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TBK1 mutation spectrum in an extended European patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis human mutation. 20 Geronimo AM, Martin A, Simmons Z. Inertial sensing of step kinematics in ambulatory patients with ALS and related motor neuron diseases. Arterial blood gas analysis: base excess and carbonate are predictive of noninvasive ventilation adaptation and survival in amyotrophic lateral sclerosis. [Extracted from the article]

This work analyzes the thermal and mechanical effects arising in a power Diffusion Metal Oxide Semiconductor (DMOS) during a Single Event Burnout (SEB) process. For studying these effects we propose a more detailed simulation structure than the previously used by other authors, solving the mathematical models by means of the Finite Element Method. We use a cylindrical heat generation region, with 5 W, 10 W, 50 W and 100 W for emulating the thermal phenomena occurring during SEB processes, avoiding the complexity of the mathematical treatment of the ion-semiconductor interaction. The simulation results show that dangerous temperatures are reached only in the substrate. By other way, the mechanical study allows observing that there are materials where the failure due to thermal-induced mechanical stresses is reached before the melting time. Additionally, the shear stress observed in the device can compromise its electrical behavior due to the propagation of dislocations present in the DMOS structure. In this way, this work establishes the importance of taking into consideration the mechanical effects that take place during SEB processes. [ABSTRACT FROM AUTHOR]

The purpose of this study was to describe direct and indirect costs associated with pain in cancer patients and to examine potential predictors of these costs. The study surveyed cancer outpatients about direct costs resulting from pain-related hospitalizations, emergency department visits, physician office visits, and use of analgesic medications and indirect costs related to money spent on pain-related transportation, complementary methods to improve pain management, educational materials, over-the counter medication, domestic support, and childcare. Furthermore, the study examined age, marital status, race, income level, pain severity, pain interference, and presence of breakthrough pain as predictors of direct and indirect costs. Three hundred and seventy-three cancer outpatients were sampled. One hundred and forty-four cancer patients (39%) reported experiencing cancer-related pain and completed the study questionnaires. Seventy-six percent (76%) of the patients had experienced at least one pain-related cost, resulting in an average monthly direct cost of US$ 891/month per patient. Sixty-nine percent (69%) of patients had experienced some type of direct medical cost due to pain, resulting in an average total direct pain-related cost of US$ 825/month per patient. Fifty-seven percent (57%) of patients reported incurring at least one indirect pain-related expense for an average indirect cost of US$ 61/month per patient. Higher pain intensity, greater pain interference, and presence of breakthrough pain predicted higher direct and indirect medical expenses. Younger age and lower income level also predicted higher direct medical expenses. [ABSTRACT FROM AUTHOR]

The Zero Acceptance of Pain (ZAP) Quality Improvement Project was a multi-site effort to improve the lives of outpatients with cancer pain by enhancing the clinical practice of pain assessment and management. Independent samples of patients completed self-report measures of severity of pain, pain interference, global quality of life, pain treatment satisfaction, general medical treatment satisfaction, pain attitudes, and pain-related medical costs before and after the implementation of ZAP. Results suggested that ZAP decreased the severity of recent pain, decreased interference of pain on daily functioning, and improved satisfaction with pain treatment and attitudes about addiction to opioid medication. Direct medical costs consisting of pain-related hospitalizations, emergency department visits, and physician office visits were greatly reduced. In summary, the findings of this study support the idea that clinic-based efforts to improve the practice of pain management are effective in improving the lives of cancer patients who are experiencing pain. [ABSTRACT FROM AUTHOR]

As experienced authors, statisticians, editors, and scientists, we present the following comments to highlight some usages or omissions that are common in research manuscripts. Consideration of these comments will improve practices of data analysis and reporting.

Introduction: Osteoarticular infections (OAIs) constitute serious paediatric conditions that may cause severe complications. Identifying the causative organism is one of the mainstays of the care process, since its detection will confirm the diagnosis, enable adjustments to antibiotic therapy and thus optimize outcomes. Two bacteria account for the majority of OAIs before 16 years of age: Staphylococcus aureus is known for affecting the older child, whereas Kingella kingae affects infants and children younger than 4 years old. We aimed to better define clinical characteristic and biological criteria for prompt diagnosis and discrimination between these two OAI. Materials and methods: We retrospectively studied 335 children, gathering 100 K. kingae and 116 S. aureus bacteriologically proven OAIs. Age, gender, temperature at admission, involved bone or joint, and laboratory data including bacterial cultures were collected for analysis. Comparisons between patients with OAI due to K. kingae and those with OAI due to S. aureus were performed using the Mann−Whitney and Kruskal−Wallis tests. Six cut-off discrimination criteria (age, admission’s T°, WBC, CRP, ESR and platelet count) were defined, and their respective ability to differentiate between OAI patients due to K. kingae versus those with S. aureus was assessed by nonparametric receiver operating characteristic (ROC) curves. Results: Univariate analysis demonstrated significant differences between the two populations for age of patients, temperature at admission, CRP, ESR, WBC, and platelet count. AUC assessed by ROC curves demonstrated an exquisite ability to discriminate between the two populations for age of the patients; whereas AUC for CRP (0.79), temperature at admission (0.76), and platelet count (0.76) indicated a fair accuracy to discriminate between the two populations. Accuracy to discriminate between the two subgroups of patients was considered as poor for WBC (AUC = 0.62), and failed for ESR (AUC = 0.58). On the basis of our results, the best model to predict K. kingae OAI included of the following cut-offs for each parameter: age < 43 months, temperature at admission < 37.9 °C, CRP < 32.5 mg/L, and platelet count > 361,500/mm3. Conclusions: OAI caused by K. kingae affects primarily infants and toddlers aged less than 4 years, whereas most of the children with OAI due to MSSA were aged 4 years and more. Considering our experience on the ground, only three variables were very suggestive of an OAI caused by K. kingae, i.e., age of less than 4 years, platelet count > 400,000, and a CRP level below 32.5 mg/L, whereas WBC and ESR were relatively of limited use in clinical practice.

The aim of this paper is to analyse the thermal effects in a wind tunnel experiment to simulate the planetary boundary layer (PBL). Experiments were performed in the wind tunnel of the Laboratory of Constructions Aerodynamics at the Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul State, Brazil. This wind tunnel is a closed return low-speed wind tunnel specifically designed for dynamic and static studies on civil construction models. As a novelty, one of the experimental sections of the wind tunnel was equipped with a metal sheet with Peltier elements coupled to it. In other words, thermal effects generating new flow patterns become feasible and open pathways to compare wind tunnel simulations to those in the PBL. Furthermore, measurements obtained with the smooth floor of the wind tunnel were repeated under the same conditions with the addition of the roughness in the floor, and the mechanical turbulence generated by the surface roughness significantly amplified the exchange of momentum and heat between the regions located in vertical direction of the wind tunnel boundary layer. In the presence of turbulent heat flux near the surface, thermal effects contribute to the increase of the turbulence intensity. Turbulent energy spectra for flow velocities and different heights were obtained using the Hilbert-Huang transform method, and the observed convective turbulence energy spectra behavior reproduced those measured in an unstable surface PBL.

Nowadays, Kingella kingae ( K. kingae ) is considered as the main bacterial cause of osteoarticular infections (OAI) in children aged less than 48 months. Next to classical acute hematogenous osteomyelitis and septic arthritis, invasive K. kingae infections can also give rise to atypical osteoarticular infections, such as cellulitis, pyomyositis, bursitis, or tendon sheath infections. Clinically, K. kingae OAI are usually characterized by a mild clinical presentation and by a modest biologic inflammatory response to infection. Most of the time, children with skeletal system infections due to K. kingae would not require invasive surgical procedures, except maybe for excluding pyogenic germs' implication. In addition, K. kingae 's OAI respond well even to short antibiotics treatments, and, therefore, the management of these infections requires only short hospitalization, and most of the patients can then be treated safely as outpatients.

Aims: We aimed to describe the epidemiological, biological, and bacteriological characteristics of osteoarticular infections (OAIs) caused by Kingella kingae ., Methods: The medical charts of all children presenting with OAIs to our institution over a 13-year period (January 2007 to December 2019) were reviewed. Among these patients, we extracted those which presented an OAI caused by K. kingae and their epidemiological data, biological results, and bacteriological aetiologies were assessed., Results: K. kingae was the main reported microorganism in our paediatric population, being responsible for 48.7% of OAIs confirmed bacteriologically. K. kingae affects primarily children aged between six months and 48 months. The highest prevalence of OAI caused by K. kingae was between seven months and 24 months old. After the patients were 27 months old, its incidence decreased significantly. The incidence though of infection throughout the year showed no significant differences. Three-quarters of patients with an OAI caused by K. kingae were afebrile at hospital admission, 11% had elevated WBCs, and 61.2% had abnormal CRPs, whereas the ESR was increased in 75%, constituting the most significant predictor of an OAI. On MRI, we noted 53% of arthritis affecting mostly the knee and 31% of osteomyelitis located primarily in the foot., Conclusion: K. kingae should be recognized currently as the primary pathogen causing OAI in children younger than 48 months old. Diagnosis of an OAI caused by K. kingae is not always obvious, since this infection may occur with a mild-to-moderate clinical and biological inflammatory response. Extensive use of nucleic acid amplification assays improved the detection of fastidious pathogens and has increased the observed incidence of OAI, especially in children aged between six months and 48 months. We propose the incorporation of polymerase chain reaction assays into modern diagnostic algorithms for OAIs to better identify the bacteriological aetiology of OAIs. Cite this article: Bone Joint J  2021;103-B(3):578-583.

Objectives: This scoping review aimed to map and compile the available evidence regarding the effectiveness of decontaminating N95 respirators against the novel coronavirus (SARS-CoV-2)., Data: We selected studies written in English assessing or discussing the decontamination strategies of N95 respirators against SARS-CoV-2. Two independent researchers performed the search and study screening. A descriptive analysis was carried out considering the study design of the included studies., Sources: PubMed, SCOPUS, and Preprint platforms (bioRxiv and medRxiv)., Study Selection: We included 55 reports from PubMed and SCOPUS. Nine articles were letters to the editors, 21 were in vitro studies, 16 were literature reviews, and 9 were classified as other study designs. We included 37 preprints. Two articles were letters to the editors, 24 were in vitro studies, 3 were literature reviews, and 8 were classified as other study designs. In general, vaporized hydrogen peroxide and ultraviolet irradiation were the strategies most cited and most promising. However, there is a lack of evidence and consensus related to the best method of N95 respirator decontamination., Conclusion: The evidence regarding decontamination strategies of N95 respirators against SARS-CoV-2 remains scarce. Vaporized hydrogen peroxide and ultraviolet irradiation seem to be the current standard for N95 respirator decontamination., Clinical Significance: Vaporized hydrogen peroxide and ultraviolet irradiation appear to be the most promising methods for N95 respirator decontamination., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Osteoarticular infections of the chest wall are relatively uncommon in pediatric patients and affect primarily infants and toddlers. Clinical presentation is often vague and nonspecific. Laboratory findings may be unremarkable in osteoarticular chest wall infections and not suggestive of an osteoarticular infection. Causative microbes are frequently identified if specific nucleic acid amplification assays are carried out. In the young pediatric population, there is evidence that Kingella kingae is 1 of the main the main causative pathogens of osteoarticular infections of the chest wall.

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth.

Fibroblast growth factor 21 (FGF21) is a hormone secreted by the liver in response to metabolic stress. In addition to its well-characterized effects on energy homeostasis, FGF21 has been shown to increase water intake in animals. In this study, we sought to further explore the effects of FGF21 on fluid homeostasis in rats. A single dose of a long-acting FGF21 analog, PF-05231023, significantly increased water consumption, which was accompanied by an elevation in urine output that appeared prior to a significant change in water intake. We observed that FGF21 rapidly and significantly increased heart rate and blood pressure in telemeter-implanted rats, before changes in urine output and water intake were observed. Our data suggest that sympathetic activation may contribute to the pathogenesis by which FGF21 increases blood pressure as the baroreceptor unloading induced reflex tachycardia was significantly elevated in FGF21-treated animals. However, FGF21 was still capable of causing hypertension in animals in which approximately 40% of the sympathetic post-ganglionic neurons were ablated. Our data suggest that FGF21-induced water intake is in fact secondary to diuresis, which we propose to be a compensatory mechanism engaged to alleviate the acute hypertension caused by FGF21., Competing Interests: All authors were Pfizer employees at the time the work was completed. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Casein kinase 1 delta (CK1δ) and casein kinase 1 epsilon (CK1ε) inhibitors are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing a CNS kinase inhibitor has been limited by an inability to identify safe brain-penetrant compounds with high kinome selectivity. Guided by structure-based drug design, potent and selective CK1δ/ε inhibitors have now been identified that address this gap, through the design and synthesis of novel 4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine derivatives. PF-5006739 (6) possesses a desirable profile, with low nanomolar in vitro potency for CK1δ/ε (IC50 = 3.9 and 17.0 nM, respectively) and high kinome selectivity. In vivo, 6 demonstrated robust centrally mediated circadian rhythm phase-delaying effects in both nocturnal and diurnal animal models. Further, 6 dose-dependently attenuated opioid drug-seeking behavior in a rodent operant reinstatement model in animals trained to self-administer fentanyl. Collectively, our data supports further development of 6 as a promising candidate to test the hypothesis of CK1δ/ε inhibition in treating multiple indications in the clinic.

How does the effectiveness of guiding cues influence the development of motor skill autonomy? We utilized two sets of guiding cues (lights vs. reversed-lights conditions) that differed in their effectiveness to control a left-right leverpress sequence in rats. We separately measured the development of stimulus control by panel lights on guiding-cues trials and the development of stimulus control by practice cues on no-cue probe trials within the same sessions. Accuracy in the presence of the guiding cues was acquired faster in the lights condition than in the reversed-lights condition, but subjects in the reversed-lights condition were more able to complete the skill autonomously than those in the lights condition. Throughout acquisition, control by guiding cues and practice cues developed at the same rate in the reversed-lights condition, but control by practice cues (autonomy) developed at a slower rate than did control by guiding cues in the lights condition. At the end of training, subjects that had been exposed to the reversed-lights condition displayed higher levels of autonomy than did those exposed to the lights condition. The less effective guiding cue (reversed-lights) produced greater levels of autonomy than did the more effective cue (lights), even though control by this guiding cue developed more slowly. Thus, guiding your child by the hand too much may reduce his or her ability to complete the task independently. We discuss the similarity to prompt dependence in children with learning disabilities and transfer of stimulus control.

Sphingolipids are polar membrane lipids present as minor components in eukaryotic cell membranes. Sphingolipids are highly enriched in nervous cells, where they exert important biological functions. They deeply affect the structural and geometrical properties and the lateral order of cellular membranes, modulate the function of several membrane-associated proteins, and give rise to important intra- and extracellular lipid mediators. Sphingolipid metabolism is regulated along the differentiation and development of the nervous system, and the expression of a peculiar spatially and temporarily regulated sphingolipid pattern is essential for the maintenance of the functional integrity of the nervous system: sphingolipids in the nervous system participate to several signaling pathways controlling neuronal survival, migration, and differentiation, responsiveness to trophic factors, synaptic stability and synaptic transmission, and neuron-glia interactions, including the formation and stability of central and peripheral myelin. In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal sphingolipid patterns and altered membrane organization that participate to several events related to the pathogenesis of these diseases. The most impressive consequence of this deregulation is represented by anomalous sphingolipid-protein interactions that are at least, in part, responsible for the misfolding events that cause the fibrillogenic and amyloidogenic processing of disease-specific protein isoforms, such as amyloid beta peptide in Alzheimer's disease, huntingtin in Huntington's disease, alpha-synuclein in Parkinson's disease, and prions in transmissible encephalopathies. Targeting sphingolipid metabolism represents today an underexploited but realistic opportunity to design novel therapeutic strategies for the intervention in these diseases.

The aim of the study was to investigate the ability of (1)HMRS to reflect proliferative activity of diffuse low-grade gliomas (WHO grade II). Between November 2002 and March 2007, a prospective study was performed on consecutive patients with suspected supratentorial hemispheric diffuse low-grade tumors. All the patients underwent MR examination using uniform procedures, and then surgical resection or biopsy within 2 weeks of the MR examination. Proliferative activity of the tumors was assessed by Ki-67 immunochemistry (Mb-1) on paraffin embedded tumor sections. Spectroscopic data was compared with Ki-67 labeling index and other histologic data such as histological subtype, cellular atypia, cellular density using univariate and multivariate analysis. 82 of 97 consecutive patients had histologically confirmed WHO grade 2 gliomas. Ki-67 proliferation index (PI) was correlated with specific spectral patterns: (1) low PI (<4%) was associated with increased Cho/Cr and absence of both free lipids or lactates; (2) intermediate PI (4-8%) was associated with resonance of lactates; and (3) high PI (>8%) was characterized by a resonance of free lipids. On multivariate analysis, resonance of lactates and resonance of free lipids appeared as independent predictors of intermediate PI (P < 0.001) and high PI (P < 0.001), respectively; moreover, free lipids resonance was correlated with cellular atypia (P < 0.05). This study suggests that (1)HMRS is a reliable tool to evaluate the proliferation activity of WHO grade 2 glioma and to identify potentially more aggressive clinical behavior.

Alterations in the mechanisms of apoptosis are responsible not only for the progression of breast cancer, but for different responses to treatment as well. Among the genes regulators of apoptosis, the tumor suppressor gene p53 and the bcl-2 gene have raised interest for their possible role as predictors of response to therapy and markers of prognosis. The purpose of our study was to prospectively analyze the prognostic value of the expression of p53 and bcl-2 genes in a series of 235 consecutive patients operated on for breast cancer at the Department of General Surgery and Surgical Oncology of the University of Siena, Italy.p53 and bcl-2 expression were evaluated by immunohistochemistry, their association with conventional clinicopathological factors was analyzed by univariate analysis and their prognostic impact was evaluated by multivariate analysis.p53 and bcl-2 were detected respectively in 15.7 and 75.7% of cases, and resulted significantly related to presence of estrogen receptors for p53 over-expression and presence of peritumor lymphovascular invasion (LVI) for bcl-2 expression. With a median follow-up of 79 months, an independent negative prognostic impact on disease free and overall survival was observed for presence of LVI, absence of bcl-2 expression and number of involved axillary lymphnodes. The expression of bcl-2 improved the prognosis of LVI positive tumors up to values similar to LVI negative cases, while its absence associated to presence of LVI resulted in a poor outcome with only 28% of patients alive at 8 years. These data may indicate that expression of bcl-2 is a marker of breast cancers with reduced capability of distant colonization, even in presence of LVI, and may be particularly useful in the clinical setting, allowing to identify a subset of patients with an high risk of relapse.

The prefrontal cortex and brainstem modulate autonomic and arousal state control but the neurotransmitter mechanisms underlying communication between prefrontal cortex and brainstem remain poorly understood. This study examined the hypothesis that microdialysis delivery of carbachol to the pontine reticular formation (PRF) of anesthetized C57BL/6J (B6) mouse modulates acetylcholine (ACh) release in the frontal association cortex. Microdialysis delivery of carbachol (8.8 mM) to the PRF caused a significant (P<0.01) decrease (-28%) in ACh release in the frontal association cortex, a significant (P<0.01) decrease (-23%) in respiratory rate, and a significant (P<0.01) increase (223%) in time to righting after anesthesia. Additional in vitro studies used the [(35)S]guanylyl-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) assay to test the hypothesis that muscarinic cholinergic receptors activate guanine nucleotide binding proteins (G proteins) in the frontal association cortex and basal forebrain. In vitro treatment with carbachol (1 mM) caused a significant (P<0.01) increase in [(35)S]GTPgammaS binding in the frontal association cortex (62%) and basal forebrain nuclei including medial septum (227%), vertical (210%) and horizontal (165%) limbs of the diagonal band of Broca, and substantia innominata (127%). G protein activation by carbachol was concentration-dependent and blocked by atropine, indicating that the carbachol-stimulated [(35)S]GTPgammaS binding was mediated by muscarinic cholinergic receptors. Together, the in vitro and in vivo data show for the first time in B6 mouse that cholinergic neurotransmission in the PRF can significantly alter ACh release in frontal association cortex, arousal from anesthesia, and respiratory rate.

The authors tested the efficacy of a mind/body wellness intervention for older adults with chronic illness. They randomly assigned 243 physician-referred patients from an urban HMO to a classroom intervention or a wait-list control group. The intervention provided instruction on mind/body relationships; relaxation training; cognitive restructuring; problem-solving; communication; and behavioral treatment for insomnia, nutrition, and exercise. At posttreatment, the intervention group had significant decreases in self-reported sleep difficulties, pain, anxiety, and depression symptoms compared with controls. The intervention also led to a significant decrease in "chance" and "powerful others" health locus of control beliefs. At 1-year follow-up, the intervention group maintained benefits in sleep and health locus of control and also reported a significant increase in health behaviors compared with controls. Pain, anxiety, and depression benefits were not maintained. This type of classroom intervention appears to have some lasting effects on health behaviors and beliefs.

Two versions of a multicomponent mind-body wellness intervention were tested. One hundred seventy-eight physician-referred HMO patients (mean age = 64.5) were randomly assigned to a classroom intervention, a home study intervention, or a wait-list control group. Both interventions provided instruction on mind-body relationships, relaxation training, cognitive restructuring, problem solving, communication, behavioral treatment for insomnia, nutrition, and exercise. The home version was delivered by class videotapes and readings. Compared with the control condition, both interventions led to significant decreases in self-reports of pain, sleep difficulties, and symptoms of depression and anxiety. The home course also led to a significant decrease in self-reported frequency of medical symptoms, and the classroom program resulted in a significant decrease in "chance" health locus of control beliefs. No effects were obtained for health behaviors, life satisfaction, HMO satisfaction, and other health locus of control beliefs. A lower cost, more accessible home study version of a mind-body wellness program can be an effective alternative to classroom instruction.