ≥10 days (OR=2.11, 95% CI: 1.25-9.32) were significantly associated with recurrent fever when compared with prolonged fever. Invasive fungal disease was a more common etiology with recurrent fever compared with primary and prolonged fever (P=0.001 and 0.01, respectively). Recurrent fever episodes were more likely to be admitted to the pediatric intensive care unit (OR=3, 95% CI: 1.27-6.23) and had a higher 30-day mortality (OR=8, 95% CI: 1.87-71.85) when compared with primary fever.

Conclusions:

Knowledge of risk factors for recurrent fever may enable the early detection infection-related complications of this high-risk group, and possible improved approaches to treatment resulting in decreased morbidity and mortality.
Unilateral Breast Uptake of 99mTc-MIBI in a Lactating Woman During Myocardial Perfusion Imaging
Authors: Malhotra Gaurav , Phadke Milind S. , Rakshit Sutapa , Bagul Swati D. , Verma Priyanka , Asopa Ramesh V.
Published: June 2021

A 34-year-old woman, who was 11 months postpartum, underwent 99mTc-MIBI myocardial perfusion SPECT imaging for atypical symptomatology with normal baseline electrocardiogram and 2-dimensional echocardiography. She was lactating on and off, preferentially from the right breast. Analysis of the raw images revealed unilateral intense tracer uptake in the right breast region that persisted in the delayed spot views (24-hour postinjection). Although bilateral breast uptake of 99mTc-MIBI may be seen in postpartum scenario, unilateral breast uptake can also occur in patients with preferential lactation from 1 breast as seen in this case and should not be mistaken for pathology.
What Is the Optimal Method on Myocardial Suppression in FDG PET/CT Evaluation of Cardiac Sarcoidosis?
Authors: Lu Yang , Sweiss Nadera J. , Macapinlac Homer A.
Published: June 2021

Based on the recent publications, including large cohort retrospective study and prospective clinical trial data, we are commenting on the optimal methods on myocardial suppression in FDG PET/CT evaluation of patients with suspected cardiac sarcoidosis.
Failure to Rescue After Pancreatoduodenectomy
Authors: Gleeson Elizabeth M. , Pitt Henry A. , Mackay Tara. M. , Wellner Ulrich F. , Williamsson Caroline , Busch Olivier R. , Koerkamp Bas Groot , Keck Tobias , van Santvoort Hjalmar C. , Tingstedt Bobby , Besselink Marc G.
Published: June 2021

Objective:

This analysis aimed to compare failure to rescue (FTR) after pancreatoduodenectomy across the Atlantic.

Summary Background Data:

FTR, or mortality after development of a major complication, is a quality metric originally created to compare hospital results. FTR has been studied in North American and Northern European patients undergoing pancreatoduodenectomy (PD). However, a direct comparison of FTR after PD between North America and Northern Europe has not been performed.

Methods:

Patients who underwent PD in North America, the Netherlands, Sweden and Germany (GAPASURG dataset) were identified from their respective registries (2014–17). Patients who developed a major complication defined as Clavien-Dindo ≥3 or developed a grade B/C postoperative pancreatic fistula (POPF) were included. Preoperative, intraoperative, and postoperative variables were compared between patients with and without FTR. Variables significant on univariable analysis were entered into a logistic regression for FTR.

Results:

Major complications occurred in 6188 of 22,983 patients (26.9%) after PD, and 504 (8.1%) patients had FTR. North American and Northern European patients with complications differed, and rates of FTR were lower in North America (5.4% vs 12%, P < 0.001). Fourteen factors from univariable analysis contributing to differences in patients who developed FTR were included in a logistic regression. On multivariable analysis, factors independently associated with FTR were age, American Society of Anesthesiology ≥3, Northern Europe, POPF, organ failure, life-threatening complication, nonradiologic intervention, and reoperation.

Conclusions:

Older patients with severe systemic diseases are more difficult to rescue. Failure to rescue is more common in Northern Europe than North America. In stable patients, management of complications by interventional radiology is preferred over reoperation.
Chemotherapy Versus Chemotherapy Plus Chemoradiation as Neoadjuvant Therapy for Resectable Gastric Adenocarcinoma
Authors: Allen Casey J. , Pointer David T. , Blumenthaler Alisa N. , Mehta Rutika J. , Hoffe Sarah E. , Minsky Bruce D. , Smith Grace L. , Blum Mariela , Mansfield Paul F. , Ikoma Naruhiko , Das Prajnan , Ajani Jaffer , Dineen Sean P. , Fleming Jason B. , Badgwell Brian D. , Pimiento Jose M.
Published: June 2021

Objective:

We compare neoadjuvant chemotherapy (CT) to neoadjuvant chemotherapy plus chemoradiation (CRT) for patients with gastric adenocarcinoma (GA).

Summary of Background Data:

The optimal neoadjuvant therapy regimen for resectable GA is not defined.

Methods:

Utilizing data from 2 high-volume cancer centers, we analyzed patients who underwent surgery for localized GA from 1/1/2000-12/31/2017. Standard CT regimens were used according to treatment period. We compared propensity matched cohorts based on age, sex, race, histology, and clinical stage.

Results:

Four-hundred five patients (age 62 ± 12 year, 58% male, 56% White) were analyzed. 231 (57%) received CRT and 174 (43%) received CT. Groups differed based on histopathologic characteristics including preoperative stage (p = 0.013). To control for these differences, propensity matched cohorts of 113 CT and 113 CRT patients were compared. CRT had similar frequencies of microscopically negative resections to CT (93% vs 91%, p = 0.81), but higher rates of complete pathologic response (15% vs 4%, p = 0.003) and lower pathologic stage (p = 0.002). Completion of intended perioperative therapy occurred in 63% of CT and 91% of CRT patients (p < 0.001). Median DFS was 45mo (95%CI: 20–70) in the CT group and 113mo (95%CI: 75–151) in the CRT group (p = 0.018). Median OS was 53mo (95%CI: 30–77) versus 120mo (95%CI: 101–138); p = 0.015.

Conclusions:

In this multi-institutional comparison of neoadjuvant CT and CRT for resectable GA, CRT is associated with higher rates of completed perioperative therapy, higher rates of complete pathologic response, lower pathologic stage, and improved survival.

Level of Evidence: Level III
Crossed Hemispheric Accumulation of β-Amyloid and Tau Protein in a Patient With Typical Alzheimer Disease
Authors: Kim Hyung-Ji , Jo Sungyang , Lee Sunju , Oh Minyoung , Lee Jae-Hong
Published: June 2021

Amyloid (Aβ) and tau proteins are pathologic hallmarks of Alzheimer disease (AD). It is well known that there is spatial disparity between Aβ and tau protein deposition but, crossed hemispheric accumulation of these 2 proteins has not been reported. Here we report the case of a 76-year-old woman with typical AD who underwent amyloid positron emission tomography (PET) ([18F]-florbetaben) and tau PET scans ([18F]PI-2620), revealing crossed accumulation of Aβ and tau in the cerebral hemisphere. A neuropsychological assessment showed impairment in memory with spared activities of daily living. In the PET analysis, amyloid deposition was observed only in the left side of the cerebral hemisphere and tau only in the right side. Neuroimaging follow-up indicated that the spatial pattern of these protein accumulations had not changed. This case suggests the possibility of independent Aβ and tau pathogenic pathways in AD.
GAD65 Autoimmune Encephalitis
Authors: Vanhoorne Alexander , Van Langenhove Tim , Miatton Marijke , Laureys Guy
Published: June 2021

We describe a patient who presented with subacute onset of short-memory impairment, disorientation, and gait instability, with progressive deterioration. Workup demonstrated glutamic acid decarboxylase antibody–related encephalitis. Aggressive immunotherapy with high-dose intravenous corticoids, followed by slow oral taper, plasmapheresis, rituximab, and cyclophosphamide did not halt disease progression. During follow-up, she developed a frontotemporal dementia phenotype. Serial imaging showed the appearance of marked atrophy of the frontal and anterior temporal regions. We conclude that glutamic acid decarboxylase antibody–related encephalitis may rarely present with a treatment-refractory frontotemporal phenotype.
Large-scale trans-ethnic replication and discovery of genetic associations for rare diseases with self-reported medical data
Authors: Shringarpure Suyash S. , Wang Wei , Jiang Yunxuan , Acevedo Alison , Dhamija Devika , Cameron Briana , Jubb Adrian , Yue Peng ,   The 23andMe Research Team, Sarov-Blat Lea , Gentleman Robert , Auton Adam
Published: June 2021

A key challenge in the study of rare disease genetics is assembling large case cohorts for well-powered studies. We demonstrate the use of self-reported diagnosis data to study rare diseases at scale. We performed genome-wide association studies (GWAS) for 33 rare diseases using self-reported diagnosis phenotypes and re-discovered 29 known associations to validate our approach. In addition, we performed the first GWAS for Duane retraction syndrome, vestibular schwannoma and spontaneous pneumothorax, and report novel genome-wide significant associations for these diseases. We replicated these novel associations in non-European populations within the 23andMe, Inc. cohort as well as in the UK Biobank cohort. We also show that mixed model analyses including all ethnicities and related samples increase the power for finding associations in rare diseases. Our results, based on analysis of 19,084 rare disease cases for 33 diseases from 7 populations, show that large-scale online collection of self-reported data is a viable method for discovery and replication of genetic associations for rare diseases. This approach, which is complementary to sequencing-based approaches, will enable the discovery of more novel genetic associations for increasingly rare diseases across multiple ancestries and shed more light on the genetic architecture of rare diseases.
Unrepresentative Big Surveys Significantly Overestimate US Vaccine Uptake
Authors: Bradley Valerie C. , Kuriwaki Shiro , Isakov Michael , Sejdinovic Dino , Meng Xiao-Li , Flaxman Seth
Published: June 2021

Surveys are a crucial tool for understanding public opinion and behavior, and their accuracy depends on maintaining statistical representativeness of their target populations by minimizing biases from all sources. Increasing data size shrinks confidence intervals but magnifies the impact of survey bias – an instance of the Big Data Paradox1. Here we demonstrate this paradox in estimates of first-dose COVID-19 vaccine uptake in US adults: Delphi-Facebook2,3(about 250,000 responses per week) and Census Household Pulse4(about 75,000 per week). By May 2021, Delphi-Facebook overestimated uptake by 17 percentage points and Census Household Pulse by 14, compared to a benchmark from the Centers for Disease Control and Prevention (CDC). Moreover, their large data sizes led to minuscule margins of error on the incorrect estimates. In contrast, an Axios-Ipsos online panel5with about 1,000 responses following survey research best practices6provided reliable estimates and uncertainty. We decompose observed error using a recent analytic framework1to explain the inaccuracy in the three surveys. We then analyze the implications for vaccine hesitancy and willingness. We show how a survey of 250,000 respondents can produce an estimate of the population mean that is no more accurate than an estimate from a simple random sample of size 10. Our central message is that data quality matters far more than data quantity, and compensating the former with the latter is a mathematically provable losing proposition.
A Warm-start Digital CRISPR-based Method for the Quantitative Detection of Nucleic Acids
Authors: Wu Xiaolin , Lee Yie Hou , Lu Timothy K. , Yu Hanry
Published: June 2021

Nucleic acids-based molecular diagnostic tools incorporating the CRISPR/Cas system are being developed as rapid and sensitive methods for pathogen detection. However, most CRISPR/Cas-based diagnostics lack quantitative detection ability. Here, we report Warm-Start RApid DIgital Crispr Approach (WS-RADICA), which uses commercially available digital chips for the rapid, sensitive, and quantitative detection of nucleic acids. WS-RADICA detected as little as 1 copy/μl SARS-CoV-2 RNA in 40 min (qualitative detection) or 60 min (quantitative detection). WS-RADICA can be easily adapted to various digital devices: two digital devices were evaluated for both DNA and RNA quantification, with linear dynamic ranges of 0.8-12777 copies/µL for DNA and 1.2-18391 copies/µL for RNA (both R2 values > 0.99). Moreover, WS-RADICA had greater sensitivity and inhibitor tolerance than a bulk RT-LAMP-Cas12b reaction and similar performance to RT-qPCR and RT-dPCR. Given its speed, sensitivity, quantification capability, and inhibitor tolerance, WS-RADICA shows great promise for a variety of applications requiring nucleic acid quantification.
SARS-CoV-2 is associated with changes in brain structure in UK Biobank
Authors: Douaud Gwenaëlle , Lee Soojin , Alfaro-Almagro Fidel , Arthofer Christoph , Wang Chaoyue , McCarthy Paul , Lange Frederik , Andersson Jesper L.R. , Griffanti Ludovica , Duff Eugene , Jbabdi Saad , Taschler Bernd , Keating Peter , Winkler Anderson M. , Collins Rory , Matthews Paul M. , Allen Naomi , Miller Karla L. , Nichols Thomas E. , Smith Stephen M.
Published: June 2021

There is strong evidence for brain-related abnormalities in COVID-191–13. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51–81) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.
Evidence for lower threshold for diagnosis of hypertension: inferences from an urban-slum cohort in India
Authors: Awadhiya Onkar , Tiwari Ankit , Solanki Premlata , Lahiri Anuja , Shrivastava Neelesh , Joshi Ankur , Pakhare Abhijit P , Joshi Rajnish
Published: June 2021

Background

Hypertension (HTN) is a key risk-factor for cardiovascular diseases (CVDs). Blood-pressure (BP) categorizations between systolic blood pressure (SBP) of 120 and 140 remain debatable. In the current study we aim to evaluate if individuals with a baseline SBP between 130-140 mm Hg (hypertension as per AHA 2017 guidelines) have a significantly higher proportion of incident hypertension on follow-up, as compared to those with SBP between 120-130 mm Hg.

Methods

Secondary data analysis was performed in a community-based cohort, instituted, and followed since 2017. Participants were aged ≥30 years, residents of urban slums in Bhopal. BP was measured at or near home by Community Health Workers (CHWs). Two-year follow up was completed in 2019. We excluded participants who were on BP reduction therapy, had fewer than two out-of-office BP measurements and who could not be followed. Eligible participants were re-classified based on baseline BP in four categories: Normal (Category-A), Elevated-BP (Category-B), Variable-BP (Category-C) and reclassified HTN based on AHA-2017 (Category-D). Proportion of individuals who developed incident hypertension on follow up was primary outcome.

Result

Out of 2649 records, 768 (28.9%), 647 (24.4%), 586 (22.1%), 648 (24.4%) belonged to Categories A, B, C and D respectively. Incident HTN with cut-off of 140/90 mm Hg was, 1.6%, 2.6%, 6.7%, 12% in categories A, B, C and D respectively. Incidence of incident hypertension in individuals with a baseline SBP between 130-140 mm Hg (Category D) was significantly higher as compared to those with SBP between 120-130 mm Hg (Category B).

Conclusion

We conclude that biological basis for AHA-2017 definition of hypertension is relatively robust also for low income and resource-limited settings. Evidence from our longitudinal study will be useful for policy makers for harmonizing national guidelines with AHA-2017.
A New Saliva-Based Lateral-Flow SARS-CoV-2 IgG Antibody Test for mRNA Vaccination
Authors: Shan Dingying , Hsiung Jessica , Bliden Kevin P. , Zhao Su , Liao Tao , Wang Guoxing , Tan Shuanglin , Liu Tiancheng , Sreedhar Deepika , Kost Jessica , Chang Shin Ting , Yuan Wei Po , Tantry Udaya , Gurbel Paul , Tang Meijie , Dai Hongjie
Published: June 2021

Sensitive detection of IgG antibodies against SARS-CoV-2 is important to assessing immune responses to viral infection or vaccination and immunity duration. Antibody assays using non-invasive body fluids such as saliva could facilitate mass testing including young children, elderly and those who resist blood draws, and easily allowing longitudinal testing/monitoring of antibodies over time. Here, we developed a new lateral flow (nLF) assay that sensitively detects SARS-CoV-2 IgG antibodies in the saliva samples of vaccinated individuals and previous COVID-19 patients. The 25-minute nLF assay detected anti-spike protein (anti-S1) IgG in saliva samples with 100% specificity and high sensitivity from both vaccinated (99.51% for samples ≥ 19 days post 1st Pfizer/BioNTech or Moderna mRNA vaccine dose) and infected individuals. Antibodies against nucleocapsid protein (anti-NCP) was detected only in the saliva samples of COVID-19 patients and not in vaccinated samples, allowing facile differentiation of vaccination from infection. SARS-CoV-2 anti-S1 IgG antibody in saliva measured by nLF demonstrated similar evolution trends post vaccination to that in matching dried blood spot (DBS) samples measured by a quantitative pGOLD lab-test, enabling the nLF to be a valid tool for non-invasive personalized monitoring of SARS-CoV-2 antibody persistence. The new salivary rapid test platform can be applied for non-invasive detection of antibodies against infection and vaccination in a wide range of diseases.
Poor Readability of COVID-19 Vaccine Information for the General Public: A Lost Opportunity
Authors: Bothun Luke S. , Feeder Scott E. , Poland Gregory A.
Published: June 2021

Background

All adults in the Unites States now have access to COVID-19 vaccines. During the vaccination process, Emergency Use Authorization (EUA) fact sheets are provided.

Objective

To analyze the ease of reading (i.e., readability) of the EUA-approved fact sheets for the vaccines currently available in the United States, the V-Safe adverse event survey script, and the Centers for Disease Control and Prevention (CDC) website on COVID-19 vaccines.

Design

We analyzed the readability of Pfizer, Moderna, and Janssen EUA fact sheets, as well as the V-Safe survey script and the vaccine-related information on the CDC website.

Measurements

Readability factors include the following: average length of paragraphs, sentences, and words; font size and style; use of passive voice; the Gunning-Fog index; the Flesch Reading Ease index; and the Flesch-Kincaid Grade Level index.

Results

Only the V-Safe adverse event survey script met readability standards for adequate comprehension. The mean readability scores of the EUA fact sheets and the CDC website were as follows: Flesch Reading Ease score (mean 44.35); Flesch-Kincaid Grade Level (mean 10.48); and Gunning-Fog index (mean 11.8). These scores indicate that a 10th-12thgrade-level education is necessary to comprehend these documents.

Conclusion

The average person in the United States would have difficulty understanding the information provided in the EUA fact sheets and CDC COVID-19 vaccine website; however, the V-Safe survey was written at an appropriate reading level. To ensure that the public fully understands information regarding COVID-19 vaccines, simplified information material should be developed.
Climate change education in public health and medical curricula in Australian and New Zealand Universities: a mixed methods study of barriers and areas for further action
Authors: Lal Aparna , Walsh Erin , Weatherell Ali , Slimings Claudia
Published: June 2021

Background

The World Health Organization deemed climate change and air pollution as the top threat to global health in 2019. The importance of climate for health is recognised by healthcare professionals, who need to be equipped to deliver environmentally sustainable healthcare and promote planetary health. There is some evidence that climate change and health is not strongly embedded in accredited master-level public health training programs and medical programs globally, however, the immersion of climate-health in Australian and New Zealand programs is unclear.

Objectives

To explore the extent to which climate-health education is currently embedded into public health and medical curricula in Australia and New Zealand.

Methods

Educators identified by their coordination, convenorship, or delivery into programs of public health and medicine at universities in Australia and New Zealand were invited to participate in a cross-sectional, exploratory mixed methods study. Participants completed an online quantitative survey and qualitative interviews regarding their experience in program and course delivery, and the prominence of climate-health content within program and course delivery. Quantitative surveys were analysed using descriptive statistics and qualitative interview content was analysed via a modified ground theory approach.

Results

The response rate of the quantitative survey was 43.7% (21/48). Ten survey respondents also completed qualitative interviews. Quantitative results showed that epidemiologists were the most common experts involved in design and delivery of this curriculum, with a reliance on guest lecturers to provide updated content. Qualitative interviews highlighted the ad-hoc role of Indigenous-led content in this field, the barriers of time and resources to develop a coherent curriculum and the important role of high-level champions to drive the inclusion of climate change and planetary health.

Conclusion

There is an urgent need to strengthen current support available for pedagogical leadership in the area of climate and broader environmental change teaching at universities.
A Patient-Reported Measure of Locomotor Function Derived from the Functional Assessment Questionnaire
Authors: Schwartz Michael H. , Aldahondo Nanette , MacWilliams Bruce A.
Published: June 2021

Background

Locomotor function is often impaired in children diagnosed with cerebral palsy (CP). Improving locomotor function is a common goal of treatment. The current gold standard for assessing locomotor function in CP is the gross motor function measure (GMFM-66). The GMFM-66 requires an in-person assessment by a trained clinician. It would be useful to have a measure of function that is like the GMFM-66 but can be assessed through patient report.

Methods

We queried the clinical databases of two motion analysis centers (Gillette Children’s Specialty Healthcare and Shriners Hospital – Salt Lake City) for individuals with a diagnosis of cerebral palsy (CP) who were 18 years old or younger and had undergone instrumented clinical gait analysis that included the functional assessment questionnaire (FAQ). We computed the transformed FAQ (FAQt) as the weighted sum of the skills an individual was able to perform, where the weighting was the difficulty of the skills. We assessed concurrent and external validity of the FAQt by comparing it to the GMFM-66.

Results

The FAQt exhibited strong concurrent and external validity. Linear regression showed that the GMFM-66 explained 54% of the variance in FAQt, and the linear fit was independent of center. The FAQt evolved with age in a manner similar to the GMFM-66, with higher functioning individuals, as measured by gross motor function classification system level, achieving higher levels of function at a higher rate and an earlier age compared to their lower functioning peers. The findings with respect to GMFM-66 did not depend on the center at which the data was acquired.

Conclusions

The FAQt demonstrates strong concurrent and external validity, making it a useful measure of locomotor function.
Quantitative definition of fever needs a change
Authors: Kumar Nitin , Kapoor Mayank , Panda Prasan Kumar , Singh Yogesh , Bhadoriya Ajeet Singh
Published: June 2021

Background

The age-old definition of fever was derived using cross-sectional population surveying utilizing old techniques without considering symptomatology. However, the diagnosis of fever must be made only in the presence of associated symptoms that can distinguish it from the mere asymptomatic physiologic rise of temperature. Association of the temperature values with the symptoms to define the cut-off for fever is need of the hour.

Methods

A longitudinal study on the healthy population of Northen-India were followed-up over 1-year. Participants were advised for self-monitoring of oral temperature with a standard digital thermometer in either left or right sublingual pocket and record it in the thermometry diary. The study was considered complete if the participant had all the three phases of the study (i.e. non-febrile, febrile, and post-febrile phases) or completed the duration of the study.

Results

Per protocol analysis done for febrile participants (n=144, temperature recordings= 23851). The mean febrile phase temperature was 100.25 ± 1.440F. A temperature of 99.10F had maximum diagnostic accuracy for feeling feverish (98.2%), along with one (98.3%) or two (99%) associated symptoms. Summer and spring months showed higher temperatures (100.38 ± 1.44 v/s 99.80 ± 1.49, P<0.001), whereas no significant temperature difference could be noted amongst the gender.

Conclusions

A revised cut-off for the temperature to decide fever is hereby proposed: 99.10F along with one or two associated symptoms. This is going to redefine fever in the modern era completely.
INCIDENCE OF VENOUS THROMBOTIC EVENTS AND EVENTS OF SPECIAL INTEREST IN A RETROSPECTIVE COHORT OF COMMERCIALLY-INSURED US PATIENTS
Authors: Weller Susan C. , Porterfield Laura , Davis John W. , Wilkinson Gregg S. , Chen Lu , Baillargeon Jacques
Published: June 2021

Objective

To estimate the US incidence of thrombotic events and related rare diagnoses.

Design

Claims-based retrospective cohort study of incidence.

Setting

US commercial health insurance administrative claims database.

Participants

Adults 25-65 years of age between 2015 and 2019 with a minimum of 12 consecutive thrombosis-free months of continuous enrollment beginning 2014 were selected.

Main Outcomes

Age (10-year intervals) and sex stratum specific incidence rates per 100,000 person-years were determined for: venous thromboembolism (VTE), cerebral venous thrombosis (CVT), and other major venous thrombotic events, and events of special interest, including immune thrombocytopenic purpura (ITP), hemolytic-uremic syndrome (HUS), and heparin-induced thrombocytopenia (HIT).

Results

Of 13,249,229 enrollees (half female/male), incidence of venous thromboembolic events (DVT, PE, CVT, or other major venous thrombotic conditions) was 247.89 per 100,000 person-years (95% CI: 245.96, 249.84). Incidence of VTE was 213.79 with ICD codes alone (95% CI: 211.99, 215.59) and 127.18 (95% CI: 125.80, 128.58) when also requiring a filled anticoagulation prescription. Incidence was 6.37 for CVT (95% CI: 6.07, 6.69), 26.06 for ITP (95% CI: 25.44, 26.78), 0.94 for HUS (95% CI: 0.82, 1.06), and 4.82 for HIT (95% CI: 4.56, 5.10). The co-occurrence of CVT with either ITP or HIT (diagnoses within 14 days of one another) was 0.090 (95% CI: 0.06, 0.13). Incidence tended to increase with age and was higher for women under 55. Incidence for CVT, HUS, and CVT with ITP or HIT was higher for women in all age groups. Incidence of PE and CVT increased significantly over the five-year period, while DVT rates decreased.

Conclusions

These results are the first US estimates for incidence of thrombotic and rare events of interest in a large, commercially-insured US population. Findings provide a critically important reference for determining excess morbidity associated with COVID-19 and more generally for vaccine pharmacovigilance.

BOX POINTS

What is already known on this topic?

Incidence of venous thromboembolic diagnoses vary by country and date.

There have been improvements in the past decade in thromboprophylaxis (e.g., for deep vein thrombosis) and detection (e.g., for cerebral venous thrombosis), but there are no recent comprehensive estimates for the United States.

What this study adds

Our results document the US incidence of thrombotic and related rare diagnoses for the most recent five-year pre-pandemic period (2015-2019) in an insured population.
Rapid antifouling nanocomposite coating enables highly sensitive multiplexed electrochemical detection of myocardial infarction and concussion markers
Authors: Timilsina Sanjay S. , Durr Nolan , Yafia Mohamed , Sallum Hani , Jolly Pawan , Ingber Donald E.
Published: June 2021

Here we describe an ultra-fast (< 1 min) method for coating electrochemical (EC) sensors with an anti-fouling nanocomposite layer that can be stored at room temperature for months, which provides unprecedented sensitivity and selectivity for diagnostic applications. We leveraged this method to develop a multiplexed diagnostic platform for detection of biomarkers that could potentially be used to triage patients with myocardial infarction and traumatic brain injury using only 15 µL of blood. Single-digit pg/mL sensitivity was obtained within minutes for all the biomarkers tested in unprocessed human plasma samples and whole blood, which is much faster and at least 50 times more sensitive than traditional ELISA methods, and the signal was stable enough to be measured after one week of storage. The multiplexed EC sensor platform was validated by analyzing 22 patient samples, which demonstrated excellent correlation with reported clinical values.
Immunogenicity and reactogenicity of a heterologous COVID-19 prime-boost vaccination compared with homologous vaccine regimens
Authors: Schmidt Tina , Klemis Verena , Schub David , Mihm Janine , Hielscher Franziska , Marx Stefanie , Abu-Omar Amina , Schneitler Sophie , Becker Sören L. , Gärtner Barbara C. , Sester Urban , Sester Martina
Published: June 2021

Heterologous priming with the ChAdOx1-nCoV-19 vector-vaccine followed by boosting with an mRNA-vaccine is currently recommended in Germany, although data on immunogenicity and reactogenicity are not available. Here we show that the heterologous regimen induced spike-specific IgG, neutralizing antibodies, and spike-specific CD4 T-cells, which were significantly more pronounced than after homologous vector boost, and higher or comparable in magnitude to the homologous mRNA regimens. Moreover, spike-specific CD8 T-cell levels after heterologous vaccination were significantly higher than after both homologous regimens. Cytokine expression profiling showed a predominance of polyfunctional T-cells expressing IFNγ, TNFα and IL-2 with subtle differences between regimens. Both recipients of the homologous vector-regimen and the heterologous vector/mRNA-combination were most affected by the priming vector-vaccination, whereas heterologous boosting was well tolerated and comparable to homologous mRNA-boosting. Taken together, heterologous vector-mRNA boosting induces strong humoral and cellular immune responses with acceptable reactogenicity profile. This knowledge will have implications for future vaccine strategies.
Similar Rates of AKI during the First Two Waves of COVID-19 in Northern Italy: a single-center study
Authors: Alfano Gaetano , Giovanella Silvia , Fontana Francesco , Milic Jovana , Ligabue Giulia , Giaroni Francesco , Ferri Camilla , Montali Martina , Melluso Andrea , Niccolò Morisi , Mori Giacomo , Magistroni Riccardo , Franceschini Erica , Bedini Andrea , Cuomo Giacomo , DiGaetano Margherita , Meschiari Marianna , Mussini Cristina , Cappelli Gianni , Guaraldi Giovanni
Published: June 2021

Introduction

Two waves of COVID-19 cases have overwhelmed most European countries during 2020. It is unclear if the incidence of acute kidney injury (AKI) has changed during the COVID-19 outbreaks. This study aims to evaluate the differences in incidence, risk factors and outcome of AKI in patients with SARS-CoV-2 infection during the first and second wave of COVID-19.

Method

We reviewed the health medical records of 792 consecutive patients with COVID-19 hospitalized at the University Hospital of Modena, Italy, from February 25 to December 14, 2020.

Results

AKI was diagnosed in 122 (15.4%) patients. Incidence of AKI remained steady rate during wave-1 (15.9%) and wave-2 (14.7%) (P=0.89). AKI patients were older (P=<0.001) and had a more severe respiratory impairment (PO2/FO2) (P=≤0.001) than their non-AKI counterparts. AKI led to a longer hospital stay (P=0.001), complicated with a higher rate of ICU admission. COVID-19-related AKI was associate with 59.7% of deaths during wave-1 and 70.6% during wave-2. At the end of the period of observation, 24% (wave-1) and 46.7% (wave-2) of survivors were discharged with a not fully recovered kidney function. Risk factors for AKI in patients with COVID-19 were diuretics (HR=5.3; 95%CI, 1.2-23.3; P=0.025) and cardiovascular disease (HR, 2.23; 95%CI, 1.05-5.1; P=0.036).

Conclusion

The incidence of AKI (about 15%) remained unchanged during 2020, regardless of the trend of COVID-19. AKI occurred in patients with severe COVID-19 symptoms and was associated with a higher incidence of deaths than non-AKI patients. The risk factors of COVID-19-related AKI were diuretic therapy and cardiovascular disease.
Quantifying concordant genetic effects of de novo mutations on multiple disorders
Authors: Guo Hanmin , Hou Lin , Shi Yu , Jin Sheng Chih , Zeng Xue , Li Boyang , Lifton Richard P. , Brueckner Martina , Zhao Hongyu , Lu Qiongshi
Published: June 2021

Exome sequencing on tens of thousands of parent-proband trios has identified numerous deleterious de novo mutations (DNMs) and implicated risk genes for many disorders. Recent studies have suggested shared genes and pathways are enriched for DNMs across multiple disorders. However, existing analytic strategies only focus on genes that reach statistical significance for multiple disorders and require large trio samples in each study. As a result, these methods are not able to characterize the full landscape of genetic sharing due to polygenicity and incomplete penetrance. In this work, we introduce EncoreDNM, a novel statistical framework to quantify shared genetic effects between two disorders characterized by concordant enrichment of DNMs in the exome. EncoreDNM makes use of exome-wide, summary-level DNM data, including genes that do not reach statistical significance in single-disorder analysis, to evaluate the overall and annotation-partitioned genetic sharing between two disorders. Applying EncoreDNM to DNM data of nine disorders, we identified abundant pairwise enrichment correlations, especially in genes intolerant to pathogenic mutations and genes highly expressed in fetal tissues. These results suggest that EncoreDNM improves current analytic approaches and may have broad applications in DNM studies.
miR-544-3p mediates arthritis pain through regulation of FcγRI
Authors: Liu Yan , Jeon Sang-Min , Caterina Michael J. , Qu Lintao
Published: June 2021

Chronic or episodic joint pain is a major symptom in rheumatoid arthritis (RA) and its adequate treatment represents an unmet medical need. However, the cellular and molecular mechanisms underlying RA pain remain elusive. Non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of RA as negative regulators of the stability or translation of specific target mRNAs. Yet, their significance in RA pain is still not well defined. We and other groups recently identified neuronally expressed FcγRI as a key driver of arthritis pain in mouse RA models. Thus, we tested the hypothesis that miRNAs that target and regulate neuronal FcγRI attenuate RA pain. Here, we show that miR-544-3p was robustly downregulated whereas FcγRI was significantly upregulated in the dorsal root ganglion (DRG) in mouse RA models. Intrathecal injection of miR-544-3p mimic attenuated established mechanical and heat hyperalgesia in a mouse model of collagen II-induced arthritis (CIA). Moreover, this effect was likely mediated, at least in part, by FcγRI since miR-544-3p mimic downregulated FcγRI in the DRG during arthritis and genetic deletion of FcγRI produced similar antihyperalgesic effects in the CIA model. This notion was further supported by a dual luciferase assay showing that miR-544-3p targeted FcγRI by directly binding to its 3’UTR. In addition, FcγRI expression in DRG neurons in vitro was downregulated by miR-544-3p mimic and upregulated by miR-544-3p inhibitor. In naïve mice, miR-544-3p mimic alleviated acute joint pain hypersensitivity induced by IgG immune complex (IgG-IC), whereas miR-544-3p inhibitor potentiated the pro-nociceptive behavioral effect of IgG-IC. These findings suggest that miR-544-3p causally participates in the maintenance of arthritis pain by targeting neuronal FcγRI, and thus define miR-544-3p as a new potential therapeutic target for treating RA pain.
Rapid Characterization of Human Serum Albumin Binding for Per- And Polyfluoroalkyl Substances Using Differential Scanning Fluorimetry
Authors: Jackson Thomas W. , Scheibly Chris M. , Polera M. E. , Belcher Scott M.
Published: June 2021

Per- and polyfluoroalkyl substances (PFAS) are a diverse class of synthetic chemicals that accumulate in the environment. Many proteins, including the primary human serum transport protein albumin (HSA), bind PFAS. The predictive power of physiologically based pharmacokinetic modeling approaches are currently limited by a lack of experimental data defining albumin binding properties for most PFAS. A novel thermal denaturation assay was optimized to evaluate changes in thermal stability of HSA in the presence of increasing concentrations of known ligands and a structurally diverse set of PFAS. Assay performance was initially evaluated for fatty acids and HSA binding drugs ibuprofen and warfarin. Concentration response relationships were determined and dissociation constants (Kd) for each compound were calculated using regression analysis of the dose-dependent changes in HSA melting temperature. Estimated Kdvalues for HSA binding of octanoic acid, decanoic acid, hexadecenoic acid, ibuprofen and warfarin agreed with established values. The binding affinities for 24 PFAS that included perfluoroalkyl carboxylic acids (C4-C12), perfluoroalkyl sulfonic acids (C4-C8), mono- and polyether perfluoroalkyl ether acids, and polyfluoroalkyl fluorotelomer substances were determined. These results demonstrate the utility of this differential scanning fluorimetry assay as a rapid high through-put approach for determining the relative protein binding properties and identification of chemical structures involved in binding for large numbers of structurally diverse PFAS.
Deep learning models for identification of splice junctions across species
Authors: Dutta Aparajita , Singh Kusum Kumari , Anand Ashish
Published: June 2021

Deep learning models like convolutional neural networks (CNN) and recurrent neural networks (RNN) have been frequently used to identify splice sites from genome sequences. Most of the deep learning applications identify splice sites from a single species. Furthermore, the models generally identify and interpret only the canonical splice sites. However, a model capable of identifying both canonical and non-canonical splice sites from multiple species with comparable accuracy is more generalizable and robust. We choose some state-of-the-art CNN and RNN models and compare their performances in identifying novel canonical and non-canonical splice sites in homo sapiens, mus musculus, and drosophila melanogaster.

The RNN-based model named SpliceViNCI outperforms its counterparts in identifying splice sites from multiple species as well as on unseen species. SpliceViNCI maintains its performance when trained with imbalanced data making it more robust. We observe that all the models perform better when trained with more than one species. SpliceViNCI outperforms the counterparts when trained with such an augmented dataset. We further extract and compare the features learned by SpliceViNCI when trained with single and multiple species. We validate the extracted features with knowledge from the literature.
CCPE: Cell Cycle Pseudotime Estimation for Single Cell RNA-seq Data
Authors: Liu Jiajia , Yang Mengyuan , Zhao Weiling , Zhou Xiaobo
Published: June 2021

The rapid development of single-cell RNA-sequencing (scRNA-seq) technologies makes it possible to characterize cellular heterogeneity by detecting and quantifying transcriptional changes at the single-cell level. Pseudotime analysis enables to characterize the continuous progression of various biological processes, such as cell cycle. Cell cycle plays an important regulatory role in cell fate decisions and differentiation and is also often regarded as a confounder in scRNA-seq data analysis when analyzing the role of other factors on transcriptional regulation. Therefore, accurate prediction of cell cycle pseudotime and identify cell stages are important steps for characterizing the development-related biological processes, identifying important regulatory molecules and promoting the analysis of transcriptional heterogeneity. Here, we develop CCPE, a novel cell cycle pseudotime estimation method to characterize cell cycle timing and determine cell cycle phases from single-cell RNA-seq data. CCPE uses a discriminative helix to characterize the circular process and estimates pseudotime in the cell cycle. We evaluated the model performance based on a variety of simulated and real scRNA-seq datasets. Our results indicate that CCPE is an effective method for cell cycle estimation and competitive in various downstream analyses compared with other existing methods. CCPE successfully identified cell cycle marker genes and is robust to dropout events in scRNA-seq data. CCPE also has excellent performance on small datasets with fewer genes or cells. Accurate prediction of the cell cycle in CCPE effectively contributes to cell cycle effect removal across cell types or conditions.
Developmental plasticity in male courtship in Bicyclus anynana butterflies is driven by hormone regulation of the yellow gene
Authors: Connahs Heidi , Tan Eunice Jingmei , Ter Yi Ting , Dion Emilie , Matsuoka Yuji , Bear Ashley , Monteiro Antónia
Published: June 2021

The organizational role for hormones in the regulation of sexual behavior is currently poorly explored. Previous work showed that seasonal variation in levels of the steroid hormone 20-hydroxyecdysone (20E) during pupal development regulates plasticity in male courtship behavior in Bicyclus anynana butterflies. Wet season (WS) males, reared at high temperature, have high levels of 20-hydroxyecdysone (20E) during pupation and become active courters. Dry season (DS) males, reared at low temperatures, have lower levels of 20E and lower courtship rates. Rescue of WS courtship rates can be achieved via injection of 20E into DS male pupae, but it is still unknown whether 20E alters gene expression in the pupal brain, and if so, the identity of those targets. Using transcriptomics, qPCR, and behavioral assays with a transgenic knockout, we show that higher expression levels of the yellow gene in DS male pupal brains, relative to WS brains, represses courtship in DS males. Furthermore, injecting DS males with 20E downregulates yellow to WS levels 4 hours post-injection, revealing a hormone sensitive window that determines courtship behavior. These findings are in striking contrast to Drosophila, where yellow is required for active male courtship behavior. We conclude that 20E plays an organizational role during pupal brain development by regulating the expression of yellow, which is a repressor of the neural circuity for male courtship behavior in B. anynana. This work shows that similar to vertebrates, hormones can also play an organizational role in insect brains, leading to permanent changes in adult sexual behavior.

Significance Statement

Behavioral plasticity in adult insects is known to be regulated by hormones, which activate neural circuits in response to environmental cues. Here, we show that hormones can also regulate adult behavioral plasticity by altering gene expression during brain development, adjusting the insect’s behavior to predictable seasonal environmental variation. We show that seasonal changes in the hormone 20E alters expression of the yellow gene in the developing pupal brain of Bicyclus anynana butterflies, which leads to differences in male courtship behavior between the dry and wet seasonal forms. This work provides one of the first examples of the organizational role of hormones in altering gene expression and adult sexual behavior in the developing insect brain.