bluuebunny/crossref_metadata_2025 huggingface dataset:
212Dose-response association and interaction between physical activity and sedentary time on premature rupture of membranes
Authors: Zhan Yongle , Jiang Yu
Published: September 2021

Background

Premature rupture of membranes (PROM) is a common pregnancy complication with multifactorial etiology. However, associations between physical activity (PA) and PROM are still unclear. Therefore, this study aims to explore the dose-response relationship and interactions between PA frequency, sedentary time (ST) and PROM.

Methods

Data on 6848 pregnant women were obtained from the Chinese Pregnant Women Cohort Study. Participants were recruited from July 2017 to November 2018 and were followed up until delivery. The International Physical Activity Questionnaire-Short Form was used to assess the frequency of PA and ST. Logistic regression and restricted cubic spline (RCS) model were used for data analyses.

Results

Women with frequencies of over 4 days/week of moderate-intensity PA (OR:1.50, 95%CI:1.01∼2.23) and light-intensity PA (OR:1.19, 95%CI:1.04∼1.37) had higher risks of PROM respectively. The RCS model showed that the risk for PROM was significant with frequencies of over 2 days/week of vigorous-intensity PA, over 5 days/week of moderate-intensity PA or over 5 days/week of light-intensity PA (ORs with 95%CI >1). Interactions analyses showed that risks for PROM increased with frequencies of moderate-intensity and light-intensity PA both over 4 days/week (OR:1.80, 95%CI:1.17∼2.77), or with a frequency of light-intensity PA of over 4 days/week and ST of over 6 hours/day (OR:1.36, 95%CI:1.10∼1.69).

Conclusions

It is necessary to propose a suitable recommendation of frequency and intensity of PA, and identify and propose the corresponding intervention ways to reduce and prevent PROM occurrence during pregnancy.

Key messages

There is a dose-response relationship and interaction between PA and ST on PROM.
1506Flexible parametric survival models investigating factors associated with diabetes-related foot ulcer time-to-healing
Authors: Zhang Yuqi , Cramb Susanna , McPhail Steven , Pacella Rosana , van Netten Jaap , Cheng Qinglu , Derhy Patrick , Kinnear Ewan , Lazzarini Peter
Published: September 2021

Background

Diabetes-related foot ulcers (DFU) take months to heal, reduce patient’s quality-of-life, and induce large healthcare expenditure. Various factors have been identified to influence DFU healing at fixed periods, however, data on factors associated with time-to-healing is scarce.

Methods

Patients presenting with DFU to Diabetic Foot Services across Queensland, Australia between July 2011 and December 2017 were included and had their demographics, disease history and treatments examined at baseline. Outcome of interest was healing of all ulcers within two-year follow-up time. Time-to-healing and associated factors were examined using flexible parametric survival models, which easily enabled including time-varying coefficients and predicting proportions healed.

Results

Of 4,709 included patients (median age 63 years, 69.5% male, 10.5% Indigenous), median time-to-healing was 112 days, and 68% healed within two years. Younger age (<60 years), geographical remoteness, smoking, neuropathy, deep ulcers, infection, not receiving offloading, and no recent podiatry treatment were independently associated with longer time-to-healing. Time-varying effects of peripheral artery disease and ulcer size were identified for the first time: both had a negative influence on healing with effects diminishing after six months. The predicted proportions healed, for example, within six months is 65.0% (63.3-66.7) for people residing in a major city, 54.6% (52.6-56.8) in regional area, and 40.3% (34.6-47.1) in remote area.

Conclusions

This study identified novel and confirmatory factors influencing time-to-healing over 24 months in a large real-world cohort of people with diabetes-related foot ulcers. Visualizing the adjusted predicted proportion healed revealed the influence each factor had on healing rates over time.

Key messages

Flexible parametric survival model provided flexibility in investigating time-varying effects and outcome prediction in those with diabetes-related foot ulcer healing.
An Artificial Intelligence System for the Detection of Bladder Cancer via Cystoscopy: A Multicenter Diagnostic Study
Authors: Wu Shaoxu , Chen Xiong , Pan Jiexin , Dong Wen , Diao Xiayao , Zhang Ruiyun , Zhang Yonghai , Zhang Yuanfeng , Qian Guang , Chen Hao , Lin Haotian , Xu Shizhong , Chen Zhiwen , Zhou Xiaozhou , Mei Hongbing , Wu Chenglong , Lv Qiang , Yuan Baorui , Chen Zeshi , Liao Wenjian , Yang Xuefan , Chen Haige , Huang Jian , Lin Tianxin
Published: September 2021

Background

Cystoscopy plays an important role in bladder cancer (BCa) diagnosis and treatment, but its sensitivity needs improvement. Artificial intelligence has shown promise in endoscopy, but few cystoscopic applications have been reported. We report a Cystoscopy Artificial Intelligence Diagnostic System (CAIDS) for BCa diagnosis.

Methods

In total, 69 204 images from 10 729 consecutive patients from 6 hospitals were collected and divided into training, internal validation, and external validation sets. The CAIDS was built using a pyramid scene parsing network and transfer learning. A subset (n = 260) of the validation sets was used for a performance comparison between the CAIDS and urologists for complex lesion detection. The diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values and 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method.

Results

The diagnostic accuracies of the CAIDS were 0.977 (95% CI = 0.974 to 0.979) in the internal validation set and 0.990 (95% CI = 0.979 to 0.996), 0.982 (95% CI = 0.974 to 0.988), 0.978 (95% CI = 0.959 to 0.989), and 0.991 (95% CI = 0.987 to 0.994) in different external validation sets. In the CAIDS vs urologists’ comparisons, the CAIDS showed high accuracy and sensitivity (accuracy = 0.939, 95% CI = 0.902 to 0.964; sensitivity = 0.954, 95% CI = 0.902 to 0.983) with a short latency of 12 seconds, much more accurate and quicker than the expert urologists.

Conclusions

The CAIDS achieved accurate BCa detection with a short latency. The CAIDS may provide many clinical benefits, from increasing the diagnostic accuracy for BCa, even for commonly misdiagnosed cases such as flat cancerous tissue (carcinoma in situ), to reducing the operation time for cystoscopy.
The value of alien roadside trees for epiphytic lichen species along an urban pollution gradient
Authors: Möller Theresa , Oldeland Jens , Schultz Matthias
Published: September 2021

Alien tree species have been introduced to Europe and often used as roadside trees. Currently, preference is given to species that are adapted to urban climate and drier conditions. Native epiphytic lichens are adapted to local tree species; however, little is known whether a shift toward more alien roadside trees would affect the diversity of epiphytic lichens within cities. We considered three genera of roadside trees that are common in Hamburg (Germany) Acer, Tilia, and Quercus, each with a native and an alien species per genus. Species numbers, frequency and diversity of epiphytic lichens were assessed and compared. Tree locations were grouped according to three classes of increasing traffic volume as a proxy for air pollution. Mean bark pH values have been recorded for each tree individual. The species pairs Quercus robur/rubra and Acer platanoides/saccharinum showed significant differences in the diversity and abundance of lichens, with the alien species showing lower values. The species pair Tilia cordata/tomentosa did not show any significant differences. The number of nitrogen-tolerant lichen species differed little among all tree species. Lichen species richness decreased with increasing traffic volume for all tree species pairs, thus demonstrating the inhibiting effect of traffic on the occurrence of lichens. Bark pH differed little between the species pairs yet high traffic volume resulted in an increased bark pH. In conclusion, two out of three alien species had negative effects on lichen diversity. Further tree species should be assessed to better estimate the effect of alien roadside trees on lichen diversity.
A Tale of Two Bridges: The Poetry and Politics of Infrastructure in Nineteenth-Century Wales
Authors: Koehler Karin
Published: September 2021

Drawing on Brian Larkin’s concept of ‘infrastructural poetics’, this article considers and compares a selection of English- and Welsh-language poems, by writers including Eliza Mary Hamilton, Frederick Faber, Richard Llwyd, and Eben Fardd, about two nineteenth-century infrastructures that transformed North Wales and Great Britain’s relationship to Ireland: the Menai Suspension Bridge (1826), and the Britannia Tubular Bridge (1850). I argue that these non-canonical poems complement perspectives derived from parliamentary records, official reports, technical planning documents, scientific manuals, and journalism, enhancing our understanding of the nineteenth-century infrastructural imagination. Specifically, building on the association of infrastructural development and modernity, I explore how the poems under discussion participate in nineteenth-century negotiations about Wales’s place and future in the United Kingdom, and how these negotiations evolved between 1819 and 1852. I show that, although Wales was the site of impressive engineering feats and accelerating industrial extraction, English-language poems present the Menai Bridge in picturesque terms, drawing on popular images of the Celtic fringe that evoke timeless, ideal beauty. Anglophone verse about Britannia Bridge, by contrast, focuses explicitly on the infrastructure’s technological modernity but claims it as an English landmark. Both strategies, I suggest, effect an erasure of Wales – as a distinct cultural and political entity – from a future conceived as Anglo-British. Poems written in Welsh, and the work of Welsh writers in English, complicate this picture, not because they reject British nationalism and imperialism, but because they seek to embed a modern Welsh nation more centrally within those political and ideological frameworks.
Accelerated expansion induced by dark matter with two charges
Authors: Hansen Steen H
Published: September 2021

The accelerated expansion of the Universe has been established through observations of supernovae, the growth of structure, and the cosmic microwave background. The most popular explanation is Einstein's cosmological constant, or dynamic variations hereof. A recent paper demonstrated that if dark matter particles are endowed with a repulsive force proportional to the internal velocity dispersion of galaxies, then the corresponding acceleration of the Universe may follow that of a cosmological constant fairly closely. However, no such long-range force is known to exist. A concrete example of such a force is derived here, by equipping the dark matter particles with two new dark charges. This result lends support to the possibility that the current acceleration of the Universe may be explained without the need for a cosmological constant.
Rituximab and mepolizumab combination therapy for glucocorticoid-resistant myocarditis related to eosinophilic granulomatosis with polyangiitis
Authors: Higashitani Kana , Yoshimi Ryusuke , Sato Yuichiro , Watanabe Toshiyuki , Ihata Atsushi
Published: September 2021

Eosinophilic granulomatosis with polyangiitis (EGPA), which belongs to the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides, is characterised by eosinophil-rich granulomatous inflammation and small- to medium-sized vessel vasculitis associated with bronchial asthma and eosinophilia. It sometimes causes severe organ damage, of which myocardial damage is one of the most important for determining the prognosis. A case of EGPA-associated myocarditis that was refractory to glucocorticoid therapy and responded successfully to rituximab (RTX) and mepolizumab (MPZ) combination therapy is presented. A 46-year-old woman was diagnosed with EGPA-associated myocarditis due to pre-existing asthma, eosinophilia, mononeuritis multiplex, and eosinophilic myocarditis by myocardial biopsy. Transthoracic echocardiography showed thickening of the cardiac wall, pericardial effusion, and left ventricular hypokinesis. Although the myocarditis was refractory to methylprednisolone pulse therapy followed by oral high-dose prednisolone, the disease activity reached remission with the successful tapering of glucocorticoid after initiation of the RTX and MPZ combination therapy. Combination therapy with RTX and MPZ can be a good treatment option for EGPA-associated myocarditis for which it is difficult to give intravenous cyclophosphamide due to cardiac dysfunction.
Zinc trafficking 1. Probing the roles of proteome, metallothionein, and glutathione
Authors: Mahim Afsana , Karim Mohammad , Petering David H
Published: September 2021

The cellular trafficking pathways that conduct zinc to its sites of binding in functional proteins remain largely unspecified. In this study, the hypothesis was investigated that nonspecific proteomic binding sites serve as intermediates in zinc trafficking. Proteome from pig kidney LLC-PK1 cells contains a large concentration of such sites, displaying an average conditional stability constant of 1010-11, that are dependent on sulfhydryl ligands to achieve high-affinity binding of zinc. As a result, the proteome competes effectively with induced metallothionein for Zn2+ upon exposure of cells to extracellular Zn2+ or during in vitro direct competition. The reaction of added Zn2+ bound to proteome with apo-carbonic anhydrase was examined as a potential model for intracellular zinc trafficking. The extent of this reaction was inversely dependent upon proteome concentration and under cellular conditions thought to be negligible. The rate of reaction was strictly first order in both Zn2+ and apo-carbonic anhydrase, and also considered to be insignificant in cells. Adding the low molecular weight fraction of cell supernatant to the proteome markedly enhanced the speed of this reaction, a phenomenon dependent on the presence of glutathione (GSH). In agreement, inclusion of GSH accelerated the reaction in a concentration-dependent manner. The implications of abundant high-affinity binding sites for Zn2+ within the proteome are considered in relation to their interaction with GSH in the efficient delivery of Zn2+ to functional binding sites and in the operation of fluorescent zinc sensors as a tool to observe zinc trafficking.
Whole-exome sequencing identifiesFOXL2,FOXA2andFOXA3as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract
Authors: Zheng Bixia , Seltzsam Steve , Wang Chunyan , Schierbaum Luca , Schneider Sophia , Wu Chen-Han Wilfred , Dai Rufeng , Connaughton Dervla M , Nakayama Makiko , Mann Nina , Stajic Natasa , Mane Shrikant , Bauer Stuart B , Tasic Velibor , Nam Hyun Joo , Shril Shirlee , Hildebrandt Friedhelm
Published: September 2021

Background

Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidneys, may also represent monogenic causes of CAKUT.

Methods

We here performed whole-exome sequencing (WES) in 541 families with CAKUT and generated four lists of CAKUT candidate genes: (A) 36 FOX genes showing high expression during renal development, (B) 4 FOX genes known to cause CAKUT to validate list A, (C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families and (D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes.

Results

To prioritize potential novel CAKUT candidates in the FOX gene family, we overlapped 36 FOX genes (list A) with lists C and D of WES-derived CAKUT candidates. Intersection with list C identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals.

Conclusions

We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.
Climate change and nephrology
Authors: Sasai Fumihiko , Roncal-Jimenez Carlos , Rogers Keegan , Sato Yuka , Brown Jared M , Glaser Jason , Garcia Gabriela , Sanchez-Lozada Laura Gabriela , Rodriguez-Iturbe Bernardo , Dawson Jaime Butler , Sorensen Cecilia , Hernando Ana Andres , Gonzalez-Quiroz Marvin , Lanaspa Miguel , Newman Lee S , Johnson Richard J
Published: September 2021

Climate change should be of special concern for the nephrologist, as the kidney has a critical role in protecting the host from dehydration, but it is also a favorite target of heat stress and dehydration. Here we discuss how rising temperatures and extreme heat events may affect the kidney. The most severe presentation of heat stress is heat stroke, which can result in severe electrolyte disturbance and both acute and chronic kidney disease (CKD). However, lesser levels of heat stress also have multiple effects, including exacerbating kidney disease and precipitating cardiovascular events in subjects with established kidney disease. Heat stress can also increase the risk for kidney stones, cause multiple electrolyte abnormalities and induce both acute and chronic kidney disease. Recently there have been multiple epidemics of CKD of uncertain etiology in various regions of the world, including Mesoamerica, Sri Lanka, India and Thailand. There is increasing evidence that climate change and heat stress may play a contributory role in these conditions, although other causes, including toxins, could also be involved. As climate change worsens, the nephrologist should prepare for an increase in diseases associated with heat stress and dehydration.
Telomerase as a therapeutic target in glioblastoma
Authors: Aquilanti Elisa , Kageler Lauren , Wen Patrick Y , Meyerson Matthew
Published: September 2021

Glioblastoma is the most common primary malignant brain tumor in adults and it continues to have a dismal prognosis. The development of targeted therapeutics has been particularly challenging, in part due to a limited number of oncogenic mutations and significant intra-tumoral heterogeneity. TERT promoter mutations were first discovered in melanoma and later found to be present in up to 80% of glioblastoma samples. They are also frequent clonal alterations in this tumor. TERT promoter mutations are one of the mechanisms for telomerase reactivation, providing cancers with cellular immortality. Telomerase is a reverse transcriptase ribonucleoprotein complex that maintains telomere length in cells with high proliferative ability. In this article, we present genomic and pre-clinical data that support telomerase as a potential “Achilles’ heel” for glioblastoma. We also summarize prior experience with anti-telomerase agents and potential new approaches to tackle this target.
Co-targeting strategy for precise, scarless gene editing with CRISPR/Cas9 and donor ssODNs in Chlamydomonas
Authors: Akella Soujanya , Ma Xinrong , Bacova Romana , Harmer Zachary P , Kolackova Martina , Wen Xiaoxue , Wright David A , Spalding Martin H , Weeks Donald P , Cerutti Heriberto
Published: September 2021

Programmable site-specific nucleases, such as the clustered regularly interspaced short palindromic repeat (CRISPR)/ CRISPR-associated protein 9 (Cas9) ribonucleoproteins (RNPs), have allowed creation of valuable knockout mutations and targeted gene modifications in Chlamydomonas (Chlamydomonas reinhardtii). However, in walled strains, present methods for editing genes lacking a selectable phenotype involve co-transfection of RNPs and exogenous double-stranded DNA (dsDNA) encoding a selectable marker gene. Repair of the dsDNA breaks induced by the RNPs is usually accompanied by genomic insertion of exogenous dsDNA fragments, hindering the recovery of precise, scarless mutations in target genes of interest. Here, we tested whether co-targeting two genes by electroporation of pairs of CRISPR/Cas9 RNPs and single-stranded oligodeoxynucleotides (ssODNs) would facilitate the recovery of precise edits in a gene of interest (lacking a selectable phenotype) by selection for precise editing of another gene (creating a selectable marker)—in a process completely lacking exogenous dsDNA. We used PPX1 (encoding protoporphyrinogen IX oxidase) as the generated selectable marker, conferring resistance to oxyfluorfen, and identified precise edits in the homolog of bacterial ftsY or the WD and TetratriCopeptide repeats protein 1 genes in ∼1% of the oxyfluorfen resistant colonies. Analysis of the target site sequences in edited mutants suggested that ssODNs were used as templates for DNA synthesis during homology directed repair, a process prone to replicative errors. The Chlamydomonas acetolactate synthase gene could also be efficiently edited to serve as an alternative selectable marker. This transgene-free strategy may allow creation of individual strains containing precise mutations in multiple target genes, to study complex cellular processes, pathways, or structures.
R2R3-MYB genes coordinate conical cell development and cuticular wax biosynthesis in Phalaenopsis aphrodite
Authors: Lu Hsiang-Chia , Lam Sio-Hong , Zhang Diyang , Hsiao Yu-Yun , Li Bai-Jun , Niu Shan-Ce , Li Chia-Ying , Lan Siren , Tsai Wen-Chieh , Liu Zhong-Jian
Published: September 2021

Petals of the monocot Phalaenopsis aphrodite (Orchidaceae) possess conical epidermal cells on their adaxial surfaces, and a large amount of cuticular wax is deposited on them to serve as a primary barrier against biotic and abiotic stresses. It has been widely reported that subgroup 9A members of the R2R3-MYB gene family, MIXTA and MIXTA-like in eudicots, act to regulate the differentiation of conical epidermal cells. However, the molecular pathways underlying conical epidermal cell development and cuticular wax biosynthesis in monocot petals remain unclear. Here, we characterized two subgroup 9A R2R3-MYB genes, PaMYB9A1 and PaMYB9A2 (PaMYB9A1/2), from P. aphrodite through the transient overexpression of their coding sequences and corresponding chimeric repressors in developing petals. We showed that PaMYB9A1/2 function to coordinate conical epidermal cell development and cuticular wax biosynthesis. In addition, we identified putative targets of PaMYB9A1/2 through comparative transcriptome analyses, revealing that PaMYB9A1/2 acts to regulate the expression of cell wall-associated and wax biosynthetic genes. Furthermore, a chemical composition analysis of cuticular wax showed that even-chain n-alkanes and odd-chain primary alcohols are the main chemical constituents of cuticular wax deposited on petals, which is inconsistent with the well-known biosynthetic pathways of cuticular wax, implying a distinct biosynthetic pathway occurring in P. aphrodite flowers. These results reveal that the function of subgroup 9A R2R3-MYB family genes in regulating the differentiation of epidermal cells is largely conserved in monocots and dicots. Furthermore, both PaMYB9A1/2 have evolved additional functions controlling the biosynthesis of cuticular wax.
Morphology of the prefrontal cortex predicts body composition in early adolescence: cognitive mediators and environmental moderators in the ABCD Study
Authors: Hall Peter A , Best John R , Beaton Elliott A , Sakib Mohammad N , Danckert James
Published: September 2021

Morphological features of the lateral prefrontal cortex (PFC) in late childhood and early adolescence may provide important clues as to the developmental etiology of clinical conditions such as obesity. Body composition measurements and structural brain imaging were performed on 11 226 youth at baseline (age 9 or 10 years) and follow-up (age 11 or 12 years). Baseline morphological features of the lateral PFC were examined as predictors of body composition. Findings revealed reliable associations between middle frontal gyrus volume, thickness and surface area and multiple indices of body composition. These findings were consistent across both time points and remained significant after covariate adjustment. Cortical thicknesses of the inferior frontal gyrus and lateral orbitofrontal cortex were also reliable predictors. Morphology effects on body composition were mediated by performance on a non-verbal reasoning task. Modest but reliable moderation effects were observed with respect to environmental self-regulatory demand after controlling for sex, race/ethnicity, income and methodological variables. Overall findings suggest that PFC morphology is a reliable predictor of body composition in early adolescence, as mediated through select cognitive functions and partially moderated by environmental characteristics.
The Diversification of Downy Mildew Species Was Not Driven by the Loss of Mycorrhizal Associations or the Evolution of C4 Photosynthesis
Authors: Davis William J. , Crouch Jo Anne
Published: September 2021

There are approximately 700 obligate biotrophic species grouped into 20 genera (Oomycota, Peronosporaceae) that cause downy mildew diseases. In 2001, Dick hypothesized that diversification of downy mildew species was driven in part by host plant secondary metabolites. Dick further speculated that this was driven by the transition of host plants away from mycorrhizal associations or the evolution of C4 photosynthesis. Specifically, loss of mycorrhizal associations or the use of C4 photosynthesis would result in more free carbon that the plants could then use to produce more secondary metabolites. If true, then there should be more downy mildew species that infect hosts from plant lineages that lack mycorrhizal associations or use C4 photosynthesis. However, analysis of 677 downy mildew species for host plant mycorrhizal associations and host plant photosynthetic pathway type shows that this is not what occurred. Seventy percent of downy mildew species parasitize hosts that form mycorrhizal associations, and 94% of downy mildew species parasitize hosts that use C3 photosynthesis. From this, it is concluded that the diversification of downy mildew species was not driven by the loss of mycorrhizal associations or the evolution of C4 photosynthesis. However, 85% of downy mildew species that parasitize Poaceae (grasses) parasitize C4 hosts. Thus, it is possible that C4 photosynthesis plays a role in the diversification of these genera.

[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, 2022.
Netrin1 and reelin signaling are required for the migration of anterolateral system neurons in the embryonic spinal cord
Authors: Roome R. Brian , Rastegar-Pouyani Shima , Ker Amy , Dumouchel Annie , Kmita Marie , Kania Artur
Published: September 2021

Projection neurons of the spinal cord dorsal horn which transmit pain, itch, and temperature information to the brain comprise the anterolateral system (AS). A recent molecular and genetic study showed that many developing AS neurons express the transcription factor Phox2a and provided insights into the mechanisms of their ontogeny and wiring of nociceptive neuronal circuits. Here, we show that the loss of the axonal guidance and neuronal migration signal netrin1 results in impaired migration of mouse Phox2a+ AS neurons into the spinal lamina I. Furthermore, we show that in the absence of Dab1, an intracellular transducer of the neuronal migration signal reelin, the migration of spinal lamina V and lateral spinal nucleus Phox2a+ AS neurons is impaired, in line with deficits in nociception seen in mice with a loss of reelin signaling. Together, these results provide evidence that netrin1 and reelin control the development of spinal nociceptive projection neurons, suggesting a mechanistic explanation for studies that link sequence variations in human genes encoding these neurodevelopmental signals and abnormal pain sensation.
Sex differences in medical cannabis-related adverse effects
Authors: Aviram Joshua , Lewitus Gil M. , Vysotski Yelena , Berman Paula , Shapira Anna , Procaccia Shiri , Meiri David
Published: September 2021

Studies have shown that women are more susceptible to adverse effects (AEs) from conventional drugs. This study aimed to investigate the differences of medical cannabis (MC)-related AEs between women and men in patients with chronic noncancer pain (CNCP). This is a cross-sectional study of adult patients licensed for MC treatment who were also diagnosed as patients with CNCP by a physician. Data included self-reported questionnaires and comprehensive MC treatment information. Simultaneously, identification and quantification of phytocannabinoids and terpenoids from the MC cultivars were performed. Comparative statistics were used to evaluate differences between men and women. Four hundred twenty-nine patients with CNCP (64% males) reported fully on their MC treatment. Subgrouping by sex demonstrated that the weight-adjusted doses were similar between men and women (0.48 [0.33-0.6] gr for men and 0.47 [0.34-0.66] gr for women). Nonetheless, women reported more than men on MC-related AEs. Further analysis revealed that women consumed different MC cultivar combinations than men, with significantly higher monthly doses of the phytocannabinoids CBD and CBC and significantly lower monthly doses of the phytocannabinoid 373-15c and the terpenoid linalool. Our findings demonstrate sex differences in MC-related AEs among patients with CNCP. Women are more susceptible to MC-related AEs, presumably because of both the inherent sex effect and the consumption of specific phytocannabinoid compositions in the MC cultivar(s). The understanding of these differences may be crucial for planning MC treatments with safer phytocannabinoid and terpenoid compositions and to better inform patients of expected AEs.
Voltage-gated calcium currents in human dorsal root ganglion neurons
Authors: Hartung Jane E. , Moy Jamie K. , Loeza-Alcocer Emanuel , Nagarajan Vidhya , Jostock Ruth , Christoph Thomas , Schroeder Wolfgang , Gold Michael S.
Published: September 2021

Voltage-gated calcium channels in sensory neurons underlie processes ranging from neurotransmitter release to gene expression and remain a therapeutic target for the treatment of pain. Yet virtually all we know about voltage-gated calcium channels has been obtained through the study of rodent sensory neurons and heterologously expressed channels. To address this, high voltage–activated (HVA) Ca2+ currents in dissociated human and rat dorsal root ganglion neurons were characterized with whole-cell patch clamp techniques. The HVA currents from both species shared basic biophysical and pharmacological properties. However, HVA currents in human neurons differed from those in the rat in at least 3 potentially important ways: (1) Ca2+ current density was significantly smaller, (2) the proportion of nifedipine-sensitive currents was far greater, and (3) a subpopulation of human neurons displayed relatively large constitutive current inhibition. These results highlight the need to for the study of native proteins in their native environment before initiating costly clinical trials.
Greater baseline pain inclusion criteria in clinical trials increase regression to the mean effect: a modelling study
Authors: Kamerman Peter R. , Vollert Jan
Published: September 2021

We modelled the effects of pain intensity inclusion thresholds (3/10, 4/10, and 5/10 on a 0- to 10-point numerical pain rating scale) on the magnitude of the regression to the mean effect under conditions that were consistent with the sample mean and variance, and intermeasurement correlation observed in clinical trials for the management of chronic pain. All data were modelled on a hypothetical placebo control group. We found a progressive increase in the mean pain intensity as the pain inclusion threshold increased, but this increase was not uniform, having an increasing effect on baseline measurements compared with study endpoint measurements as the threshold was increased. That is, the regression to the mean effect was magnified by increasing inclusion thresholds. Furthermore, the effect increasing pain inclusion thresholds had on the regression to the mean effect was increased by decreasing sample mean values at baseline and intermeasurement correlations, and increasing sample variance. At its smallest, the regression to the mean effect was 0.13/10 (95% confidence interval: 0.03/10-0.24/10; threshold: 3/10, baseline mean pain: 6.5/10, SD: 1.6/10, and correlation: 0.44), and at its greatest, it was 0.78/10 (95% confidence interval: 0.63/10-0.94/10; threshold: 5/10, baseline mean pain: 6/10, SD: 1.8/10, and correlation: 0.19). We have shown that using pain inclusion thresholds in clinical trials drives progressively larger regression to the mean effects. We believe that a threshold of 3/10 offers the best compromise between maintaining assay sensitivity (the goal of thresholds) and the size of the regression to the mean effect.
Biopsy in interstitial lung disease: specific diagnosis and the identification of the progressive fibrotic phenotype
Authors: Ravaglia Claudia , Nicholson Andrew G.
Published: September 2021

Purpose of review

The evaluation of progression in fibrotic interstitial lung diseases (ILDs) may require a multidimensional approach. This review will cover the role and usefulness of lung biopsy in diagnosis and assessment of the progressive fibrotic phenotype.

Recent findings

The identification of specific findings and the balance between inflammation and fibrosis on lung biopsy may help distinguishing different disease entities and may likely determine the effect of treatment and possibly prognosis. The fibrotic morphological patterns potentially associated with a progressive phenotype include usual interstitial pneumonia (UIP), fibrotic nonspecific interstitial pneumonia, pleuroparenchymal fibroelastosis, desquamative interstitial pneumonia, fibrotic hypersensitivity pneumonitis and other less common fibrotic variants, with histopathological findings of UIP at the time of diagnosis being predictive of worse outcome compared with other patterns. The prognostic significance of lung biopsy findings has been assessed after both surgical lung biopsy (SLB) and transbronchial lung cryobiopsy (TBLC), the latter becoming a valid alternative to SLB, if performed in experienced centres, due to significantly lower morbidity and mortality.

Lung biopsy plays an important role in diagnosis and identification of the progressive fibrotic phenotype. The introduction of less invasive procedures could potentially expand the role of lung sampling, including for example patients with a known diagnosis of ILD or at an earlier stage of the disease.
Reduced Fractional Absorption of Zinc in Children With Environmental Enteropathy in Zambia
Authors: Zyambo Kanekwa , Hodges Phoebe , Chandwe Kanta , Mweetwa Monica , Westcott Jamie , Krebs Nancy F. , Amadi Beatrice , Kelly Paul
Published: September 2021

Objectives:

We measured fractional absorption of zinc (FAZ) in children with environmental enteropathy (EE) and carried out transcriptomic analysis of biopsies from these children in order to compare FAZ to histology of intestinal biopsies, expression of zinc transporter genes, and biomarkers of enteropathy.

Methods:

Fractional absorption of a standardized aqueous dose of zinc was measured by a dual isotope ratio technique in a cohort of children ages between 9 and 24 months in Lusaka, Zambia, who all had non‐responsive stunting. Gene expression analysis was carried out on biopsies through RNA sequencing using an Illumina HiSeq2000 platform.

Results:

All 33 children had histological features of environmental enteropathy and plasma zinc concentrations below the lower limit of normal. Measured FAZ ranged from 0.18 to 0.93; all values >0.55 were observed in girls. FAZ was negatively correlated with faecal myeloperoxidase (MPO) (ρ = −0.51, n = 17; P = 0.04) and faecal calprotectin (ρ = −0.50, n = 16; P = 0.05), but not blood biomarkers. Of 41 genes with known roles in zinc metabolism, only three metallothionein genes were significantly correlated with FAZ.

Conclusions:

Zinc homeostasis is impaired in children with environmental enteropathy, and was inversely correlated with mucosal inflammation. Reduced FAZ without specific changes in expression of most zinc transporter genes could be explained by reduced absorptive surface area due to villus/microvillus atrophy.
Pain in Homebound Older Adults with Heart Failure after Hospital Discharge
Authors: Kang Youjeong , Choi Yong K. , Stehlik Josef , Nielsen Jane Deakin , Reid M. Carrington
Published: September 2021

Pain is not uncommon in older adult patients with heart failure (HF) and has been identified as a risk factor for rehospitalization of homebound patients with HF. Little is known about the pain experiences and management of older adults with HF after hospital discharge. We sought to describe pain and other symptoms among homebound older adults with HF using a qualitative and descriptive approach. We conducted semistructured interviews to obtain qualitative data and used the Brief Pain Instrument-Short Form and the Edmonton Symptom Assessment Scale to obtain descriptive data on symptom burden. We interviewed 18 participants within 10 days after hospital discharge. Participants' mean age was 75.8 ± 9.0 years; 78% were White. The mean pain score at its worst was 5.2 ± 3.1, and for pain interfering with sleep was 4.3 ± 3.41. Most participants managed pain with medications. Using thematic analysis of qualitative data, we identified three distinct categories: (1) the diversity of patients' pain experiences, (2) the diversity of pain management routines, and (3) patients' experiences with healthcare providers' pain assessment and management practices. Our findings show that homebound older adults with HF experience various pain symptoms and receive inconsistent education about how to manage pain from healthcare providers. This study supports the need for better pain assessment and education about the appropriate use of pain medications and nonpharmacologic approaches to pain control for homebound older adults with HF.
Outcomes of Hospital at Home for Older Adults with and without High Levels of Social Support
Authors: Augustine Matthew R. , Siu Albert L. , Boockvar Kenneth S. , DeCherrie Linda V. , Leff Bruce A. , Federman Alex D.
Published: September 2021

The evaluation of social support within hospital at home (HaH) programs has been limited. We performed a secondary analysis of a prospective cohort evaluation of 295 participants receiving HaH care and 212 patients undergoing traditional hospitalization from November of 2014 to August of 2017. We examined the confounding and moderating effects of instrumental and informational social support upon length of stay and 30-day rehospitalization, emergency department (ED) visit, and skilled nursing facility admission. Instrumental social support attenuated the effects of HaH upon any ED visit (base model: OR 0.61, p = 0.037; controlling for social support: OR 0.71, p = 0.15). The association of HaH with other outcomes remained unchanged. Interactions between HaH and informational or instrumental social support for all outcomes were not significant. Lack of high levels of social support had little effect on the positive outcomes of HaH care, suggesting similar benefits of HaH services for patients with lower levels of social support.
Risk Factors for Syphilis at a Large Urban Emergency Department
Authors: Ford James S. , Shevchyk Ivan , Yoon Joseph , Chechi Tasleem , Voong Stephanie , Tran Nam , May Larissa
Published: September 2021

Background

The prevalence of syphilis is increasing in the United States. The emergency department (ED) is an important setting to screen and treat underserved populations. To tailor testing protocols to the local population, we aimed to identify risk factors for syphilis positivity in ED patients.

Methods

We performed a retrospective analysis of ED patients who were screened for syphilis between November 2018 and August 2020. Patients were screened for Treponema pallidum antibody using a multiplex flow immunoassay, and positive results were confirmed by rapid plasma reagin or T. pallidum particle agglutination. Risk factors for new syphilis diagnoses were identified using multiple logistic regression.

Results

We screened 1974 patients for syphilis (mean age, 37 ± 16 years; 56% female). We identified 201 patients with new infections without previous treatment. Independent risk factors for a new diagnosis of syphilis included housing status (undomiciled, 23% [60 of 256]; domiciled, 9% [133 of 1559]; adjusted odds ratio [aOR], 1.9 [95% confidence interval {CI}, 1.2–3.0]), history of HIV (positive, 44% [28 of 63]; negative, 9% [173 of 1893]; aOR, 5.8 [95% CI, 3.0–11.2]), tobacco use (positive, 15% [117 of 797]; negative, 4% [29 of 665]; aOR, 2.4 [95% CI, 1.5–3.9]), and illicit drug use (positive, 14% [112 of 812]; negative, 8% [52 of 678]; aOR, 2.2 [95% CI, 1.0–2.5]).

Conclusions

Undomiciled housing status, history of HIV, history of tobacco use, and history of illicit drug use were independently associated with a new diagnosis of syphilis in the ED. Broadening targeted syphilis screening algorithms beyond sexually transmitted disease–related complaints could help identify new syphilis cases for treatment.
Quantifying Meibomian Gland Morphology Using Artificial Intelligence
Authors: Wang Jiayun , Li Shixuan , Yeh Thao N. , Chakraborty Rudrasis , Graham Andrew D. , Yu Stella X. , Lin Meng C.
Published: September 2021

SIGNIFICANCE

Quantifying meibomian gland morphology from meibography images is used for the diagnosis, treatment, and management of meibomian gland dysfunction in clinics. A novel and automated method is described for quantifying meibomian gland morphology from meibography images.

PURPOSE

Meibomian gland morphological abnormality is a common clinical sign of meibomian gland dysfunction, yet there exist no automated methods that provide standard quantifications of morphological features for individual glands. This study introduces an automated artificial intelligence approach to segmenting individual meibomian gland regions in infrared meibography images and analyzing their morphological features.

METHODS

A total of 1443 meibography images were collected and annotated. The dataset was then divided into development and evaluation sets. The development set was used to train and tune deep learning models for segmenting glands and identifying ghost glands from images, whereas the evaluation set was used to evaluate the performance of the model. The gland segmentations were further used to analyze individual gland features, including gland local contrast, length, width, and tortuosity.

RESULTS

A total of 1039 meibography images (including 486 upper and 553 lower eyelids) were used for training and tuning the deep learning model, whereas the remaining 404 images (including 203 upper and 201 lower eyelids) were used for evaluations. The algorithm on average achieved 63% mean intersection over union in segmenting glands, and 84.4% sensitivity and 71.7% specificity in identifying ghost glands. Morphological features of each gland were also fed to a support vector machine for analyzing their associations with ghost glands. Analysis of model coefficients indicated that low gland local contrast was the primary indicator for ghost glands.

CONCLUSIONS

The proposed approach can automatically segment individual meibomian glands in infrared meibography images, identify ghost glands, and quantitatively analyze gland morphological features.
A physiatrist's understanding and application of the current literature on chronic pelvic pain: a narrative review
Authors: Shrikhande Allyson , Ullger Cory , Seko Kyle , Patil Soha , Natarajan Janaki , Tailor Yogita , Thompson-Chudy Carolyn
Published: September 2021

Chronic pelvic pain (CPP) is a highly prevalent condition which is underdiagnosed and poorly understood. The purpose of this review is to outline the various aspects of the nature of CPP, including its etiologies, clinical presentation, and nonoperative treatment options. For data collection, a PubMed search was conducted using indexing terms such as chronic pelvic pain and pelvic pain. Literature reviews and studies focusing on etiologies, clinical presentation, and/or the diagnosis of CPP were compiled for review by a team of 3 physiatrists. Studies investigating conservative treatments, medications, and interventional procedures for CPP and related conditions with comparable etiologies were also included. Of the 502 articles retrieved, 116 were deemed suitable by the team for this study. Although CPP is a complex, multifaceted condition, a particular susceptibility to nociceptive stimuli was demonstrated as an underlying theme in its evolution. There are many treatment options currently used; however, more robust evidence, such as randomized controlled trials, are needed before creating comprehensive guidelines for treating CPP.
Accuracy of Dual-Energy Computed Tomography Techniques for Fat Quantification in Comparison With Magnetic Resonance Proton Density Fat Fraction and Single-Energy Computed Tomography in an Anthropomorphic Phantom Environment
Authors: Wu Zi Jun , Hippe Daniel S. , Zamora David A. , Briller Noah , Amin Kathan A. , Kolokythas Orpheus , Mileto Achille
Published: September 2021

Objective

To investigate in an anthropomorphic phantom study the accuracy of dual-energy computed tomography (DECT) techniques for fat quantification in comparison with magnetic resonance (MR) proton density fat fraction (PDFF) and single-energy computed tomography (SECT), using known fat content as reference standard.

Methods

Between August 2018 and November 2020, organic material-based cylinders, composed of mixtures of lean and fat tissues mimics, iodine, and iron, were constructed to simulate varying fat content levels (0%, 10%, 15%, 25%, 50%, 75%, and 100%) in a parenchymal organ and were embedded into an anthropomorphic phantom simulating 3 patient sizes (circumference, 91, 126, and 161 cm). The phantom was imaged with multiecho MR, DECT, and SECT. Magnetic resonance PDFF, DECT fat fraction, and computed tomography (CT) numbers (SECT polychromatic and DECT monochromatic data, virtual unenhanced images) were estimated. Performances of MR PDFF and CT techniques to detect differences in fat content were measured using the area under the curve (AUC). Noninferiority of each CT technique relative to MR PDFF was tested using a noninferiority margin of −0.1.

Results

MR PDFF, DECT 140 keV monochromatic data, and fat fraction most closely correlated with known fat content (R
2 = 0.98, 0.98, and 0.96, respectively). Unlike SECT and all other DECT techniques, DECT fat fraction was not affected by presence of iodine (mean difference, 0.3%; 95% confidence interval [CI], −0.9% to 1.5%). Dual-energy computed tomography fat fraction showed noninferiority to MR PDFF in detecting differences of 5% in fat content in medium-sized phantoms (ΔAUC, −0.05; 95% CI, −0.08 to −0.01), and 7% in large (ΔAUC, −0.04; 95% CI, −0.0 to 0.00) or extralarge sized phantoms (ΔAUC, −0.02; 95% CI, −0.07 to 0.00).

Conclusions

Dual-energy computed tomography fat fraction shows linear correlation with true fat content in the range up to 50% fat fraction. Dual-energy computed tomography fat fraction has comparable estimation error and shows noninferiority to MR PDFF in detecting small differences in fat content across different body sizes.