bluuebunny/crossref_metadata_2025 huggingface dataset:
A Spatially Explicit Model of Stabilizing Selection for Improving Phylogenetic Inference
Authors: Beaulieu Jeremy M , O’Meara Brian C , Gilchrist Michael A
Published: December 2020

Ultraconserved elements (UCEs) are stretches of hundreds of nucleotides with highly conserved cores flanked by variable regions. Although the selective forces responsible for the preservation of UCEs are unknown, they are nonetheless believed to contain phylogenetically meaningful information from deep to shallow divergence events. Phylogenetic applications of UCEs assume the same degree of rate heterogeneity applies across the entire locus, including variable flanking regions. We present a Wright–Fisher model of selection on nucleotides (SelON) which includes the effects of mutation, drift, and spatially varying, stabilizing selection for an optimal nucleotide sequence. The SelON model assumes the strength of stabilizing selection follows a position-dependent Gaussian function whose exact shape can vary between UCEs. We evaluate SelON by comparing its performance to a simpler and spatially invariant GTR+Γ model using an empirical data set of 400 vertebrate UCEs used to determine the phylogenetic position of turtles. We observe much improvement in model fit of SelON over the GTR+Γ model, and support for turtles as sister to lepidosaurs. Overall, the UCE-specific parameters SelON estimates provide a compact way of quantifying the strength and variation in selection within and across UCEs. SelON can also be extended to include more realistic mapping functions between sequence and stabilizing selection as well as allow for greater levels of rate heterogeneity. By more explicitly modeling the nature of selection on UCEs, SelON and similar approaches can be used to better understand the biological mechanisms responsible for their preservation across highly divergent taxa and long evolutionary time scales.
Genome Reduction Is Associated with Bacterial Pathogenicity across Different Scales of Temporal and Ecological Divergence
Authors: Murray Gemma G R , Charlesworth Jane , Miller Eric L , Casey Michael J , Lloyd Catrin T , Gottschalk Marcelo , Tucker Alexander W (Dan) , Welch John J , Weinert Lucy A
Published: December 2020

Emerging bacterial pathogens threaten global health and food security, and so it is important to ask whether these transitions to pathogenicity have any common features. We present a systematic study of the claim that pathogenicity is associated with genome reduction and gene loss. We compare broad-scale patterns across all bacteria, with detailed analyses of Streptococcus suis, an emerging zoonotic pathogen of pigs, which has undergone multiple transitions between disease and carriage forms. We find that pathogenicity is consistently associated with reduced genome size across three scales of divergence (between species within genera, and between and within genetic clusters of S. suis). Although genome reduction is also found in mutualist and commensal bacterial endosymbionts, genome reduction in pathogens cannot be solely attributed to the features of their ecology that they share with these species, that is, host restriction or intracellularity. Moreover, other typical correlates of genome reduction in endosymbionts (reduced metabolic capacity, reduced GC content, and the transient expansion of nonfunctional elements) are not consistently observed in pathogens. Together, our results indicate that genome reduction is a consistent correlate of pathogenicity in bacteria.
Unique k-mer sequences for validating cancer-related substitution, insertion and deletion mutations
Authors: Lee HoJoon , Shuaibi Ahmed , Bell John M , Pavlichin Dmitri S , Ji Hanlee P
Published: December 2020

Cancer genome sequencing has led to important discoveries such as the identification of cancer genes. However, challenges remain in the analysis of cancer genome sequencing. One significant issue is that mutations identified by multiple variant callers are frequently discordant even when using the same genome sequencing data. For insertion and deletion mutations, oftentimes there is no agreement among different callers. Identifying somatic mutations involves read mapping and variant calling, a complicated process that uses many parameters and model tuning. To validate the identification of true mutations, we developed a method using k-mer sequences. First, we characterized the landscape of unique versus non-unique k-mers in the human genome. Second, we developed a software package, KmerVC, to validate the given somatic mutations from sequencing data. Our program validates the occurrence of a mutation based on statistically significant difference in frequency of k-mers with and without a mutation from matched normal and tumor sequences. Third, we tested our method on both simulated and cancer genome sequencing data. Counting k-mer involving mutations effectively validated true positive mutations including insertions and deletions across different individual samples in a reproducible manner. Thus, we demonstrated a straightforward approach for rapidly validating mutations from cancer genome sequencing data.
Quality of Literature Searches Published in Leading Neurosurgical Journals: A Review of Reviews
Authors: O’Donohoe Tom J , Bridson Tahnee L , Shafik Christopher G , Wynne David , Dhillon Rana S , Tee Jin W
Published: December 2020

BACKGROUND

There is mounting evidence that the search strategies upon which systematic reviews (SRs) are based frequently contain errors are incompletely reported or insensitive.

OBJECTIVE

To appraise the quality of search strategies in the 10 leading specialty neurosurgical journals and identify factors associated with superior searches.

METHODS

This research-on-research study systematically surveyed SRs published in the 10 leading neurosurgical journals between 01/10/2017 and 31/10/2019. All SRs were eligible for assessment using a predefined coding manual that was adapted from the preferred reporting items for systematic reviews and meta-analyses (PRISMA), a measurement tool to assess systematic reviews (AMSTAR), and Cochrane Collaboration guidelines. The PubMed interface was used to search the MEDLINE database, which was supplemented by individual journal searches. Descriptive statistics were utilized to identify factors associated with improved search strategies.

RESULTS

A total of 633 articles were included and contained a median of 19.00 (2.00-1654.00) studies. Less than half (45.97%) of included search strategies were considered to be reproducible. Aggregated reporting score was positively associated with in-text reference to reporting guideline adherence (τb = 0.156,P < .01). The number of articles retrieved by a search (τb = 0.11,P < .01) was also associated with the reporting of a reproducible search strategy.

CONCLUSION

This study demonstrates that the search strategies used in neurosurgical SRs require improvement. In addition to increasing awareness of reporting standards, we propose that this be achieved by the incorporation of PRISMA and other guidelines into article submission and peer-review processes. This may lead to the conduct of more informative SRs, which may result in improved clinician decision-making and patient outcomes.
Spatial decoupling of light absorption and reaction sites in n-Si photocathodes for solar water splitting
Authors: Wang Shujie , Wang Tuo , Liu Bin , Li Huimin , Feng Shijia , Gong Jinlong
Published: December 2020

Metal-insulator-semiconductor (MIS) photocathodes offer a simple alternative to p-n junction photocathodes in photoelectrochemical water splitting. However, the parasitic light absorption of catalysts and metal layers in the MIS junction, as well as the lack of low work function metals to form a large band offset with p-Si, severely limit their performance. This paper describes an MIS photocathode fabricated from n-Si, rather than the commonly used p-Si, to spatially decouple light absorption from reaction sites, which enables the majority carriers, instead of the commonly used minority carriers, to drive the surface reaction, making it possible to place the reaction sites far away from the light absorption region. Thus, the catalysts could be moved to the backside of the MIS junction to avoid light shielding. Moreover, the adoption of n-Si unlocks a variety of high work function materials for photovoltage generation. The obtained n-Si MIS photocathode exhibits an applied bias photon-to-current efficiency of 10.26% with a stability up to 300 h.
Affordability of nutritious foods for complementary feeding in South Asia
Authors: Ryckman Theresa , Beal Ty , Nordhagen Stella , Murira Zivai , Torlesse Harriet
Published: December 2020

The high prevalence of stunting and micronutrient deficiencies among children in South Asia has lifelong health, educational, and economic consequences. For children aged 6–23 months, undernutrition is influenced by inadequate intake of complementary foods containing nutrients critical for growth and development. The affordability of nutrients lacking in young children’s diets in Bangladesh, India, and Pakistan was assessed in this study. Using data from nutrient gap assessments and household surveys, household food expenditures were compared with the cost of purchasing foods that could fill nutrient gaps. In all 3 countries, there are multiple affordable sources of vitamin A (orange-fleshed vegetables, dark leafy greens, liver), vitamin B12 (liver, fish, milk), and folate (dark leafy greens, liver, legumes, okra); few affordable sources of iron and calcium (dark leafy greens); and no affordable sources of zinc. Affordability of animal-source protein varies, with several options in Pakistan (fish, chicken, eggs, beef) and India (fish, eggs, milk) but few in Bangladesh (eggs). Approaches to reduce prices, enhance household production, or increase incomes are needed to improve affordability.
Observations of the [C i] (3P1–3P0) emission toward the massive star-forming region RCW 38: Further evidence for highly-clumped density distribution of the molecular gas
Authors: Izumi Natsuko , Fukui Yasuo , Tachihara Kengo , Fujita Shinji , Torii Kazufumi , Kamazaki Takeshi , Kaneko Hiroyuki , Silva Andrea , Iono Daisuke , Momose Munetake , Sugimoto Kanako , Nakazato Takeshi , Kosugi George , Maekawa Jun , Takahashi Shigeru , Yoshino Akira , Asayama Shin’ichiro
Published: December 2020

We present observations of the 3P1–3P0 fine-structure line of atomic carbon using the ASTE 10m sub-mm telescope towards RCW 38, the youngest super star cluster in the Milky Way. The detected [C i] emission is compared with the CO J = 1–0 image cube presented in Fukui et al. (2016, ApJ, 820, 26) which has an angular resolution of 40″ (∼0.33 pc). The overall distribution of the [C i] emission in this cluster is similar to that of the 13CO emission. The optical depth of the [C i] emission was found to be τ = 0.1–0.6, suggesting mostly optically thin emission. An empirical conversion factor from the [C i] integrated intensity to the H2 column density was estimated as X[C i]$= 6.3 \times 10 ^{20}\:$cm−2 K−1 km−1 s (for visual extinction: AV ≤ 10 mag) and 1.4 × 1021 cm−2 K−1 km−1 s (for AV of 10–100 mag). The column density ratio of the [C i] to CO (N[C i]$/N_{\rm CO}$) was derived as ∼0.1 for AV of 10–100 mag, which is consistent with that of the Orion cloud presented in Ikeda et al. (2002, ApJ, 571, 560). However, our results cover an AV regime of up to 100 mag, which is wider than the coverage found in Orion, which reaches up to ∼60 mag. Such a high [C i]$/$CO ratio in a high-AV region is difficult to explain via the plane-parallel photodissociation region model, which predicts that this ratio is close to 0 due to the heavy shielding of the ultraviolet (UV) radiation. Our results suggest that the molecular gas in this cluster is highly clumpy, allowing deep penetration of UV radiation even at averaged AV values of 100 mag. Recent theoretical works have presented models consistent with such clumped gas distribution with a sub-pc clump size (e.g., Tachihara et al. 2018, arXiv:1811.02224).
A Healing Journey with Chronic Pain: A Meta-Ethnography Synthesizing 195 Qualitative Studies
Authors: Toye Francine , Belton Joletta , Hannink Erin , Seers Kate , Barker Karen
Published: December 2020

Objective

There is a large body of research exploring what it means for a person to live with chronic pain. However, existing research does not help us understand what it means to recover. We aimed to identify qualitative research that explored the experience of living with chronic pain published since 2012 and to understand the process of recovery.

Design

A synthesis of qualitative research using meta-ethnography.

Methods

We used the seven stages of meta-ethnography. We systematically searched for qualitative research, published since 2012, that explored adults’ experiences of living with, and being treated for, chronic pain. We used constant comparison to distill the essence of ideas into themes and developed a conceptual model.

Results

We screened 1,328 titles and included 195 studies. Our conceptual model indicates that validation and reconnection can empower a person with chronic pain to embark on a journey of healing. To embark on this journey requires commitment, energy, and support.

Conclusions

The innovation of our study is to conceptualize healing as an ongoing and iterating journey rather than a destination. Health interventions for chronic pain would usefully focus on validating pain through meaningful and acceptable explanations; validating patients by listening to and valuing their stories; encouraging patients to connect with a meaningful sense of self, to be kind to themselves, and to explore new possibilities for the future; and facilitating safe reconnection with the social world. This could make a real difference to people living with chronic pain who are on their own healing journeys.
Sensitivity to change and clinical correlations of the novel DACtylitis glObal Sonographic (DACTOS) score in psoriatic arthritis
Authors: Girolimetto Nicolò , Zabotti Alen , Tinazzi Ilaria , Possemato Niccolò , Costa Luisa , Batticciotto Alberto , Canzoni Marco , Citriniti Giorgia , Lucia Orazio De , Figus Fabiana , Idolazzi Luca , McConnel Rebecca , Peluso Rosario , Sakellariou Garifallia , Tullio Annarita , Salvarani Carlo , Scarpa Raffaele , Iagnocco Annamaria , Caso Francesco , Macchioni Pierluigi
Published: December 2020

Objective

The aim of the study is to assess the performance of the DACTOS (DACtylitis glObal Sonographic) score in a PsA dactylitis clinical setting. In particular, we evaluated the ability of DACTOS to identify the affected fingers, its sensitivity to change after treatment, the correlations between DACTOS and clinical parameters, and the capacity of the score to identify the treatment responders.

Methods

Forty-six consecutive patients with symptomatic PsA hand dactylitis were enrolled. A total of seventy-three dactylitic digits were evaluated clinically and sonographically before and after treatment in this observational and prospective study. Clinical assessment included the Leeds Dactylitis Index-basic (LDI-b) score and visual analogue scales for pain (VAS-p) and functional impairment (VAS-FI). Sonographic lesions were investigated using high-frequency ultrasound with grey scale and power Doppler features according to the DACTOS score. Correlations between the DACTOS score and the clinical parameters were assessed at baseline, 1 month (T1) and 3 months (T3).

Results

We observed significant improvements in all of the assessed clinical parameters and the DACTOS scores after dactylitis treatment. There was a statistically significant correlation between the variation of all clinical parameters (VAS-p, VAS-FI and LDI-b) and the DACTOS score at T1 and T3 evaluations. We found statistically significant differences in the DACTOS score between clinical responder and non-responder groups (P < 0.001) and between clinical remission and non-remission groups (P < 0.001).

Conclusion

The DACTOS score performs well in real-life clinical settings in terms of sensitivity to change and correlations with clinical features in PsA dactylitis.
APPLICATIONS OF OPTICALLY STIMULATED LUMINESCENCE IN MEDICAL DOSIMETRY
Authors: Yukihara Eduardo G , Kron Tomas
Published: December 2020

If the first decade of the new millennium saw the establishment of a more solid foundation for the use of the Optically Stimulated Luminescence (OSL) in medical dosimetry, the second decade saw the technique take root and become more widely used in clinical studies. Recent publications report not only characterization and feasibility studies of the OSL technique for various applications in radiotherapy and radiology, but also the practical use of OSL for postal audits, estimation of staff dose, in vivo dosimetry, dose verification and dose mapping studies. This review complements previous review papers and reports on the topic, providing a panorama of the new advances and applications in the last decade. Attention is also dedicated to potential future applications, such as LET dosimetry, 2D/3D dosimetry using OSL, dosimetry in magnetic resonance imaging-guided radiotherapy (MRIgRT) and dosimetry of extremely high dose rates (FLASH therapy).
Gene Tree Estimation Error with Ultraconserved Elements: An Empirical Study onPseudapisBees
Authors: Bossert Silas , Murray Elizabeth A , Pauly Alain , Chernyshov Kyrylo , Brady Seán G , Danforth Bryan N
Published: December 2020

Summarizing individual gene trees to species phylogenies using two-step coalescent methods is now a standard strategy in the field of phylogenomics. However, practical implementations of summary methods suffer from gene tree estimation error, which is caused by various biological and analytical factors. Greatly understudied is the choice of gene tree inference method and downstream effects on species tree estimation for empirical data sets. To better understand the impact of this method choice on gene and species tree accuracy, we compare gene trees estimated through four widely used programs under different model-selection criteria: PhyloBayes, MrBayes, IQ-Tree, and RAxML. We study their performance in the phylogenomic framework of $>$800 ultraconserved elements from the bee subfamily Nomiinae (Halictidae). Our taxon sampling focuses on the genus Pseudapis, a distinct lineage with diverse morphological features, but contentious morphology-based taxonomic classifications and no molecular phylogenetic guidance. We approximate topological accuracy of gene trees by assessing their ability to recover two uncontroversial, monophyletic groups, and compare branch lengths of individual trees using the stemminess metric (the relative length of internal branches). We further examine different strategies of removing uninformative loci and the collapsing of weakly supported nodes into polytomies. We then summarize gene trees with ASTRAL and compare resulting species phylogenies, including comparisons to concatenation-based estimates. Gene trees obtained with the reversible jump model search in MrBayes were most concordant on average and all Bayesian methods yielded gene trees with better stemminess values. The only gene tree estimation approach whose ASTRAL summary trees consistently produced the most likely correct topology, however, was IQ-Tree with automated model designation (ModelFinder program). We discuss these findings and provide practical advice on gene tree estimation for summary methods. Lastly, we establish the first phylogeny-informed classification for Pseudapis s. l. and map the distribution of distinct morphological features of the group. [ASTRAL; Bees; concordance; gene tree estimation error; IQ-Tree; MrBayes, Nomiinae; PhyloBayes; RAxML; phylogenomics; stemminess]
Phylogenomic Discordance in the Eared Seals is best explained by Incomplete Lineage Sorting following Explosive Radiation in the Southern Hemisphere
Authors: Lopes Fernando , Oliveira Larissa R , Kessler Amanda , Beux Yago , Crespo Enrique , Cárdenas-Alayza Susana , Majluf Patricia , Sepúlveda Maritza , Brownell Robert L , Franco-Trecu Valentina , Páez-Rosas Diego , Chaves Jaime , Loch Carolina , Robertson Bruce C , Acevedo-Whitehouse Karina , Elorriaga-Verplancken Fernando R , Kirkman Stephen P , Peart Claire R , Wolf Jochen B W , Bonatto Sandro L
Published: December 2020

The phylogeny and systematics of fur seals and sea lions (Otariidae) have long been studied with diverse data types, including an increasing amount of molecular data. However, only a few phylogenetic relationships have reached acceptance because of strong gene-tree species tree discordance. Divergence times estimates in the group also vary largely between studies. These uncertainties impeded the understanding of the biogeographical history of the group, such as when and how trans-equatorial dispersal and subsequent speciation events occurred. Here, we used high-coverage genome-wide sequencing for 14 of the 15 species of Otariidae to elucidate the phylogeny of the family and its bearing on the taxonomy and biogeographical history. Despite extreme topological discordance among gene trees, we found a fully supported species tree that agrees with the few well-accepted relationships and establishes monophyly of the genus Arctocephalus. Our data support a relatively recent trans-hemispheric dispersal at the base of a southern clade, which rapidly diversified into six major lineages between 3 and 2.5 Ma. Otaria diverged first, followed by Phocarctos and then four major lineages within Arctocephalus. However, we found Zalophus to be nonmonophyletic, with California (Zalophus californianus) and Steller sea lions (Eumetopias jubatus) grouping closer than the Galapagos sea lion (Zalophus wollebaeki) with evidence for introgression between the two genera. Overall, the high degree of genealogical discordance was best explained by incomplete lineage sorting resulting from quasi-simultaneous speciation within the southern clade with introgresssion playing a subordinate role in explaining the incongruence among and within prior phylogenetic studies of the family. [Hybridization; ILS; phylogenomics; Pleistocene; Pliocene; monophyly.]
The Use of Aerated Steam as a Heat Treatment for Managing Angular Leaf Spot in Strawberry Nursery Production and Its Effect on Plant Yield
Authors: Turechek William W. , Myhrene Ole , Slovin Janet , Peres Natalia A.
Published: December 2020

Xanthomonas fragariae, the bacterium causing angular leaf spot (ALS) of strawberry, is found routinely on strawberry nursery stock. Although ALS can be a serious disease in production fields, it can be particularly problematic in the sale and trade of commercial nursery stock because of international trade regulations. Heat treatment has been shown to be an effective treatment for managing ALS on nursery stock in small-scale experimental trials. The objective of this research was to design, build, and trial precision thermotherapy units for managing ALS for both research and commercial applications and to test a new thermotherapeutic protocol on strawberry nursery stock that combines a conditioning thermal treatment with an eradicative thermal treatment. Small-plot trials were conducted to evaluate the efficacy of precision thermotherapy on control of ALS using known sources of infected nursery stock. Additionally, trials were conducted in cooperation with commercial nurseries to determine the impact of thermotherapy on plant health and yield and on the natural development of ALS. In the small-plot trials, ALS incidence was significantly lower in plots treated with precision thermotherapy. In the commercial trials, precision thermotherapy had a variable, but negligible, effect on plant growth and yield. ALS, when it occurred, was always lower in thermotherapy-treated plots. Heat is a near-universal biocide. Thus, in addition to managing ALS, the commercial application of precision thermal therapy to strawberry nursery stock may be effective for managing a wide range of pest and disease threats to strawberry while simultaneously reducing pesticide usage.

[Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law. 2021
A Multisystemic Pictorial Review of Diabetes Mellitus
Authors: Shah Tejen , Farooq Zerwa , Cohen-Addad Dan , DeAlwis Delan
Published: December 2020

Diabetes mellitus is a leading cause of death with immense burden on the health care system. The number of patients suffering from diabetes is expected to rise dramatically in the coming years secondary to lifestyle changes. Diabetes is a multisystemic disease that exerts its effects through decreased insulin sensitivity leading to various degrees of metabolic dysregulation. The pathogenesis of complications associated with diabetes is largely dependent on the duration of the disease and common coexisting conditions such as hyperlipidemia, hypertension, and obesity. Acute hyperglycemic and hypoglycemic events can lead to life-threatening illness such as acute coronary syndrome, hyperosmolar state, and diabetic ketoacidosis. The deleterious effects of long-standing diabetes are usually mediated by microvascular disease leading to diabetic retinopathy, nephropathy, cardiomyopathy, and neuropathy.
Instacash: The Ethics of Leveraging Medical Student Status on Social Media
Authors: Dugdale L.S. , Braswell H.
Published: December 2020

Some medical students leverage their medical student status for profit as social media influencers on platforms such as Instagram. Depending on the size of their following and the brand they are promoting, students can make thousands of dollars per year by advertising products ranging from scrubs to protein powder to mattresses. Yet, they receive few tools as part of their education to help them understand how to reconcile their professional obligations with a desire to generate an income. After examining the potential benefits and harms of social media use, this article considers the possibility of medical student financial gain from being an influencer in light of seasoned physicians’ own efforts to profit from industry alliances. Through both historical and contemporary lenses, the authors consider the tension between doctors as healers and moneymakers, before concluding with practical and philosophical approaches for guiding medical student influencers.
The Cyclical and Evolving Nature of Methamphetamine Use: An Evaluation of Near Real-time Urine Drug Test Results
Authors: LaRue Leah , Guevara Maria G. , Whitley Penn , Dawson Eric , Twillman Robert K. , Huskey Angela
Published: December 2020

Objective:

To determine methamphetamine positivity and copositivity with other drugs in urine drug test (UDT) results geographically through time.

Methods:

This cross-sectional study of UDT results from January 1, 2014, through December 31, 2019, included patient specimens submitted by health care professionals across the United States. The analysis used LC-MS/MS to detect cocaine, heroin, alcohol, marijuana and nonprescribed methamphetamine, fentanyl, methadone, buprenorphine, benzodiazepines, and other opioids. Logistic regression was used to evaluate association of demographic features and model yearly methamphetamine detection patterns across US census divisions. Odds ratios (OR) from logistic modeling were used to evaluate the impact of methamphetamine positivity on the spatio-temporal detection patterns of additional nonprescribed or illicit drugs.

Results:

The probability of being positive for methamphetamine increased nationally from 0.010 [0.010–0.011] in 2014 to 0.044 [0.042–0.046] in 2019, a 340% increase after correction for demographic covariates. The highest predicted positivity rate was in male patients, 25- to 34-years-old, from the West North Central division and from substance use disorder treatment centers. Nationally, copositivity ORs for fentanyl, heroin, and other opioids with methamphetamine were highest in 2019. Increases in ORs from 2014 through 2019 were statistically significant for heroin (P = 0.024) and fentanyl (P = 0.0085). Copositivity ORs for methamphetamine and other substances varied by census division.

Conclusions:

The probability of being positive for methamphetamine in UDT increased nationwide between 2014 and 2019. Not all census divisions are increasing at the same rate. Copositivity with additional substances is increasing in some census divisions, which further increases the risk of overdose and poor treatment outcomes.
Adaptation of a System of Treatment for Substance Use Disorders During the COVID-19 Pandemic
Authors: Komaromy Miriam , Tomanovich Mary , Taylor Jessica L. , Ruiz-Mercado Glorimar , Kimmel Simeon D. , Bagley Sarah M. , Saia Kelley M. , Costello Eileen , Park Tae Woo , LaBelle Colleen , Weinstein Zoe , Walley Alexander Y.
Published: December 2020

The Grayken Center for Addiction at Boston Medical Center includes programs across the care continuum for people with substance use disorders (SUDs), serving both inpatients and outpatients. These programs had to innovate quickly during the COVID-19 outbreak to maintain access to care. Federal and state regulatory flexibility allowed these programs to initiate treatment for people experiencing homelessness and maximize patient safety through physical distancing practices. Programs switched to telehealth with high levels of acceptability and patient retention. Some programs also maintained some face-to-face clinic visits to see patients with complex problems and to provide injectable medications. Text-messaging proved invaluable with adolescent and young adult clients, and a mobile-health outreach program was initiated to reach mother/child dyads affected by SUDs. A 24-hour hotline was implemented to support seamless access to treatment for hundreds released from incarceration early due to the pandemic. Boston Medical Center also launched the COVID Recuperation Unit to allow patients experiencing homelessness to recover from mild to moderate COVID-19 infection in an environment that took a harm-reduction approach to SUDs and provided rapid initiation of medication treatment. Many of these innovations increased access to treatment and retention of patients during the pandemic. Maintaining the revised regulations would allow flexibility to provide telehealth, extended prescriptions, and remote access to buprenorphine initiation to support and engage more patients with SUDs.
A 5-year Longitudinal Study of Low Back Pain in Survivors of the Great East Japan Earthquake
Authors: Yabe Yutaka , Hagiwara Yoshihiro , Sekiguchi Takuya , Sugawara Yumi , Tsuchiya Masahiro , Yoshida Shinichirou , Sogi Yasuhito , Onoki Takahiro , Suzuki Kazuaki , Takahashi Tadahisa , Iwatsu Jun , Tsuji Ichiro , Itoi Eiji
Published: December 2020

Study Design.

A longitudinal panel study.

Objective.

The aim of this study was to examine the occurrence of low back pain (LBP), especially the association of previous LBP with further episodes of LBP, in survivors of the Great East Japan Earthquake (GEJE) during the course of 5 years.

Summary of Background Data.

LBP is common among survivors of natural disasters, but its long-term course is not clear.

Methods.

A 5-year longitudinal study was conducted among survivors of the GEJE (n = 1821). The presence of LBP was assessed using a self-reported questionnaire at 2, 4, and 7 years after the disaster (termed the first, second, and third time points, respectively). Multiple logistic regression analysis was performed to assess a potential association between LBP at the first and second time points with LBP at the third time point, and the odds ratios (ORs) and 95% confidence intervals (CI) were calculated.

Results.

The prevalence of LBP was 25.3%, 27.3%, and 27.2% at the first, second, and third time points, respectively. The occurrence of LBP at the first time point was significantly associated with LBP at the third time point, and the adjusted odds ratio (OR) (95% confidence interval [CI]) was 5.47 (4.28–6.98). Furthermore, LBP at the first and second time points was significantly associated with LBP at the third time point. Compared to no LBP at the first and second time points, the adjusted OR (95% CIs) for LBP at the third time point was 4.12 (3.14–5.41) in the case of LBP at either of the first or second time points and 10.73 (7.80–14.76) for LBP at both time points (P for trend < 0.001).

Conclusion.

Previous LBP was associated with LBP 5 years later among survivors of the GEJE. Furthermore, the effect on subsequent LBP was stronger with a higher frequency of previous LBP episodes.

Level of Evidence: 3
GSDME maintains hematopoietic stem cells by balancing pyroptosis and apoptosis
Authors: Yang Xiuxiu , Cong Tingting , He Hanqing , Wang Jianwei
Published: December 2020

GSDME contains a pore-forming domain at its N-terminal region to execute pyroptosis. Our previous study has reported that forced expression of Gsdme impairs the reconstitution capacity of hematopoietic stem cells (HSCs). While, how GSDME-mediated pyroptosis regulates HSCs remains unknown. Here, we show that hematopoietic stem and progenitor cells are capable to undergo pyroptosis in response to cisplatin treatment and GSDME is one of the genes mediating such process. Gsdme

−/−
mice revealed no difference in the steady state of blood system while Gsdme

−/−
HSCs exhibited compromised reconstitution capacity due to increased apoptosis. Briefly, this study reveals that GSDME modulates HSC function by coordinating pyroptosis and apoptosis.
Vulvar Elastosis: A Novel Diagnostic Entity
Authors: See Sharlene Helene C. , Tan Timothy L. , Kurtzer Traci A. , Gerami Pedram , Guitart Joan , Yazdan Pedram
Published: December 2020

In vulvar biopsies, we have observed histopathologic abnormalities of elastic fibers identical to solar elastosis, with thick, curled, and irregular pale grey fibers in the dermis. In severe cases, changes resemble nodular solar elastosis. We retrospectively evaluated 238 vulvar biopsies with the goal of defining and characterizing changes of vulvar elastosis. Of 238 vulvar biopsies reviewed, 107 (45%) exhibited vulvar elastosis. Patients with vulvar elastosis were older (mean = 65 years old) compared to those without (mean = 44 years old). Sixty-six (62%) were graded as mild, 27 (25%) moderate, and 14 (13%) severe. Vulvar elastosis was significantly more common in women ≥45 years old (P-value < 0.001). There was moderate correlation between age and severity (correlation coefficient = 0.55, P-value < 0.001). Vulvar elastosis was observed in a variety of inflammatory and non-inflammatory pathologies. In 5 cases, the sole pathology was vulvar elastosis presenting clinically as either a pruritic or painful white to white-yellow papule or plaque, or vulvar pain or burning without a clinical lesion. Vulvar elastosis is a novel diagnostic entity occurring in a sun-protected site and its pathogenesis may be a degenerative phenomenon possibly related to advancing age and/or hormonal changes.
Heat Shock Protein 70 Is Associated With Cardioversion Outcome and Recurrence of Symptomatic Recent Onset Atrial Fibrillation in Hypertensive Patients
Authors: Rigopoulos Angelos G. , Kalogeropoulos Andreas S. , Tsoporis James N. , Sakadakis Eleftherios A. , Triantafyllis Andreas S. , Noutsias Michel , Gupta Sahil , Parker Thomas G. , Rizos Ioannis
Published: December 2020

Accumulating evidence indicates that heat shock proteins (HSPs) may represent a suitable biomarker to predict atrial fibrillation (AF). We investigated the relation of circulating serum HSP70 (sHSP70) with inflammatory cytokines and recurrence of symptomatic recent onset AF (ROAF). We enrolled 90 patients with ROAF (the duration from onset of symptoms ≤24 hours) and 30 controls. Patients received amiodarone for cardioversion and rhythm control. The association of serum HSP70, serum interleukin-2 (sIL-2), and serum interleukin-4 (sIL-4) with the presence of cardioversion and AF recurrence within a year was investigated. Toll-like receptor 4 (TLR4) signaling dependence for IL-2 and IL-4 induction in response to stimulation with HSP70 was tested in rat aortic vascular smooth muscle cell cultures. Patients had higher sHSP70 and sIL-2 and lower sIL-4 compared with controls. Serum HSP70 was independently associated with ROAF (P = 0.005) and correlated with sIL-2 (r = 0.494, P < 0.001) and sIL-4 (r = −0.550, P < 0.001). By 48 hours, 71 of the 90 patients were cardioverted, with noncardioverted patients having higher sHSP70 and sIL-2 and lower sIL-4, which were the only independent factors associated with cardioversion. AF recurred in 38 of the 71 cardioverted patients in 1 year. A cutoff value of sHSP70 ≥0.65 ng/mL and sIL-2 ≥0.21 pg/mL was the only independent factor associated with AF recurrence (hazard ratio: 3.311, 95% confidence interval: 1.503–7.293, P = 0.003 and hazard ratio: 3.144, 95% confidence interval: 1.341–7.374, P = 0.008, respectively). The exposure of smooth muscle cell to HSP70 in vitro increased the expression of IL-2 (5×) and IL-4 (1.5×) through TLR4-dependent and receptor-independent mechanisms. In conclusion, sHSP70 and sIL-2 might constitute a prognostic tool for determining the cardioversion and recurrence likelihood in ROAF.
Circular RNA Circ-BANP Regulates Oxidized Low-density Lipoprotein-induced Endothelial Cell Injury Through Targeting the miR-370/Thioredoxin-interacting Protein Axis
Authors: Chen Guang , Li Yongjun , Zhang Ailing , Gao Lijun
Published: December 2020

Dysfunction of endothelial cells is now recognized as an important contributor to the pathogenesis of atherosclerosis (AS). Circular RNAs (circRNAs) have been demonstrated to be involved in AS pathogenesis. The purpose of this study was to explore the biological action of circRNA BTG3–associated nuclear protein (circ-BANP, hsa_circ_0040824) on the dysfunction of human umbilical vein endothelial cells (HUVECs) induced by oxidized low-density lipoprotein (ox-LDL). The levels of circ-BANP, miR-370, and thioredoxin-interacting protein (TXNIP) were gauged by quantitative real-time polymerase chain reaction or Western blot. The subcellular fractionation assay was used to determine the localization of circ-BANP, and the ribonuclease R assay was performed to evaluate the stability of circ-BANP. Cell viability, apoptosis, migration, invasion, and tube formation abilities were assessed by the Cell Counting Kit-8, flow cytometry, transwell, and tube formation assays. The levels of interleukin-6, tumor necrosis factor-α, and interleukin-1β were detected by enzyme-linked immunosorbent assay. Targeted relationships among circ-BANP, miR-370, and TXNIP were confirmed by a dual-luciferase reporter assay. Our data showed that circ-BANP expression was upregulated in AS blood and ox-LDL-induced HUVECs. The inhibition of circ-BANP promoted cell viability, migration, invasion, tube formation, and repressed cell inflammation and apoptosis in ox-LDL-induced HUVECs, demonstrating that circ-BANP silencing alleviated ox-LDL-induced HUVEC injury. Mechanistically, circ-BANP directly targeted miR-370. Moreover, miR-370 mediated the regulation of circ-BANP in ox-LDL-induced cell injury in HUVECs. TXNIP was a target of miR-370, and miR-370 overexpression relieved ox-LDL-induced HUVEC injury by downregulating TXNIP. Furthermore, circ-BANP modulated TXNIP expression by targeting miR-370. Our findings demonstrated that circ-BANP regulated ox-LDL-induced cell injury in HUVECs at least in part through targeting the miR-370/TXNIP axis, illuminating circ-BANP as a potential target for AS detection and treatment.
Evaluation of Sacubitril/Valsartan Initiation in Outpatient Heart Failure Patients
Authors: Rerick Lindsey , Elston Colleen , Kester Jordan , Montepara Courtney , Gengler Brooke
Published: December 2020

Despite sacubitril/valsartan being on the market since 2015, clinicians are still determining the best way to initiate therapy to optimize outcomes and minimize potential for side effects. The purpose of this study is to investigate real-world outpatient experience of prescribing sacubitril/valsartan therapy based on appropriate patient selection, dosing conversion, and tolerability. This retrospective cohort study evaluated patients' prescribed sacubitril/valsartan therapy in cardiology clinics associated with an academic institution between February 1, 2016, and August 30, 2018. Patients were excluded if they were less than 18 years of age, enrolled in a clinical trial involving sacubitril/valsartan, or had insufficient data. The primary outcome was to determine how many heart failure patients initiated on sacubitril/valsartan were performed so appropriately based on guideline and package insert recommendations. Select secondary outcomes included rates of adverse events and need for adjustment of concomitant heart failure medications. A total of 250 patients were included in this study. For the primary outcome, 125 patients (50%) were appropriately initiated on sacubitril/valsartan. Those who were inappropriately initiated on the medication experienced more symptoms of hypotension (16% in the appropriate start group vs. 28% in the inappropriate start group; P = 0.022) and required more dose decreases of sacubitril/valsartan (6% in the appropriate start group vs. 13% in the inappropriate start group; P = 0.049). In outpatient clinical practice, almost half of patients initiated on sacubitril/valsartan were performed so outside of guideline recommendations, which was associated with an increased risk of hypotension and dose reductions.
A Perspective on Personalized Therapies in Hypertrophic Cardiomyopathy
Authors: Goldspink Paul H. , Warren Chad M. , Kitajewski Jan , Wolska Beata M. , Solaro R. John
Published: December 2020

A dominant mechanism of sudden cardiac death in the young is the progression of maladaptive responses to genes encoding proteins linked to hypertrophic cardiomyopathy. Most are mutant sarcomere proteins that trigger the progression by imposing a biophysical defect on the dynamics and levels of myofilament tension generation. We discuss approaches for personalized treatments that are indicated by recent advanced understanding of the progression.
Levamisole—a Toxic Adulterant in Illicit Drug Preparations: a Review
Authors: Midthun Kari M. , Nelson Lewis S. , Logan Barry K.
Published: December 2020

Discovered in the 1960s, the common anthelminthic levamisole has seen widespread use in veterinary applications. Its use rapidly expanded thereafter to include human medical treatments for a variety of acute and chronic disorders. Because of reports of severe adverse effects, the US Food and Drug Administration withdrew levamisole's approval for human use in 2000; however, medical options outside the United States and illicit options worldwide allow continued accessibility to levamisole. The compound is rapidly metabolized in the body, with at least 2 known active metabolites. Levamisole has a broad range of immunomodulatory effects, including both stimulatory and inhibitory effects on immune responses. It is generally well tolerated at therapeutic concentrations, although a variety of autoimmune-related adverse effects have been reported, including agranulocytosis, leukopenia, purpura, and visible necrotized skin tissue. Individuals with levamisole-compromised immune systems are more susceptible to infections, including COVID-19. Since the early 2000's, levamisole has been frequently used as an adulterating agent in illicit street drugs, especially cocaine, fentanyl, and heroin. Although its prevalence has varied over time and geographically, levamisole has been detected in up to 79% of the street supply of cocaine at levels up to 74% by weight. Its presence in illicit drug markets also raises concern over the potential for exposure of children and neonates, although this is supported by only limited anecdotal evidence. Levamisole is not currently included in routine drug testing panels, although a variety of confirmatory testing techniques exist across a range of antemortem and postmortem specimen options. Because of its varying presence in illicit drug markets, both the medical and forensic communities need to be aware of levamisole and its potential impact on toxicological investigations.
Intravenous Infusion of Fentanyl Has No Effect on Blood Concentration of Tacrolimus in Patients Receiving Hematopoietic Stem-Cell Transplantation
Authors: Ishiwata Yasuyoshi , Nagata Masashi , Kiuchi Shota , Ippongi Chika , Takeda Hirofumi , Takahashi Hiromitsu
Published: December 2020

Background:

Both tacrolimus (TAC) and fentanyl are frequently used in patients receiving allogeneic hematopoietic stem-cell transplantation. A recently published report demonstrated that fentanyl can reduce the total body clearance of TAC; however, most patients in this study were administered concomitantly with azole antifungal agents, which are known to be strong inhibitors of CYP3A. Hence, the exact effect of fentanyl on TAC pharmacokinetics was unclear. In the current study, the authors retrospectively investigated the pharmacokinetic interaction between TAC and fentanyl in patients who were not concomitantly administered drugs that affect TAC metabolism.

Methods:

Patients with continuous infusion of TAC and fentanyl after hematopoietic stem-cell transplantation at the Tokyo Medical and Dental University between January 2014 and December 2018 were enrolled. The total body clearance of TAC was compared before and after the initiation or discontinuation of fentanyl.

Results:

Thirty patients (24 men and 6 women; median age, 11 years) were screened for their eligibility. Twenty-eight patients were enrolled for evaluating the effects of the fentanyl initiation on TAC pharmacokinetics; 2 patients were excluded because of the absence of data related to the TAC blood concentrations or the concomitant use of azole antifungals. Twenty patients were enrolled for investigating the effects of fentanyl discontinuation on TAC pharmacokinetics, whereas 10 patients were excluded because of the absence of data related to the blood concentration of TAC or the additional administration of azole antifungals. Furthermore, the total body clearance of TAC was not significantly affected by the initiation or discontinuation of fentanyl, although there were large interindividual variations. In addition, the results remained the same even when the analysis was performed independently for adults and children.

Conclusions:

Intravenous infusion of fentanyl does not affect the pharmacokinetics of TAC.
Polycystic Ovarian Syndrome Genetics and Epigenetics
Authors: COMBS JOSHUA C. , HILL MICAH J. , DECHERNEY ALAN H.
Published: December 2020

Polycystic ovarian syndrome and its associated endocrine abnormalities comprise one of the most common metabolic spectrum disorders within the human race. Because of the variance in phenotypic expression among individuals and within family lineages, attention has been turned to genetic and epigenetic changes in which the root cause of the disorder may lie. Further understanding of DNA/histone methylation and microRNA patterns may help to improve the accuracy of diagnosis and lead to future treatment options.
Clinical Obstetrics & Gynecology: Polycystic Ovary Disease Ethnicity, Diversity, and Psychosocial Ramifications
Authors: BURGART JENNIFER M.
Published: December 2020

Polycystic ovary disease is a heterogenous disorder that presents differently in each individual. Some of this variation is due to racial and ethnic differences, which has been shown to affect hirsutism scores, metabolic comorbidities, cardiovascular risk factors, and long-term health outcomes. Psychosocial factors, including mental health diagnoses, body image distress measures, and disordered eating behaviors have also been shown to affect women with polycystic ovarian syndrome at a higher rate than the general population, and contribute to a decreased quality of life among many patients with this chronic condition.