bluuebunny/crossref_metadata_2025 huggingface dataset:
Alternative pain management via endocannabinoids in the time of the opioid epidemic: Peripheral neuromodulation and pharmacological interventions
Authors: Lee Ming Tatt , Mackie Ken , Chiou Lih‐Chu
Published: December 2021

The use of opioids in pain management is hampered by the emergence of analgesic tolerance, which leads to increased dosing and side effects, both of which have contributed to the opioid epidemic. One promising potential approach to limit opioid analgesic tolerance is activating the endocannabinoid system in the CNS, via activation of CB1 receptors in the descending pain inhibitory pathway. In this review, we first discuss preclinical and clinical evidence revealing the potential of pharmacological activation of CB1 receptors in modulating opioid tolerance, including activation by phytocannabinoids, synthetic CB1 receptor agonists, endocannabinoid degradation enzyme inhibitors, and recently discovered positive allosteric modulators of CB1 receptors. On the other hand, as non‐pharmacological pain relief is advocated by the US‐NIH to combat the opioid epidemic, we also discuss contributions of peripheral neuromodulation, involving the electrostimulation of peripheral nerves, in addressing chronic pain and opioid tolerance. The involvement of supraspinal endocannabinoid systems in peripheral neuromodulation‐induced analgesia is also discussed.

LINKED ARTICLES

This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc
Effect of cenobamate on the single‐dose pharmacokinetics of multiple cytochrome P450 probes using a cocktail approach in healthy subjects
Authors: Greene Stephen A. , Kwak Charles , Kamin Marc , Vernillet Laurent , Glenn Kelli J. , Gabriel Lana , Kim Hong Wook
Published: December 2021

This study was designed to evaluate the effects of cenobamate, an antiseizure medication for focal seizures, on the pharmacokinetics of cytochrome P450 probes (bupropion, CYP2B6; midazolam, CYP3A4/5; warfarin, CYP2C9; and omeprazole, CYP2C19) in healthy subjects. Probes were administered alone on days 1 (bupropion) and 7 (midazolam/warfarin/omeprazole), and with cenobamate 100 mg/day on day 69 (midazolam) and cenobamate 200 mg/day on days 99 (bupropion) and 105 (midazolam/warfarin/omeprazole). No significant interaction was concluded if 90% confidence intervals (CIs) for geometric mean ratios (GMRs) for area under the curve (AUC) and maximum concentration of CYP substrates and/or their metabolites were within the no‐effect interval (0.80–1.25). When co‐administered with cenobamate 100 mg/day, AUC from time of administration up to the time of the last quantifiable concentration (AUC0–last) GMR (90% CIs) for midazolam was 0.734 (0.647–0.832). When co‐administered with cenobamate 200 mg/day, AUC0–last GMRs (90% CI) for midazolam, bupropion, S‐warfarin, and omeprazole were 0.277 (0.238–0.323), 0.615 (0.522–0.724), 1.14 (1.10–1.18), and 2.07 (1.44–2.98), respectively. Co‐administration of cenobamate with midazolam and bupropion probes led to values that were outside and below the no effect boundary, indicating that cenobamate induces the CYP3A4/5 and CYP2B6 enzymes. Co‐administration of cenobamate led to omeprazole values which were outside and above the no‐effect boundary, but with high variability, suggesting that cenobamate may moderately inhibit CYP2C19 activity. No effect on CYP2C9 was observed with the cenobamate and warfarin combination. Co‐administration of cenobamate with these probes drugs was well‐tolerated. In this study, 200 mg/day cenobamate moderately induced CYP3A4/5 (dose‐dependently; 100 mg/day was a weak inducer), was a weak inducer of CYP2B6, moderately inhibited CYP2C19, and had a negligible effect on CYP2C9.
Malignancy‐associated acquired vulvar lymphangioma circumscriptum: A clinicopathologic study of 71 cases
Authors: Luu Yen T. , Kimmis Brooks D. , Bodine Jared S. , Gloyeske Nika C. , Dai Hongyan
Published: December 2021

Background

Acquired lymphangioma circumscriptum of the vulva is rare and can occur subsequent to malignancies of the anogenital and pelvic region. We sought to investigate the clinicopathologic characteristics of malignancy‐associated acquired vulvar lymphangioma circumscriptum (AVLC).

Methods

We identified all cases of AVLC within our institution with history of prior malignancy between 2005 and 2021. A similar search was performed in the PubMed database to identify published cases to date. The clinical and histopathologic information was recorded.

Results

A total of 71 cases were identified. The most common preceding malignancy was cervical carcinoma (71.8%, 51/71). Radiation therapy was given to 91.4% (64/70) of the patients and lymph node dissection was made on 70.2% (40/57). Median interval between the diagnosis of malignancy and the AVLC was 10 years (range 0‐32 years). AVLC frequently presented as vesicular (31.6%, 18/57) or verrucous (28.1%, 16/57) lesions clinically. Common treatments for AVLC included excision (53.1%, 26/49) and laser therapy (16.3%, 8/49), with an overall recurrence rate of 42.9% (24/56) at a median follow‐up interval of 1.8 years (range 0.04‐32.3 years).

Conclusion

AVLC is a rare, late complication of anogenital and pelvic malignancies causing debilitating physical symptoms and psychological stress. Further studies are warranted to determine the most effective treatment modalities to mitigate recurrence.
Evidence for the presence of a human saprophytic oral bacterium, Mycoplasma faucium, in the skin lesions of a psoriatic patient
Authors: Arabatzis Michael , Velegraki Aristea
Published: December 2021

Psoriasis is currently regarded a mixed autoimmune and autoinflammatory disease. This report describes for the first time the detection of a saprophytic, human oral Tenericutes species, Mycoplasma faucium, in the skin lesions of a patient presenting initially guttate and later plaque psoriasis. An unusual finding in standard histopathology investigation consisted of round and oval thinly stained or unstained, possibly intracellular structures, apparently directly pressing on keratinocyte nuclei of the psoriatic stratum spinosum. In ultrastructural study, wall‐less bacteria were present intracellularly in the keratinocytes, mainly of the psoriatic stratum spinosum, and extracellularly in the upper dermis of the psoriatic lesions. M. faucium was consistently detected and identified in the psoriatic skin by general Tenericutes polymerase chain reaction and sequencing in two biopsies performed 31 months apart. This case raises new questions concerning the pathogenesis of psoriasis and its accepted autoimmune/autoinflammatory nature.
Joint impact of BMI, physical activity and diet on type 2 diabetes: Findings from two population‐based cohorts in China
Authors: Shen Qiu‐Ming , Li Hong‐Lan , Li Zhuo‐Ying , Jiang Yu‐Fei , Ji Xiao‐Wei , Tan Yu‐Ting , Xiang Yong‐Bing
Published: December 2021

Aims

Limited epidemiological data on the combined impact of several lifestyle factors on type 2 diabetes (T2D) incidence was reported in Chinese population. This study aimed to examine how combinations of BMI, physical activity and diet relate to T2D incidence and estimate corresponding population attributable risk in the general population.

Methods

A total of 56,691 male and 70,849 female participants aged 40–74 years old in two population‐based cohorts from the Shanghai Men's and Women's Health Studies were used for analysis. The Cox regression model was used to estimate the association between lifestyle factors collected at baseline and T2D incidence. Multivariable‐adjusted population attributable risks were calculated for specific combinations of lifestyle factors.

Results

There were 3315 male and 5925 female incident T2D, with corresponding density incidence rates of 6.39 and 6.04 per 1000 person‐years. If the healthiest group of healthy lifestyle index (HLI) was used as a reference, the hazard ratios (95% confidence intervals) of T2D increased monotonically in men [2.04 (1.75, 2.38); 2.94 (2.53, 3.42); 4.31 (3.66, 5.07)] and women [1.85 (1.64, 2.08); 2.79 (2.49, 3.13); 4.14 (3.66, 4.67)]. One point increase of HLI was related to 35% and 35% lower risk in men and women. About 52.7% and 58.4% cases in men and women could have been avoided if participants had been adherent to a healthy lifestyle of maintaining healthy body weight, eating a healthy diet and keeping physically active.

Conclusions

An increased number of healthy lifestyle factors were associated with a decreased risk of T2D in the Chinese population. Future interventions targeted at combined healthy lifestyle factors are needed to reduce the burden of T2D.
Complete blood count and cell population data parameters from the Abbott Alinity hq analyzer are useful in differentiating myelodysplastic syndromes from other forms of cytopenia
Authors: Hwang Sang Mee , Nam Youngwon
Published: December 2021

Introduction

Myelodysplastic syndromes (MDS) are characterized by morphologic dysplasia and cytopenia and have a propensity for acute leukemic transformation. However, dysplasia is diagnosed by morphology, thus having cell population data (CPD) that can differentiate cytopenic patients with MDS from other conditions may facilitate accurate diagnosis. We assessed the utility of complete blood count (CBC) parameters and CPD derived from an Abbott Alinity hq analyzer to discriminate MDS‐related cytopenia.

Methods

The patient cohort (n = 345) included 64 samples from patients with MDS, 162 from patients with other cytopenia, and 119 from healthy controls. The hematological parameters and research use‐only parameters of the Abbott Alinity hq analyzer were compared between the cytopenic groups. The effectiveness of the individual standard and research CBC parameters to differentiate MDS from other forms of cytopenia was assessed through a receiver operating characteristics (ROC) analysis.

Results

The percentage of MAC (Macrocytic RBCs) and hemoglobin distribution width (HDW) were higher in the MDS group than in the other cytopenia group and showed the greatest difference between both groups, with an area under the curve (AUC) of 0.766 (0.678–0.855) and 0.786 (0.702–0.870), respectively. The platelet distribution width was higher in the MDS group than in the other cytopenia group, with an AUC of 0.697 (0.623–0.770). WBC CPD extracted from histograms, especially Atyp‐PMN‐loc and Neu‐ALL‐M, showed high AUCs of 0.815 (0.750–0.879) and 0.778 (0.711–0.845), respectively.

Conclusion

Our findings demonstrate the clinical utility of CPD and hematology parameters of the Abbott Alinity hq analyzer in the differential diagnosis of MDS.
Analysing neutron radiation damage in YBa2Cu3O7–x high‐temperature superconductor tapes
Authors: Linden Y. , Iliffe W.R. , He G. , Danaie M. , Fischer D.X. , Eisterer M. , Speller S.C. , Grovenor C.R.M.
Published: December 2021

Superconducting windings will be necessary in future fusion reactors to generate the strong magnetic fields needed to confine the plasma, and these superconducting materials will inevitably be exposed to neutron damage. It is known that this exposure results in the creation of isolated damage cascades, but the presence of these defects alone is not sufficient to explain the degradation of macroscopic superconducting properties and a quantitative method is needed to assess the subtle lattice damage in between the clusters.

We have studied REBCO‐coated conductors irradiated with neutrons to a cumulative dose of 3.3 × 1022 n/m2 that show a degradation of both Tc and Jc values, and use HRTEM analysis to show that this irradiation introduces ∼10 nm amorphous collision cascades. In addition, we introduce a new method for the analysis of these images to quantify the degree of lattice disorder in the apparently perfect matrix between these cascades. This method utilises Fast Fourier and Discrete Cosine Transformations of a statistically relevant number of HRTEM images of pristine, neutron‐irradiated and amorphous samples and extracts the degree of randomness in terms of entropy values. Our results show that these entropy values in both mid‐frequency band FFT and DCT domains correlate with the expected level of lattice damage, with the pristine samples having the lowest and the fully amorphous regions the highest entropy values.  Our methodology allows us to quantify ‘invisible’ lattice damage to and correlate these values to the degradation of superconducting properties, and also has relevance for a wider range of applications in the field of electron microscopy where small changes in lattice perfection need to be measured.
Relevant prognostic factors in patients with stage IV small intestine neuroendocrine neoplasms
Authors: Maurer Elisabeth , Heinzel‐Gutenbrunner Monika , Rinke Anja , Rütz Johannes , Holzer Katharina , Figiel Jens , Luster Markus , Bartsch Detlef Klaus
Published: December 2021

There are few, but controversial data on the prognostic role of upfront primary tumour resection and mesenteric lymph node dissection (PTR) in patients with diffuse metastatic small intestinal neuroendocrine neoplasia (SI‐NEN). Therefore, the prognostic role of PTR and other factors was determined in this setting. This retrospective cohort study included patients with stage IV SI‐NETs with unresectable distant metastases without clinical and radiological signs of acute bowel obstruction or ischaemia. Patients diagnosed from January 2002 to May 2020 were retrieved from a prospective SI‐NEN database. Disease specific overall survival (OS) was analysed with regard to upfront PTR and a variety of other clinical (e.g., gender, age, Hedinger disease, carcinoid syndrome, diarrhoea, laboratory parameters, metastatic liver burden, extrahepatic and extra‐abdominal metastasis) and pathological (e.g., grading, mesenteric gathering) parameters by uni‐ and multivariate analysis. A total of 138 patients (60 females, 43.5%) with a median age of 60 years, of whom 101 (73%) underwent PTR and 37 (27%) did not, were included in the analysis. Median OS was 106 (95% CI: 72.52–139.48) months in the PTR group and 52 (95% CI: 30.55–73.46) in the non‐PTR group (p = 0.024), but the non‐PTR group had more advanced metastatic disease (metastatic liver burden ≥50% 32.4% vs. 13.9%). There was no significant difference between groups regarding the rate of surgery for bowel complications during a median follow‐up of 51 months (PTR group 10.9% and non‐PTR group 16.2%, p = 0.403). Multivariate analysis revealed age < 60 years, normal C‐reactive protein (CRP) at baseline, absence of diarrhoea, less than 50% of metastatic liver burden, and treatment with PRRT as independent positive prognostic factors, whereas PTR showed a strong tendency towards better OS, but level of significance was missed (p = 0.067). However, patients who underwent both, PTR and peptide radioreceptor therapy (PRRT) had the best survival compared to the rest (137 vs. 73 months, p = 0.013). PTR in combination with PRRT significantly prolongs survival in patients with stage IV SI‐NEN. Prophylactic PTR does also not result in a lower reoperation rate compared to the non‐PTR approach regarding bowel complications.
Evolutionary dynamics of piRNA clusters in Drosophila
Authors: Wierzbicki Filip , Kofler Robert , Signor Sarah
Published: December 2021

Small RNAs produced from transposable element (TE)‐rich sections of the genome, termed piRNA clusters, are a crucial component in the genomic defence against selfish DNA. In animals, it is thought the invasion of a TE is stopped when a copy of the TE inserts into a piRNA cluster, triggering the production of cognate small RNAs that silence the TE. Despite this importance for TE control, little is known about the evolutionary dynamics of piRNA clusters, mostly because these repeat‐rich regions are difficult to assemble and compare. Here, we establish a framework for studying the evolution of piRNA clusters quantitatively. Previously introduced quality metrics and a newly developed software for multiple alignments of repeat annotations (Manna) allow us to estimate the level of polymorphism segregating in piRNA clusters and the divergence among homologous piRNA clusters. By studying 20 conserved piRNA clusters in multiple assemblies of four Drosophila species, we show that piRNA clusters are evolving rapidly. While 70%–80% of the clusters are conserved within species, the clusters share almost no similarity between species as closely related as D. melanogaster and D. simulans. Furthermore, abundant insertions and deletions are segregating within the Drosophila species. We show that the evolution of clusters is mainly driven by large insertions of recently active TEs and smaller deletions mostly in older TEs. The effect of these forces is so rapid that homologous clusters often do not contain insertions from the same TE families.
The natural, the fundamental, and the perfectly similar: Unraveling a metaphysical braid
Authors: Funkhouser Eric
Published: December 2021

Some of our most prominent metaphysicians have argued for a notion of naturalness that combines the roles of joint‐carving, fundamentality, and perfect similarity. This paper argues that it is a mistake to think that there are select properties fulfilling all these roles. Toward this end, epistemologically tractable diagnostic markers for naturalness are presented. From these it follows that there can be perfect naturalness and similarity at nonfundamental levels; and the fundamental need not be perfectly natural or yield perfect similarities. Metaphysicians of naturalness are encouraged to attend to insights from metaphysical property theory and the interdisciplinary study of patterns and complexity, both of which support these conclusions. Distinct metaphysical projects are distinguished.
Mechanism for the genomic and functional evolution of the MIR2118 family in the grass lineage
Authors: Lan Ting , Yang Xiaoyu , Chen Jiwei , Tian Peng , Shi Lina , Yu Yu , Liu Lin , Gao Lei , Mo Beixin , Chen Xuemei , Tang Guiliang
Published: December 2021

The MIR2118 family has undergone tremendous expansion in the grass lineage, in which the miRNA targets numerous noncoding PHAS loci to produce 21‐nt phased small interfering RNAs (phasiRNAs) involved in male fertility. However, the evolutionary trajectory of the grass MIR2118 genes and the functions of phasiRNAs have not yet been fully elucidated.

We conducted comparative genomic, molecular evolution, expression and parallel analysis of RNA ends (PARE) analyses of MIR2118 and the miR2118‐mediated regulatory pathway in grasses, focusing on Oryza sativa.

In total, 617 MIR2118 and eight MIR1859 novel members were identified. Phylogenetic analyses showed that grass MIR2118 genes form a distinct clade from the MIR482/2118 genes of nongrass species. We reconstructed hypothetical evolutionary histories of the grass MIR2118 clusters and its MIR1859 variants, and examined the polycistronic composition and the differential expression of the osa‐MIR2118 clusters. PARE data showed that osa‐miR2118 might also direct the cleavage of some protein‐coding gene transcripts. Importantly, we found that PARE analysis is inherently prone to false‐positive target predictions when a large number of small RNAs, such as phasiRNAs, are analysed.

Our results revealed the evolution and diversification of the MIR2118 family, and provide new insights into the functions of phasiRNAs in the grasses.
The Impact of Top Incomes Biases on the Measurement of Inequality in the United States
Authors: Hlasny Vladimir , Verme Paolo
Published: December 2021

The paper assesses how top incomes biases affect the estimation of income inequality in the United States using the Current Population Survey (the March Annual Social and Economic Supplement) and two alternative correction methods – a stochastic approach based on reweighting and a semi‐parametric approach based on replacing observations. Consistently with previous studies, both methods and their joint application show that income inequality in the United States between 1979 and 2014 has been consistently underestimated by several percentage points. The level of underestimation is positively and significantly associated with mean income, non‐response rates and the initial level of inequality. Reweighting is found to address top incomes biases – specifically those related to unit and item non‐response – consistently and more effectively than replacing, possibly because widely used parametric distributions do not represent US top incomes accurately.
Global Representation of the Conditional LATE Model: A Separability Result*
Authors: Chen Yu‐Chang , Xie Haitian
Published: December 2021

This paper studies the latent index representation of the conditional LATE model, making explicit the role of covariates in treatment selection. We find that if the directions of the monotonicity condition are the same across all values of the conditioning covariate, which is often assumed in the literature, then the treatment choice equation has to satisfy a separability condition between the instrument and the covariate. This global representation result establishes testable restrictions imposed on the way covariates enter the treatment choice equation. We later extend the representation theorem to incorporate multiple ordered levels of treatment.
Understanding pediatric ventilation in the operative setting. Part II: Setting perioperative ventilation
Authors: Spaeth Johannes , Schumann Stefan , Humphreys Susan
Published: December 2021

Approaches toward lung‐protective ventilation have increasingly been investigated in recent years. Despite evidence being found in adults undergoing surgery, data in younger children are still scarce and controversial. From a physiological perspective, however, the continuously changing characteristics of the respiratory system from birth through adolescence require an approach based on the analysis of each individual patient. The modern anesthesia workstation provides such information, with the technical strengths and weaknesses being discussed in a review preceding the present work (see Part I). The present summary aims to provide ideas on how to translate the information displayed on the anesthesia workstation to patient‐oriented clinical ventilation settings.
Sugammadex for reversal of neuromuscular blockade in pediatric patients: Results from a phase IV randomized study
Authors: Voss Tiffini , Wang Aobo , DeAngelis Matthew , Speek Marcel , Saldien Vera , Hammer Gregory B. , Wrishko Rebecca , Herring W. Joseph
Published: December 2021

Background

Few randomized studies have assessed recovery from rocuronium‐ or vecuronium‐induced moderate or deep neuromuscular blockade with sugammadex in pediatric participants.

Aim

To assess sugammadex for reversal of neuromuscular blockade in pediatric participants.

Methods

This was a randomized, phase IV, active comparator‐controlled, double‐blind study. Participants aged 2 to <17 years, under moderate or deep neuromuscular blockade, were administered sugammadex (2 or 4 mg/kg) or neostigmine (50 µg/kg; for moderate neuromuscular blockade only). Predefined adverse events of clinical interest, including clinically relevant bradycardia, hypersensitivity, and anaphylaxis, were monitored. The primary efficacy endpoint was time to recovery to a train‐of‐four ratio of ≥0.9 in participants receiving sugammadex 2 mg/kg versus neostigmine for reversal of moderate neuromuscular blockade, analyzed by analysis of variance adjusted for neuromuscular blocking agent and age.

Results

Of 288 randomized participants, 272 completed the study and 276 were included in the analyses. Clinically relevant bradycardia was experienced by 2.0%, 1.6%, and 5.9% of participants in the sugammadex 2 mg/kg, sugammadex 4 mg/kg, and neostigmine groups, respectively. No hypersensitivity or anaphylaxis events were observed. Recovery to a train‐of‐four ratio of ≥0.9 with sugammadex 2 mg/kg was faster than neostigmine (1.6 min, 95% CI 1.3 to 2.0 vs. 7.5 min, 95% CI 5.6 to 10.0; p < .0001) and was comparable to sugammadex 4 mg/kg (2.0 min, 95% CI 1.8 to 2.3).

Conclusions

Pediatric participants recovered from rocuronium‐ or vecuronium‐induced moderate neuromuscular blockade significantly faster with sugammadex 2 mg/kg than with neostigmine. Time to reversal of deep neuromuscular blockade with sugammadex 4 mg/kg was consistent with that of moderate neuromuscular blockade reversal. No meaningful differences in clinically relevant bradycardia, hypersensitivity, or anaphylaxis were seen with sugammadex vs neostigmine. These results support the use of sugammadex for reversal of moderate and deep rocuronium‐ and vecuronium‐induced neuromuscular blockade in patients aged 2 to <17 years.

Clinical Trial Registration: NCT03351608/EudraCT 2017‐000692‐92.
Effects of floor pattern on flight behaviour of the smaller tea tortrix, Adoxophyes honmai, during orientation flight in a sex pheromone plume
Authors: Miyamoto Ryusuke , Tabata Jun , Kainoh Yooichi
Published: December 2021

Insects control their flight toward a distant odour source by integrating multimodal sensory information, such as olfactory and visual information. Control of flight speed in orientation flight toward an odour source using visual patterning below has been observed in many species of moths. However, there are few reports about moth flight behaviour over solid‐coloured floors. To examine, which visual stimuli affect flight behaviour of moths, male smaller tea tortrix (Adoxophyes honmai) were released in a pheromone plume over two striped floors (longitudinal and transverse stripes) and two unpatterned floors (solid white and solid black). Flight behaviours were videotaped, and upwind flight speed, height (altitude) and the number of backward movements moths made as they approached the pheromone source were determined. Male moths significantly increased mean and maximum upwind flight speed over longitudinal stripes relative to their speed over transverse stripes. Their speed over a solid black floor was the fastest of all floor patterns tested. As males approached the pheromone source, their mean upwind speed decreased significantly over all floor patterns, except for the black floor. Fewer moths made backward movements over the black floor compared with the other three floors. In addition, male moths flew significantly higher over the white floor than over the other three floors, while 60–40 cm from the pheromone source. This is the first time that differences in moth flight behaviour over two patternless floors have been reported. These results suggest that orientation flight behaviour of male moths is affected not only by visual patterns, but also by the reflectance or reflected wavelength spectrum of the floor.
Synthetic Controls with Staggered Adoption
Authors: Ben-Michael Eli , Feller Avi , Rothstein Jesse
Published: December 2021

Staggered adoption of policies by different units at different times creates promising opportunities for observational causal inference. Estimation remains challenging, however, and common regression methods can give misleading results. A promising alternative is the synthetic control method (SCM), which finds a weighted average of control units that closely balances the treated unit’s pre-treatment outcomes. In this paper, we generalize SCM, originally designed to study a single treated unit, to the staggered adoption setting. We first bound the error for the average effect and show that it depends on both the imbalance for each treated unit separately and the imbalance for the average of the treated units. We then propose ‘partially pooled’ SCM weights to minimize a weighted combination of these measures; approaches that focus only on balancing one of the two components can lead to bias. We extend this approach to incorporate unit-level intercept shifts and auxiliary covariates. We assess the performance of the proposed method via extensive simulations and apply our results to the question of whether teacher collective bargaining leads to higher school spending, finding minimal impacts. We implement the proposed method in the augsynth R package.
How Do Women Learn They Are Pregnant? The Introduction of Clinics and Pregnancy Awareness in Nepal
Authors: Musse Isabel , Thornton Rebecca , Ghimire Dirgha
Published: December 2021

The earlier a woman learns about her pregnancy status, the sooner she can make decisions about her own and infant's health. This paper examines how women learn about their pregnancy status and measures how access to pregnancy tests affects earlier pregnancy knowledge. Using 10 years of individual‐level monthly panel data in Nepal, we find that, on average, women learn they are pregnant in their 4.6th month of pregnancy. Living approximately a mile further from a clinic offering pregnancy tests increases the time a woman knows she is pregnant by one week (5 percent increase) and decreases the likelihood of knowing in the first trimester by 4.5 percentage points (16 percent decrease). Women with prior pregnancies experience the most substantial effects of distance within the first two trimesters, while, for women experiencing their first pregnancy, distance does not affect knowledge. These results suggest that, while access to clinics can increase pregnancy awareness for women who recognize pregnancy symptoms, other complementary policies are needed to increase pregnancy awareness of women in their first pregnancy.
BRAF mutation status and its prognostic significance in 79 canine urothelial carcinomas: A retrospective study (2006–2019)
Authors: Gedon Julia , Kehl Alexandra , Aupperle‐Lellbach Heike , von Bomhard Wolf , Schmidt Jarno M.
Published: December 2021

Urothelial carcinoma (UC) is the most common tumour of the canine urinary bladder. Recently, BRAF mutation testing emerged as a diagnostic option, but its prognostic significance is unknown. This study investigates the relationship between BRAF (variant V595E) mutation status and overall survival in UC‐bearing dogs. Seventy‐nine patients histologically diagnosed with UC of the bladder and/or urethra between 2006 and 2019 were included in this retrospective single‐centre‐study. Treatment consisted of meloxicam (n = 39, group 1 ‘Melox’), mitoxantrone and meloxicam (+/− followed by metronomic chlorambucil; n = 23, group 2 ‘Chemo’) or partial cystectomy followed by meloxicam +/− mitoxantrone (n = 17, group 3 ‘Sx’). Survival was significantly influenced by treatment (p = .0002) and tumour location (p < .001) in both uni‐ and multivariable analyses. BRAF mutation was identified in 51 tumours (=64.6%) and had no statistically significant influence on overall survival: MST for BRAF‐negative patients 359 versus 214 days for BRAF‐positive dogs (p = .055). However, in BRAF‐positive dogs, survival depended significantly on type of treatment in univariable analysis: MSTs for groups 1–3 were 151, 244 and 853 days, respectively (p = .006); In BRAF‐positive group 2 (‘Chemo’)‐patients, adjuvant metronomic chlorambucil after mitoxantrone more than doubled MST compared to patients receiving mitoxantrone alone (588 vs. 216 days; p = .030). In contrast, MSTs were not significantly different in BRAF‐negative patients among the three treatment groups (p = .069). Multivariate analysis of these data was not possible due to group size limitations. This study identified tumour location and treatment type, but not BRAF mutation status, as independent prognostic factors for overall survival.
Outcome in dogs with curative‐intent treatment of localized primary pulmonary histiocytic sarcoma
Authors: Murray Caroline A. , Willcox Jennifer L. , De Mello Souza Carlos H. , Husbands Brian , Cook Matthew R. , Clifford Craig , Leeper Haley , Pellin MacKenzie , Richardson Danielle , Herrera Chamisa L. , Krick Erika , McMillan Sarah , Al‐Nadaf Sami , Skorupski Katherine A.
Published: December 2021

Primary pulmonary histiocytic sarcoma (PHS) is a rare form of dendritic cell or macrophage neoplasia originating within the pulmonary parenchyma. There is limited literature describing prognosis in dogs with PHS receiving curative‐intent treatment consisting of surgical excision and adjuvant chemotherapy. The primary objective of this study was to report outcomes in dogs with localized PHS treated with standardized local and systemic therapy. A secondary objective was to identify prognostic factors in this population. A multi‐institutional retrospective study was performed and medical records including all surgical and histopathologic reports were retrospectively reviewed. For inclusion, dogs were required to have confirmed localized PHS and they must have undergone curative‐intent surgery with resection of all gross primary tumour and enlarged tracheobronchial lymph nodes; additionally, they must have received curative‐intent treatment with adjuvant single‐agent CCNU chemotherapy. Twenty‐seven dogs from six veterinary teaching hospitals and five private practices treated from 2008–2019 were included. The overall median survival time was 432 days. Higher CCNU dose was demonstrated to have a negative impact on survival on univariate, but not multivariable, analysis. Factors that were not found to be associated with survival on univariate analysis included body weight, breed, clinical signs at the time of diagnosis, hypoalbuminaemia, tumour size, lung lobe affected, lymph node metastasis, surgical margins and CCNU dose reductions. This study supports a favourable prognosis for dogs diagnosed with localized PHS treated with curative‐intent surgery in addition to adjuvant CCNU chemotherapy and suggests that multimodal treatment may be advisable to attempt to prolong survival.
Development and Validation of a Design Tool for an Improved Pitot-Tube Jet-Pump Allowing Continuous Fluid-Fluid Separation
Authors: von Deylen Jan , Köpplin J. , Thévenin D.
Published: December 2021

A pitot-tube jet-pump (PTJ pump) has been considerably modified and extended in order to continuously separate and transport liquids of different densities. As a first application, an oil–water mixture is considered in this work. The modified PTJ pump could be used as a primary separator for oil-polluted water (e.g., around off-shore platforms, after oil spills from ships), while additionally being able to transport the resulting fluid to further heaters, exchangers, centrifuges, distillation columns, etc., without necessitating additional machinery. The performance behavior of the separating PTJ pump (abbreviated SPP in what follows) has been first investigated with computational fluid dynamics (CFD), and then validated by comparison with experimental data acquired on a small-scale prototype. Based on these observations, a design tool has been developed to (i) predict performance and (ii) support proper device scaling. This tool is based on dimensionless parameters that are already employed for classical turbomachinery, similar to the Cordier chart. However, since the SPP works at an extremely low specific speed, its operating points lie outside the standard Cordier chart. To verify the accuracy of the design tool, a scale-up test has been conducted and validated by CFD, delivering a good agreement. A separation efficiency better than 99% has been obtained in the experiments for suitable operation conditions, while the numerical scale-up test reveals a head of 15.1 m and an oil content below 0.2% in the purified water at the high-pressure outlet.
Do Older Brazilian Women Who Participate in a Regular Physical Exercise Program Have Higher Habitual Physical Activity Levels? A Cross-Sectional Study Based on Accelerometer Data
Authors: Pinhal Kaio Cesar , Moreira Bruno de Souza , Vieira Renata Alvarenga , Alcântara Marcus Alessandro , Dias João Marcos Domingues , Dias Rosângela Correa , Kirkwood Renata Noce , Bastone Alessandra de Carvalho
Published: December 2021

A cross-sectional study was conducted to compare the habitual physical activity level, measured by accelerometry, gait performance, assessed by the GAITRite® system, handgrip strength, and static balance between older Brazilian women who participate (n = 50; 70.7 ± 5.5 years) and do not participate (n = 50; 70.1 ± 5.6 years) in a regular physical exercise program, and to investigate whether participation in a regular exercise program ensures compliance with physical activity recommendations. Older women who participated in a regular physical exercise program had significantly shorter sedentary activity time (effect size [ES] = 0.54), longer moderate activity time (ES = 0.85), and higher energy expenditure (ES = 0.64), number of steps (ES = 0.82), gait speed (ES = 0.49), and step length (ES = 0.45). However, regular participation in an exercise program did not guarantee compliance with physical activity recommendations. Behavioral changes to increase physical activity levels among older women who do and do not participate in a regular exercise program are necessary.
The Role of Physical Activity and Depression on Quality of Life in Community-Dwelling Older Adults: Using Propensity Score Matching Approaches
Authors: Bae Suyeong , Pappadis Monique R. , Nam Sanghun , Hong Ickpyo
Published: December 2021

This study examined the association between achieving the recommended physical activity level and quality of life after controlling for depression. Health information from adults aged 65 years and older, who had participated in the seventh 2018 Korea National Health and Nutrition Examination Survey, was used. Five covariate adjustment models were used to derive robust estimates of the association between physical activity practice levels, depression, and older adults’ quality of life. A total of 1,336 older adults was extracted from the seventh 2018 Korea National Health and Nutrition Examination Survey, and 31% of the older adults achieved the recommended physical activity level, whereas 69% did not. We found that the achievement of physical activity practice levels is significantly associated with the quality of life of the older adults (β = 0.024–0.031, all p < .05). Our results could be used for advocating for welfare policy changes that promote physical activity to prepare for the upcoming super-aging society.
Sleep onset is a creative sweet spot
Authors: Lacaux Célia , Andrillon Thomas , Bastoul Céleste , Idir Yannis , Fonteix-Galet Alexandrine , Arnulf Isabelle , Oudiette Delphine
Published: December 2021

A single minute of sleep onset is sufficient to boost the probability of insight by a factor of three compared to wake.
Scaling of mortality in 742 metropolitan areas of the Americas
Authors: Bilal Usama , de Castro Caio P. , Alfaro Tania , Barrientos-Gutierrez Tonatiuh , Barreto Mauricio L. , Leveau Carlos M. , Martinez-Folgar Kevin , Miranda J. Jaime , Montes Felipe , Mullachery Pricila , Pina Maria Fatima , Rodriguez Daniel A. , dos Santos Gervasio F. , Andrade Roberto F. S. , Diez Roux Ana V.
Published: December 2021

The scaling of mortality in cities of the Americas varies widely by cause and region.
Realization of a coupled-mode heat engine with cavity-mediated nanoresonators
Authors: Sheng Jiteng , Yang Cheng , Wu Haibin
Published: December 2021

Both single-cylinder and straight-twin nanomechanical heat engines are implemented in the cavity-mediated nanomembranes.
The exercise-induced long noncoding RNA
CYTOR
promotes fast-twitch myogenesis in aging
Authors: Wohlwend Martin , Laurila Pirkka-Pekka , Williams Kristine , Romani Mario , Lima Tanes , Pattawaran Pattamaprapanont , Benegiamo Giorgia , Salonen Minna , Schneider Bernard L. , Lahti Jari , Eriksson Johan G. , Barrès Romain , Wisløff Ulrik , Moreira José B. N. , Auwerx Johan
Published: December 2021

Exercise activates the lncRNA
Cytor
, which reestablishes fast-twitch muscle fibers in aged skeletal muscle, improving morphology and function.
Prevalence of intratumoral regulatory T cells expressing neuropilin-1 is associated with poorer outcomes in patients with cancer
Authors: Chuckran Christopher A. , Cillo Anthony R. , Moskovitz Jessica , Overacre-Delgoffe Abigail , Somasundaram Ashwin S. , Shan Feng , Magnon Grant C. , Kunning Sheryl R. , Abecassis Irina , Zureikat Amer H. , Luketich James , Pennathur Arjun , Sembrat John , Rojas Mauricio , Merrick Daniel T. , Taylor Sarah E. , Orr Brian , Modugno Francesmary , Buckanovich Ron , Schoen Robert E. , Kim Seungwon , Duvvuri Umamaheswar , Zeh Herbert , Edwards Robert , Kirkwood John M. , Coffman Lan , Ferris Robert L. , Bruno Tullia C. , Vignali Dario A. A.
Published: December 2021

Persistent T cell receptor stimulation drives neuropilin-1 on intratumoral regulatory T cells, which is associated with poor clinical outcome.
Glycosylation of ALV-J Envelope Protein at Sites 17 and 193 Is Pivotal in the Virus Infection
Authors: Xu Moru , Qian Kun , Shao Hongxia , Yao Yongxiu , Nair Venugopal , Ye Jianqiang , Qin Aijian
Published: December 2021

ALV-J is a retrovirus that can cause multiple types of tumors in chickens. Among all the viral proteins, the heavily glycosylated envelope protein is especially crucial.
Human Herpesvirus 6A U4 Inhibits Proteasomal Degradation of the Amyloid Precursor Protein
Authors: Tang Tian , Jia Junli , Garbarino Emanuela , Chen Luyao , Ma Jingjing , Li Peipei , Chen Xiangjun , Wang Lily , Wen Yiqun , Wang Yuhang , Li Lingyun , Yao Kun , Tang Huamin
Published: December 2021

The association of HHV-6A infection with Alzheimer’s disease has attracted increasing attention, although its role and molecular mechanism remain to be established. Our results here indicate that HHV-6A U4 inhibits amyloid precursor protein (APP) degradation.
Epigenetic Silencing of Recombinant Adeno-associated Virus Genomes by NP220 and the HUSH Complex
Authors: Das Anshuman , Vijayan Madhuvanthi , Walton Eric M. , Stafford V. Grace , Fiflis David N. , Asokan Aravind
Published: December 2021

Recombinant AAV vectors can enable long-term gene expression in a wide variety of tissues. However, transgene silencing has been reported in some human gene therapy clinical trials. Here, we demonstrate the HUSH complex can suppress transcript formation from rAAV vector genomes by epigenetic modification of associated host histones. Further, the AAV capsid appears to play an important role in this pathway. We postulate that modulation of epigenetic pathways could help improve rAAV expression.
The Facts and Family Secrets of Plasmids That Replicate via the Rolling-Circle Mechanism
Authors: Garcillán-Barcia M. Pilar , Pluta Radoslaw , Lorenzo-Díaz Fabián , Bravo Alicia , Espinosa Manuel
Published: December 2021

Plasmids are self-replicative DNA elements that are transferred between bacteria. Plasmids encode not only antibiotic resistance genes but also adaptive genes that allow their hosts to colonize new niches.
O
-Acetylation of Capsular Polysialic Acid Enables
Escherichia coli
K1 Escaping from Siglec-Mediated Innate Immunity and Lysosomal Degradation of
E. coli
-Containing Vacuoles in Macrophage-Like Cells
Authors: Yang Jinghua , Ma Wei , Wu Yuanyuan , Zhou Hui , Song Siyu , Cao Yuqi , Wang Chengxu , Liu Xiangyuan , Ren Jinwei , Duan Jinyou , Pei Zhichao , Jin Cheng
Published: December 2021

Escherichia coli
K1 is a leading cause of neonatal meningitis. The mortality and morbidity of this disease remain significantly high despite antibiotic therapy.
Plasmodium falciparum and Helminth Coinfections Increase IgE and Parasite-Specific IgG Responses
Authors: Santano Rebeca , Rubio Rocío , Grau-Pujol Berta , Escola Valdemiro , Muchisse Osvaldo , Cuamba Inocência , Vidal Marta , Cisteró Pau , Ruiz-Olalla Gemma , Aguilar Ruth , Demontis Maria , Jamine Jose Carlos , Cossa Anélsio , Sacoor Charfudin , Cano Jorge , Izquierdo Luis , Chitnis Chetan E. , Coppel Ross L. , Chauhan Virander , Cavanagh David , Dutta Sheetij , Angov Evelina , Gaur Deepak , van Lieshout Lisette , Zhan Bin , Muñoz Jose , Moncunill Gemma , Dobaño Carlota
Published: December 2021

Coinfection withPlasmodium falciparumand helminths may impact the immune response to these parasites because they induce different immune profiles. We compared the antibody profile between groups of Mozambican individuals defined byP. falciparumand helminth previous exposure and/or current infection.
Minimum Inhibitory Concentrations before and after Antibacterial Treatment in Patients with Mycobacterium abscessus Pulmonary Disease
Authors: Fujiwara Keiji , Uesugi Fumiko , Furuuchi Koji , Tanaka Yoshiaki , Yoshiyama Takashi , Saotome Mikio , Ohta Ken , Mitarai Satoshi , Morimoto Kozo
Published: December 2021

The MICs of isolates from 86 patients with
Mycobacterium abscessus
(MABS); 46 with
Mycobacterium abscessus
subsp.
abscessus
(Mab), and 40 with
Mycobacterium abscessus
subsp.
massiliense
(Mma) were retrospectively analyzed. The main findings are as follows: i) Mma were significantly more susceptible to clarithromycin and azithromycin than Mab, and both subspecies tended to be more susceptible to clarithromycin than azithromycin. ii) Most isolates were susceptible to amikacin (93.0%), and over half to linezolid (55.8%). iii) Fifty-one isolates (59.3%) had MIC values of less than 1 μg/mL for sitafloxacin, and 65 (75.6%) had less than 0.5 μg/mL for clofazimine, which seems worth clinical investigating. iv) Among nine cases analyzed chronological changes, only two patients showed obvious MIC result changes even after the long-term multidrug treatment.
AdpA Positively Regulates Morphological Differentiation and Chloramphenicol Biosynthesis in Streptomyces venezuelae
Authors: Płachetka Małgorzata , Krawiec Michał , Zakrzewska-Czerwińska Jolanta , Wolański Marcin
Published: December 2021

Streptomyces are well-known producers of valuable secondary metabolites which include a large variety of antibiotics and important model organisms for developmental studies in multicellular bacteria. The conserved transcriptional regulator AdpA of
Streptomyces
exerts a pleiotropic effect on cellular processes, including the morphological differentiation and biosynthesis of secondary metabolites.
Incidence and mortality of uveal melanoma in Australia (1982–2014)
Authors: Beasley Aaron B , Preen David B , McLenachan Samuel , Gray Elin S , Chen Fred K
Published: December 2021

Aims

We aimed to estimate the incidence and mortality of uveal melanoma (UM) in Australia from 1982 to 2014.

Methods

Deidentified unit data for all cases of ocular melanoma were extracted from the Australian Cancer Database from 1 January 1982 to 31 December 2014. UM cases were extracted and trends in incidence and disease-specific mortality were calculated. Incidence rates were age-standardised against the 2001 Australian Standard Population. Mortality was assessed using Cox regression.

Results

From 1982 to 2014, there were 5087 cases of ocular melanoma in Australia, of which 4617 were classified as UM. The average age-standardised incidence rate of UM was 7.6 (95% CI 7.3 to 7.9) per million. There was an increase (p=0.0502) in the incidence of UM from 1982 to 1993 with an annual percent change (APC) of +2.5%, followed by a significant decrease in the incidence of UM from 1993 to 2014 (APC −1.2%). The average 5-year survival from 1982 to 2011 did not significantly change from an average of 81%, with an average APC (AAPC) of +0.1%. A multivariate Cox regression revealed that residence in Western Australia (p=0.001) or Tasmania (p=0.05), age ≥60 years (p<0.001) and histological classification as mixed (p<0.001) or epithelioid cells (p<0.001) were significantly associated with reduced survival.

Conclusion

In conclusion, we found that the incidence of UM peaked in the 1990s. Although treatment for primary UM has improved in the last 30 years, overall survival did not change significantly in the last 30 years.