bluuebunny/crossref_metadata_2025 huggingface dataset:
Bounce-Back
Authors: Roberts Pamela , Aronow Harriet , Ouellette Debra , Sandhu Meenu , DiVita Margaret
Published: September 2021

Objective

The aim of the study was to identify demographic, medical, and functional risk factors for discharge to an acute hospital before completion of an inpatient rehabilitation program and 7- and 30-day readmissions after completion of an inpatient rehabilitation program.

Design

This cohort study included 138,063 fee-for-service Medicare beneficiaries with a primary diagnosis of new onset stroke discharged from an inpatient rehabilitation facility from June 2009 to December 2011. Multivariate models examined readmission outcomes and included data from 6 mos before onset of the stroke to 30 days after discharge from the inpatient rehabilitation facility.

Results

In the acute discharge model (n = 9870), comorbidities and complications added risk, and the longer the stroke onset to admission to inpatient rehabilitation facility, the more likely discharge to the acute hospital. In the 7-day (n = 4755) and 30-day (n = 9861) readmission models, patients who were more complex with comorbidities, were black, or had managed care Medicare were more likely to have a readmission. Functional status played a role in all three models.

Conclusions

Results suggest that certain demographic, medical, and functional characteristics are associated differentially with rehospitalization after completion inpatient rehabilitation. The strongest model was the discharge to the acute hospital model with concordance statistic (c-statistic) of 0.87.
Targeting the stress response in pediatric pain: current evidence for psychosocial intervention and avenues for future investigation
Authors: Nelson Sarah , Borsook David , Bosquet Enlow Michelle
Published: September 2021

Nonpharmacological treatments for chronic pain in youth have been identified as first-line treatments over and above medication. Therapies such as cognitive-behavioral therapy and mindfulness-based stress reduction have shown good efficacy in reducing the psychological correlates (eg, anxiety, depression, and stress) and social or behavioral sequelae (eg, limited physical activity and lack of school engagement) associated with pediatric chronic pain. However, minimal research has examined the physiological mechanism(s) of action for these interventions. A recent review (Cunningham, et al., 2019) emphasized the need for objective (ie, physiological) assessment of treatment response in pediatric pain populations. The current review adds to this literature by identifying the physiological stress response as a particular target of interest in interventions for pediatric pain. Research indicates that youth with chronic pain report high rates of psychological stress, posttraumatic stress symptoms, and exposure to adverse childhood experiences (abuse/neglect, etc). In addition, a host of research has shown strong parallels between the neurobiology of pain processing and the neurobiology of stress exposure in both youth and adults. Interventions such as narrative or exposure therapy (eg, trauma-focused cognitive-behavioral therapy) and mindfulness-based or meditation-based therapies have shown particular promise in alleviating the neurobiological impact that stress and pain can have on the body, including reduction in allostatic load and altered connectivity in multiple brain regions. However, no study to date has specifically looked at these factors in the context of pediatric pain treatment. Future research should further explore these constructs to optimize prevention in and treatment of these vulnerable populations.
Tenofovir-diphosphate in peripheral blood mononuclear cells during low, medium and high adherence to emtricitabine/ tenofovir alafenamide vs. emtricitabine/ tenofovir disoproxil fumarate
Authors: Yager Jenna L. , Brooks Kristina M. , Castillo-Mancilla Jose R. , Nemkov Cricket , Morrow Mary , Peterson Skyler , Ibrahim Mustafa , Bushman Lane , Kiser Jennifer J. , MaWhinney Samantha , Anderson Peter L.
Published: September 2021

Objective:

Tenofovir alafenamide (TAF) preferentially loads peripheral blood mononuclear cells (PBMCs), resulting in higher PBMC tenofovir-diphosphate (TFV-DP) vs. tenofovir disoproxil fumarate (TDF). No studies have yet compared TFV-DP in PBMC from lower than daily dosing between prodrugs, which has potential implications for event-driven preexposure prophylaxis and pharmacologic forgiveness.

Design:

Two separate randomized, directly observed therapy (DOT) crossover studies (DOT-DBS and TAF-DBS) were conducted to mimic low, medium and high adherence.

Methods:

HIV-negative adults were randomized to two 12-week DOT regimens of 33, 67 or 100% of daily dosing with emtricitabine (F)/TAF 200 mg/25 mg (TAF-DBS) or F/TDF 200 mg/300 mg (DOT-DBS), separated by a 12-week washout. PBMC steady-state concentrations (Css) of TFV-DP and FTC-TP were estimated using nonlinear mixed models and compared between F/TAF and F/TDF.

Results:

Thirty-five participants contributed to 33% (n = 23), 67% (n = 23) and 100% (n = 23) of daily F/TAF regimens. Forty-four contributed to 33% (n = 15), 67% (n = 16) and 100% (n = 32) of daily F/TDF regimens. PBMC TFV-DP Css were 7.3 [95% confidence interval (95% CI): 6.4–8.2], 7.1 (5.9–8.2) and 6.7- (4.4–8.9) fold higher (P < 0.0001) following F/TAF vs. F/TDF; 593 vs. 81.7, 407 vs. 57.4, and 215 vs. 32.3 fmol/106 cells, respectively. TFV-DP was 2.6 (2.1–3.1) fold higher with 33% F/TAF vs. 100% F/TDF. Estimated half-lives (95% CI) of TFV-DP in PBMC were 2.9 (1.5–5.5) days for F/TAF and 2.1 (1.5–2.9) days for F/TDF. FTC-TP was similar in both studies (P = 0.119).

Conclusion:

F/TAF produced 6.7 to 7.3-fold higher TFV-DP in PBMC vs. F/TDF across adherence levels, supporting increased potency and pharmacologic forgiveness with F/TAF in the PBMC compartment.
Single nucleotide polymorphisms in PNPLA3, ADAR-1 and IFIH1 are associated with advanced liver fibrosis in patients co-infected with HIV-1//hepatitis C virus
Authors: Franco Sandra , Horneros Judith , Soldevila Laura , Ouchi Dan , Galván-Femenía Iván , de Cid Rafael , Tenesa Montserrat , Bechini Jordi , Perez Ricardo , Llibre Josep M. , Clotet Bonaventura , Tural Cristina , Martínez Miguel Angel
Published: September 2021

Objective:

Nonalcoholic fatty liver disease (NAFLD), insulin resistance and liver fibrosis are prevalent in individuals co-infected with HIV type 1 (HIV-1)/hepatitis C virus (HCV), even after HCV eradication. Our aim was to evaluate single nucleotide polymorphisms (SNPs) associated with advanced liver fibrosis in HIV-1/HCV co-infected patients.

Design/methods:

In a cohort of 102 participants, we genotyped 16 SNPs in 10 genes previously associated with NAFLD and the innate immune response and correlated the genotypes with liver fibrosis and fat accumulation.

Results:

Multinomial logistic regression analysis identified three metabolic parameters that were significantly associated with advanced liver fibrosis (stage F3–F4): albumin [odds ratio (OR) 0.80, 95% confidence interval (CI) 0.69–0.91, P = 0.001], percentage of visceral fat area (PVFA) (OR 1.06, 95% CI 1.01–1.12, P = 0.03) and BMI (OR 1.47, 95% CI 1.22–1.77, P < 0.0001). After adjustment for sex, albumin, PVFA and BMI, we found that three SNPs were significantly associated with advanced fibrosis, one each in PNPLA3/rs738409 (P = 0.016), ADAR-1/rs1127313 (P = 0.029) and IFIH1/rs1990760 (P = 0.033).

Conclusion:

Our results indicate that genotyping for these SNPs can be a useful predictive tool for liver fibrosis progression and liver fat accumulation in patients co-infected with HIV-1/HCV.
Phylogenetic signal in the vocalizations of vocal learning and vocal non-learning birds
Authors: Arato Jozsef , Fitch W. Tecumseh
Published: September 2021

Some animal vocalizations develop reliably in the absence of relevant experience, but an intriguing subset of animal vocalizations is learned: they require acoustic models during ontogeny in order to develop, and the learner's vocal output reflects those models. To what extent do such learned vocalizations reflect phylogeny? We compared the degree to which phylogenetic signal is present in vocal signals from a wide taxonomic range of birds, including both vocal learners (songbirds) and vocal non-learners. We used publically available molecular phylogenies and developed methods to analyse spectral and temporal features in a carefully curated collection of high-quality recordings of bird songs and bird calls, to yield acoustic distance measures. Our methods were initially developed using pairs of closely related North American and European bird species, and then applied to a non-overlapping random stratified sample of European birds. We found strong similarity in acoustic and genetic distances, which manifested itself as a significant phylogenetic signal, in both samples. In songbirds, both learned song and (mostly) unlearned calls allowed reconstruction of phylogenetic trees nearly isomorphic to the phylogenetic trees derived from genetic analysis. We conclude that phylogeny and inheritance constrain vocal structure to a surprising degree, even in learned birdsong.

This article is part of the theme issue ‘Vocal learning in animals and humans’.
Global cultural evolutionary model of humpback whale song
Authors: Zandberg Lies , Lachlan Robert F. , Lamoni Luca , Garland Ellen C.
Published: September 2021

Humpback whale song is an extraordinary example of vocal cultural behaviour. In northern populations, the complex songs show long-lasting traditions that slowly evolve, while in the South Pacific, periodic revolutions occur when songs are adopted from neighbouring populations and rapidly spread. In this species, vocal learning cannot be studied in the laboratory, learning is instead inferred from the songs' complexity and patterns of transmission. Here, we used individual-based cultural evolutionary simulations of the entire Southern and Northern Hemisphere humpback whale populations to formalize this process of inference. We modelled processes of song mutation and patterns of contact among populations and compared our model with patterns of song theme sharing measured in South Pacific populations. Low levels of mutation in combination with rare population interactions were sufficient to closely fit the pattern of diversity in the South Pacific, including the distinctive pattern of west-to-east revolutions. Interestingly, the same learning parameters that gave rise to revolutions in the Southern Hemisphere simulations gave rise to evolutionary patterns of cultural evolution in the Northern Hemisphere populations. Our study demonstrates how cultural evolutionary approaches can be used to make inferences about the learning processes underlying cultural transmission and how they might generate emergent population-level processes.

This article is part of the theme issue ‘Vocal learning in animals and humans’.
Vocal production learning in mammals revisited
Authors: Janik Vincent M. , Knörnschild Mirjam
Published: September 2021

Vocal production learning, the ability to modify the structure of vocalizations as a result of hearing those of others, has been studied extensively in birds but less attention has been given to its occurrence in mammals. We summarize the available evidence for vocal learning in mammals from the last 25 years, updating earlier reviews on the subject. The clearest evidence comes from cetaceans, pinnipeds, elephants and bats where species have been found to copy artificial or human language sounds, or match acoustic models of different sound types. Vocal convergence, in which parameter adjustments within one sound type result in similarities between individuals, occurs in a wider range of mammalian orders with additional evidence from primates, mole-rats, goats and mice. Currently, the underlying mechanisms for convergence are unclear with vocal production learning but also usage learning or matching physiological states being possible explanations. For experimental studies, we highlight the importance of quantitative comparisons of seemingly learned sounds with vocal repertoires before learning started or with species repertoires to confirm novelty. Further studies on the mammalian orders presented here as well as others are needed to explore learning skills and limitations in greater detail.

This article is part of the theme issue ‘Vocal learning in animals and humans’.
Re-evaluating vocal production learning in non-oscine birds
Authors: ten Cate Carel
Published: September 2021

The study of vocal production learning in birds is heavily biased towards oscine songbirds, making the songbird model the reference for comparative studies. However, as vocal learning was probably ancestral in songbirds, interspecific variations might all be variations on a single theme and need not be representative of the nature and characteristics of vocal learning in other bird groups. To assess the possible mechanisms of vocal learning and its evolution therefore requires knowledge about independently evolved incidences of vocal learning. This review examines the presence and nature of vocal production learning in non-songbirds. Using a broad definition of vocal learning and a comparative phylogenetic framework, I evaluate the evidence for vocal learning and its characteristics in non-oscine birds, including well-known vocal learners such as parrots and hummingbirds but also (putative) cases from other taxa. Despite the sometimes limited evidence, it is clear that vocal learning occurs in a range of different, non-related, taxa and can be caused by a variety of mechanisms. It is more widespread than often realized, calling for more systematic studies. Examining this variation may provide a window onto the evolution of vocal learning and increase the value of comparative research for understanding vocal learning in humans.

This article is part of the theme issue ‘Vocal learning in animals and humans’.
Species information in whistle frequency modulation patterns of common dolphins
Authors: Oswald Julie N. , Walmsley Sam F. , Casey Caroline , Fregosi Selene , Southall Brandon , Janik Vincent M.
Published: September 2021

The most flexible communication systems are those of open-ended vocal learners that can acquire new signals throughout their lifetimes. While acoustic signals carry information in general voice features that affect all of an individual's vocalizations, vocal learners can also introduce novel call types to their repertoires. Delphinids are known for using such learned call types in individual recognition, but their role in other contexts is less clear. We investigated the whistles of two closely related, sympatric common dolphin species,Delphinus delphisandDelphinus bairdii, to evaluate species differences in whistle contours. Acoustic recordings of single-species groups were obtained from the Southern California Bight. We used an unsupervised neural network to categorize whistles and compared the resulting whistle types between species. Of the whistle types recorded in more than one encounter, 169 were shared between species and 60 were species-specific (32D. delphistypes, 28D. bairdiitypes).Delphinus delphisused 15 whistle types with an oscillatory frequency contour while only one such type was found inD. bairdii. Given the role of vocal learning in delphinid vocalizations, we argue that these differences in whistle production are probably culturally driven and could help facilitate species recognition betweenDelphinusspecies.

This article is part of the theme issue ‘Vocal learning in animals and humans’.
Sickle cell disease children’s gut colonization by extended-spectrum β-lactamase (ESBL)-producing Enterobacterales: an antibiotic prophylaxis effect?
Authors: Monteiro Adriano de Souza Santos , Oliveira Eduardo Gomes de , Santos Djanilson Barbosa dos , Cordeiro Soraia Machado , Couto Ricardo David , Couto Fábio David
Published: September 2021

Introduction. Sickle cell disease (SCD) children have a high susceptibility to pneumococcal infection. For this reason, they are routinely immunized with pneumococcal vaccines and use antibiotic prophylaxis (AP).

Hypothesis/Gap Statement. Yet, little is known about SCD children’s gut microbiota. If antibiotic-resistant

Enterobacterales

may colonize people on AP, we hypothesized that SCD children on AP are colonized by resistant enterobacteria species.

Objective. To evaluate the effect of continuous AP on

Enterobacterales

gut colonization from children with SCD.

Methodology. We analysed 30 faecal swabs from SCD children on AP and 21 swabs from children without the same condition.

Enterobacterales

was isolated on MacConkey agar plates and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) (bioMérieux, Marcy l'Etoile, France). We performed the antibiogram by Vitek 2 system (bioMérieux, Marcy l'Etoile, France), and the resistance genes were identified by multiplex PCR.

Results. We found four different species with resistance to one or more different antibiotic types in the AP-SCD children’s group:

Escherichia coli

,

Klebsiella pneumoniae

,

Citrobacter freundii

, and

Citrobacter farmeri

. Colonization by resistant

E. coli

was associated with AP (prevalence ratio 2.69, 95 % confidence interval [CI], 1.98–3.67, P<0.001). Strains producing extended-spectrum β-lactamases (ESBL) were identified only in SCD children,

E. coli

, 4/30 (13 %), and

K. pneumoniae

, 2/30 (7 %). The ESBL-producing

Enterobacterales

were associated with penicillin G benzathine use (95 % CI, 22.91–86.71, P<0.001). CTX-M-1 was the most prevalent among ESBL-producers (3/6, 50 %), followed by CTX-M-9 (2/6, 33 %), and CTX-M-2 (1/6, 17 %).

Conclusion. Resistant enterobacteria colonize SCD children on AP, and this therapy raises the chance of ESBL-producing

Enterobacterales

colonization. Future studies should focus on prophylactic vaccines as exclusive therapy against pneumococcal infections.
The fall and rise of group B Streptococcus in dairy cattle: reintroduction due to human-to-cattle host jumps?
Authors: Crestani Chiara , Forde Taya L. , Lycett Samantha J. , Holmes Mark A. , Fasth Charlotta , Persson-Waller Karin , Zadoks Ruth N.
Published: September 2021

Group B

Streptococcus

(GBS;

Streptococcus agalactiae

) is a major neonatal and opportunistic bacterial pathogen of humans and an important cause of mastitis in dairy cattle with significant impacts on food security. Following the introduction of mastitis control programmes in the 1950s, GBS was nearly eradicated from the dairy industry in northern Europe, followed by re-emergence in the 21st century. Here, we sought to explain this re-emergence based on short and long read sequencing of historical (1953–1978; n=44) and contemporary (1997–2012; n=76) bovine GBS isolates. Our data show that a globally distributed bovine-associated lineage of GBS was commonly detected among historical isolates but never among contemporary isolates. By contrast, tetracycline resistance, which is present in all major GBS clones adapted to humans, was commonly and uniquely detected in contemporary bovine isolates. These observations provide evidence for strain replacement and suggest a human origin of newly emerged strains. Three novel GBS plasmids were identified, including two showing >98 % sequence similarity with plasmids from

Streptococcus pyogenes

and

Streptococcus dysgalactiae

subsp.

equisimilis

, which co-exist with GBS in the human oropharynx. Our findings support introduction of GBS into the dairy population due to human-to-cattle jumps on multiple occasions and demonstrate that reverse zoonotic transmission can erase successes of animal disease control campaigns.
Biofilm hydrophobicity in environmental isolates of Bacillus subtilis
Authors: Kalamara Margarita , Abbott James C. , MacPhee Cait E. , Stanley-Wall Nicola R.
Published: September 2021

Biofilms are communities of bacteria that are attached to a surface and surrounded by an extracellular matrix. The extracellular matrix protects the community from stressors in the environment, making biofilms robust. The Gram-positive soil bacterium Bacillus subtilis, particularly the isolate NCIB 3610, is widely used as a model for studying biofilm formation.

B. subtilis

NCIB 3610 forms colony biofilms that are architecturally complex and highly hydrophobic. The hydrophobicity is linked, in part, to the localisation of the protein BslA at the surface of the biofilm, which provides the community with increased resistance to biocides. As most of our knowledge about

B. subtilis

biofilm formation comes from one isolate, it is unclear if biofilm hydrophobicity is a widely distributed feature of the species. To address this knowledge gap, we collated a library of

B. subtilis

soil isolates and acquired their whole genome sequences. We used our novel isolates to examine biofilm hydrophobicity and found that, although BslA is encoded and produced by all isolates in our collection, hydrophobicity is not a universal feature of

B. subtilis

colony biofilms. To test whether the matrix exopolymer poly γ-glutamic acid could be masking hydrophobicity in our hydrophilic isolates, we constructed deletion mutants and found, contrary to our hypothesis, that the presence of poly γ-glutamic acid was not the reason for the observed hydrophilicity. This study highlights the natural variation in the properties of biofilms formed by different isolates and the importance of using a more diverse range of isolates as representatives of a species.
Trabecular Bone Score Could Not Predict the Bone Mineral Density of Proximal Humerus
Authors: Jeong Hyeon Jang , Ahn Joong Mo , Oh Joo Han
Published: September 2021

Background: Osteoporosis is an important clinical factor for tendon healing after arthroscopic rotator cuff repair (ARCR). Conventional dual energy X-ray absorptiometry (DXA) of the hip and lumbar spine (LS) does not represent proximal humeral bone mineral density (BMD). Theoretically, direct measurement of the BMD of the proximal humerus is the best method; however, it is not popular and is non-standardized. Therefore, we evaluate whether the trabecular bone score (TBS) using LS DXA would represent proximal humeral BMD.Methods: Conventional hip and LS DXA and proximal humeral BMD were measured in 212 consecutive ARCR patients, and TBS was calculated using LS DXA. Comparative analysis between the affected and contralateral asymptomatic shoulders was done; moreover, correlation analysis was conducted to evaluate the representativity of TBS for proximal humeral BMD. Regression analysis was performed to elucidate the risk factor of intraoperative suture anchor failure (ISAF).Results: BMDs of the affected shoulder were significantly lower than those of the contralateral side (all P<0.05). TBS failed to present a strong correlation with proximal humeral BMD (correlation coefficients 0.155-0.506, all P<0.05), and the BMD of the greater tuberosity (GT) of the proximal humerus was revealed to be a sole risk factor for ISAF (odds ratio, 0.01, P=0.020).Conclusions: TBS and conventional hip and LS DXA did not represent proximal humeral BMD. Furthermore, among the various radiological measurements, the BMD of the GT was a sole risk factor of ISAF. Therefore, further research for the direct measurement of proximal humeral BMD is mandatory to predict proximal humeral focal osteoporosis.
Development of a multimodal machine-learning fusion model to non-invasively assess ileal Crohn’s disease endoscopic activity
Authors: Guez Itai , Focht Gili , C.Greer Mary-Louise , Cytter-Kuint Ruth , Pratt Li-Tal , Castro Denise A. , Turner Dan , Griffiths Anne M. , Freiman Moti
Published: September 2021

Background and Objective

Recurrent attentive non-invasive observation of intestinal inflammation is essential for the proper management of Crohn’s disease (CD). The goal of this study was to develop and evaluate a multimodal machine-learning (ML) model to assess ileal CD endoscopic activity by integrating information from Magnetic Resonance Enterography (MRE) and biochemical biomarkers.

Methods

We obtained MRE, biochemical and ileocolonoscopy data from the multi-center ImageKids study database. We developed an optimized multimodal fusion ML model to non-invasively assess terminal ileum (TI) endoscopic disease activity in CD from MRE data. We determined the most informative features for model development using a permutation feature importance technique. We assessed model performance in comparison to the clinically recommended linear-regression MRE model in an experimental setup that consisted of stratified 2-fold validation, repeated 50 times, with the ileocolonoscopy-based Simple Endoscopic Score for CD at the TI (TI SES-CD) as a reference. We used the predictions’ mean-squared-error (MSE) and the receiver operation characteristics (ROC) area under curve (AUC) for active disease classification (TI SEC-CD≥3) as performance metrics.

Results

121 subjects out of the 240 subjects in the ImageKids study cohort had all required information (Non-active CD: 62 [51%], active CD: 59 [49%]). Length of disease segment and normalized biochemical biomarkers were the most informative features. The optimized fusion model performed better than the clinically recommended model determined by both a better median test MSE distribution (7.73 vs. 8.8, Wilcoxon test, p<1e-5) and a better aggregated AUC over the folds (0.84 vs. 0.8, DeLong’s test, p<1e-9).

Conclusions

Optimized ML models for ileal CD endoscopic activity assessment have the potential to enable accurate and non-invasive attentive observation of intestinal inflammation in CD patients. The presented model will be made available to the community through a dedicated website upon acceptance.
Elevation of Neurodegenerative Serum Biomarkers among Hospitalized COVID-19 Patients
Authors: Frontera Jennifer A. , Boutajangout Allal , Masurkar Arjun V. , Betensky Rebecca A. , Ge Yulin , Vedvyas Alok , Debure Ludovic , Moreira Andre , Lewis Ariane , Huang Joshua , Thawani Sujata , Balcer Laura , Galetta Steven , Wisniewski Thomas
Published: September 2021

INTRODUCTION

Older adults hospitalized with COVID-19 are susceptible to neurological complications, particularly encephalopathy, which may reflect age-related neurodegenerative processes.

METHODS

Serum total tau, ptau-181, GFAP, NFL, UCHL1, and amyloid-beta(Aβ-40,42) were measured in hospitalized COVID-19 patients without a history of dementia, and compared among patients with or without encephalopathy, in-hospital death versus survival, and discharge home versus other dispositions using multivariable Cox proportional hazards regression analyses.

RESULTS

Among 251 patients, admission serum ptau-181 and UCHL1 were significantly elevated in patients with encephalopathy (both P<0.05) and total tau, GFAP, and NFL were significantly lower in those discharged home(all P<0.05). These markers correlated significantly with severity of COVID illness. NFL, GFAP and UCH-L1 were significantly higher in hospitalized COVID patients than in non-COVID controls with mild cognitive impairment or Alzheimer’s disease(AD).

DISCUSSION

Age-related neurodegenerative biomarkers were elevated to levels observed in AD and associated with encephalopathy and worse outcomes among hospitalized COVID-19 patients.
Efficacy versus abundancy: which vaccination schemes can better prohibit deaths and active infections?
Authors: Deeb Omar El , Jalloul Maya
Published: September 2021

In this paper, we introduce a general novel compartmental model accounting for the effects of vaccine efficacy, deployment rates and timing of initiation of deployment. It consists of compartments corresponding to susceptible, vaccinated susceptible, infectious, vaccinated infectious, active, and dead populations with various vaccine efficacies and vaccination deployment rates.

We simulate different scenarios and initial conditions, and we find that the abundance and higher rate of deployment of low efficacy vaccines would lower the cumulative number of deaths in comparison to slower deployment of high efficacy vaccines. However, the latter can lower the number of active cases and achieve faster and higher herd immunity. We also forecast that, at the same daily deployment rate, the earlier introduction of vaccination schemes with lower efficacy would also lower the number of deaths with respect to a delayed introduction of high efficacy vaccines, which can however, still achieve lower numbers of infections and better herd immunity.
Interrelations between delta waves, spindles and slow oscillations in human NREM sleep and their functional role in memory
Authors: Wüst Larissa N. , Antonenko Daria , Malinowski Robert , Khakimova Liliia , Grittner Ulrike , Obermayer Klaus , Ladenbauer Julia , Flöel Agnes
Published: September 2021

Certain neurophysiological characteristics of sleep, in particular slow oscillations (SO), sleep spindles, and their temporal coupling, have been well characterized and associated with human memory formation. Delta waves, which are somewhat higher in frequency and lower in amplitude compared to SO, have only recently been found to play a critical role in memory processing of rodents, through a competitive interplay between SO-spindle and delta-spindle coupling. However, human studies that comprehensively address delta waves, their interactions with spindles and SOs as well as their functional role for memory are still lacking.

Electroencephalographic data were acquired across three naps of 33 healthy older human participants (17 female) to investigate delta-spindle coupling and the interplay between delta and SO-related activity. Additionally, we determined intra-individual stability of coupling measures and their potential link to the ability to form novel memories.

Our results revealed weaker delta-spindle compared to SO-spindle coupling. Contrary to our initial hypothesis, we found that increased delta activity was accompanied by stronger SO-spindle coupling. Moreover, we identified the ratio between SO- and delta-nested spindles as the sleep parameter that predicted ability to form novel memories best.

Our study suggests that SOs, delta waves and sleep spindles should be jointly considered when aiming to link sleep physiology and memory formation in aging.

Significance statement

Interrelations between delta waves, slow oscillations and sleep spindles have recently been causally linked to the balance between consolidation and forgetting in rats using optogenetics. In humans, SO-spindle coupling has been intensively investigated, but delta waves and their interaction with spindles were only studied jointly as SWA. Here we delineate the coupling of delta waves to spindles, investigate interactions of delta- and SO-related activity and investigate their role for the ability to form novel memories in healthy older individuals. Our results show differences as well as dependencies between SO- and delta-related activities including spindle coupling. Further, our results indicate that the ratio of SO- to delta-nested spindles might be the most informative sleep parameter for memory formation of older adults.
Relationship Between Inter-individual Variation in Circadian Rhythm and Sociality: A case Study Using Halictid Bees
Authors: Cartagena Sofía Meléndez , Ortiz-Alvarado Carlos A. , Ordoñez Patricia , Cordero-Martínez Claudia S. , Ambrose Alexandria F. , Roman Lizasoain Luis A , Santos Vega Milexis A , Velez Velez Andrea V , Acevedo-Gonzalez Jenny P. , Gibbs Jason , Petanidou Theodora , Tscheulin Thomas , Barthell John T. , González Victor H. , Giray Tugrul , Agosto-Rivera José L.
Published: September 2021

The bee family Halictidae is considered to be an optimal model for the study of social evolution due to its remarkable range of social behaviors. Past studies in circadian rhythms suggest that social species may express more diversity in circadian behaviors than solitary species. However, these previous studies did not make appropriate taxonomic comparisons. To further explore the link between circadian rhythms and sociality, we examine four halictid species with different degrees of sociality, three social species of Lasioglossum, one from Greece and two from Puerto Rico, and a solitary species of Systropha from Greece. Based on our previous observations, we hypothesized that species with greater degree of sociality will show greater inter-individual variation in circadian rhythms than solitary species. We observed distinct differences in their circadian behavior that parallel differences across sociality, where the most social species expressed the highest inter-individual variation. We predict that circadian rhythm differences will be informative of sociality across organisms.
Intronic elements associated with insomnia and restless legs syndrome exhibit cell type-specific epigenetic features contributing to MEIS1 regulation
Authors: Lam Daniel D. , Nikolic Ana Antic , Zhao Chen , Mirza-Schreiber Nazanin , Krężel Wojciech , Oexle Konrad , Winkelmann Juliane
Published: September 2021

A highly evolutionarily conserved MEIS1 intronic region is strongly associated with restless legs syndrome (RLS) and insomnia. To understand its regulatory function, we dissected the region by analyzing chromatin accessibility, enhancer-promoter contacts, DNA methylation, and eQTLs in different human neural cell types and tissues. We observed specific activity with respect to cell type and developmental maturation, indicating a prominent role for distinct highly conserved intronic elements in forebrain inhibitory neuron differentiation. Two elements were hypomethylated in neural cells with higher MEIS1 expression, suggesting a role of enhancer demethylation in gene regulation. MEIS1 eQTLs showed a striking modular chromosomal distribution, with forebrain eQTLs clustering in intron 8/9. CRISPR interference targeting of individual elements in this region attenuated MEIS1 expression, revealing a complex regulatory interplay of distinct elements. In summary, we found that MEIS1 regulation is organized in a modular pattern. Disease-associated intronic regulatory elements control MEIS1 expression with cell type and maturation stage specificity, particularly in the inhibitory neuron lineage. The precise spatiotemporal activity of these elements likely contributes to the pathogenesis of insomnia and RLS.
Integrative multi-omics identifies high risk Multiple Myeloma subgroup associated with significant DNA loss and dysregulated DNA repair and cell cycle pathways
Authors: Ortiz-Estévez María , Samur Mehmet , Towfic Fadi , Flynt Erin , Stong Nicholas , Jang In Sock , Wang Kai , Vyas Paresh , Munshi Nikhil , Avet-Loiseau Herve , Trotter Matthew W. B. , Morgan Gareth J. , Walker Brian A. , Thakurta Anjan
Published: September 2021

Despite significant therapeutic advances in improving lives of Multiple Myeloma (MM) patients, it remains mostly incurable, with patients ultimately becoming refractory to therapies. MM is a genetically heterogeneous disease and therapeutic resistance is driven by a complex interplay of disease pathobiology and mechanisms of drug resistance. We applied a multi-omics strategy using tumor-derived gene expression, single nucleotide variant, copy number variant, and structural variant profiles to investigate molecular subgroups in 514 newly diagnosed MM (NDMM) samples and identified 12 molecularly defined MM subgroups (MDMS1-12) with distinct genomic and transcriptomic features.

Our integrative approach let us identify ndMM subgroups with transversal profiles to previously described ones, based on single data types, which shows the impact of this approach for disease stratification. One key novel subgroup is our MDMS8, associated with poor clinical outcome [median overall survival, 38 months (global log-rank pval<1×10−6)], which uniquely presents a broad genomic loss (>9% of entire genome, t.test pval<1e-5) driving dysregulation of various transcriptional programs affecting DNA repair and cell cycle/mitotic processes. This subgroup was validated on multiple independent datasets, and a master regulator analyses identified transcription factors controlling MDMS8 transcriptomic profile, including CKS1B and PRKDC among others, which are regulators of the DNA repair and cell cycle pathways.

Statement of Significance

Using multi-omics unsupervised clustering we discovered a new high-risk multiple myeloma patient segment. We linked its diverse genetic markers (previously known, and new including genomic loss) to transcriptional dysregulation (cell cycle, DNA repair and DNA damage) and identified master regulators that control these key biological pathways.
The genetics of eating behaviors: research in the age of COVID-19
Authors: Hannum Mackenzie E. , Lin Cailu , Bell Katherine , Toskala Aurora , Koch Riley , Galaniha Tharaka , Nolden Alissa , Reed Danielle R , Joseph Paule
Published: September 2021

How much pleasure we take in eating is more than just how much we enjoy the taste of food. Food involvement – the amount of time we spend on food beyond the immediate act of eating and tasting – is key to the human food experience. We took a biological approach to test whether food-related behaviors, together capturing food involvement, have genetic components and are partly due to inherited variation. We collected data via an internet survey from a genetically informative sample of 419 adult twins (114 monozygotic twin pairs, 31 dizygotic twin pairs, and 129 singletons). Because we conducted this research during the pandemic, we also ascertained how many participants had experienced COVID-19-associated loss of taste and smell. Since these respondents had previously participated in research in person, we measured their level of engagement to evaluate the quality of their online responses. Additive genetics explained 16-44% of the variation in some measures of food involvement, most prominently various aspects of cooking, suggesting some features of the human food experience may be inborn. Other features reflected shared (early) environment, captured by respondents’ twin status. About 6% of participants had a history of COVID-19 infection, many with transitory taste and smell loss, but all but one had recovered before the survey. Overall, these results suggest that people may have inborn as well as learned variations in their involvement with food. We also learned to adapt to research during a pandemic by considering COVID-19 status and measuring engagement in online studies of human eating behavior.
Scallop2 enables accurate assembly of multiple-end RNA-seq data
Authors: Zhang Qimin , Shi Qian , Shao Mingfu
Published: September 2021

Transcript assembly (i.e., to reconstruct the full-length expressed transcripts from RNA-seq data) has been a critical but yet unsolved step in RNA-seq analysis. Modern RNA-seq protocols can produce paired-/multiple-end RNA-seq reads, where information is available that two or more reads originate from the same transcript. The long-range constraints implied in these paired-/multiple-end reads can be much beneficial in correctly phasing the complicated spliced isoforms. However, there often exist gaps among individual ends, which may even contain junctions, making the efficient use of such constraints algorithmically challenging. Here we introduce Scallop2, a new reference-based transcript assembler optimized for multiple-end (including paired-end) RNA-seq data. Scallop2 uses an algorithmic frame-work that first represents reads from the same molecule as the so-called multiple-end phasing paths in the context of a splice graph, then “bridges” each multiple-end phasing path into a long, single-end phasing path, and finally decomposes the splice graph into paths (i.e., transcripts) guided by the bridged phasing paths. An efficient bridging algorithm is designed to infer the true path connecting two consecutive ends following a novel formulation that is robust to sequencing errors and transcript noises. By observing that failing to bridge two ends is mainly due to incomplete splice graphs, we propose a new method to determine false starting/ending vertices of the splice graphs which has been showed efficient in reducing false positive rate. Evaluations on both (multiple-end) single-cell RNA-seq datasets from Smart-seq3 protocol and Illumina paired-end RNA-seq samples demonstrate that Scallop2 vastly outperforms recent assemblers including StringTie2, Scallop, and CLASS2 in assembly accuracy.
Protein embeddings and deep learning predict binding residues for various ligand classes
Authors: Littmann Maria , Heinzinger Michael , Dallago Christian , Weissenow Konstantin , Rost Burkhard
Published: September 2021

One important aspect of protein function is the binding of proteins to ligands, including small molecules, metal ions, and macromolecules such as DNA or RNA. Despite decades of experimental progress many binding sites remain obscure. Here, we proposed bindEmbed21, a method predicting whether a protein residue binds to metal ions, nucleic acids, or small molecules. The Artificial Intelligence (AI)-based method exclusively uses embeddings from the Transformer-based protein Language Model (pLM) ProtT5 as input. Using only single sequences without creating multiple sequence alignments (MSAs), bindEmbed21DL outperformed MSA-based predictions. Combination with homology-based inference increased performance to F1=48±3% (95% CI) and MCC=0.46±0.04 when merging all three ligand classes into one. All results were confirmed by three independent data sets. Focusing on very reliably predicted residues could complement experimental evidence: For the 25% most strongly predicted binding residues, at least 73% were correctly predicted even when ignoring the problem of missing experimental annotations. The new method bindEmbed21 is fast, simple, and broadly applicable - neither using structure nor MSAs. Thereby, it found binding residues in over 42% of all human proteins not otherwise implied in binding and predicted about 6% of all residues as binding to metal ions, nucleic acids, or small molecules.
Emergent intra-pair sex differences and behavioral coordination in pair bonded prairie voles
Authors: Brusman Liza E. , Protter David S. W. , Fultz Allison C. , Paulson Maya U. , Chapel Gabriel D. , Elges Isaiah O. , Cameron Ryan T. , Beery Annaliese K. , Donaldson Zoe R.
Published: September 2021

In pair bonding animals, coordinated behavior between partners is required for the pair to accomplish shared goals such as raising young. Despite this, experimental designs rarely assess the behavior of both partners within a bonded pair. Thus, we lack an understanding of the interdependent behavioral dynamics between partners that likely facilitate relationship success. To identify intra-pair behavioral correlates of pair bonding, we used socially monogamous prairie voles, a species in which females and males exhibit both overlapping and distinct pair bond behaviors. We tested both partners using social choice and non-choice tests at short- and long-term pairing timepoints. Females developed a preference for their partner more rapidly than males, with preference driven by different behaviors in each sex. Further, as bonds matured, intra-pair behavioral sex differences and coordinated behavior emerged – females consistently huddled more with their partner than males did, and partner huddle time became correlated between partners. When animals were allowed to freely interact with a partner or a novel in sequential free interaction tests, pairs spent more time interacting together than either animal did with a novel. Pair interaction was correlated with female, but not male, behavior. Via a social operant paradigm, we found that pair-bonded females, but not males, are more motivated to access and huddle with their partner than a novel vole. Together, our data indicate that as pair bonds mature, sex differences and coordinated behavior emerge, and that these intra-pair behavioral changes are likely organized and driven by the female animal.
The visual coupling between neighbors explains ‘flocking’ in human crowds
Authors: Dachner Gregory C. , Wirth Trenton D. , Richmond Emily , Warren William H.
Published: September 2021

Patterns of collective motion or ‘flocking’ in birds, fish schools, and human crowds are believed to emerge from local interactions between individuals. Most models of collective motion attribute these interactions to hypothetical rules or forces, often inspired by physical systems, and described from an overhead view. We develop a visual model of human flocking from an embedded view, based on optical variables that actually govern pedestrian interactions. Specifically, people control their walking speed and direction by canceling the average optical expansion and angular velocity of their neighbors, weighted by visual occlusion. We test the model by simulating data from experiments with virtual crowds and real human ‘swarms’. The visual model outperforms our previous overhead model and explains basic properties of physics-inspired models: ‘repulsion’ forces reduce to canceling optical expansion, ‘attraction’ forces to canceling optical contraction, and ‘alignment’ to canceling the combination of expansion/contraction and angular velocity. Critically, the neighborhood of interaction follows from Euclid’s Law of perspective and the geometry of occlusion. We conclude that the local interactions underlying human flocking are a natural consequence of the laws of optics. Similar principles may apply to collective motion in other species.
The treatment of scaphoid non-unions with partial and total scaphoid in titanium custom-made 3D-printed prostheses and reconstruction of scapholunate interosseous ligament: a preliminary study
Authors: Cioffi Alessio , Rossello Mario Igor
Published: September 2021

The treatment of sequelae of scaphoid fractures is still one of the unsolved problems of hand surgery. Between January 2019 and July 2020 in the Hand Surgery Department of San Paolo’s Hospital in Savona (Italy) 9 partial scaphoid in titanium custom-made 3D-printed prosthesis have performed in 9 patients (all men) with an average age of 27.5 years (minimum 18-maximum 37 years). The aim of the study is to evaluate over time the clinical-functional and radiographic results of the wrists treated with partial and total scaphoid titanium custom-made 3D-printed prostheses and reconstruction of SLIL.
Novel classes and evolutionary turnover of histone H2B variants in the mammalian germline
Authors: Raman Pravrutha , Rominger Callie , Young Janet M. , Molaro Antoine , Tsukiyama Toshio , Malik Harmit S.
Published: September 2021

Histones and their post-translational modifications facilitate diverse chromatin functions in eukaryotes. Core histones (H2A, H2B, H3, and H4) package genomes after DNA replication. In contrast, variant histones promote specialized chromatin functions, including DNA repair, genome stability, and epigenetic inheritance. Previous studies have identified only a few H2B variants in animals; their roles and evolutionary origins remain largely unknown. Here, using phylogenomic analyses, we reveal the presence of five H2B variants broadly present in mammalian genomes. In addition to three previously described variants (H2B.1, subH2B, and H2B.W), we identify and describe two new variants, H2B.L and H2B.N. Four of these five H2B variants originated in mammals, whereas H2B.L arose prior to the last common ancestor of bony vertebrates. We find that though mammalian H2B variants are subject to high gene turnover, most are broadly retained in mammals, including humans. Despite an overall signature of purifying selection, H2B variants evolve more rapidly than core H2B with considerable divergence in sequence and length. All five H2B variants are expressed in the germline. H2B.L and H2B.N are predominantly expressed in oocytes, an atypical expression site for mammalian histone variants. Our findings suggest that H2B variants likely encode potentially redundant but vital functions via unusual chromatin packaging or non-chromatin functions in mammalian germline cells. Our discovery of novel histone variants highlights the advantages of comprehensive phylogenomic analyses and provides unique opportunities to study how innovations in chromatin function evolve.