Self-report and urine drug screen concordance among women with co-occurring PTSD and substance use disorders participating in a clinical trial: Impact of drug type and participant characteristics.

BACKGROUND: Self-report measures are important in substance use assessment, yet they are susceptible to reporting errors. Urine drug screens (UDS) are often considered a more valid alternative. However, collecting in-person UDS may not always be feasible, contributing to the need to understand factors that influence the validity of self-reported substance use. METHODS: In this secondary analysis of data from 295 women with co-occurring PTSD and substance use disorders (SUD) who participated in a clinical trial testing behavioral interventions, we examined concordance and discordance between self-reported drug use and associated UDS results. Generalized linear mixed models were used to examine the impact of treatment type and participant characteristics on the associations between self-reported drug use and UDS results. RESULTS: Findings revealed higher disagreement between self-report and UDS for opioids and sedatives (ranging from.77 to.90) and lower disagreement rates for cannabis and cocaine (ranging from.26 to.33). Treatment type was not a significant moderator of the associations between self-report and UDS across all drugs. Among those with a positive opioid UDS, those who reported employment in the past three years were more likely to self-report no opioid use compared to their counterparts without employment in the past three years. CONCLUSIONS: Findings add to the literature that supports the validity of self-reported cannabis and cocaine use. The greater discrepancies between self-report and UDS test results of opioids and sedatives suggest adjunctive UDS may be required, although a variety of factors other than inaccurate self-report may be associated with this discrepancy.

The novel Mechanical Ventilator Milano for the COVID-19 pandemic.

This paper presents the Mechanical Ventilator Milano (MVM), a novel intensive therapy mechanical ventilator designed for rapid, large-scale, low-cost production for the COVID-19 pandemic. Free of moving mechanical parts and requiring only a source of compressed oxygen and medical air to operate, the MVM is designed to support the long-term invasive ventilation often required for COVID-19 patients and operates in pressure-regulated ventilation modes, which minimize the risk of furthering lung trauma. The MVM was extensively tested against ISO standards in the laboratory using a breathing simulator, with good agreement between input and measured breathing parameters and performing correctly in response to fault conditions and stability tests. The MVM has obtained Emergency Use Authorization by U.S. Food and Drug Administration (FDA) for use in healthcare settings during the COVID-19 pandemic and Health Canada Medical Device Authorization for Importation or Sale, under Interim Order for Use in Relation to COVID-19. Following these certifications, mass production is ongoing and distribution is under way in several countries. The MVM was designed, tested, prepared for certification, and mass produced in the space of a few months by a unique collaboration of respiratory healthcare professionals and experimental physicists, working with industrial partners, and is an excellent ventilator candidate for this pandemic anywhere in the world.

α-Synuclein deficiency and efferent nerve degeneration in the mouse cochlea: a possible cause of early-onset presbycusis.

OBJECTIVES/HYPOTHESIS: Efferent nerves under the outer hair cells (OHCs) play a role in the protection of these cells from loud stimuli. Previously, we showed that cochlear α-synuclein expression is localized to efferent auditory synapses at the base of the OHCs. To prove our hypothesis that α-synuclein deficiency and efferent auditory deficit might be a cause of hearing loss, we compared the morphology of efferent nerve endings and α-synuclein expression within the cochleae of two mouse models of presbycusis. STUDY DESIGN: Comparative animal study of presbycusis. METHODS: The C57BL/6J(C57) mouse strain, a well-known model of early-onset hearing loss, and the CBA mouse strain, a model of relatively late-onset hearing loss, were examined. Auditory brainstem responses and distortion product otoacoustic emissions were recorded, and cochlear morphology with efferent nerve ending was compared. Western blotting was used to examine α-synuclein expression in the cochlea. RESULTS: Compared with CBA mice, C57 mice showed earlier onset high-frequency hearing loss and decreased function in OHCs, especially within high-frequency regions. C57 mice demonstrated more severe pathologic changes within the cochlea, particularly within the basal turn, than CBA mice of the same age. Weaker α-synuclein and synaptophysin expression in the efferent nerve endings and cochlear homogenates in C57 mice was observed. CONCLUSIONS: Our results support the hypothesis that efferent nerve degeneration, possibly due to differential α-synuclein expression, is a potential cause of early-onset presbycusis. Further studies at the cellular level are necessary to verify our results.

The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in ß-cells.

Diabetes is an epidemic of worldwide proportions caused by ß-cell failure. Nutrient fluctuations and insulin resistance drive ß-cells to synthesize insulin beyond their capacity for protein folding and secretion and thereby activate the unfolded protein response (UPR), an adaptive signalling pathway to promote cell survival upon accumulation of unfolded protein in the endoplasmic reticulum (ER). Protein kinase-like endoplasmic reticulum kinase (PERK) signals one component of the UPR through phosphorylation of eukaryotic initiation factor 2 on the α-subunit (eIF2α) to attenuate protein synthesis, thereby reducing the biosynthetic burden. ß-Cells uniquely require PERK-mediated phosphorylation of eIF2α to preserve cell function. Unabated protein synthesis in ß-cells is sufficient to initiate a cascade of events, including oxidative stress, that are characteristic of ß-cell failure observed in type 2 diabetes. In contrast to acute adaptive UPR activation, chronic activation increases expression of the proapoptotic transcription factor CAAT/enhancer-binding protein homologous protein (CHOP). Chop deletion in insulin-resistant mice profoundly increases ß-cell mass and prevents ß-cell failure to forestall the progression of diabetes. The findings suggest an unprecedented link by which protein synthesis and/or misfolding in the ER causes oxidative stress and should encourage the development of novel strategies to treat diabetes.

Characteristics for electrochemical machining with nanoscale voltage pulses.

Electrochemical machining has traditionally been used in highly specialized fields, such as those of the aerospace and defense industries. It is now increasingly being applied in other industries, where parts with difficult-to-cut material, complex geometry and tribology, and devices of nanoscale and microscale are required. Electric characteristic plays a principal function role in and chemical characteristic plays an assistant function role in electrochemical machining. Therefore, essential parameters in electrochemical machining can be described current density, machining time, inter-electrode gap size, electrolyte, electrode shape etc. Electrochemical machining provides an economical and effective method for machining high strength, high tension and heat-resistant materials into complex shapes such as turbine blades of titanium and aluminum alloys. The application of nanoscale voltage pulses between a tool electrode and a workpiece in an electrochemical environment allows the three-dimensional machining of conducting materials with sub-micrometer precision. In this study, micro probe are developed by electrochemical etching and micro holes are manufactured using these micro probe as tool electrodes. Micro holes and microgroove can be accurately achieved by using nanoscale voltages pulses.

Cutaneous lymphangiectasia associated with photoageing and topical corticosteroid application.

We report the case of a 69-year-old man with a history of multiple erythematous bullae on both forearms, which had been present for about 1 month. The lesions appeared after several years of topical corticosteroid application and photoageing. A biopsy revealed lymphangiectasia with solar elastosis and increase in the ratio of elastic to collagen fibres in the dermis. We suggest that this patient's lymphangiectasia resulted from abnormal structure and function of the dermis due to photoageing and steroid-related atrophy.

Verification of dynamic radiotherapy: the potential for 3D dosimetry under respiratory-like motion using polymer gel.

Following the implementation of advanced treatment procedures in radiotherapy, there is a need for dynamic dose verification in 3D. Gel dosimetry could potentially be used for such measurements. However, recently published data show that certain types of gels have a dose rate and fractionation dependence. The aim of this study was to investigate the feasibility of using a polymer gel dosimeter for dose verification of dynamic radiotherapy. To investigate the influence of dose rate dependence during respiratory-like motion in and out of the beam, a respiration robot together with two types of gel systems (normoxic methacrylic acid gel (nMAG) and normoxic polyacrylamide gel (nPAG)) were used. Reference measurements were obtained using a linear diode array (LDA). Expected results, if there was no influence of the dose rate variation, were calculated by convolving the static irradiated gel data with the motion function controlling the robot. To investigate the fractionation dependence, the gels were irradiated using gated and ungated deliveries. Magnetic resonance imaging was used to evaluate the absorbed dose response of the gel. The measured gel data coincided well with the LDA data. Also, the calculated data agreed well with the measured dynamic gel data, i.e. no dose rate dependence due to motion was observed. The difference in the R2 response for the gels receiving ungated and gated, i.e. fractionated, deliveries was less than 1% for the nPAG and 4% for the nMAG, for absorbed doses up to 2 Gy. The maximum difference was 1.2% for the nPAG and 9% for the nMAG, which occurred at the highest given dose (4 Gy). The investigated gels were found to be feasible detectors for dose measurements under respiratory-like motion. For dose verification of dynamic RT involving gated delivery, e.g. breathing-adapted radiotherapy, relative absorbed dose evaluation should be used in order to minimize the effects of fractionated irradiation.

Prediction of relative glomerular filtration rate in adults: new improved equations based on Swedish Caucasians and standardized plasma-creatinine assays.

OBJECTIVE: To evaluate newly developed equations predicting relative glomerular filtration rate(GFR) in adult Swedish Caucasians and to compare with the Modification of Diet in Renal Disease(MDRD) and Mayo Clinic equations using enzymatic and zero-calibrated plasma creatinine assays. MATERIAL AND METHODS: GFR was measured with iohexol clearance adjusted to 1.73 m(2). One population sample (n=436/Lund) was used to derive an equation based on plasma-creatinine/age/gender, and a second with the addition of lean body mass (LBM). Both equations were validated in a separate sample (n=414/Malmö). The coefficients of the equations were eventually fine-tuned using all 850 patients and yielding Lund-Malmö equations without (LM) and with LBM-term (LM(LBM)). Their performance was compared with the MDRD(CC) (conventional creatinine calibration), MDRD(IDMS) (isotope dilution mass spectroscopy traceable calibration) and Mayo Clinic equations. RESULTS: The Lund equations performed similarly in both samples. In the combined set, the Mayo Clinic/MDRD(CC) resulted in +19.0/+10.2 % median bias, while bias for the other equations was < 10 %. LM(LBM) had the highest accuracy (86 % of estimates within 30 % of measured GFR), significantly (p < 0.001) better than for MDRD(IDMS) (80 %). In men with BMI < 20 kg/m(2), MDRD(IDMS)/LM had +46 %/+19 % median bias. MDRD(IDMS) also overestimated GFR by 22 %/14 % in men/women above 80 years of age. The LM(LBM) equation had < 10 % bias irrespective of BMI, age or GFR except for a 15 % negative bias at GFR > 90 mL/min/1.73 m(2). CONCLUSION: The newly developed Lund-Malmö equations for GFR estimation performed better than the MDRD(IDMS) and Mayo Clinic equations in a Swedish Caucasian sample. Inclusion of an LBM term improved performance markedly in certain subgroups.

Dose integration characteristics in normoxic polymer gel dosimetry investigated using sequential beam irradiation.

Dose integration properties were investigated for normoxic polymer gels based on methacrylic acid (nMAG) and acrylamide/N, N'-methylenebisacrylamide (nPAG). The effect of sequential irradiation was studied for different fractionation schemes and varying amounts of methacrylic acid for the nMAG gels. Magnetic resonance imaging (MRI) was used for read out of the absorbed dose response. The investigated gels exhibited a dependence on the fractionation scheme. The response when the total dose was divided into fractions of 0.5 Gy was compared with the response when the total dose was delivered in a single fraction. The slope of the R2 versus the absorbed dose response decreased when the absorbed dose per fraction was increased. Also, for higher amounts of methacrylic acid in the nMAG system the difference in the response increased. For gels containing 2, 4, 6 and 8% methacrylic acid, the R2 versus the absorbed dose response increased by 35, 37, 63 and 93%, respectively. Furthermore, the effect of the fractionation was larger when a higher total absorbed dose was given. The effect was less pronounced for the investigated nPAG, containing 3% acrylamide and 3% N, N'-methylenebisacrylamide, than for the nMAG systems. Consequently, this study indicates that the nPAG system has preferable beam integration characteristics compared with the nMAG system.

Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase-5.

Chronic inflammatory and neuropathic pain is often difficult to manage using conventional remedies. The underlying mechanisms and therapeutic strategies required for the management of chronic pain need to be urgently established. The cyclic AMP (cAMP) second messenger system has been implicated in the mechanism of nociception, and the inhibition of the cAMP pathway by blocking the activities of adenylyl cyclase (AC) and protein kinase A has been found to prevent chronic pain in animal models. However, little is known regarding which of the 10 known isoforms of AC are involved in nociceptive pathways. Therefore, we investigated the potential pronociceptive function of AC5 in nociception using recently developed AC5 knockout mice (AC5-/-). We found that AC5-/- mice show markedly attenuated pain-like responses in acute thermal and mechanical pain tests as compared with the wildtype control. Also, AC5-/- mice display hypoalgesic responses to inflammatory pain induced by subcutaneous formalin injection into hindpaws, and to non-inflammatory and inflammatory visceral pain induced by injecting magnesium sulfate or acetic acid into the abdomen. Moreover, AC5-/- mice show strongly suppressed mechanical and thermal allodynia in two nerve injury-induced neuropathic pain models. These results suggest that AC5 is essential for acute and chronic pain, and that AC5 knockout mice provide a useful model for the evaluation of the pathophysiological mechanisms of pain.

Standardization of p-creatinine assays and use of lean body mass allow improved prediction of calculated glomerular filtration rate in adults: a new equation.

OBJECTIVE: To evaluate the Cockcroft-Gault (CG) equation, using various body weight expressions, and the Sawyer equation in predicting glomerular filtration rate (GFR) using an enzymatic and zero-calibrated Jaffe plasma-creatinine assay, and to derive a new robust equation in adults. MATERIAL AND METHODS: The CG weight measures included total, ideal and adjusted body weight (ABW; lowest of total and ideal) and two lean body mass (LBM) expressions, while the Sawyer equation is based primarily on LBM. Iohexol clearance was used to measure GFR. One derivation set (n = 436; enzymatic assay) was used to evaluate and bias-adjust existing equations when indicated, and to derive a new equation based on plasma-creatinine, age, gender and the body weight measure yielding the best adjusted R2. All equations were then validated in a separate set (n = 414; Jaffe assay). RESULTS: The existing equations all performed similarly in both sets. Prediction errors of equations based on LBM showed no correlation with BMI. The CGABW and Sawyer equations performed best. The new equation with LBM yielded the highest adjusted R2. In the combined set (n = 850), its accuracy (86 %/98 % of estimates within 30 %/50 % of measured GFR) was significantly better than for the CGABW (79 %/95 %) and Sawyer equations (79 %/93 %) (p<0.001) for each 30 mL/min GFR subgroup within +/-30 % and +/-50 %, except within +/-30 % >120 mL/min. Prediction error did not correlate with BMI, age or gender. CONCLUSION: A new creatinine-based equation derived in a mainly Caucasian patient sample is a better predictor of GFR than CG-type equations irrespective of the body weight measure used or, if bias-adjusted, when using zero-calibrated creatinine assays.

Dose response evaluation of a low-density normoxic polymer gel dosimeter using MRI.

A low-density (approximately 0.6 g cm(-3)) normoxic polymer gel, containing the antioxidant tetrakis (hydroxymethyl) phosponium (THP), has been investigated with respect to basic absorbed dose response characteristics. The low density was obtained by mixing the gel with expanded polystyrene spheres. The depth dose data for 6 and 18 MV photons were compared with Monte Carlo calculations. A large volume phantom was irradiated in order to study the 3D dose distribution from a 6 MV field. Evaluation of the gel was carried out using magnetic resonance imaging. An approximately linear response was obtained for 1/T2 versus dose in the dose range of 2 to 8 Gy. A small decrease in the dose response was observed for increasing concentrations of THP. A good agreement between measured and Monte Carlo calculated data was obtained, both for test tubes and the larger 3D phantom. It was shown that a normoxic polymer gel with a reduced density could be obtained by adding expanded polystyrene spheres. In order to get reliable results, it is very important to have a uniform distribution of the gel and expanded polystyrene spheres in the phantom volume.

Molecular networks perturbed in a developmental animal model of brain injury.

Methylazoxymethanol (MAM) is widely used as a developmental neurotoxin and exposure to its glucoside (i.e., cycasin) is associated with the prototypical neurological disorder western Pacific ALS/PDC. However, the specific molecular targets that play a key role in MAM-induced brain injury remain unclear. To reveal potential molecular networks targeted by MAM in the developing nervous system, we examined characteristic phenotypic changes (DNA damage, cytoarchitecture) induced by MAM and their correlation with gene expression differences using microarray assays (27,648 genes). Three day-old postnatal C57BL/6 mice (PND3) received a single injection of MAM and the cerebellum and cerebral cortex of PND4, 8, 15, and 22 mice were analyzed. DNA damage was detected in both the cerebellum (N7-mGua, TUNEL labeling) and cerebral cortex (N7-mGua) of PND4 mice, but progressive disruption of the cytoarchitecture was restricted to the cerebellum. A majority (>75%) of the genes affected (cerebellum 636 genes, cortex 1080 genes) by MAM were developmentally regulated, with a predominant response early (PND4) in the cerebellum and delayed (PND8 and 15) in the cerebral cortex. The genes and pathways (e.g., proteasome) affected by MAM in the cerebellum are distinct from cortex. The genes perturbed in the cerebellum reflect critical cellular processes such as development (17%), cell cycle (7%), protein metabolism (12%), and transcriptional regulation (9%) that could contribute to the observed cytoarchitectural disruption of the cerebellum. This study demonstrates for the first time that specific genes and molecular networks are affected by MAM during CNS development. Further investigation of these targets will help to understand how disruption of these developmental programs could contribute to chronic brain injury or neurodegenerative disease.

Parents' assessments of how much time they spend with their children at different ages.

The self-reported amount of active engagement time parents (n = 1107) and children (n = 773) spend together was investigated with questionnaires. Mothers spent more time with their children than fathers did. The amount of parental quality time decreased with the age of the child, the average across age groups being 4.4 +/- 3.0 hr. for mothers and 3.0 +/- 2.9 hr. for fathers per day. Children reported spending roughly 1 hour more time with their parents than the latter reported.

Development and optimization of a 2-hydroxyethylacrylate MRI polymer gel dosimeter.

In this study, radiation induced changes in a polymer gel dosimeter manufactured using 2-hydroxyethylacrylate (HEA) and N,N'-methylene-bisacrylamide (BIS) were investigated using magnetic resonance imaging (MRI) and FT-Raman spectroscopy. The variation in magnetic resonance relaxation time (T2) with absorbed dose was modelled assuming fast exchange of magnetization. Overall good agreement between the model and experimental data was obtained. However, comparison with FT-Raman data suggests that not all the protons attached to the polymer contribute to the relaxation process. Furthermore, for certain compositions improved agreement with experimental data was achieved when a lower fraction of polymer protons available for exchange with water was assumed in the low dose region. This indicates that the T2 value is influenced by the composition and topology of the formed polymer, which may vary with absorbed dose. The concept of percentage dose resolution (Dp delta, %) was introduced to enable optimization of gel compositions for use in relative dosimetry applications. This concept was applied to demonstrate the effects of varying the gelatine concentration, the total fraction of monomer/crosslinker (%T) and the relative fraction of crosslinker (%C) on gel performance in HEA gels as well as compare the performance of HEA and a standard polyacrylamide gel (PAG). The percentage dose resolution was improved for all HEA gels compared to the PAG dosimeter containing 3% acrylamide and 3% BIS. Increasing the total concentration of monomer was shown to have the largest single effect. In the range of doses of interest for clinical radiation therapy, Dp delta, % for the optimal HEA gel (4% HEA, 4% BIS) was lower than 2.3%, compared to 3.8% for the PAG dosimeter.

Investigation of the NMR relaxation rate dose-response of a ceric sulphate dosimeter.

The relationship between the radiation absorbed dose and the NMR longitudinal and transversal relaxation rates, R1 and R2, respectively, of a ceric sulphate dosimeter was examined. By adding copper sulphate, the R1 and R2 dose-responses were found to be linear up to 60 kGy with dose sensitivities of 13 x 10(-6) and 15 x 10(-6) s(-1) Gy(-1) , respectively. There is thus the potential for a three-dimensional ceric dosimeter for high dose applications, provided a suitable gelling substance is used.

Magnetization transfer imaging for polymer gel dosimetry.

Off-resonance RF pre-saturation was used to obtain contrast in MRI images of polymer gel dosimeters irradiated to doses up to 50 Gy. Two different polymer gel dosimeters composed of 2-hydroxyethyl-acrylate or methacrylic acid monomers mixed with N, N'-methylene-bisacrylamide (BIS), dispersed in an aqueous gelatin matrix were evaluated. Radiation-induced polymerization of the co-monomers generates a fast-relaxing insoluble polymer. Saturation of the polymer using off-resonance Gaussian RF pulses prior to a spin-echo readout with a short echo time leads to contrast that is dependent on the absorbed dose. This contrast is attributed to magnetization transfer (MT) between free water and the polymer, and direct saturation of water was found to be negligible under the prevailing experimental conditions. The usefulness of MT imaging was assessed by computing the dose resolution obtained with this technique. We found a low value of dose resolution over a wide range of doses could be obtained with a single experiment. This is an advantage over multiple spin echo (MSE) experiments using a single echo spacing where an optimal dose resolution is achieved over only very limited ranges of doses. The results suggest MT imaging protocols may be developed into a useful tool for polymer gel dosimetry.

Sympathetic sprouting in sensory ganglia depends on the number of injured neurons.

We examined whether the extent of sympathetic sprouting in the dorsal root ganglion was a function of the number of injured nerve fibers. We compared two groups of rats. One group was subjected to unilateral superior and inferior caudal trunk transections at the level between the S1 and S2 spinal nerves (S-I group) and the other group was subjected to unilateral superior caudal trunk transection at the same level (S group). Immunohistochemical staining with tyrosine hydroxylase (TH) antibody of the S1 DRG revealed that the degree of TH-immunoreactive fibers was more extensive in the S-I group than in the S group. However, there was no difference in the severity of neuropathic pain behaviors between the two groups. These results suggest that the extent of sympathetic sprouting in the DRG following peripheral nerve injury is proportionally related to the amount of injured nerve fibers, but not related to the degree of neuropathic pain behaviors.

Simple methods for the correction of T2 maps of phantoms.

Two simple methodologies for correcting the errors in T2 maps for phantom measurements are presented; they both give accurate MRI maps with a low coefficient of variation (CV). The rate correction method is based on an equation relating the true T2 (T2,t) and that determined experimentally (T2,exp) for homogenous phantoms. The response matrix method is a phenomenological analysis of the difference between T2,exp and T2,t, from which correction factors are computed for a range of T2 values and for every pixel of an image. The factors were obtained from phantoms filled with a homogeneous gelatin gel and having different T2,t values. The CV in homogeneous phantom measurements were reduced from 2.5-4.0% to approximately 0.6-2.0% for T2,t values ranging from 180-600 ms. Examples are shown for the correction of T2 maps of phantoms filled with polymer dosimeter gel irradiated with photon beams from a linear accelerator. The methodologies presented can easily be implemented on a clinical MRI scanner.

Dose resolution optimization of polymer gel dosimeters using different monomers.

Polymer gel dosimeters of different formulations were manufactured from different monomers of acrylamide, acrylic acid, methacrylic acid, 1-vinyl-2-pyrrolidinone, 2-hydroxyethyl methacrylate and 2-hydroxyethyl acrylate. Gelatin and agarose were used as the gelling agents and N,N'-methylene-bis-acrylamide was used as a co-monomer in each polymer gel dosimeter. The T2 dependence of each dosimeter was analysed using a model of fast exchange of magnetization. The influence of the half-dose and the apparent T2 of the polymer-proton pool on the dose resolution (Dpdelta) were examined. Comparisons are made with the commonly employed R2-dose sensitivity. Differences exist suggesting that experiments reported in the literature using what were thought to be more optimal dosimeters may not actually be so. Based on Dpdelta of each formulation, conclusions are drawn on the optimal formulation required for a specific range of absorbed doses. In addition, information about the extent of polymerization of the monomers used along with some characteristics of the polymer network formed are reported. The influence of the concentration of monomers and gelling agent was subsequently evaluated using a model of fast exchange of magnetization. Based on these calculations, further improvement in Dpdelta can be expected.