bluuebunny/crossref_metadata_2025 huggingface dataset:
0457 Development and utility of a mobile health application integrated with the electronic heath record for treatment of chronic insomnia disorder
Authors: Morgenthaler Timothy , Kolla Bhanuprakash , Anderson Sandra , Luedke Tabitha , McColley Samantha , Phillips Sarah , Smith Justin , Boudreau Nancy , Harper Sarah
Published: May 2022

Introduction

Cognitive behavior therapy for insomnia (CBT-I), a first-line therapy for patients with chronic insomnia disorder (ChID), is underutilized due to reduced access to trained providers and other barriers. We developed an interactive care plan (ICP) combining individual aspects of CBT-I. This ICP, which integrates with the electronic health record (EHR), is designed to deliver personalized and scalable CBT-I to patients with ChID. We report data from initial implementation and evaluation of a ChID ICP deployed at a tertiary sleep medicine clinic.

Methods

The ICP was developed following patient and provider interviews and focus groups. Patients diagnosed with ChID were offered enrollment and engaged in the ICP through an app. The ICP has embedded logic that may escalate care or offer an exit from the program, depending upon the patient’s response to questions. Key variables ascertained from the patient included sleep efficiency (SE), sleep timing and the Insomnia Severity Index (ISI), and how satisfied they were with their progress (Likert scale). We also measured In Basket messaging related to use of the ICP.

Results

A total of 222 patients [57% female, age=56.4±15.9 years (average ±SD), 92.7% white] were enrolled in the initial 120 days of ICP implementation. Most referrals were initiated by physicians or advanced practitioners (77.9%). ISI at initiation was 15±5.18 and SE was 74.55±16.65%. Patients spent 35.9±26.25 days engaging with the ICP. The ISI score at 28 days was 12.89±4.98 and SE was 78.9±13.4% with both showing significant improvement from baseline (p=0.013; p=0.002; respectively). Self-rated satisfaction with progress did not significantly correlate with actual improvement in ISI or SE (p>0.05). The ICP generated 3.89±2.3 In Basket messages per patient.

Conclusion

Patients who actively engaged with the ICP showed significant improvements in insomnia severity and sleep efficiency. While a majority of the patients were neutral towards the ICP and only a small minority expressed dissatisfaction, these data indicate that the ICP will have clinical utility in busy sleep medicine practices with reduced access to behavioral sleep specialists.

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0460 First-line treatment patterns in patients with insomnia: a large-scale, real-world cohort study
Authors: Grandner Michael , Ahuja Ajay , Meijer Paulien , Büsser Alexander , McCall William , Lettieri Christopher
Published: May 2022

Introduction

Current pharmacologic treatments for insomnia are not universally effective, are associated with a range of adverse events, can cause daytime impairment, and have the potential to be abused. With no consistent standard of care, many patients with insomnia experience multiple dose changes and medication switches. The current study leveraged large-scale, real-world data to investigate the pharmacological treatment patterns of patients with insomnia.

Methods

Exploratory analyses were performed on claims data from the HealthVerity US primary care claims database. Data from 10/2015 to 3/2020 were obtained for patients aged 18+. Prescribing patterns, including initial treatment, switching, concomitant treatment, and discontinuation were explored.

Results

Of approximately 1.4 million individuals, 265,382 (~19%) had an insomnia diagnosis and 42.4% of that group were prescribed hypnotic medications. Among those, first prescriptions were most frequently a Z-drug (zolpidem, eszopiclone, zaleplon; 35.8%), trazodone (25.0%), a benzodiazepine (15.6%), or another class (23.6%; includes orexin receptor antagonists, antidepressants, melatonin agonists, etc.). For those receiving a benzodiazepine first, median treatment duration was 55 days, 80.4% of subjects discontinued, 11.6% were switched to a different medication, and 7.9% received concomitant treatment with another sleep medicine. For those first receiving a Z-drug, median treatment duration was 81 days, 87.3% discontinued, 8.2% were switched, and 4.4% received concomitant treatment. For those receiving trazodone first, median treatment duration was 104 days, 85.8% of patients eventually discontinued, 5.8% of patients received concomitant treatment with an additional hypnotic agent, and 8.4% switched to a different hypnotic. Furthermore, of those switched from trazodone, 22% were switched to a benzodiazepine, 31% to a Z-drug, and 47% to a medication of another class.

Conclusion

These results demonstrate a lack of a standard first-line treatment approach for insomnia; it is likely that physicians have their own preferences, or that they might tailor treatment choice to individual patient characteristics. Additionally, more insomnia patients are discontinued from medical treatment than are switched to a different medicine. Further study is needed to determine what proportion of treatment discontinuation is due to successful treatment, versus being due to adverse events or lack of efficacy.

Support (If Any)

Idorsia Pharmaceuticals, Ltd.
0495 Sleep Disturbance Features Differentially Influence Inflammatory Markers in Adolescents
Authors: Chiem Emily , O'Hora Kathleen , Grigoryan Vardui , Amir Carolyn , Irwin Michael , Chiang Jessica , Bearden Carrie
Published: May 2022

Introduction

Sleep disruption has profound effects on immune function. Many adolescents do not get adequate amounts of sleep each night, and chronic sleep disturbance has been associated with increased risk of several inflammatory diseases. However, the relationship between sleep disturbances and inflammation during adolescence is not well understood. In this study, we examined the relationship between specific features of sleep disruption and cytokine levels in adolescents.

Methods

A total of 88 adolescents (18.36 ± 0.51 years, 56.8% female) completed the Pittsburgh Sleep Quality Index (PSQI), a self-reported questionnaire used to assess subjective sleep quality over a 1-month time period. Blood plasma samples were obtained for each participant at the same timepoint to measure levels of pro-inflammatory cytokines (Interleukin (IL)-6, IL-8, tumor-necrosis factor (TNF)-alpha, and interferon (IFN)-gamma), anti-inflammatory cytokine (IL-10), and C-reactive protein (CRP). Samples were assayed using a Meso Scale Discovery multiplex immunoassay. Linear regression models were used to test the effect of PSQI sleep latency, duration, efficiency, quality, disturbance, and total score on each cytokine level, while covarying for sex and body mass index. We corrected for multiple comparisons using a False Discovery Rate (FDR) correction.

Results

Overall, disruption in sleep was associated with distinct cytokine differences. Worse sleep, reflected by the PSQI total score and greater sleep disturbance, was associated with lower IL-6 levels (p=0.013, p=0.015, respectively), however theses associations were attenuated to a trend after FDR correction (q=0.083, q=0.092, respectively). Longer sleep latency was also associated with lower IL-6 (p=0.028), and IFN (p=0.016) levels, however these effects were also attenuated after FDR correction (q=0.138, q=0.094, respectively). Reduced sleep efficiency was associated with higher TNF (q=0.046) and CRP (q=0.021) levels.

Conclusion

Our findings show that different components of sleep disruption have varying effects on cytokine release, resulting in an overall blunted immune response. This underscores the significant impact of sleep disturbances on perturbing immune function during this critical developmental period.

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0587 Sleep Problems are Associated with Treatment for Anemia in the US Population
Authors: Shah Sayani , Mason Brooke , Wills Chloe , Tubbs Andrew , Killgore William , Grandner Michael
Published: May 2022

Introduction

Anemia is characterized as low circulating hemoglobin and is often treated with an increase in iron consumption. Previous studies have linked anemia with Restless Legs Syndrome. Regarding other sleep disorders, Insomnia has been found to be associated with anemia in children, but the relationship has been understudied in adults.

Methods

A multinomial logistic regression was conducted on the data collected from 2017 to March 2020 for the National Health and Nutrition Examination Survey, to explore a relationship between those with self-assessed sleep problems and whether the participant was treated for anemia. Sleep problems were assessed using a item asking participants how often they have been bothered by difficulties “falling asleep, staying asleep, or sleeping too much,” categorized as “Never,” “Several Days,” “More Than Half the Days” and “Nearly Every Day” in the past 2 weeks. Anemia treatment was characterized as “yes” or “no” based on self-report, with any form of treatment in the past 3 months was considered as “yes.” Reported results were unweighted; weighted results forthcoming.

Results

Unadjusted results indicate that those being treated for anemia show an increased likelihood of sleep difficulties several days (OR:1.36, [1.07,1.73] p=0.011), more than half the days (OR: 1.59, [1.13,2.25] p=0.008), and nearly every day (OR: 1.85, [1.37,2.50] p<0.001), compared to those who report that they never have sleep difficulties. When adjusted for sex, age, race/ethnicity, education, and marital status, those being treated for anemia show significant increased odds of sleep problems several days (OR: 1.29, [1.01,1.65] p=0.041), more than half the days (OR: 1.50, [1.06,2.14] p=0.024), and nearly every day (OR: 1.55, [1.13,2.13] p=0.006), compared to never. Those being treated for anemia also had a higher likelihood of having short sleep (≤ 6 hours) during the week (OR: 1.56, [1.13,2.15], p=0.007) as well as long sleep( ≥ 9 hours) (OR: 1.75, [1.30,2.36], p<0.001) compared to those that slept a healthy amount, 6.5-8.5 hours a night.

Conclusion

There was a significant relationship between those treated for anemia the presence of sleep difficulties, as well as short and long sleep. Future studies should assess the associations between anemia and specific sleep characteristics, as sleep problems may be a cause, a consequence, or a marker of anemia. Also, the degree to which these sleep difficulties represent overlap with Restless Legs symptoms should be explored at the population level.

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0721 Correlation between Oxygen Desaturation Index and Apnea Hypopnea Index for Diagnosis of Obstructive Sleep Apnea
Authors: Jamil Saad Bin , Kachechian Talar , Armache Maria , Alapati Rahul , Tsao Jaime , Huntley Colin , Fast Zhanna
Published: May 2022

Introduction

Obstructive sleep apnea (OSA) is diagnosed through polysomnography (PSG) which can be done in lab or outpatient. PSG is conventionally not approved by insurance companies’ in-patient which can result in delay in diagnosis and treatment of OSA. High resolution pulse oximetry (HRPO) done inpatient is easy to perform and calculates oxygen desaturation index (ODI) to asses’ nocturnal desaturations which solely, is insufficient for diagnoses of OSA according to current treatment guidelines. We hypothesize that there may be a correlation between ODI and apnea hypopnea index (AHI) which can facilitate in earlier diagnosis of OSA.

Methods

We conducted a retrospective chart review to compare patients who underwent HRPO resulting in a sleep medicine consult inpatient followed by polysomnography outpatient over a 2-year period at a tertiary care academic center. Demographic data, ODI, AHI and oxygen nadir levels were collected.

Results

Sixty-five patients (47 males, 18 females; mean age of 59.1 years) with suspected OSA underwent inpatient HRPO during their hospital stay, followed by a PSG in the outpatient setting. The strength of association between ODI and AHI was determined using a Pearson’s analysis after adjusting to a logarithmic scale. There was a statistically significant weakly positive association between ODI and AHI (Pearson correlation=0.33, p=0.008). Linear regression analysis demonstrated a predictive value of 0.419 (p=0.008) between AHI and ODI. However, there was no statistically significant predictive value between ODI and AHI when adjusted for age, sex, body mass index (BMI) and ethnicity (beta =0.169; p=0.330). This may be limited by small sample size. HRPO nadir oxygen saturation (NOS) also correlated with polysomnography NOS with a Pearson correlation coefficient of 0.353 (p=0.006). Linear regression analysis showed a predictive value beta of 0.149 (p=0.006). When adjusted for age, sex, BMI and race, beta was equal to 0.156 (p=0.007).

Conclusion

ODI calculated through HRPO may be correlated with AHI. NOS determined through HRPO is weakly positively predictive of NOS calculated through PSG. To initiate treatment of OSA sooner, HRPO may be considered for screening or diagnostic purposes. The correlation between ODI and AHI needs to establish further in randomized controlled setting.

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0782 Changes in markers of ventricular repolarization and positive airway pressure therapy: A pilot study
Authors: Perez Karolina , Zareba Wojciech , LaFleur Bonnie , Xia Xiaojuan , Woosley Raymond , Patel Imran , Quan Stuart , Grandner Michael , Youngstedt Shawn , Miller Jerod , Parthasarathy Sairam , Patel Salma
Published: May 2022

Introduction

Positive airway pressure (PAP) therapy is the mainstay treatment for obstructive sleep apnea (OSA). Continuous PAP (CPAP) therapy has been shown to decrease QTc length in electrocardiograms in patients with OSA in small studies. The impact of higher pressures of CPAP and Bilevel PAP (BPAP) on ventricular repolarization—QTc length and QT variability in OSA is unknown. The goal of this pilot study is to explore this relationship.

Methods

10 consecutive patients who underwent polysomnography during which they had a diagnostic, CPAP titration, and BPAP titration portion were included for analysis. Bazett’s heart rate correction was used to calculate QTc. QT variability was measured as short-term interval QT variability (STVQT) and normalized QT interval variance (QTVN). All variables were analyzed for the entire duration of the diagnostic period, on the highest CPAP pressure and highest BPAP pressure delivered.

Results

The patients were 49 ± 15 years of age and 60% women. Median CPAP pressure was 14.5 cm H2O (mean 13.5 ± 5 cm H2O). For BPAP, the median inspiratory PAP was 21.5 cm H2O (mean 20.5 ± 5 cm H2O) and EPAP median was 16 cm H2O (mean 15.9 ± 4 cm H2O). Mean QTc for the diagnostic portion, highest CPAP pressure and highest BPAP pressure were 430 ± 17 ms, 445 ± 15 ms and 441 ± 21 ms, respectively (p=0.141). Mean QTVN for the diagnostic portion, highest CPAP pressure and highest BPAP pressure settings were 0.0011 ± 0.0008 dimensionless units (du), 0.0012± 0.0008 du and 0.002 ± 0.0012 du, respectively (p=0.127). STVQT for the diagnostic portion, highest CPAP pressure and highest BPAP pressure settings were 6.62 ± 4.13 ms, 9.12 ± 4.7271 ms and 12.62 ± 4.99 ms, respectively (P=0.041). Post-hoc pairwise comparisons between BPAP and diagnostic portions of the study were significant for STVQT (P=0.034).

Conclusion

Short-term QT variability, STVQT, was significantly increased on BPAP when compared to the diagnostic portion of the study.

Support (If Any)

American Academy of Sleep Medicine Foundation (203-JF-18), National Institutes of Health (HL126140, 2L30HL154400-023) University of Arizona Health Sciences Career Development Award (5299903), and University of Arizona Faculty Seed Grant (5833261)
A new family for ‘termite gut treponemes’: description of Breznakiellaceae fam. nov., Gracilinema caldarium gen. nov., comb. nov., Leadbettera azotonutricia gen. nov., comb. nov., Helmutkoenigia isoptericolens gen. nov., comb. nov., and Zuelzera stenostrepta gen. nov., comb. nov., and proposal of Rectinemataceae fam. nov.
Authors: Brune Andreas , Song Yulin , Oren Aharon , Paster Bruce J.
Published: May 2022

The intestinal tracts of termites are abundantly colonized by a diverse assemblage of spirochetes. Most of them belong to ‘termite cluster I’, a monophyletic group within the radiation of the genus

Treponema

that occurs exclusively in termite guts. Phylogenomic analysis revealed that members of the genus

Treponema

are extremely diverse and represent two separate, family-level lineages: the Treponemataceae sensu stricto, which comprise the majority of the validly described

Treponema

species, and a second lineage that comprises the remaining members of the genus

Treponema

, including all members of ‘termite cluster I’ from termites and the recently isolated

Breznakiella homolactica

from cockroaches. Here, we present the formal description of

Breznakiellaceae

fam. nov. and of the new genera required to accommodate the misplaced

Treponema

species in the new family as new combinations (

Leadbettera azotonutricia

,

Gracilinema caldarium

,

Helmutkoenigia isoptericolens

and Zuelzera stenostrepta). To avoid paraphyly of

Treponemataceae

, we propose

Rectinemataceae

fam. nov. to include the genus

Rectinema

.
Rotavirus incapable of NSP6 expression can cause diarrhea in suckling mice
Authors: Fukuda Saori , Kugita Masanori , Higashimoto Yuki , Shiogama Kazuya , Tsujikawa Hanako , Moriguchi Kyoko , Ito Naoto , Sugiyama Makoto , Nagao Shizuko , Murata Takayuki , Taniguchi Koki , Komoto Satoshi
Published: May 2022

The group A rotavirus (RVA) genome comprising 11 double-stranded RNAs encodes six structural proteins (VP1-VP4, VP6, and VP7) and six non-structural proteins (NSP1-NSP6). Among these 12 rotaviral proteins, NSP6 has been less studied as to its function. We previously prepared a recombinant NSP6-deficient RVA derived from simian strain SA11-L2 by reverse genetics, and found that the NSP6-deficient virus grew well in cell culture, although its growth was less abundant than that of the parental SA11-L2 strain. In this study, we examined the potency of a recombinant RVA incapable of NSP6 expression to cause diarrhoea in suckling mice. The suckling mice infected with the NSP6-deficient virus apparently experienced diarrhoea, although the symptom was milder and the duration of diarrhoea was shorter than in the mice infected with the authentic SA11-L2 strain. Thus, together with the results obtained for cultured cells in the previous study, it can be concluded that NSP6 is not necessarily required for replication and pathogenicity in vitro and in vivo.
How brain networks tic: predicting tic severity through rs-fMRI dynamics in Tourette syndrome
Authors: Ramkiran Shukti , Veselinović Tanja , Dammers Jürgen , Rajkumar Ravichandran , Shah N. Jon , Neuner Irene
Published: May 2022

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and phonic tics, which several different theories, such as basal ganglia-thalamo-cortical loop dysfunction and amygdala hypersensitivity, have sought to explain. Previous research has shown dynamic changes in the brain prior to tic onset leading to tics, and this study aims to investigate the contribution of network dynamics to them. For this, we have employed three methods of functional connectivity to resting-state fMRI data - namely the static, the sliding window dynamic and the ICA based estimated dynamic; followed by an examination of the static and dynamic network topological properties. A leave-one-out (LOO-) validated regression model with LASSO regularization was used to identify the key predictors. Most relevant predictors were related to regions belonging to the amygdala-mediated visual social processing network. This is in line with a recently proposed social decision-making dysfunction hypothesis, opening new horizons in understanding tic pathophysiology.
Characterization and Profiling of Gut Bacterial Microbiome and Pathobionts among HIV-negative and HIV-infected individuals in Cameroon
Authors: Ako Simon Eyongabane , Nkenfou Celine N. , Assob Jules N. , Pokam Thumamo Benjamin , Njopin Christopher , Eteneneng Enoh Jude , Nchang Cho Frederick , Mbanya Mbanya Gladice , Gilles-Fils Woguia , Franck Ngoume Moukoma Y. , Akum Eric Achidi
Published: May 2022

Background

Knowledge of the core gut microbiome among Cameroonians is a preliminary step for a better implementation of treatment strategies to correct dysbiosis and improve health care management. HIV infection has continued to cause high mortality among those infected, but the types and frequency of human gut microbiota associated with or without HIV/AIDS presence have not been identified in the adult populations in Cameroon.

Methods

This was a case-control and comparative study design that ran from June 2018 to September 2019. Stool Samples were purposively collected from 40 participants (15 HIV-negative and 25 HIV-positive) for the 16S rRNA gene sequencing on the next-generation Illumina® MiSeq™ sequencer. Blood samples were collected for HIV determine testing, CD4 Tcell count and HIV viral load. Sequences were clustered into operational taxonomic units (OTUs) at ninety-nine percent identity and their representatives were accustomed to using a phylogenetic approach.

Results

The study showed a phylogenetic taxonomy of the gut microbiome communities in two kingdoms (Archea and Bacteria) and eight Phylum [Firmicutes (44.7%), Bacteroidetes (43.7%), Proteobacteria (8.7%), Actinobacteria (1%), Fusobacteria (0.2%), Euryarchaeota (0.01%), Synergistetes (0.01%), Verrucomicrobia (0.01%) and unclassified phylum (1.7%)]. A total of 347 gut microbiota species were identified, 55 unique species/oligotypes and 28 pathobionts from the study population. HIV infection was characterized by significant gut microbiota compositional changes with HIV-positive less diverse (56 strains absent) with significant increased OTUs of the butyrate-producing microbiome species as compared to HIV-negative individuals (p=0.001).

Conclusions

A profile of 347 gut microbiome bacterial species where identified in the Cameroonian community. Particularly, from the 347 gut microbiome bacterial species profiled, eight phyla were identified, with 55 unique species/oligotypes containing more than one sequence and 28 pathobionts. A host of unknown/unclassified gut microbiome bacterial species were also noted circulating among the study population.

Key Points

There is high diversity and specie uniqueness of the gut microbiome in Cameroon. Functionality of the gut microbiome needs to be investigated.

There are gut pathobionts circulating among HIV-infected and HIV-negative individuals in Cameroon. The origin of pathobionts is a call for concern.

Unique gut microbiome OTU sequences are significantly high among HIV-infected. Emerging strains of new microorganisms are on a rise.
Coregistered transcranial optoacoustic and magnetic resonance angiography of the human brain
Authors: Ni Ruiqing , Dean-Ben Xose Luis , Treyer Valarie , Gietl Anton , Hock Christoph , Klohs Jan , Nitsch Roger M. , Razansky Daniel
Published: May 2022

Imaging modalities capable of visualizing the human brain have led to major advances in neurology and brain research. Multi-spectral optoacoustic tomography (MSOT) has gained importance for studying cerebral function in rodent models due to its unique capability to map changes in multiple hemodynamic parameters and to directly visualize neural activity within the brain. The technique further provides molecular imaging capabilities that can facilitate early disease diagnosis and treatment monitoring. However, transcranial imaging of the human brain is hampered by acoustic attenuation and other distortions introduced by the skull. Here, we demonstrate noninvasive transcranial MSOT angiography through the temporal bone of an adult healthy volunteer. Time-of-flight (TOF) magnetic resonance angiography (MRA) and T1-weighted structural MRI were further acquired to facilitate anatomical registration and interpretation. The superior middle cerebral vein in the temporal cortex was identified in the MSOT images, matching its location observed in the TOF-MRA images. These initial results pave the way toward the application of MSOT in clinical brain imaging.
Development and scaling of a sequencing pipeline for genomic surveillance of SARS-CoV-2 in New York City
Authors: Hammerling Michael J. , Kang Shinyoung Clair , Ward William , Escapa Isabel F. , Bugga Pradeep , Del Castillo Cybill , Hopkins Melissa , Chase Steven , Rey Sol , Law Dylan , Carpio Alexander , Nelson Katharine , Chhabria Simran , Gupta Simran , Rivera Tiara , Laurent Jon M. , Hao Haiping , Lee Henry H.
Published: May 2022

In the ongoing COVID-19 pandemic, detecting the appearance and spread of variants of concern (VOC) is a critical capability in the fight to quell the virus and return to normalcy. Genomic surveillance of the emergence, propagation, and geographical spread of VOCs is thus an important tool for public health officials and government leaders to make policy decisions and advise the public. As part of our role as a major SARS-CoV-2 diagnostic testing facility in New York City, the Pandemic Response Lab (PRL) has been performing genomic surveillance on the large number of positive samples processed by the facility on a daily basis from throughout the New York metropolitan area. Here we describe the development and optimization of a high-throughput SARS-CoV-2 genome sequencing facility at PRL serving New York City.
Active remodeling of the chromatin landscape directs extravillous trophoblast cell lineage development
Authors: Varberg Kaela M. , Dominguez Esteban M. , Koseva Boryana , Varberg Joseph M. , McNally Ross P. , Moreno-Irusta Ayelen , Wesley Emily R. , Iqbal Khursheed , Cheung Warren A. , Schwendinger-Schreck Carl , Smail Craig , Okae Hiroaki , Arima Takahiro , Lydic Michael , Holoch Kristin , Marsh Courtney , Soares Michael J. , Grundberg Elin
Published: May 2022

The extravillous trophoblast (EVT) cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving EVT cell development is limited. Here, we mapped the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem (TS) cells and their transition into EVT cells. Integration of chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor (TF) binding motif enrichment enabled identification of TFs and regulatory mechanisms associated with EVT cell development. Functional roles forTFAP2C,SNAI1,andEPAS1in the regulation of EVT cell development were elucidated.EPAS1was identified as an upstream regulator of key EVT cell TFs, includingASCL2andSNAI1and together with its target genes, was linked to pregnancy loss and birth weight. Collectively, we have revealed activation of a dynamic regulatory network that provides a framework for understanding EVT cell specification in trophoblast cell lineage development and human placentation.
SARS-CoV-2 variants in the making: Sequential intrahost evolution and forward transmissions in the context of persistent infections
Authors: Gonzalez-Reiche Ana S. , Alshammary Hala , Schaefer Sarah , Patel Gopi , Polanco Jose , Carreño Juan Manuel , Amoako Angela A. , Rooker Aria , Cognigni Christian , Floda Daniel , van de Guchte Adriana , Khalil Zain , Farrugia Keith , Assad Nima , Zhang Jian , Alburquerque Bremy ,   PARIS/PSP study group, Sominsky Levy , Gleason Charles , Srivastava Komal , Sebra Robert , Ramirez Juan David , Banu Radhika , Shrestha Paras , Krammer Florian , Paniz-Mondolfi Alberto , Sordillo Emilia Mia , Simon Viviana , van Bakel Harm
Published: May 2022

Abstract

Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been reported in immune-compromised individuals and people undergoing immune-modulatory treatments. Although intrahost evolution has been documented, to our knowledge, no direct evidence of subsequent transmission and stepwise adaptation is available.

Here we describe sequential persistent SARS-CoV-2 infections in three individuals that led to the emergence, forward transmission, and continued evolution of a new Omicron sublineage, BA.1.23, over an eight-month period. The initially transmitted BA.1.23 variant encoded seven additional amino acid substitutions within the spike protein (E96D, R346T, L455W, K458M, A484V, H681R, A688V), and displayed substantial resistance to neutralization by sera from boosted and/or Omicron BA.1-infected study participants. Subsequent continued BA.1.23 replication resulted in additional substitutions in the spike protein (S254F, N448S, F456L, M458K, F981L, S982L) as well as in five other virus proteins.

Our findings demonstrate that the Omicron BA.1 lineage can diverge further from its already exceptionally mutated genome during persistent infection in more than one host, and also document ongoing transmission of these novel variants. There is an urgent need to implement strategies to prevent prolonged SARS-CoV-2 replication and to limit the spread of newly emerging, neutralization-resistant variants in vulnerable patients.
Optimizing the antiretroviral treatment focusing on long-term effectiveness and a person-centred approach. Consensus Guidance Using a Delphi Process
Authors: Maggiolo Franco , Caputo Sergio Lo , Bonora Stefano , Borderi Marco , Cingolani Antonella , D’Ettorre Gabriella , Di Biagio Antonio , Di Giambenedetto Simona , Gervasoni Cristina , Guaraldi Giovanni , Maggi Paolo , Taramasso Lucia
Published: May 2022

Background

Modern antiretroviral therapy (ART) offers several treatment options characterized by high efficacy and tolerability, and new strategies with new drugs are now available for the treatment of HIV infection. As definitive data on the long-term success of these new strategies are lacking, a panel of infectious diseases specialists was convened to develop a consensus on how to tailor and follow in time a person-centered ART approach.

Methods

Panelists used a Delphi technique to develop a list of statements describing preferred management approaches for ART and patient monitoring and quality of life evaluation. Panelists provided level of agreement and feedback on consensus statements generated and refined them from the first round through 2 subsequent rounds of voting.

Results

Ninety infectious diseases specialists from different Infectious Diseases Centres in Italy participated in the consensus process. A consensus was reached on virological and immunological parameters to use to monitor long term efficacy of antiretroviral treatment, while there was no consensus on the use of specific inflammation and immune-activation markers in clinical routine. The panel agreed on the need of an antiretroviral treatment with the lowest impact on bone, kidney and cardiovascular toxicity and on the utility of quality of life monitoring during the standard follow up of people living with HIV.

Conclusions

The consensus statements developed by a panel of infectious diseases specialists may provide guidance to practitioners for a person-centered approach aimed at obtaining long-term virological and clinical success for people living with HIV.

Key points

A panel of experts in the care of HIV infection expressed their consensus on which could be the best strategy to achieve and maintain long-term effectiveness in course of antiretroviral therapy, using Delphi methodology.
A hospital-based study to assess various biomarkers for prognostic prediction of clinical outcome in COVID-19 disease
Authors: Padhi Abhishek , Shaw Dipika , Khatoon Shagufta , Ranjan Swekcha , Bhargava Anudita , Negi Sanjay Singh
Published: May 2022

COVID-19 pandemic has inflicted a painful unforgettable number of deaths throughout the world. Hematological inflammatory and organ-specific biomarkers are universally practiced in helping clinical decisions in various infectious diseases. Accordingly, their role in predicting progression and severity, and fatal outcome of COVID-19 was investigated to take initial appropriate treatment measures to reduce associated mortality.

Methods

The retrospective analysis of a total of 126 COVID-19 cases representing mild, moderate, severe, and succumbed cases were assessed for the pattern of hematological, inflammatory, and organ-specific biomarkers.

Results

A total of 126 proven cases of SARS-CoV-2 infection were retrospectively analyzed for the association of various biomarkers with the COVID-19 disease progression. The CBC analysis showed that the median TLC was high for the severe group of both males (12.49 × 103/μl) and females (14.23 x103/μl). Similarly, the neutrophil count was also found high in the severe group, whereas the monocytes count showed low median values in severe cases, but both these parameters had no significant difference among the males and the females. The platelet count showed a significant difference (p=0.018) among the non-severe and severe groups between males and females. Among inflammatory markers, D-dimer, CRP, LDH, and APTT showed a higher median value in severe cases among both the males and females while ESR value was higher in non-severe cases and ferritin showed similar values in both severe and non-severe cases. The liver and kidney function parameters were also analyzed and a significant P-value was found for ALP (p=0.004), ALT (p=0.032), and AST (p=0.009) in the non-severe vs. severe category of COVID-19 patients.

Discussion

High TLC, neutrophilia, lymphopenia, thrombocytopenia, and eosinopenia are the potential risk factor for the progression of COVID-19 disease for severe and fatal outcomes. Inflammatory markers of D-dimer, CRP, LDH, APTT, and ferritin above normal range also carries the potential risk of severe and fatal outcome in COVID-19 disease. Higher ALT, AST, and serum creatinine may also carry a poor prognosis.
COVID-19 pandemic impact on preterm birth and stillbirth rates associated with socioeconomic disparities: A quasi-experimental study
Authors: Aboulatta Laila , Kowalec Kaarina , Leong Christine , Delaney Joseph , Falk Jamie , Alessi-Severini Silvia , Chateau Dan , Tan Qier , Kearns Katherine , Raimondi Christina , Lavu Alekhya , Haidar Lara , Vaccaro Christine , Eltonsy Sherif
Published: May 2022

Background

Conflicting evidence exists on the impact of the COVID-19 pandemic restrictions on preterm birth (PTB) and stillbirth rates. We aimed to evaluate changes in PTB and stillbirth rates before and during the pandemic period and assess the potential effect modification of socioeconomic status (SES).

Methods

Using the linked administrative health databases from Manitoba, Canada, we conducted a quasi-experimental study among all pregnant women, comparing 3.5 years pre-pandemic (1 October 2016 to 29 February 2020) to the first year of the pandemic (1 March 2020 to 31 March 2021). We used interrupted time series analysis using autoregressive integrated moving average models to assess the quarterly rates of PTB (<37 weeks) and stillbirths. We calculated the predicted trends based on pre-pandemic period data. Finally, we evaluated the lower and higher SES (average annual household income) using subgroup analysis and interaction models.

Results

We examined 70,931 pregnancies in Manitoba during the study period. Following the implementation of COVID-19 restrictions in March 2020, there were no statistically significant changes in the rates of both PTB (p=0.094) and stillbirths (p=0.958). However, over the pandemic, the PTB rate significantly decreased as a rebound effect by 0.63% per quarter(p=0.005); whereas the stillbirth rate did not change significantly (p=0.878) compared to pre-pandemic period. During the first quarter of 2021, the absolute differences in the observed and expected PTB and stillbirth percentages were 2.05% and 0.04%, respectively. We observed a statistically significant effect modification by SES for PTB rates (p=0.047).

Conclusion

While the onset of COVID-19 pandemic restrictions was not associated with significant effects on PTB and stillbirth rates, we observed a statistically significant rebound effect on PTB rates. The impact of COVID-19 on preterm birth was dependent on SES, with higher influence on families with lower SES. Further studies are needed to detect future trend changes during pandemic waves after 2021 and assess potential underlying mechanisms.
Effects of Hormone Therapy on survival, cancer, cardiovascular and dementia risks in 7 million menopausal women over age 65: a retrospective observational study
Authors: Baik Seo H. , Baye Fitsum , McDonald Clement J.
Published: May 2022

Background

The long-term influence of menopausal hormone therapy remains unanswered due to the termination of randomized clinical trials and discordant findings from observational studies.

Methods

From 2007-2019 enrollment records of 100% Medicare beneficiaries, we identified 7 million female enrollees aged 65 or more. We identified type, route and strength of estrogen based on their prescription drug utilization records. Using vital status record and encounter records, we defined the first onset of thirteen patient outcomes; all-cause mortality; 5 cancers (breast, lung, endometrial, colorectal, ovarian cancers); 6 CV conditions (ischemic heart diseases, heart failure, venous thromboembolism, stroke, atrial fibrillation, acute myocardial infarction); and dementia. Then, we implemented an extended Cox regression analysis to examine the effects of type, route, and strength of estrogens on each of 13 study outcomes.

Findings

Estrogen monotherapy (ET) exhibited a significant, 20% (aHR=0.80; 95% CI 0.78-0.82), relative risk reduction of mortality. The reduction was greater with estradiol (aHR=0.78; 95% CI 0.75-0.80) than conjugated estrogen (aHR=0.86; 95% CI 0.85-0.88), and with vaginal (aHR=0.69; 95% CI 0.65-0.74) than oral (aHR=0.89; 95% CI 0.87-0.90) and transdermal (aHR=0.78; 95% CI 0.75-0.81) preparations. ET also exhibited significant risk reductions for all study cancers, breast (aHR=0.82; 95% CI 0.80-0.84), lung (aHR=0.87; 95% CI 0.84-0.90), endometrial (aHR=0.65; 95% CI 0.62-0.69), colorectal (aHR=0.86; 95% CI 0.82-0.90) and ovarian (aHR=0.83; 95% CI 0.79-0.88). ET slightly increased risks of ischemic heart diseases (aHR=1.03; 95% CI 1.01-1.04). However, such risk was not observed with low dose ET (aHR=0.98; 95% CI 0.97-0.99). Both combination therapy (aHR=1.11; 95% CI 1.08-1.14) and progestogen monotherapy (aHR=1.09; 95% CI 1.05-1.13) exhibited a significantly increased risk of breast cancer. Oral HT exhibited a moderately increased risk of dementia.

Conclusions

Among female Medicare beneficiaries aged ≥65, the effect of menopausal hormone therapy varies by type, route, and strength but overall estrogen seemed beneficial.
Motivation, intention and action: wearing masks to prevent the spread of COVID-19
Authors: Kaine Geoff , Wright Vic , Greenhalgh Suzie
Published: May 2022

Governments around the world are seeking to slow the spread of COVID-19 by implementing measures that encourage, or mandate, changes in people’s behaviour. These changes include the wearing of face masks, social distancing, and testing and self-isolating when unwell. The success of these measures depends on (1) the willingness of individuals to change their behaviour and (2) their commitment and capacity to translate that intention into actions. Consequently, understanding and predicting the willingness of individuals to change their behaviour, and their enthusiasm to act on that willingness, is critical in assessing the likely effectiveness of these measures in slowing the spread of the virus.

In this paper we analyse responses to two separate regional surveys about people’s intentions and behaviour with respect to preventing the spread of COVID-19 in New Zealand. While motivations and intentions were largely similar across the regions, there was marked difference in action across the regions, specifically with respect to the frequency of wearing face masks. Our analysis suggests that the translation of intention (preventing the spread of COVID-19) into action (as measured by self-reported frequency of face mask use) was strongly associated with perceptions of the risk of infection (as measured by regional case numbers).

The results highlight the importance to policy design of distinguishing the factors that might influence the formation of behavioural intentions from those that might influence the implementation of those intentions.
First brain de-novo transcriptome of Tyrrenhian tree frog, Hyla sarda, for the study of dispersal-related behavioral variation
Authors: Libro Pietro , Bisconti Roberta , Chiocchio Andrea , Spadavecchia Giada , Castrignanò Tiziana , Canestrelli Daniele
Published: May 2022

Dispersal is a key process in ecology and evolution as it contributes to shaping the spatial patterns of biological diversity at all its levels of organization. Growing evidence is unveiling the role of phenotypic trait variation in affecting dispersal dynamics of populations, and that substantial, rapid, and directional changes in the phenotypic makeup of populations would occur during range expansions by spatial sorting of dispersal-related traits. Accordingly, selective pressures at the front of a range expansion wave would actively promote individuals with higher dispersal abilities. Although many studies have been focusing on phenotypic trait evolution during range expansion, its genomic underpinnings are almost unexplored, hampering a thorough understanding of the evolutionary processes involved during dispersal.

The Tyrrhenian tree frog Hyla sarda is a small amphibian endemic to the Tyrrhenian islands. According to previous phylogeographic studies, H. sarda underwent a northward range expansion from the north of Sardinia (western Mediterranean sea) during the last glacial phase. The colonization of the Corsica island was allowed by the temporary formation of a wide land bridge connecting Sardinia and Corsica, induced by the marine regression occurred during the last glacial maximum. The postglacial loss of this land bridge prevented any subsequent gene flow between Corsican and Sardinian populations. As a consequence, the genetic and phenotypic legacies of this range expansion event can still be detected in current populations, which makes H. sarda an interesting candidate species for the study of the genetic underpinnings of phenotypic trait evolution during range expansions.

Here, we contribute to the investigation of the genetic underpinning phenotypic trait evolution during range expansion, by generating the first brain de-novo transcriptome of H. sarda. We focused on the brain transcriptome as behavioural variation at personality traits has been identified as a key component of the dispersal syndromes, substantial personality traits variation has been observed within H. sarda populations, and brain gene expression patterns have been linked to a vast number of behavioural responses to environmental stimuli.
Modeling Down syndrome neurodevelopment with isogenic cerebral organoids
Authors: Czerminski Jan T. , King Oliver D. , Lawrence Jeanne B.
Published: May 2022

As a model of early fetal brain development in Down syndrome, this study examines cortical organoids generated from isogenic trisomic and disomic iPSC lines. Initially pools of organoids from a trisomic versus disomic line found broad transcriptomic differences and modest differences in cell-type representation, suggesting a potential neurodevelopmental phenotype due to Trisomy 21. To better control for multiple sources of variation, we undertook a very robust study of ~1,200 organoids, using an expanded panel of six isogenic subclones (three disomic and three trisomic). The power of the experimental design was indicated by exceptionally strong detection of the ~1.5-fold difference in most chr21 genes. Despite some variability in secreted Aβ-40 levels between “identical” cell lines, this Alzheimer-related phenotype was detected as clearly correlated with Trisomy 21. However, the many statistically significant non-chr21 DEGs found in the small experiment fell away in the expanded study design, such that just three non-chr21 DEGs correlated to T21 status. Similarly, differences in cell-type representation of organoids varied somewhat between the six isogenic lines, but did not correlate with T21 status. Overall, our results indicate that even when organoid and batch variability are better controlled, common, subtle differences between isogenic cell lines (even subclones) may obscure, or be confused with, differences due to Trisomy 21. Interestingly, the neurodegenerative increase in Aβ due to T21 was strong enough to be evident in “fetal” organoids. In contrast, any neurodevelopmental phenotype that may be present in the ~2ndtrimester of DS brain development may be more subtle, and within the range of variability in neurodifferentiation potential (unrelated to Trisomy 21) of our isogenic iPSC lines. The potential significance of two non-Chr21 DEGs that results suggest correlate with T21 is discussed.
Astronauts Gaze Behavior in Visual Target Acquisition during Space Shuttle Flights
Authors: Kolev Ognyan I. , Reschke Millard F. , Clément Gilles
Published: May 2022

We explored how weightlessness during space flight altered the astronauts’ gaze behavior with respect to flight day and target eccentricity. Thirty-four astronauts of 20 Space Shuttle missions had to acquire visual targets with angular offsets of 20°, 30°, and 49°. Measurements of eye, head, and gaze positions collected before and during flight days 1 to 15 indicated changes during target acquisition that varied as a function of flight days and target eccentricity. The in-flight changes in gaze behavior were presumably the result of a combination of several factors, including a transfer from allocentric to egocentric reference for spatial orientation in absence of a gravitational reference, the generation of slower head movements to prevent space motion sickness, and a decrease in smooth pursuit and vestibulo-ocular reflex performance. These results confirm that humans have several strategies for gaze behavior, between which they switch depending on the environmental conditions.
Spatiotemporal Ecological Chaos Enables Gradual Evolutionary Diversification Without Niches or Tradeoffs
Authors: Mahadevan Aditya , Pearce Michael T. , Fisher Daniel S.
Published: May 2022

Ecological and evolutionary dynamics are intrinsically entwined. On short time scales, ecological interactions determine the fate of new mutants and changes in the community they induce, while on longer time scales evolution shapes the whole community. How eco-evolutionary dynamics gives rise to the extensive coexisting diversity of strains found in many bacterial species is a major puzzle. In this paper we study the evolution of large numbers of closely related strains with generalized Lotka Volterra interactions but no niche structure. The host-pathogen-like interactions drive the ecological dynamics into a spatiotemporally chaotic state characterized by continual local blooms and busts. Upon the slow serial introduction of new strains, the community is found to diversify indefinitely, accommodating arbitrarily large numbers of strains in the absence of any kind of stabilizing niche interactions. This diversifying phase is robust to changes in evolutionary parameters, and persists even in the presence of a distribution of general, nonspecific fitness differences between individual strains, which explicitly break the assumption of tradeoffs inherent in much previous work. However, gradual increase of the general fitnesses in the ecosystem slows down the diversification. Quantitative analysis of the range of behaviors is carried out by a combination of analytical methods and simulations. Building on a dynamical-mean field-theory understanding of the ecological dynamics, an approximate effective model captures the effects of evolution on the distributions of key properties, such as strain abundances. This work establishes a potential scenario and a theoretical framework for understanding how the interplay between evolution and ecology can give rise to extensive fine-scale diversity. Future avenues for investigation are suggested, including the effects of the build-up of relatedness between strains, how conditioning on the evolutionary history affects the ecological interactions and dynamics, and application to coevolution of the diversity of a bacterial and a phage species.