Dual-Energy Computed Tomography and Beyond: Musculoskeletal System.

Traditional monoenergetic computed tomography (CT) scans in musculoskeletal imaging provide excellent detail of bones but are limited in the evaluation of soft tissues. Dual-energy CT (DECT) overcomes many of the traditional limitations of CT and offers anatomical details previously seen only on MR imaging. In addition, DECT has benefits in the evaluation and characterization of arthropathies, bone marrow edema, and collagen applications in the evaluation of tendons, ligaments, and vertebral discs. There is current ongoing research in the application of DECT in arthrography and bone mineral density calculation.

Depressive symptom trajectories and polygenic risk scores in individuals with an immune-mediated inflammatory disease.

OBJECTIVE: To develop group-based trajectories of depressive symptoms in immune-mediated inflammatory disease (IMID) to understand their evolution and identify any associated factors, with the overall goal of identifying those at highest risk of higher depressive symptom burden. METHOD: 922 participants had an IMID or anxiety/depression. The PHQ-9 was administered at four visits, and polygenic risk scores (PRS) for major depressive disorder, depressive symptoms, and body mass index (BMI) were generated. Group-based trajectory modelling of PHQ-9 scores estimated distinct trajectories. Regression tested whether specific factors were associated with the trajectories. Mediation analyses assessed whether IMID mediated the association between BMI PRS and trajectories. RESULTS: Three trajectories were identified. Regression demonstrated those in Group 3 ('high symptoms') had significantly higher PRS for the three traits, compared to Group 1 ('minimal symptoms') (OR: 1.34-1.66, P < 0.01). Stratified analyses in the IMID subgroup revealed an increased effect for BMI PRS in Group 3 (OR: 2.31, P < 0.001), in contrast, BMI PRS was no longer associated in the non-IMID sample. No significant indirect effect of BMI PRS on depressive symptoms trajectories was identified via IMID. CONCLUSIONS: A significant association between polygenicity and PHQ-9 trajectories supports a role for genetic inheritance in the variability in depressive symptoms in IMID.

Prevalence and Risk Factors of Substance Use Disorder in Rheumatoid Arthritis.

OBJECTIVE: In this study, we aimed to determine the lifetime prevalence of substance use disorder (SUD) in a Canadian rheumatoid arthritis (RA) cohort and factors associated with SUD in RA. METHODS: Participants with RA (N = 154) were recruited via rheumatology clinics as part of a larger cohort study of psychiatric comorbidity in immune-mediated inflammatory diseases. SUD is defined as the uncontrolled use of a substance despite the harmful consequences of its use. To identify lifetime SUD, the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition was administered to participants. Participants' sociodemographic and RA clinical characteristics were also assessed. We examined factors associated with lifetime SUD using unadjusted and adjusted logistic regression modeling. RESULTS: Twenty-three (14.9%) of 154 participants with RA met the criteria for a lifetime diagnosis of SUD. The majority of the participants were women, were White, had postsecondary education, and were on a disease-modifying antirheumatic drug. Factors associated with increased odds of SUD were male sex (adjusted odds ratio [aOR]: 3.63, 95% confidence interval [CI]: 1.03-12.73), younger age (aOR: 0.94, 95% CI: 0.90-0.98), and ever smoking (aOR: 6.44, 95% CI: 1.53-27.07). CONCLUSION: We found that approximately 1 in 7 individuals with RA had a lifetime diagnosis of SUD, highlighting the importance of identifying and treating SUD in those with RA. In particular, the following factors were associated with higher odds of SUD: male sex, younger age, and smoking behaviors.

Comparison of Outcomes of Enoxaparin Bridge Therapy in HeartMate II versus HeartWare HVAD Recipients.

BACKGROUND: There is a lack of robust data evaluating outcomes of enoxaparin "bridge" therapy in left ventricular assist device (LVAD) patients. METHODS: We performed a retrospective study of HeartMate II (HM II) and HeartWare HVAD recipients that received therapeutic enoxaparin as "bridge" therapy to describe bleeding and thrombotic events and compare outcomes between devices. The primary endpoint was the incidence of bleeding within 30 days of "bridge" episode. Major bleeding was defined by INTERMACS criteria. RESULTS: We evaluated 257 "bridge" episodes in 54 patients, 35 with a HM II device and 19 with an HVAD device that underwent 176 and 81 bridging episodes, respectively. The median INR prior to "bridge" was lower in the HM II group compared to the HVAD group (1.5 vs 1.7, P < .01), however, there was no difference in the median duration of "bridge" therapy (7 vs 7 days, P = .42). There were a total of 30 (12%) bleeding episodes, with the majority in the HM II group vs HVAD (26 [15%] vs 4 [5%], P = .02). We observed 3 (1%) thromboembolic events in 2 (4%) patients with an HVAD device. On multivariate analysis, the presence of a HM II device was associated with a 4-fold increased risk of bleeding. CONCLUSION: We found the use of enoxaparin "bridge" therapy to be associated with a higher incidence of bleeding in patients with a HM II device compared with an HVAD device. Assessment of device- and patient-specific factors should be evaluated to minimize bleeding events.

Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis.

BACKGROUND: Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear. OBJECTIVE: The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR). METHODS: We selected genetic instruments associated with risk of MDD (n = 660,937 cases; 1,453,489 controls) and MS (n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR. RESULTS: We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90-1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99-1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09-1.65) and MDD (OR = 1.08, 95% CI = 1.01-1.15). CONCLUSION: This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.

Molecular Evolution of the Glutathione S-Transferase Family in the Bemisia tabaci Species Complex.

The glutathione S-transferase (GST) family plays an important role in the adaptation of herbivorous insects to new host plants and other environmental constrains. The family codes for enzymes that neutralize reactive oxygen species and phytotoxins through the conjugation of reduced glutathione. Here, we studied the molecular evolution of the GST family in Bemisia tabaci, a complex of >35 sibling species, differing in their geographic and host ranges. We tested if some enzymes evolved different functionality, by comparing their sequences in six species, representing five of the six major genetic clades in the complex. Comparisons of the nonsynonymous to synonymous substitution ratios detected positive selection events in 11 codons of 5 cytosolic GSTs. Ten of them are located in the periphery of the GST dimer, suggesting a putative involvement in interactions with other proteins. Modeling the tertiary structure of orthologous enzymes, identified additional 19 mutations in 9 GSTs, likely affecting the enzymes' functionality. Most of the mutation events were found in the environmentally responsive classes Delta and Sigma, indicating a slightly different delta/sigma tool box in each species. At a broader genomic perspective, our analyses indicated a significant expansion of the Delta GST class in B. tabaci and a general association between the diet breadth of hemipteran species and their total number of GST genes. We raise the possibility that at least some of the identified changes improve the fitness of the B. tabaci species carrying them, leading to their better adaptation to specific environments.

Sedation Requirements in Patients on Venovenous or Venoarterial Extracorporeal Membrane Oxygenation.

Background:There is a paucity of data evaluating optimal dosing strategies of commonly utilized opioids and sedatives for patients on extracorporeal membrane oxygenation (ECMO) support where pharmacokinetic and pharmacodynamic variables of these administered agents are altered. Objective: To assess the daily dosing requirement of sedatives and analgesics for patients on venovenous (VV) and venoarterial (VA) ECMO after the initial ECMO cannulation period. Methods: We performed a retrospective, observational study of adult patients receiving sedation and analgesia while receiving ECMO support for at least 24 hours. Patients cannulated at an outside hospital more than 24 hours before transfer, those with a history of intravenous drug use or acute alcohol withdrawal, or those who died within 48 hours of ECMO initiation were excluded. Results: We evaluated 26 patients on ECMO, including 13 on VV and 13 on VA ECMO. The median dose of fentanyl was 140 µg/h, with the VV group requiring a higher dose compared with the VA group (167 vs 106 µg/h, P < 0.001). The median doses of dexmedetomidine and propofol were 0.7 µg/kg/h and 26 µg/kg/min, respectively, with no significant differences between groups (P = 0.38 and P = 0.24, respectively). The median daily doses of fentanyl, dexmedetomidine, and propofol did not significantly increase throughout the time on ECMO support. Conclusions and Relevance: We found that the overall opioid daily dosing requirements were lower than previously reported in the literature. Additionally, light sedation strategies with a target RASS of -1 to 0 are feasible in this patient population.

Publisher Correction: Insight into the microbial world of Bemisia tabaci cryptic species complex and its relationships with its host.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Dalbavancin Use in the Emergency Department Setting.

Background: Although dalbavancin's (DBV's) long half-life and one-time dosing strategy confer ideal administration in the ambulatory setting, the optimal role of DBV in the management of acute bacterial skin and skin structure infections (ABSSSIs) remains to be elucidated. Objectives: The primary objective of this study was to compare treatment outcomes of ABSSSI between patients who received DBV in the emergency department (ED) as part of standard care versus patients who received DBV as part of a telehealth program. Methods: This was a retrospective cohort study evaluating patients who received DBV at 3 urban EDs. The primary end point was the incidence of ABSSSI recurrence. Secondary outcomes included need for hospital admission and ED length of stay (LOS; in hours). Results: A total of 65 ABSSSI treatment courses were included; 42 were included in the telehealth criteria (TC) cohort and 23 in the initial criteria (IC) cohort. There were 14% (6/42) infection recurrences in the TC cohort and 22% (5/23) in the IC cohort, with median time to recurrence being 4 and 14 days, respectively. Median ED LOS was significantly shorter in the TC (5 vs 25 hours, P < 0.05). Numerically fewer individuals in the TC cohort required inpatient admission (0 vs n = 2, 9%). Conclusion and Relevance: Our results suggest that patients may be safely administered DBV in an ED setting, with telehealth follow-up. Providing structured patient selection criteria is an effective method of assisting ED providers in selecting appropriate DBV candidates to limit potential recurrences and readmissions.

Insight into the microbial world of Bemisia tabaci cryptic species complex and its relationships with its host.

The 37 currently recognized Bemisia tabaci cryptic species are economically important species and contain both primary and secondary endosymbionts, but their diversity has never been mapped systematically across the group. To achieve this, PacBio sequencing of full-length bacterial 16S rRNA gene amplicons was carried out on 21 globally collected species in the B. tabaci complex, and two samples from B. afer were used here as outgroups. The microbial diversity was first explored across the major lineages of the whole group and 15 new putative bacterial sequences were observed. Extensive comparison of our results with previous endosymbiont diversity surveys which used PCR or multiplex 454 pyrosequencing platforms showed that the bacterial diversity was underestimated. To validate these new putative bacteria, one of them (Halomonas) was first confirmed to be present in MED B. tabaci using Hiseq2500 and FISH technologies. These results confirmed PacBio is a reliable and informative venue to reveal the bacterial diversity of insects. In addition, many new secondary endosymbiotic strains of Rickettsia and Arsenophonus were found, increasing the known diversity in these groups. For the previously described primary endosymbionts, one Portiera Operational Taxonomic Units (OTU) was shared by all B. tabaci species. The congruence of the B. tabaci-host and Portiera phylogenetic trees provides strong support for the hypothesis that primary endosymbionts co-speciated with their hosts. Likewise, a comparison of bacterial alpha diversities, Principal Coordinate Analysis, indistinct endosymbiotic communities harbored by different species and the co-divergence analyses suggest a lack of association between overall microbial diversity with cryptic species, further indicate that the secondary endosymbiont-mediated speciation is unlikely to have occurred in the B. tabaci species group.

Species-complex diversification and host-plant associations in Bemisia tabaci: A plant-defence, detoxification perspective revealed by RNA-Seq analyses.

Insect-plant associations and their role in diversification are mostly studied in specialists. Here, we aimed to identify macroevolution patterns in the relationships between generalists and their host plants that have the potential to promote diversification. We focused on the Bemisia tabaci species complex containing more than 35 cryptic species. Mechanisms for explaining this impressive diversification have focused so far on allopatric forces that assume a common, broad, host range. We conducted a literature survey which indicated that species in the complex differ in their host range, with only few showing a truly broad one. We then selected six species, representing different phylogenetic groups and documented host ranges. We tested whether differences in the species expression profiles of detoxification genes are shaped more by their phylogenetic relationships or by their ability to successfully utilize multiple hosts, including novel ones. Performance assays divided the six species into two groups of three, one showing higher performance on various hosts than the other (the lower performance group). The same grouping pattern appeared when the species were clustered according to their expression profiles. Only species placed in the lower performance group showed a tendency to lower the expression of multiple genes. Taken together, these findings bring evidence for the existence of a common detoxification "machinery," shared between species that can perform well on multiple hosts. We raise the possibility that this "machinery" might have played a passive role in the diversification of the complex, by allowing successful migration to new/novel environments, leading, in some cases, to fragmentation and speciation.

iS-CellR: a user-friendly tool for analyzing and visualizing single-cell RNA sequencing data.

Summary: Interactive platform for single-cell RNA-sequencing (iS-CellR) is a web-based Shiny application that is designed to provide user-friendly, comprehensive analysis of single-cell RNA sequencing data. iS-CellR has the capability to run on any modern web browser and provides an accessible graphical user interface that enables the user to perform complex single-cell RNA-sequencing analysis without requiring programming skills. Availability and implementation: iS-CellR is open source and available through GitHub at https://github.com/immcore/iS-CellR. iS-CellR is implemented in Docker and can be launched on any operating system with Docker installed. Supplementary information: Supplementary data are available at Bioinformatics online.

Effect of excipient properties, water activity, and water content on the disproportionation of a pharmaceutical salt.

Excipients are crucial components of most pharmaceutical formulations. In the case of a solid oral dosage formulation containing the salt form of a weakly ionizable drug, excipient selection is critical, as some excipients are known to cause salt disproportionation (conversion of salt to the free form). Therefore, robust formulation design necessitates an in-depth understanding of the factors impacting salt disproportionation during processing or storage as this can negatively impact product quality and performance. To date, there is an incomplete understanding of key excipient properties influencing salt disproportionation. Specifically, the potential roles of amorphous excipient glass transition temperature and excipient hygroscopicity, if any, on salt disproportionation are still not well understood. Furthermore, the relationship between the compression and the extent of salt disproportionation is an unknown factor. Herein, by utilizing various grades of polyvinylpyrrolidone (PVP), its copolymer, copovidone (PVPVA), and magnesium stearate, a systematic investigation of disproportionation was performed using pioglitazone HCl as a model salt of a weak base. It was observed that there was a poor correlation between excipient hygroscopicity and the rate and extent of disproportionation. However, powder compression into compacts enhanced the rate and extent of disproportionation. This work focused on disproportionation of the salt of a weak base, as basic drugs are more prevalent, however, salts of weak acids may have similar tendencies under relevant conditions. The knowledge gained from this study will help in understanding the role of various excipients with respect to salt disproportionation, paving the way for designing stable salt formulations.

African ancestry of New World, Bemisia tabaci-whitefly species.

Bemisia tabaci whitefly species are some of the world's most devastating agricultural pests and plant-virus disease vectors. Elucidation of the phylogenetic relationships in the group is the basis for understanding their evolution, biogeography, gene-functions and development of novel control technologies. We report here the discovery of five new Sub-Saharan Africa (SSA) B. tabaci putative species, using the partial mitochondrial cytochrome oxidase 1 gene: SSA9, SSA10, SSA11, SSA12 and SSA13. Two of them, SSA10 and SSA11 clustered with the New World species and shared 84.8‒86.5% sequence identities. SSA10 and SSA11 provide new evidence for a close evolutionary link between the Old and New World species. Re-analysis of the evolutionary history of B. tabaci species group indicates that the new African species (SSA10 and SSA11) diverged from the New World clade c. 25 million years ago. The new putative species enable us to: (i) re-evaluate current models of B. tabaci evolution, (ii) recognise increased diversity within this cryptic species group and (iii) re-estimate divergence dates in evolutionary time.

Impact of Solid-State Form on the Disproportionation of Miconazole Mesylate.

Approximately 50% of solid oral dosage forms utilize salt forms of the active pharmaceutical ingredient (API). A major challenge with the salt form is its tendency to disproportionate to produce the un-ionized API form, decreasing the solubility and negatively impacting product stability. However, many of the factors dictating the tendency of a given salt to undergo disproportionation remain to be elucidated. In particular, the role of the solid-state properties of the salt on the disproportionation reaction is unknown. Herein, various solid forms of a model salt, miconazole mesylate (MM), were evaluated for their tendency to undergo disproportionation when mixed with basic excipients, namely tribasic sodium phosphate dodecahydrate (TSPd) and croscarmellose sodium (CCS), and exposed to moderate relative humidity storage conditions. It was observed that the rate and extent of salt disproportionation were significantly different for the various solid forms of MM. As expected, the amorphous salt was highly susceptible to disproportionation, while the dihydrate salt form was resistant to conversion under the conditions tested. In addition, binary excipient blends of amorphous and anhydrous forms exhibited a reduced extent of disproportionation at a higher relative humidity storage condition. This was due to the competitive kinetics between disproportionation to the free base and conversion to the dihydrate salt form. The results of this study provide important insights into the impact of solid-state form on susceptibility to disproportionation that can be utilized for rationally designing robust pharmaceutical formulations.

The discovery and investigation of a crystalline solid solution of an active pharmaceutical ingredient.

Understanding the phase behavior of crystal forms is essential in drug formulation development, as physical stability of the active pharmaceutical ingredient (API) is critical to achieving the desired bioavailability. Solvents greatly impact the physical stability of crystalline solids, resulting in a variety of well-known phase transitions, such as hydrate/solvate formation. However, solvent incorporation may also result in the formation of a less-known crystalline solid solutions (CSSs). The identification and characterization of CSSs and their effect on API physicochemical properties have not been investigated. This is the first reported instance of a CSS for an API. An exhaustive study of the phase behavior of the enantiotropically related polymorphs, I and II, of Benzocaine in water and ethanol revealed that Form I formed a CSS with water below 294.5K. Construction of the phase diagrams of Forms I and II in water and ethanol revealed that CSS formation significantly decreased the phase transition temperature between Forms I and II in water. This change resulted from the increased disorder in the lattice of Form I due to the presence of water. This work demonstrates the importance of understanding the formation of CSSs on the thermodynamic behavior of crystalline pharmaceutical solids.

Long-term sustainable dendritic cell-specific depletion murine model for periodontitis research.

Dendritic cells (DCs) are specialized antigen-presenting cells that play a pivotal role in the pathogenesis of periodontitis. The use of animal models to study the role of DCs in periodontitis has been limited by lack of a method for sustained depletion of DCs. Hence, the objectives of this study were to validate the zDC-DTR knockin mouse model of conventional DCs (cDCs) depletion, as well as to investigate whether this depletion could be sustained long enough to induce alveolar bone loss in this model. zDC-DTR mice were treated with different dose regimens of diphtheria toxin (DT) to determine survival rate. A loading DT dose of 20ng/bw, followed and maintained with doses of 10ng/bm every 3days for up to 4weeks demonstrated 80% survival. Animals were weighed weekly and peripheral blood was obtained to confirm normal neutrophil counts. Five animals per group were euthanized at baseline, 24h, 1 and 4weeks. Bone marrow (BM), spleen (SP) and gingival tissue (GT) were harvested, and cells were isolated, separated and stained for Pre-DCs precursors (CD45R-MHCII+CD11c+Flt3+CD172a+) in BM, cDCs (CD11c+MHCII+CD209+) in spleen, and DCs in GT (CD45R+MHCII+CD11c+ DC-SIGN/CD209+). Pre-DCs in BM were significantly depleted at 24h and depletion maintained for up to 4weeks, as compared to blank (PBS) controls. Circulating cDCs in spleen demonstrated a non-significant trend to deplete in 1week with high variability among mice. GT also showed a similar non-significant trend to deplete in 24h. The zDC-DTR model seems to be viable for evaluating the role of DCs immune homeostasis disruption and alveolar bone loss pathogenesis in response to long-term oral infection.

The effect of ionotropic gelation residence time on alginate cross-linking and properties.

The ability to engineer biocompatible polymers with controllable properties is highly desirable. One such approach is to cross-link carbohydrate polymers using ionotropic gelation (IG). Previous studies have investigated the effect of curing time on alginate cross-linking. Herein, we discuss a novel study detailing the effect of IG residence time (IGRT) on the cross-linking of alginate with calcium ions (Ca2+) along with water migration (syneresis) and their subsequent impact on the pharmaceutical properties of alginate particles. IGRT was shown to have a significant effect on particle size, porosity, density, mechanical strength and swelling of calcium alginate particles as well as drug release mechanism. Furthermore, we describe a novel application of electron dispersive spectroscopy (EDS), in conjunction with Fourier Transform- infra red (FT-IR) spectroscopy, to analyze and monitor the changes in Ca2+ concentration during cross-linking. A simple procedure to determine the concentration and distribution of the surface and internal Ca2+ involved in alginate cross-linking was successfully developed.

Identification and evaluation of suitable reference genes for gene expression studies in the whitefly Bemisia tabaci (Asia I) by reverse transcription quantitative realtime PCR.

This study presents a reliable method for performing reverse transcription quantitative realtime PCR (RT-qPCR) to measure gene expression in the whitefly Bemisia tabaci (Asia I) (Gennadius) (Hemiptera: Aleyrodidae), utilising suitable reference genes for data normalisation. We identified orthologs of commonly used reference genes (actin (ACT), cyclophilin 1 (CYP1), elongation factor 1α (EF1A), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), ribosomal protein L13a (RPL13A), and α-tubulin (TUB1A)), measured the levels of their transcripts by RT-qPCR during development and in response to thermal stress, and evaluated their suitability as endogenous controls using geNorm, BestKeeper, and NormFinder programs. Overall, TUB1A, RPL13A, and CYP1 were the most stable reference genes during B. tabaci development, and TUB1A, GAPDH, and RPL13A were the most stable reference genes in the context of thermal stress. An analysis of the effects of reference gene choice on the transcript profile of a developmentally-regulated gene encoding vitellogenin demonstrated the importance of selecting the correct endogenous controls for RT-qPCR studies. We propose the use of TUB1A, RPL13A, and CYP1 as endogenous controls for transcript profiling studies of B. tabaci development, whereas the combination of TUB1A, GAPDH, and RPL13A should be employed for studies into thermal stress. The data pre- sented here will assist future transcript profiling studies in whiteflies.

Oxidized-phospholipids in reconstituted high density lipoprotein particles affect structure and function of recombinant paraoxonase 1.

Paraoxonase 1 (PON1) is an HDL-associated enzyme and exhibits anti-inflammatory, anti-diabetic, and anti-atherogenic properties. Association of PON1 to HDL particles increases the stability and activity of PON1 and is important for the normal functioning of the enzyme. HDL particles are made up of lipid and protein constituents and apolipoprotein A-I (apoA-I) is a principal protein constituent of HDL that facilitates various biological activities of HDL. In many disease conditions the oxidized phospholipid (Ox-PL) content of HDL is found to be increased and an inverse correlation between the activity of PON1 and oxidation of the HDL is observed. However, the molecular details of the inhibitory action of the Ox-PL-containing HDL on the function of PON1 are not clear yet. In this study we have assembled reconstituted HDL (rHDL) particles with and without Ox-PL and compared their effect on the structure and function of (13)C-labeled recombinant PON1 ((13)C-rPON1) by employing attenuated total reflectance Fourier transformed infrared (ATR-FTIR) spectroscopy and enzymatic assay. Our results show that the presence of the Ox-PL in the rHDL particles alters the structure of rPON1 and decreases its lactonase activity.