bluuebunny/crossref_metadata_2025 huggingface dataset:
Is There a Difference in Whole Body Standing Posture in Women With Urinary Incontinence Based on the Presence of Myofascial Dysfunction in the Pelvic Floor Muscles?
Authors: Reis Amanda Martins , Brito Luiz Gustavo Oliveira , Teixeira Cláudia Pignatti Frederice , de Araújo Camila Carvalho , Facio Fábio Augusto , Herrmann Viviane , Juliato Cassia Raquel Teatin
Published: July 2021

Objective

The purpose of this study was to assess the prevalence of postural changes in women who had urinary incontinence (UI) with myofascial dysfunction (MD) and women who had UI without MD in the pelvic floor muscles (PFM).

Methods

A cross-sectional study was performed with 234 women who had UI and were at least 18 years old at the urogynecology outpatient clinic of a tertiary academic hospital. The International Consultation on Incontinence Questionnaire—Short Form and the International Consultation on Incontinence Questionnaire—Overactive Bladder were used to collect urinary data. Standing postural assessment was performed using photogrammetry in anterior, posterior, and right and left lateral views and was analyzed with Postural Assessment Software. MD was defined as pain of any intensity during palpation of the PFM, and the strength of these muscles was evaluated using the Modified Oxford Scale.

Results

The prevalence of MD in women with UI was 51.7% (121/234). Women with MD had significantly smaller angles in the horizontal alignment of the pelvis in the right-side view (mean [SD] = −11.9 [6.9] degrees and −9.6 [7.1] degrees), left-side view (−13.6 [6] degrees and −11.5 [6.6] degrees), and vertical alignment of the body in the left-side view (3 [1.5] degrees and 3.4 [1.5] degrees), showing anterior pelvic tilt and posterior displacement of the body.

Conclusion

Women with UI and MD had greater anterior pelvic tilt and posterior displacement of the body than women without dysfunction.

Impact

This study informs physical therapists and other health care professionals about the prevalence of MD in the pelvic floor muscles of women with UI and highlights the need to rule out MD, because it appears to be a concomitant impairment in women who self-report UI. During a postural screen, health care professionals should look for anterior pelvic tilt relative to horizon when evaluating posture in women with UI and MD. The findings of postural changes in women with MD and UI may influence the PFM assessment.

Lay Summary

Women with involuntary urinary loss, pain, and stiffness in the pelvic area may show changes in posture associated with this condition.
Does screening or routine enquiry for adverse childhood experiences (ACEs) meet criteria for a screening programme? A rapid evidence summary
Authors: Gentry S V , Paterson B A
Published: July 2021

Background

Adverse childhood experiences (ACEs) are traumatic events in childhood that can have impacts throughout life. It has been suggested that ACEs should be ‘screened’ for, or routinely enquired about, in childhood or adulthood. The aim of this work is to review evidence for this against the United Kingdom National Screening Committee (UKNSC) programme criteria.

Methods

A rapid review of evidence on ACEs screening was conducted using the approach of the UKNSC.

Results

Good quality evidence was identified from meta-analyses for associations between ACEs and a wide range of adverse outcomes. There was no consistent evidence on the most suitable screening tool, setting of administration, and time or frequency of use. Routine enquiry among adults was feasible and acceptable to service users and professionals in various settings. A wide range of potentially effective interventions was identified. Limited evidence was available on the potential for screening or routine enquiry to reduce morbidity and mortality or possible harms of screening.

Conclusions

Based on the application of available evidence to UKNSC screening criteria, there is currently insufficient evidence to recommend the implementation of a screening programme for ACEs. Further research is needed to determine whether routine enquiry can improve morbidity, mortality, health and wellbeing.
Longitudinal associations of military-related factors on self-reported sleep among U.S. service members
Authors: Cooper Adam D , Kolaja Claire A , Markwald Rachel R , Jacobson Isabel G , Chinoy Evan D
Published: July 2021

Study Objectives

Sleep loss is common in the military, which can negatively affect health and readiness; however, it is largely unknown how sleep varies over a military career. This study sought to examine the relationships between military-related factors and the new onset and reoccurrence of short sleep duration and insomnia symptoms.

Methods

Millennium Cohort Study data were used to track U.S. military service members over time to examine longitudinal changes in sleep. Outcomes were self-reported average sleep duration (categorized as ≤5 h, 6 h, or 7–9 h [recommended]) and/or insomnia symptoms (having trouble falling or staying asleep). Associations between military-related factors and the new onset and reoccurrence of these sleep characteristics were determined, after controlling for multiple health and behavioral factors.

Results

Military-related factors consistently associated with an increased risk for new onset and/or reoccurrence of short sleep duration and insomnia symptoms included active duty component, Army or Marine Corps service, combat deployment, and longer than average deployment lengths. Military officers and noncombat deployers had decreased risk for either sleep characteristic. Time-in-service and separation from the military were complex factors; they lowered risk for ≤5 h sleep but increased risk for insomnia symptoms.

Conclusions

Various military-related factors contribute to risk of short sleep duration and/or insomnia symptoms over time, although some factors affect these sleep characteristics differently. Also, even when these sleep characteristics remit, some military personnel have an increased risk of reoccurrence. Efforts to improve sleep prioritization and implement interventions targeting at-risk military populations, behaviors, and other significant factors are warranted.
Assessment of morning sleep propensity with lemborexant in adults with insomnia disorder in a randomized, placebo-controlled crossover study
Authors: Mayleben David , Rosenberg Russell , Pinner Kate , Hussein Ziad , Moline Margaret
Published: July 2021

Objective

To evaluate effects of lemborexant (LEM), a dual orexin receptor antagonist, on next-morning sleep propensity assessed by a modified Multiple Sleep Latency Test (M-MSLT) in adults with insomnia disorder.

Methods

Study 107 (E2006-A001-107) was a phase 1, randomized, double-blind, four-period crossover study. Subjects (n = 69) received oral single-dose placebo, LEM 5 mg (LEM5), and LEM 10 mg (LEM10) at bedtime in periods 1–3 in a randomized crossover and open-label flurazepam 30 mg in period 4. After an 8-hour overnight sleep opportunity, the M-MSLT measured average sleep onset latency (SOL). Mean change from baseline in average SOL versus placebo of −6.0 min or more was considered clinically meaningful. Other sleep propensity assessments included the proportion of subjects with average SOL >6 min shorter than placebo. LEM plasma concentrations, safety, and tolerability were also assessed.

Results

M-MSLT assay sensitivity was confirmed by a clinically meaningful decrease in average SOL with flurazepam versus placebo (least squares mean [LSM] difference –6.06 min; 1-sided p < 0.0001). In contrast, decreases in average SOL with LEM5 (LSM difference vs. placebo –1.15 min; 1-sided p = 0.0262) and LEM10 (–3.48 min; p < 0.0001) did not meet the predefined threshold for a clinically meaningful effect (LEM5, –2.12; LEM10, –4.46). Some individuals did experience higher sleep propensity (average SOL >6.0 min shorter than placebo), particularly with LEM10 (LEM10, 29.4%; LEM5, 13.2%).

Conclusions

In contrast to flurazepam, LEM5 and LEM10 did not show clinically meaningful mean increases in next-morning sleep propensity versus placebo. The possibility that some subjects may experience residual morning effects cannot be excluded.

Clinical trial registration: ClinicalTrials.gov, NCT02350309
Revision of the montane New Guinean skink genus Lobulia (Squamata: Scincidae), with the description of four new genera and nine new species
Authors: Slavenko Alex , Tamar Karin , Tallowin Oliver J S , Kraus Fred , Allison Allen , Carranza Salvador , Meiri Shai
Published: July 2021

The skink genus Lobulia is endemic to New Guinea, the largest and highest tropical island in the world. Lobulia and its related genera represent an important component of the montane herpetofauna of New Guinea, but it remains understudied and poorly known. We here provide the first, large-scale, systematic revision of Lobulia, using molecular phylogenetic and morphological comparisons to assess the monophyly of the genus and the diversity of species within it. We find that Lobulia, as currently defined, is polyphyletic. The eight species currently assigned to it form three clades. Furthermore, many specimens from New Guinea of unknown specific affinity are genetically and morphologically distinct from each other. Based on these data, we re-diagnose Lobulia and two of its closely related genera, Prasinohaema and Papuascincus. We erect four new genera (Alpinoscincus gen. nov., Nubeoscincus gen. nov., Ornithuroscincus gen. nov. and Palaia gen. nov.) to address the problem of polyphyly and describe nine new species Lobulia fortis sp. nov., Lobulia huonensis sp. nov., Loublia marmorata sp. nov., Lobulia vogelkopensis sp. nov., Ornithuroscincus bengaun sp. nov., Ornithuroscincus inornatus sp. nov., Ornithuroscincus pterophilus sp. nov., Ornithuroscincus shearmani sp. nov. and Ornithuroscincus viridis sp. nov. We supplement this taxonomic revision by investigating the biogeographic history of Lobulia s.l. and find evidence for a large radiation in the accreted terranes of New Guinea, with multiple independent colonizations of montane habitats and subsequent recolonization of lowland habitats. Our study reinforces the uniqueness and richness of the montane herpetofauna of New Guinea and the importance of mountains to biodiversity in the Tropics.
Characterization of a novel transitional group Rickettsia species (Rickettsia tillamookensis sp. nov.) from the western black-legged tick, Ixodes pacificus
Authors: Gauthier David T. , Karpathy Sandor E. , Grizzard Stephanie L. , Batra Dhwani , Rowe Lori A. , Paddock Christopher D.
Published: July 2021

A previously unrecognizedRickettsiaspecies was isolated in 1976 from a pool ofIxodes pacificusticks collected in 1967 from Tillamook County, Oregon, USA. The isolate produced low fever and mild scrotal oedema following intraperitoneal injection into male guinea pigs (Cavia porcellus). Subsequent serotyping characterized this isolate as distinct from recognized typhus and spotted fever groupRickettsiaspecies; nonetheless, the isolate remained unevaluated by molecular techniques and was not identified to species level for the subsequent 30 years.Ixodes pacificusis the most frequently identified human-biting tick in the western United States, and as such, formal identification and characterization of this potentially pathogenicRickettsiaspecies is warranted. Whole-genome sequencing of the Tillamook isolate revealed a genome 1.43 Mbp in size with 32.4 mol% G+C content. Maximum-likelihood phylogeny of core proteins places it in the transitional group ofRickettsiabasal to bothRickettsia felisandRickettsia asembonensis. It is distinct from existing named species, with maximum average nucleotide identity of 95.1% toR. asembonensisand maximum digital DNA–DNA hybridization score similarity toR. felisat 80.1%. The closest similarity at the 16S rRNA gene (97.9%) andsca4 (97.5%/97.6% respectively) is toCandidatus‘Rickettsia senegalensis’ andRickettsiasp. cf9, both isolated from cat fleas (Ctenocephalides felis). We characterized growth at various temperatures and in multiple cell lines. The Tillamook isolate grows aerobically in Vero E6, RF/6A and DH82 cells, and growth is rapid at 28 °C and 32 °C. Using accepted genomic criteria, we propose the nameRickettsia tillamookensissp. nov., with the type strain Tillamook 23. Strain Tillamook 23 is available from the Centers for Disease Control and Prevention Rickettsial Isolate Reference Collection (WDCM 1093), Atlanta, GA, USA (CRIRC accession number RTI001T) and the Collection de Souches de l’Unité des Rickettsies (WDCM 875), Marseille, France (CSUR accession number R5043). Using accepted genomic criteria, we propose the nameRickettsia tillamookensissp. nov., with the type strain Tillamook 23 (=CRIRC RTI001=R5043).
Unsupervised Spatially Embedded Deep Representation of Spatial Transcriptomics
Authors: Fu Huazhu , Xu Hang , Chong Kelvin , Li Mengwei , Ang Kok Siong , Lee Hong Kai , Ling Jingjing , Chen Ao , Shao Ling , Liu Longqi , Chen Jinmiao
Published: July 2021

Spatial transcriptomics enable us to dissect tissue heterogeneity and map out inter-cellular communications. Optimal integration of transcriptomics data and associated spatial information is essential towards fully exploiting the data. We present SEDR, an unsupervised spatially embedded deep representation of both transcript and spatial information. The SEDR pipeline uses a deep autoencoder to construct a low-dimensional latent representation of gene expression, which is then simultaneously embedded with the corresponding spatial information through a variational graph autoencoder. We applied SEDR on human dorsolateral prefrontal cortex data and achieved better clustering accuracy, and correctly retraced the prenatal cortex development order with trajectory analysis. We also found the SEDR representation to be eminently suited for batch integration. Applying SEDR to human breast cancer data, we discerned heterogeneous sub-regions within a visually homogenous tumor region, identifying a tumor core with pro-inflammatory microenvironment and an outer ring region enriched with tumor associated macrophages which drives an immune suppressive microenvironment.
Low frequency of community-acquired bacterial co-infection in patients hospitalized for COVID-19 based on clinical, radiological and microbiological criteria; a retrospective cohort study
Authors: Coenen Sophie , de la Court Jara R. , Buis David T.P. , Meijboom Lilian J. , Schade Rogier P. , Visser Caroline E. , van Hest Reinier , Kuijvenhoven Marianne , Prins Jan M. , Nijman Suzan F.M. , Sieswerda Elske , Sigaloff Kim C.E.
Published: July 2021

Background

To define the frequency of respiratory community-acquired bacterial co-infection in patients with coronavirus disease 2019 (COVID-19) based on a complete clinical assessment, including prior antibiotic use, clinical characteristics, inflammatory markers, chest computed tomography (CT) results and microbiological test results.

Methods

This study was conducted within a cohort of prospectively included patients admitted for COVID-19 in our tertiary medical centres between 1-3-2020 and 1-6-2020. A multidisciplinary study team developed a diagnostic protocol to retrospectively categorize patients as unlikely, possible or probable bacterial co-infection based on clinical, radiological and microbiological parameters in the first 72 hours of admission. Within the three categories, we summarized patient characteristics and antibiotic consumption.

Results

Among 281 included COVID-19 patients, bacterial co-infection was classified as unlikely in 233 patients (82.9%), possible in 35 patients (12.4%) and probable in 3 patients (1.1%). Ten patients (3.6%) could not be classified due to inconclusive data. Within 72 hours of hospital admission, 81% of the total study population and 78% of patients classified as unlikely bacterial co-infection received antibiotics.

Conclusions

COVID-19 patients are unlikely to have a respiratory community-acquired bacterial co-infection. Prospective studies should define the safety of restrictive antibiotic use in COVID-19 patients.
The COVID-related mental health load of neonatal healthcare professionals: A multicentre study in Italy
Authors: Gagliardi Luigi , Grumi Serena , Gentile Marzia , Cacciavellani Roberta , Placidi Giulia , Vaccaro Angelina , Maggi Claudia , Gambi Beatrice , Magi Letizia , Crespin Laura , Memmini Graziano , DeFilippo Marcello , Verucci Elena , Malandra Liliana , Mele Laura , Azzarà Angelo , Provenzi Livio
Published: July 2021

Background

The COVID-19 pandemic has dramatically affected healthcare professionals’ lives. We investigated the potential mental health risk faced by healthcare professionals working in neonatal units in a multicentre cross-sectional observational study.

Methods

We included all healthcare personnel of 7 level-3 and 6 level-2 neonatal units in Tuscany, Italy. We measured the level of physical exposure to COVID-19 risk, self-reported COVID-related stress, and mental health load outcomes (anxiety, depression, burnout, psychosomatic, and post-traumatic symptoms) via validated, self-administered, on-line questionnaires.

Results

We analysed 314 complete answers. Scores above the clinical cutoff were reported by 91% of participants for anxious symptoms, 29% for post-traumatic symptoms, 13% for burnout, and 3% for depressive symptoms. Moreover, 50% of the participants reported at least one psychosomatic symptom. COVID-related stress (but not actual physical exposure) was significantly associated with all the measured mental health load outcomes, with a Risk Ratio of 3.33 (95% Confidence interval: 1.89, 5.85) for clinically relevant anxiety, 2.39 (1.69, 3.38) for post-traumatic symptoms, 1.79 (1.16, 2.75) for emotional exhaustion, and 2.51 (0.98, 6.44) for depression.

Conclusions

Despite a low clinical impact of COVID-19 in neonatology, neonatal professionals are a specific population at risk for psychological consequences during the pandemic.

Keynotes

We studied the mental health load (anxiety, post-traumatic, psychosomatic symptoms, burnout, depression) of healthcare professionals working in 13 neonatal units in Tuscany during the COVID-19 pandemic.

We found very high levels of anxiety and psychosomatic symptoms, and moderate-high post-traumatic and burnout symptoms.

Mental health load was higher in neonatal intensive (vs non-intensive) settings and in nurses (vs physicians). Mental health load outcomes were associated with COVID-related stress (rather than actual physical exposure to the virus).
Nowcasting food insecurity on a global scale
Authors: Martini Giulia , Bracci Alberto , Jaiswal Sejal , Corea Matteo , Riches Lorenzo , Rivers Jonathan , Omodei Elisa
Published: July 2021

Lack of regular physical or economic access to safe, nutritious and sufficient food is a critical issue affecting millions of people world-wide. Estimating how many and where these people are is of fundamental importance for governments and humanitarian organizations to take informed and timely decisions on relevant policies and programmes. In this study, we propose a machine learning approach to predict the prevalence of people with insufficient food consumption and of people using crisis or above crisis food-based coping when primary data is not available. Making use of a unique global data set, we show that the proposed models can explain up to 78% of the variation in insufficient food consumption and crisis or above food-based coping levels. We also show that the proposed models can be used to nowcast the food security situation in near-real time and propose a method to identify which variables are driving the changes observed in predicted trends, which is key to make predictions serviceable to decision makers.
Genomic epidemiology of SARS-CoV-2 in Pakistan
Authors: Song Shuhui , Li Cuiping , Kang Lu , Tian Dongmei , Badar Nazish , Ma Wentai , Zhao Shilei , Jiang Xuan , Wang Chun , Sun Yongqiao , Li Wenjie , Lei Meng , Li Shuangli , Qi Qiuhui , Ikram Aamer , Salman Muhammad , Umair Massab , Shireen Huma , Batool Fatima , Zhang Bing , Chen Hua , Yang Yungui , Abbasi Amir Ali , Li Mingkun , Xue Yongbiao , Bao Yiming
Published: July 2021

Pakistan has been severely affected by the COVID-19 pandemic. To investigate the initial introductions and transmissions of the SARS-CoV-2 in the country, we performed the largest genomic epidemiology study of COVID-19 in Pakistan and generated 150 complete SARS-CoV-2 genome sequences from samples collected before June 1, 2020. We identified a total of 347 variants, 29 of which were over-represented in Pakistan. Meanwhile, we found over one thousand intra-host single-nucleotide variants. Several of them occurred concurrently, indicating possible interactions among them. Some of the hypermutable positions were not observed in the polymorphism data, suggesting strong purifying selections. The genomic epidemiology revealed five distinctive spreading clusters. The largest cluster consisted of 74 viruses which were derived from different geographic locations and formed a deep hierarchical structure, indicating an extensive and persistent nation-wide transmission of the virus that was probably contributed by a signature mutation of this cluster. Twenty-eight putative international introductions were identified, several of which were consistent with the epidemiological investigations. No progenies of any of these 150 viruses have been found outside of Pakistan, most likely due to the nonphmarcological intervention to control the virus. This study has inferred the introductions and transmissions of SARS-CoV-2 in Pakistan, which could provide a guidance for an effective strategy for disease control.
Gut microbiome diversity measures for metabolic conditions: a systematic scoping review
Authors: Samuthpongtorn Chatpol , Nopsopon Tanawin , Pongpirul Krit
Published: July 2021

Objective

Evidence on the association between the gut microbiome and metabolic conditions has been increasing during the past decades. Unlike the straightforward identification of beneficial non-pathogenic bacteria as a potential probiotic for clinical use, the analysis of gut microbiome diversity is more complex and required a better understanding of various measures. We aim to summarize an elaborated list of gut microbiome diversity measures.

Design

Systematic search was conducted in three databases: PubMed, Embase, and Cochrane Central Register of Clinical Trials for randomized controlled trials, quasi-experimental and observational studies for the relationship between gut microbiota and metabolic diseases published in 2019 with the English language.

Results

The measurement methods of alpha diversity and beta diversity were explored. Of 5929 potential studies, 47 were included in the systematic review (14632 patients). Of 13 alpha diversity measures, the Shannon index was the most commonly used in 37 studies (78.7%), followed by Chao1 index (19 studies), Operational Taxonomic Unit (OTU) richness (15 studies), Simpson index (13 studies), and Abundance-based Coverage Estimators (ACE) index (10 studies). Of 2 beta diversity measures, the UniFrac was the most commonly used in 24 studies (unweighted 17 studies and weighted 16 studies), followed by Bray-Curtis dissimilarity (16 studies).

Conclusion

Various measurement of gut microbiome diversity have been used in the literature. All measurements have unique characteristics, advantages, and disadvantages which lead to different usage frequency. The measures were chosen considering cost, simplicity, and types of research.

Significance of this study

What is already known on this subject?

▸

Alpha diversity, including Shannon index diversity, chao1 diversity, etc., is the average species diversity within a habitat type at a local scale while beta-diversity, such as Bray-Curtis dissimilarity and UniFrac, indicates the differentiation between microbial communities from different environments.

▸

Alpha- and beta-diversity are the two most diverse measures of gut microbiota diversity with no consensus on which measurement methods should be used in metabolic condition study.

What are the new findings?

▸

Distinct characteristics, advantages, and disadvantages of each microbiome diversity measurement method lead to a variety of usage frequencies in metabolic condition studies. Shannon diversity is the most widely used alpha diversity while there is no predilection for beta diversity.

How might it impact on clinical practice in the foreseeable future?

▸

Further researchers on metabolic condition with microbiome diversity measurement will have impartial evidence on which measurement methods are most rationally appropriate for their studies regarding simplicity, cost, and efficacy.
A Cascaded Droplet Microfluidic Platform Enables High-throughput Single Cell Antibiotic Susceptibility Testing at Scale
Authors: Zhang Pengfei , Kaushik Aniruddha , Hsieh Kuangwen , Li Sixuan , Lewis Shawna , Mach Kathleen E. , Liao Joseph C. , Carroll Karen C. , Wang Tza-Huei
Published: July 2021

Single-cell antibiotic susceptibility testing (AST) offers a promising technology by achieving unprecedented rapid testing time; however, its potential for clinical use is marred by its limited capacity for performing AST with scalable antibiotic numbers and concentrations. To lift the one antibiotic condition per device restriction common in single-cell AST, we develop a cascaded droplet microfluidic platform that uses an assembly line design to enable scalable single-cell AST. Such scalability is achieved by executing bacteria/antibiotic mixing, single-cell encapsulation, incubation, and detection in a streamlined workflow, facilitating susceptibility testing of each new antibiotic condition in 2 min after a 90 min setup time. As a demonstration, we test 3 clinical isolates and 8 positive urine specimens against 15 antibiotic conditions for generating antiprograms in ∼2 h and achieve 100% and 93.8% categorical agreement, respectively, compared to laboratory-based clinical microbiology reports which becomes available only after 48 h.
Runners with mid-portion Achilles tendinopathy have greater triceps surae intracortical inhibition than healthy controls
Authors: Fernandes Gabriel L. , Orssatto Lucas B. R. , Shield Anthony J. , Trajano Gabriel S.
Published: July 2021

Objectives

This study aimed to investigate short-interval intracortical inhibition (SICI) and muscle function in the Triceps surae of runners with mid-portion Achilles tendinopathy (AT).

Methods

Runners with (n=11) and without (n=13) AT were recruited. Plantar flexor isometric peak torque and rate of torque development (RTD) were measured using an isokinetic dynamometer. Triceps surae endurance was measured as single leg heel raise (SLHR) to failure test. SICI was assessed using paired-pulse transcranial magnetic stimulation during a sustained contraction at 10% of plantar flexor isometric peak torque.

Results

Triceps surae SICI was 14.3% (95%CI: -2.1 to 26.4) higher in AT than control group (57.9%, 95%CI: 36.2, to 79.6; and 43.6% 95%CI:16.2 to 71.1; p=0.032) irrespective of the tested muscle. AT performed 16 (95%CI: 7.9 to 23.3, p<0.001) fewer SLHR repetitions on the symptomatic side compared to controls, and 14 (95%CI: 5.8 to 22.0, p=0.004), fewer SLHR repetitions on the non-symptomatic compared to controls. We found no between-groups differences in isometric peak torque (p=0.971) or RTD (p=0.815).

Perspective

Our data suggest greater intracortical inhibition for the Triceps surae muscles for the AT group accompanied by reduced SLHR endurance, without deficits in isometric peak torque or RTD. The increased SICI observed in the AT group could be negatively influencing Triceps surae endurance; thus, rehabilitation aiming to reduce intracortical inhibition should be considered to improve patient outcomes. Furthermore, SLHR is a useful clinical tool to assess plantar flexor function in AT patients.
Moderate-Intensity Exercise Versus High-Intensity Interval Training to Recover Walking Post-Stroke: Protocol for a Randomized Controlled Trial
Authors: Miller Allison , Reisman Darcy S. , Billinger Sandra A. , Dunning Kari , Doren Sarah , Ward Jaimie , Wright Henry , Wagner Erin , Carl Daniel , Gerson Myron , Awosika Oluwole , Khoury Jane , Kissela Brett , Boyne Pierce
Published: July 2021

Background

Stroke results in neurologic impairments and aerobic deconditioning that contribute to limited walking capacity which is a major barrier post-stroke. Current exercise recommendations and stroke rehabilitation guidelines recommend moderate-intensity aerobic training post-stroke. Locomotor high-intensity interval training is a promising new strategy that has shown significantly greater improvements in aerobic fitness and motor performance than moderate-intensity aerobic training in other populations. However, the relative benefits and risks of high-intensity interval training and moderate-intensity aerobic training remain poorly understood following stroke. In this study, we hypothesize that locomotor high-intensity interval training will result in greater improvements in walking capacity than moderate-intensity aerobic training.

Methods

Using a single-blind, 3-site randomized controlled trial, 50 chronic (>6 months) stroke survivors are randomly assigned to complete 36 locomotor training sessions of either high-intensity interval training or moderate-intensity aerobic training. Main eligibility criteria are: age 40-80 years, single stroke for which the participant received treatment (experienced 6 months to 5 years prior to consent), walking speed ≤1.0 m/s, able to walk at least 3 minutes on the treadmill at ≥ 0.13 m/s (0.3 mph), stable cardiovascular condition (American Heart Association class B), and the ability to walk 10 meters overground without continuous physical assistance. The primary outcome (walking capacity) and secondary outcomes (self-selected and fast gait speed, aerobic fitness and fatigue) are assessed prior to initiating training and after 4 weeks, 8 weeks, and 12 weeks of training.

Discussion

This study will provide fundamental new knowledge to inform the selection of intensity and duration dosing parameters for gait recovery and optimization of aerobic training interventions in chronic stroke. Data needed to justify and design a subsequent definitive trial will also be obtained. Thus, the results of this study will inform future stroke rehabilitation guidelines on how to optimally improve walking capacity following stroke.

Trial Registration

ClinicalTrials.govIdentifier:NCT03760016. First posted: November 30, 2018.https://clinicaltrials.gov/ct2/show/NCT03760016
Empirical evaluation of the sensitivity of background incidence rate characterization for adverse events across an international observational data network
Authors: Ostropolets Anna , Li Xintong , Makadia Rupa , Rao Gowtham , Rijnbeek Peter R. , Duarte-Salles Talita , Sena Anthony G. , Shaoibi Azza , Suchard Marc A. , Ryan Patrick B. , Prieto-Alhambra Daniel , Hripcsak George
Published: July 2021

Background incidence rates are routinely used in safety studies to evaluate the association of an exposure and an outcome. Systematic research on the sensitivity of background rates to the choice of the study parameters is lacking. We used 12 electronic health record and administrative claims data sources to calculate incidence rates of 15 adverse events. We examined the influence of age, race, sex, database, time-at-risk start (anchoring) event and duration, season and year, prior observation and clean window. For binary comparisons, we calculated incidence rate ratios and performed random-effect model meta-analysis. Background rates were highly sensitive to demographic characteristics of the population, especially age, with rates varying up to a factor of 1,000 across age groups. Rates varied by up to a factor of 100 by database. Incidence rates were highly influenced by the choice of anchoring (e.g., health visit, vaccination, or arbitrary date) for the time-at-risk start, especially at short times at risk, and less influenced by secular or seasonal trends. Therefore, comparing background to observed rates requires appropriate adjustment, and results should be interpreted in the context of design choices.

Short Figure
Effects of supervised high-intensity hardstyle kettlebell training on grip strength and health-related physical fitness in insufficiently active older adults: The BELL pragmatic controlled trial
Authors: Meigh Neil J. , Keogh Justin W.L. , Schram Ben , Hing Wayne , Rathbone Evelyne N.
Published: July 2021

The Ballistic Exercise of the Lower Limb (BELL) trial examined efficacy and safety of a pragmatic hardstyle kettlebell training program in older adults. Insufficiently active men and women aged 59-79 years, were recruited to a 6-month repeated measures study, involving 3-months usual activity and 3-months progressive hardstyle kettlebell training. Health-related physical fitness outcomes included: grip strength [GS], 6-min walk distance [6MWD], resting heart rate [HR], stair-climb [SC], leg extensor strength [LES], hip extensor strength [HES], Sit-To-Stand [STS], vertical jump [CMVJ], five-times floor transfer [5xFT], 1RM deadlift, body composition (DXA), attendance, and adverse events. Sixteen males (68.8 ± 4.6 yrs, 176.2 ± 7.8 cm, 90.7 ± 11.0 kg, 29.2 ± 2.6 kg/m2) and sixteen females (68.6 ± 4.7 yrs, 163.9 ± 5.4 cm, 70.4 ± 12.7 kg, 26.3 ± 4.9 kg/m2) were recruited. Compliance to the supervised exercise program was very high (91.5%). Kettlebell training increased GS (R: MD = 7.1 kg 95% CI [4.9, 9.3],p< 0.001, L: MD = 6.3 kg 95% CI [4.1, 8.4],p< 0.001), 6MWD (41.7 m, 95% CI [17.9, 65.5],p< .001), 1RM (16.2 kg, 95% CI [2.4, 30.0],p= 0.013), 30s STS (3.3 reps, 95% CI [0.9, 5.7],p= 0.003), LES (R: MD = 61.6 N, 95% CI [4.4, 118.8],p= 0.028), HES (L: MD = 21.0 N, 95% CI [4.2, 37.8],p= 0.007), appendicular skeletal lean mass (MD = 0.65 kg, 95% CI [0.08, 1.22],p= 0.016), self-reported health change (17.1%, 95% CI [4.4, 29.8],p= 0.002) and decreased SC time (2.7 sec, 95% CI [0.2, 5.2],p= 0.025), 5xFT time (6.0 sec, 95% CI [2.2, 9.8],p< 0.001) and resting HR (7.4 bpm, 95% CI [0.7, 14.1],p= 0.032). There were four non-serious adverse events. Mean individual training load for group training sessions during the trial was 100,977 ± 9,050 kg. High-intensity hardstyle kettlebell training was well tolerated and improved grip strength and measures of health-related physical fitness in insufficiently active older adults.
An improved codon modeling approach for accurate estimation of the mutation bias
Authors: Latrille T. , Lartillot N.
Published: July 2021

Nucleotide composition in protein-coding sequences is the result of the equilibrium between mutation and selection. In particular, the nucleotide composition differs between the three coding positions, with the third position showing more extreme composition than the first and the second positions. Yet, phylogenetic codon models do not correctly capture this phenomenon and instead predict that the nucleotide composition should be the same for all 3 positions of the codons. Alternatively, some models allow for different nucleotide rates at the three positions, a problematic approach since the mutation process should in principle be blind to the coding structure and homogeneous across coding positions. Practically, this misconception could have important consequences in modelling the impact of GC-biased gene conversion (gBGC) on the evolution of protein-coding sequences, a factor which requires mutation and fixation biases to be carefully disentangled. Conceptually, the problem comes from the fact that phylogenetic codon models cannot correctly capture the fixation bias acting against the mutational pressure at the mutation-selection equilibrium. To address this problem, we present an improved codon modeling approach where the fixation rate is not seen as a scalar anymore, but as a tensor unfolding along multiple directions, which gives an accurate representation of how mutation and selection oppose each other at equilibrium. Thanks to this, this modelling approach yields a reliable estimate of the mutational process, while disentangling fixation probabilities in different directions.
Epigenetic mediation of AKT1 rs1130233’s effect on delta-9-tetrahydrocannabinol-induced medial temporal function during fear processing
Authors: Blest-Hopley Grace , Colizzi Marco , Prata Diana , Giampietro Vincent , Brammer Michael , McGuire Philip , Bhattacharyya Sagnik
Published: July 2021

High doses of delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, have been shown to have anxiogenic effects. Also, THC effects have been shown to be modulated by genotype, including the single nucleotide polymorphism (SNP) rs1130233 at the protein kinase AKT1 gene, a key component of the dopamine signaling cascade. As such, it is likely that epigenetic methylation around this SNP may affect AKT gene expression, which may in turn impact on the acute effects of THC on brain function. We investigated the genetic (AKT1 rs1130233) and epigenetic modulation of brain function during fear processing in a 2-session, double-blind, cross-over, randomized placebo-controlled THC administration, in 36 healthy males. Fear processing was assessed using an emotion (fear processing) paradigm, under functional magnetic resonance imaging (fMRI). Complete genetic and fMRI data was available for 34 participants. THC caused an increase in anxiety and transient psychotomimetic symptoms and para-hippocampal gyrus/ amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methylation at the CpG11-12 site, were independently associated with a greater effect of THC on activation in a network of brain regions including left and right parahippocampal gyri, respectively. AKT1 rs1130233 moderation of the THC effect on left parahippocampal activation persisted after covarying for methylation percentage, and was partially mediated in sections of the left parahippocampal gyrus/ hippocampus by methylation percentage. These results may offer an example of how genetic and epigenetic variations influence the psychotomimetic and neurofunctional effects of THC.
Development of epigenetic clocks for New Zealand livestock
Authors: Caulton Alex , Dodds Ken G. , McRae Kathryn M. , Couldrey Christine , Horvath Steve , Clarke Shannon M.
Published: July 2021

Robust biological biomarkers of chronological age have been developed in humans and model mammalian species such as rats and mice using DNA methylation data. The concept of these so-called “epigenetic clocks” has emerged from a large body of literature describing the correlation between genome-wide methylation levels and age. Epigenetic clocks exploit this phenomenon and use small panels of differentially methylated cytosine (CpG) sites to make robust predictions of chronological age, independent of tissue type.

Here we present highly accurate livestock epigenetic clocks whereby we have used the custom mammalian methylation array “HorvathMammalMethyl40”1 to construct the first epigenetic clock for domesticated goat (Capra hircus), cattle (Bos taurus), Red (Cervus elaphus) and Wapiti deer (Cervus canadensis) and composite-breed sheep (Ovis aries). Additionally, we have constructed a New Zealand livestock ‘farm animal clock’ for all animals included in the study, which will enable robust predictions to be extended to various breeds. The farm animal clock shows similarly high accuracies to the individual species’ clocks (r>0.97), utilising only 217 CpG sites to estimate age (relative to the maximum lifespan of the species) with a single mathematical model.

We envision that the applications of this livestock clock could extend well beyond the scope of chronological age estimates. Many independent studies have demonstrated that a deviation between true age and clock derived molecular age is indicative of past and/or present health (including stress) status. There is, therefore, untapped potential to utilise livestock clocks in breeding programmes as a predictor for age-related, production traits.
Vitamin D modulates cortical transcriptome and behavioral phenotypes in an Mecp2 heterozygous Rett syndrome mouse model
Authors: Ribeiro Mayara C. , MacDonald Jessica L.
Published: July 2021

Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the transcriptional regulator MECP2. Mecp2 loss-of-function leads to the disruption of many cellular pathways, including aberrant activation of the NF-κB pathway. Genetically attenuating the NF-κB pathway in Mecp2-null mice ameliorates hallmark phenotypes of RTT, including reduced dendritic complexity, raising the question of whether NF-κB pathway inhibitors could provide a therapeutic avenue for RTT. Vitamin D is a known inhibitor of NF-κB signaling; further, vitamin D deficiency is prevalent in RTT patients and male Mecp2-null mice. We previously demonstrated that vitamin D rescues the aberrant NF-κB activity and reduced neurite outgrowth of Mecp2-knockdown cortical neurons in vitro, and that dietary vitamin D supplementation rescues decreased dendritic complexity and soma size of neocortical projection neurons in both male hemizygous Mecp2-null and female heterozygous mice in vivo. Here, we have identified over 200 genes whose dysregulated expression in the Mecp2+/- cortex is modulated by dietary vitamin D. Genes normalized with vitamin D supplementation are involved in dendritic complexity, synapses, and neuronal projections, suggesting that the rescue of their expression could underpin the rescue of neuronal morphology. Further, motor and anxiety-like behavioral phenotypes in Mecp2+/- mice correlate with circulating vitamin D levels, and there is a disruption in the homeostasis of the vitamin D synthesis pathway in Mecp2+/- mice. Thus, our data indicate that vitamin D modulates RTT pathology and its supplementation could provide a simple and cost-effective partial therapeutic for RTT.
Reducing Movement Synchronization to Increase Interest Improves Interpersonal Liking
Authors: Ravreby Inbal , Shilat Yoel , Yeshurun Yaara
Published: July 2021

Synchronization has been identified as a key aspect of achieving mutual goals and enhancing social bonding. While synchronization could be maximized by increasing the predictability of an interaction, such predictability is in tension with individuals’ level of interest, which is tied to the interaction’s complexity and novelty. In this study, we tested the interplay between synchronization and interest. We asked 104 female dyads to play the Mirror Game, in which they were instructed to move their hands as coordinately as possible, and then report how much they liked each other. Utilizing information theory and video processing tools, we found that a combination of movement synchronization and complexity explained liking almost two times better than movement synchronization alone. Moreover, we found that people initiated novel and challenging interactions, even though they paid a price – being less synchronized. Examining the interactions’ dynamics, we found that people who liked each other moved in a more synchronized, complex, and novel manner during most of the interaction. This suggests that in addition to synchronization, maintaining interest may be critical for positive social bonding. Thus, we propose a new framework in which balancing synchronization and interest, rather than merely maximizing synchronization, optimizes the interaction quality.
Reduced Lytic Activity of Bacteriophages in Presence of Antibiotics Targeting Bacterial Protein Synthesis
Authors: Vashisth Medhavi , Yashveer Shikha , Virmani Nitin , Bera Bidhan Chandra , Vaid Rajesh Kumar , Anand Taruna
Published: July 2021

Combination therapy of bacteriophage and antibiotics offers promise to treat multiple drug resistant bacterial infections through phage antibiotic synergy. However, its usage requires careful assessment as most antibiotics with mechanisms dependent upon inhibiting cell growth through interfering bacterial protein synthesis machinery were found to have an antagonistic effect on phage activity.
Functional Characterization of Lipid Regulatory Effects of Three Genes Using Knockout Mouse Models
Authors: Yao Chen , Savage Holly , Hao Tong , Lee Gha Young , Takemon Yuka , Bian Wenting , Hill David E , Vidal Marc , Korstanje Ron , Levy Daniel
Published: July 2021

Integrative analysis that combines genome-wide association data with expression quantitative trait analysis and network representation may illuminate causal relationships between genes and diseases. To identify causal lipid genes, we utilized genotype, gene expression, protein-protein interaction networks, and phenotype data from 5,257 Framingham Heart Study participants and performed Mendelian randomization to investigate possible mechanistic explanations for observed associations. We selected three putatively causal candidate genes (ABCA6, ALDH2, and SIDT2) for lipid traits (LDL cholesterol, HDL cholesterol and triglycerides) in humans and conducted mouse knockout studies for each gene to confirm its causal effect on the corresponding lipid trait. We conducted the RNA-seq from mouse livers to explore transcriptome-wide alterations after knocking out the target genes. Our work builds upon a lipid-related gene network and expands upon it by including protein-protein interactions. These resources, along with the innovative combination of emerging analytical techniques, provide a groundwork upon which future studies can be designed to more fully understand genetic contributions to cardiovascular diseases.
Low mitochondrial copy number drives atherogenic cardiovascular disease: evidence from prospective cohort analyses in the UK Biobank combined with Mendelian Randomization
Authors: Luo Jiao , Noordam Raymond , Jukema J Wouter , van Dijk Ko Willems , Hägg Sara , Grassmann Felix , Cessie Saskia le , van Heemst Diana
Published: July 2021

Background

Mitochondrial DNA (mtDNA) content might be involved in the risk of cardiovascular disease. We aimed to investigate the association of mtDNA copy number (mtDNA-CN), as a proxy of mtDNA content, and coronary artery disease (CAD) and heart failure (HF) using multivariable adjusted and Mendelian Randomizations (MR) analyses.

Methods

Multivariable-adjusted analyses were conducted using Cox-proportional hazard models in 273,619 unrelated European descendants from UK Biobank (UKB). MtDNA-CN in peripheral blood cells was computed based on the weighted intensities of the mitochondrial genome probes. For the two-sample MR analyses, single nucleotide polymorphisms (SNPs) associated with mtDNA-CN were retrieved from genome-wide association studies in UKB. SNP-outcome associations were obtained for CAD from CARDIoGRAMplusC4D, UKB and FinnGen, comprising 902,538 participants (134,759 cases), and for HF from the HERMES consortium and FinnGen, collectively having data on 1,195,531 participants (70,706 cases). MR analyses were performed per database and results were subsequently meta analyzed using fixed-effects models per study.

Results

During a median follow-up of 11.8 years, participants in the lowest quintile of mtDNA-CN had higher risk for CAD (hazard ratio [95% CI]: 1.08 [1.03, 1.14]) and HF (hazard ratio [95% CI]: 1.15 [1.05, 1.24]) compared to those in the highest quintile. In MR analyses, the pooled odds ratios of genetically predicted per one-SD decrease in mtDNA were 1.16 (95% CI: 1.05, 1.27) for CAD and 1.00 (95% CI: 0.90, 1.10) for HF, respectively.

Conclusion

Our findings support a possible causal role of lower mtDNA-CN in higher CAD risk, but not in higher HF risk.