Search

The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with multiple sclerosis (MS) who are commonly on long-term immunotherapies. Managing MS during the pandemic remains challenging with little published experience and no evidence-based guidelines. We present five teriflunomide-treated patients with MS who subsequently developed active COVID-19 infection. The patients continued teriflunomide therapy and had self-limiting infection, without relapse of their MS. These observations have implications for the management of MS in the setting of the COVID-19 pandemic.

Neurodegenerative disorders, particularly in the elderly population, represent one of the most pressing social and health-care problems in the world. Besides the well-established role of both oxidative stress and inflammation, alterations of the immune response have been found to be closely linked to the development of neurodegenerative diseases. Interestingly, various scientific evidence reported that an altered gut microbiota composition may contribute to the development of neuroinflammatory disorders. This leads to the proposal of the concept of the gut-brain-immune axis. In this scenario, polyphenols play a pivotal role due to their ability to exert neuroprotective, immunomodulatory and microbiota-remodeling activities. In the present review, we summarized the available literature to provide a scientific evidence regarding this neuroprotective and immunomodulatory effects and the interaction with gut microbiota of polyphenols and, the main signaling pathways involved that can explain their potential therapeutic application in neurodegenerative diseases.

An increase in the number of multidrug-resistant microbial strains is the biggest threat to global health and is projected to cause >10 million deaths by 2055. The carbapenem family of antibacterial drugs are an important class of last-resort treatment of infections caused by drug-resistant bacteria and are only available as an injectable formulation. Given their instability within the gut and poor permeability across the gut wall, oral carbapenem formulations show poor bioavailability. Meropenem (MER), a carbapenem antibiotic, has broad-spectrum antibacterial activity, but suffers from the above-mentioned issues. In this review, we discuss strategies for improving the oral bioavailability of MER, such as inhibiting tubular secretion, prodrug formulations, and use of nanomedicine. We also highlight challenges and emerging approaches for the development of oral MER.

The objective of this study is to investigate the effect of type of pregnancy (singleton, dizygotic, and monozygotic) on infant neurodevelopment and to explore how laterality operates in this relationship.We constructed a prospective cohort of low-risk women with singleton, monozygotic, and dizygotic pregnancies. Laterality was evaluated using the Edinburgh's scale of laterality, while neurodevelopment was assessed using the AgesStages Questionnaire (ASQ). The confounding, modifying, and mediating effect of laterality on the relationship between multiple pregnancy and neurodevelopment was explored by linear regression.We included 207 singletons, 77 dizygotic, and 75 monozygotic pregnancies. The mean age (SD) at assessment of neurodevelopment was 48.5 (7.5) months. There was a significant trend to poorer neurodevelopment across singleton, dizygotic and monozygotic pregnancies in communication (52.2, 47.6 and 42.3;The association of multiple pregnancy to poorer neurodevelopment was independent of children laterality.

Meropenem (MER) is an effective broad-spectrum antibiotic currently only available in the parenteral form requiring frequent drug preparation and administration due to its extremely poor stability. The unavailability of oral Meropenem is primarily due to its ultrapoor handling and processing stability, hydrophilic nature that inhibits the passive diffusion across the gastrointestinal (GI) epithelium, degradation in the harsh gastric environment, and GI expulsion through enterocyte efflux glycoproteins. In this regard, we have developed an oral drug delivery system that confines MER into mesoporous silica nanoparticles (MSNs i.e, MCM-41 ∼141 nm) using a novel liquid carbon dioxide (CO2) method. MER was efficiently encapsulated within pristine, phosphonate (negatively charged MSN), and amine (positively charged MSN) modified MSNs with loading capacity ranging between 25 wt % and 31 wt %. Next, the MER-MCM-NH2 particles were electrostatically coated with Eudragit S100 enteric polymer that protected MER against gastric pH (pH 1.9) and enabled site-specific delivery in the small intestine (pH 6.8). Cellular uptake results in RAW 264.7 macrophage, Caco-2, and LS174T cells confirming the efficient cellular uptake of nanoparticles in all three cell lines. More importantly, the bidirectional transport (absorptive and secretory) of MER across Caco-2 monolayer was significantly improved for both MSN-based formulations, particularly MSNs coated with a polymer (Eud-MER-MCM-NH2) where permeability was significantly enhanced (∼2.4-fold) for absorptive transport and significantly reduced (∼1.8-fold) for secretory transport. Finally, in vitro antibacterial activity [minimum inhibitory concentration (MIC)] and time-kill assay against S. aureus and P. aeruginosa showed that drug-loaded nanoparticles were able to retain antibacterial activity comparable to that of free MER in a solution at equivalent dose. Thus, Eudragit-coated silica nanoparticles could offer a promising and novel solution for oral delivery of Meropenem and other such drugs.

ObjectivesPseudomonas aeruginosa frequently show MDR/XDR profiles, which are associated with worldwide-disseminated high-risk clones (HRCs). We developed a PCR assay for the detection in clinical samples of ST175, an HRC that is widespread in European countries.MethodsThe whole-genome sequence was obtained for one ST175 isolate using a PacBio RSII sequencer. Reads from multiple isolates belonging to ST175 and the PAO1 reference strain were mapped against the ST175 genome to identify potentially specific regions. Once curated, using the BLAST database to search for the presence of those regions in any other organism, we designed a specific PCR for the detection of ST175.ResultsAssembly of the ST175 PacBio-sequenced genome resulted in three contigs with a total length of 7 087 985 bases, encoding 6566 coding sequences. Specific regions for ST175 genomes were detected and a PCR targeting a 318 bp fragment located within a 3177 bp ORF coding for a putative reverse transcriptase was designed. The PCR test was first evaluated in silico against 229 XDR P. aeruginosa genomes (73 ST175) from two multicentre studies, yielding 100% sensitivity and specificity. Then, the PCR was evaluated in vitro in 25 isolates (12 ST175) and in 120 clinical samples (30 urine samples, 30 blood cultures, 30 sputum samples and 30 rectal swabs) of which 10% contained ST175, yielding again 100% sensitivity and specificity.ConclusionsThe PCR assay developed, showing high sensitivity and specificity for the detection of the ST175 HRC directly from clinical samples, could become a useful tool for guiding infection control and treatment strategies in areas with a high prevalence of this clone.

Introduction We characterized AmpC β-lactamase mutations that resulted in ceftolozane/tazobactam resistance in extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates recovered from patients treated with this agent from June 2016 to December 2018. Methods Five pairs of ceftolozane/tazobactam susceptible/resistant P. aeruginosa XDR isolates were included among a total of 49 patients treated. Clonal relationship among isolates was first evaluated by pulsed-field gel electrophoresis (PFGE). Multilocus sequence typing (MLST) was further performed. AmpC mutations were investigated by PCR amplification of the blaPDC gene followed by sequencing. Results The ST175 high-risk clone was detected in four of the pairs of isolates and the ST1182 in the remaining one. All resistant isolates showed a mutation in AmpC: T96I in two of the isolates, and E247K, G183V, and a deletion of 19 amino acids (G229–E247) in the other three. The G183V mutation had not been described before. The five isolates resistant to ceftolozane/tazobactam showed cross-resistance to ceftazidime/avibactam and lower MICs of imipenem and piperacillin/tazobactam than the susceptible isolates. Conclusions Ceftolozane/tazobactam resistance was associated in all of the cases with AmpC mutations, including a novel mutation (G183V) not previously described. There is a vital need for surveillance and characterization of emerging ceftolozane/tazobactam resistance, in order to preserve this valuable antipseudomonal agent.

The evolution of social cognition throughout the course of schizophrenia is unclear not being possible to state whether it remains stable from early stages to chronicity, or it changes as the disease develops. For this purpose, 90 patients with schizophrenia and 139 healthy controls have been compared establishing 4 different groups paired by age and gender: first episode of psychosis patients (FEP), young healthy controls (YHC), chronic patients with schizophrenia (CS) and adult healthy controls (AHC). Performance in Theory of Mind (ToM) has been assessed using The Hinting Task and The Reading the Mind in the Eyes Test (RMET). In the Hinting Task, when comparing patients with their respective control group, differences found between CS patients and their corresponding controls (p < .001) are much bigger (almost twice) than differences between FEP patients and young controls (p = .001). In fact, young and adult healthy controls did not significantly differ in their scores, while the CS group showed significant worse performance than the FEP group. In the Reading the Mind in the Eyes test (RMET), patients globally performed worse than controls (p < .001). However, the Cohort x Diagnosis interaction was not significant (p = .27). In this task, there were no differences between CS and FEP scores. In conclusion, data suggest poor performance in all phases of the disease with a probable worsening related to chronicity especially in the aspects of social cognition measured by the Hinting Task.

BackgroundPseudomonas aeruginosa may develop resistance to novel cephalosporin/β-lactamase inhibitor combinations during therapy through the acquisition of structural mutations in AmpC.ObjectivesTo describe the molecular and biochemical mechanisms involved in the development of resistance to ceftolozane/tazobactam in vivo through the selection and overproduction of a novel AmpC variant, designated PDC-315.MethodsPaired susceptible/resistant isolates obtained before and during ceftolozane/tazobactam treatment were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. Characterization of the novel PDC-315 variant was performed through genotypic and biochemical studies. The effects at the molecular level of the Asp245Asn change were analysed by molecular dynamics simulations using Amber.ResultsWGS identified mutations leading to modification (Asp245Asn) and overproduction of AmpC. Susceptibility testing revealed that PAOΔC producing PDC-315 displayed increased MICs of ceftolozane/tazobactam, decreased MICs of piperacillin/tazobactam and imipenem and similar susceptibility to ceftazidime/avibactam compared with WT PDCs. The catalytic efficiency of PDC-315 for ceftolozane was 10-fold higher in relation to the WT PDCs, but 3.5- and 5-fold lower for piperacillin and imipenem. IC50 values indicated strong inhibition of PDC-315 by avibactam, but resistance to cloxacillin inhibition. Analysis at the atomic level explained that the particular behaviour of PDC-315 is linked to conformational changes in the H10 helix that favour the approximation of key catalytic residues to the active site.ConclusionsWe deciphered the precise mechanisms that led to the in vivo emergence of resistance to ceftolozane/tazobactam in P. aeruginosa through the selection of the novel PDC-315 enzyme. The characterization of this new variant expands our knowledge about AmpC-mediated resistance to cephalosporin/β-lactamase inhibitors in P. aeruginosa.

Background and objective Mechanisms underpinning symptoms in non-traumatic neck pain (NTNP) and whiplash-associated disorder (WAD) are not comprehensively understood. There is emerging evidence of systemic inflammation in musculoskeletal pain conditions, including neck and back pain. The aim of this systematic review was to determine if raised blood inflammatory markers are associated with neck pain. Databases and data treatment MEDLINE, EMBASE, Cochrane Library, CINAHL and Web of Science databases were searched. Two independent reviewers identified studies for inclusion and extracted data. Meta-analysis was performed by random effects model to calculate standard mean differences (SMDs). Risk of bias of individual studies was assessed using the Newcastle-Ottawa Scale. Overall quality of evidence from meta-analysis was assessed by Grades of Recommendation, Assessment, Development and Evaluation approach. Results In total, 10 studies were included comprising 706 participants. Three studies provided data for acute WAD, two for chronic WAD, four for chronic NTNP and one for chronic mixed WAD and NTNP. Meta-analysis indicated increased interleukin 1β (SMD: 0.84 [95% CI 0.24, 1.44], p = .01, I2 = 59%) and tumour necrosis factor α (SMD: 0.59 [0.09, 1.09], p = .02, I2 = 45%) in chronic neck pain compared to controls, but no increase in monocyte chemoattractant protein-1. Some inflammatory markers were associated with clinical variables (including pain intensity and disability). Quality of evidence was mostly low due to small samples and high heterogeneity. Conclusions Findings imply that raised blood inflammatory markers are present in chronic neck pain, which may represent an ongoing inflammatory process in this population. Significance This systematic review advances our understanding of neck pain pathophysiology by demonstrating the presence of systemic inflammation in chronic neck pain, in the form of raised IL-1β and TNFα. Further, numerous inflammatory markers were associated with clinical variables, including pain intensity, disability and hyperalgesia. These findings imply that systemic inflammation may contribute to mechanisms underlying neck pain.

Endoscope contamination is infrequent but can be the source of nosocomial infections and outbreaks. In August 2016, an unexpected increase in the incidence of amikacin-resistant P. aeruginosa isolates (AK-Pae) was observed at a tertiary care center in the south of Spain. An epidemiological and microbiological investigation (August-October 2016) was performed to explain this finding. Isolates from clinical and environmental samples (2 endoscopes used for retrograde cholangiopancreatography; ERCP) were identified by MALDI-TOF. Antimicrobial susceptibility testing was performed using the MicroScan system. Whole-Genome-Sequencing (Miseq, Illumina) was performed to determine the resistome and virulome. Clonal relatedness among isolates was assessed by SpeI-PFGE and MLST. A Caenorhabditis elegans killing assay was performed for virulence testing. Biofilm formation was performed using a colorimetric assay. Four of the 5 patients infected and/or colonized with AK-Pae in August 2016 had undergone ERCP ≤5 days before sample collection. Two endoscopes were contaminated with AK-Pae. Isolates from one endoscope showed an identical PFGE pattern to 9 isolates (cluster I) and differed (1–2 bands) to 5 isolates (cluster II). Isolates from these clusters belonged to the ST17 clone. This S17 clone was characterized by its low virulence in the C. elegans killing assay, and its biofilm-forming ability, slightly superior to that of high-risk clones of P. aeruginosa ST175 and ST235. This outbreak was caused by an endoscope used for ERCP contaminated with an invasive, moderately virulent, biofilm-forming AK-Pae ST17 clone, suggesting the possible emergence of a new high-risk lineage of this clone.

OBJECTIVE To evaluate the utility of commercially available reagent test strips for estimation of BUN concentration and detection of azotemia in pet rabbits (Oryctolagus cuniculus) and ferrets (Mustela putorius furo). SAMPLE 65 blood samples from 53 rabbits and 71 blood samples from 50 ferrets of various health statuses. PROCEDURES BUN concentrations were measured with a clinical laboratory biochemical analyzer and estimated with a reagent test strip. Results obtained with both methods were assigned to a BUN category (range, 1 to 4; higher categories corresponded to higher BUN concentrations). Samples with a biochemical analyzer BUN concentration ≥ 27 mg/dL (rabbits) or ≥ 41 mg/dL (ferrets) were considered azotemic. A test strip BUN category of 3 or 4 (rabbits) or 4 (ferrets) was considered positive for azotemia. RESULTS Test strip and biochemical analyzer BUN categories were concordant for 46 of 65 (71%) rabbit blood samples and 58 of 71 (82%) ferret blood samples. Sensitivity, specificity, and accuracy of the test strips for detection of azotemia were 92%, 79%, and 82%, respectively, for rabbit blood samples and 80%, 100%, and 96%, respectively, for ferret blood samples. CONCLUSIONS AND CLINICAL RELEVANCE Test strips provided reasonable estimates of BUN concentration but, for rabbits, were more appropriate for ruling out than for ruling in azotemia because of false-positive test strip results. False-negative test strip results for azotemia were more of a concern for ferrets than rabbits. Testing with a biochemical analyzer remains the gold standard for measurement of BUN concentration and detection of azotemia in rabbits and ferrets.

Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. Vinca alkaloids such as vincristine (VCR), widely used in cancer treatment, are no exception, as their beneficial actions are often supplanted by resistance. In the present work we utilized HL-60 human leukemia cells and a VCR-resistant counterpart, HL-60/VCR, as a model to determine potential interplay between SL metabolism and mitochondrial bioenergetics supportive of multidrug resistance (MDR). Relative to wild-type cells, HL-60/VCR presented with global alterations in SL composition, typified by upregulated expression of sphingosine kinase (SPHK1), which catalyzes formation of sphingosine 1-phosphate (S1P), glucosylceramide synthase (GCS), which catalyzes formation of glucosylceramides (GC), and acid ceramidase, responsible for ceramide hydrolysis. In support of these changes, VCR resistance was also characterized by increases in S1P, several molecular species of ceramide and GC, and changes in sphingomyelin (SM) molecular species. With respect to mitochondria, despite increased basal respiration in HL-60/VCR cells, direct interrogation of the mitochondrial network revealed intrinsic respiratory complex insufficiency, largely localized to complex I (CI). Importantly, forced ceramide accumulation in wild-type cells phenocopied the respiratory insufficiency observed in HL-60/VCR, and co-targeting SL metabolism and CI induced synergistic cytotoxicity in HL-60/VCR cells, as well as in other MDR leukemia models. Together, these data underscore the intimate connection between cellular sphingolipids and mitochondrial metabolism and suggest that pharmacological intervention across both pathways may represent a novel treatment strategy against MDR.

International audience; Combustion instabilities are an undesired phenomenon in premix burners, leading to vibrations and potential flame problems such as lift-off or flashback. The combustion stability in a premix burner is highly sensitive to fuel composition and local environmental conditions. Consequently, this work presents the effect of air humidity and fuel composition on the degree of combustion instability in a swirl stabilized premix burner at atmospheric pressure, initiating in both unstable and stable states. The experimental setup consists of a swirl stabilized 20 kW burner with a square combustion section of 100 mm ×100 mm, with optical access to the reaction zone on three sides. Three types of fuel were evaluated: methane (CH4), CUSIANA (85% CH4; 10% C2H6; 5% C3H8), and propane (C3H8). Atmospheric humidity was emulated over a range from 0% to 5%, molar basis, the high point corresponding to the greatest atmospheric humidity. The degree of burner instability was characterized by the standard deviation of the pressure signal. It was found that atmospheric humidity can reduce combustion instability, affecting methane more significantly than propane at low air preheat temperature (315 K); at high preheat temperature, the water content was found to have no effect on combustion instability. The flame structure, i.e. shape and size, was similar for all fuel types at the same adiabatic flame and air preheat tem-peratures. Under unstable operating conditions, a similar flame shape and area of oscillation were found with the same resonant frequencies. This indicates that the variables characterizing thermoacoustic instability maintain similar values or proportions, regardless of the fuel type.

Passive integrated transponder (PIT) and visible implant elastomer (VIE) tags are commonly used to identify reptiles, amphibians, and fish. Despite reports of good retention rates and little to no negative effect on survival time, migration remains a concern and histologic changes have not been widely evaluated. Fifty-six wild-caught marine toads (Rhinella marina) were marked with a PIT tag in the left caudal thigh and a VIE tag over the right gastrocnemius muscle prior to transport to the North Carolina Zoo. Fourteen toads were then humanely euthanized on day 9, 15, 32, and 62 for postmortem examination and histopathology which were compared to 10 control toads with no tags. All PIT tags were functional and 95% remained at the insertion site with minimal to no histologic changes. Externally, 48% of VIE tags were visible through the skin at the original site of injection under fluorescent or UV light. Upon gross examination of the tissues, VIE tags had an overall retention rate of 62% at the injection site, with similar retention rates across time points. Migrated VIE material was visible grossly and histologically in the kidneys of 98% of toads and along the right leg, proximally and distally, in 25% of toads. VIE material was also found sporadically in mesentery, colon, and free in the coelomic cavity. Histologically, VIE material in the skin was surrounded by minimal to mild granulomatous inflammation while in the kidney it was associated with dilation of the small vessels, edema, and granulomatous nephritis that progressed in severity over time. Based on these findings, the authors recommend the use of PIT tags over VIE tags for identification of adult anurans, when feasible.

This study applied two mathematical algorithms, lattice up-stream targeting (LUST) and D-basis, to the identification of prognostic signatures from cancer gene expression data. The LUST algorithm l...

Background Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center. Methods We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care. Results Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool’s ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5–6 portal messages. Conclusions Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice.

Background: The American College of Surgeons Risk Calculator (ACS-RC) provides an assessment of a patient's risk of thirty-day postoperative complications. The Surgeon Adjusted Risk (SAR) parameter of the calculator allows for ad hoc adjustment of risk based on risk factors not considered by the model. This study aims to evaluate the predictive accuracy of the ACS-RC in vascular surgery patients undergoing major lower-extremity amputation (LEA) and identify additional risk factors that warrant use of the SAR parameter. Methods: This is a retrospective study of 298 sequential amputations at a single institution. At the population level, the mean of predicted thirty-day outcomes from the ACS-RC with a SAR score of 1 (no adjustment necessary) and 2 (risk somewhat higher than estimate) were compared to the rate of observed outcomes. Predictive accuracy at the individual level was completed using receiver operating curve area under the curve (AUC). Logistic regression with respect to mortality was performed over variables not considered by the ACS-RC. Efficacy of selectively utilizing the SAR parameter in predicting mortality was analyzed with a stratified analysis in which patients with risk factors significant for mortality were assigned increased risk. Results: At the population level, ACS-RC grossly underpredicted serious complications, SSI, VTE, and unplanned RTOR, while overpredicting mortality and cardiac complications. At the individual level, SAR1 was more predictive for serious complications (AUC = 0.624), SSI (AUC = 0.610), and unplanned RTOR (AUC = 0.541). Conversely, SAR2 was more predictive for mortality (AUC=0.709), cardiac complications (AUC = 0.561), and VTE (AUC = 0.539). Logistic regression identified history of CVA with a residual deficit (OR = 4.61, p=0.033) and ischemic rest pain without tissue loss (OR= 4.497, p=0.047) as independent risk factors for postoperative mortality. Stratified analysis with utilization of the SAR2 based on the two independent risk factors improved AUC in predicting mortality (AUC 0.792 from 0.709). Conclusions: Major LEAs are associated with high perioperative morbidity and mortality. In a veteran population, the ACS-RC showed mixed predictability at the population level and fair predictability at the individual level with regards to postoperative outcomes. Rest pain without tissue loss and history of CVA with residual deficit were identified as risk factors for postoperative mortality. Although ad hoc adjustment with the subjective SAR modifier based on the presence of these two risk factors increased the calculator's accuracy, this study highlights some potential limitations of the ACS-RC when applied to vascular surgery patients undergoing major LEA.

Although lithium is widely used in current practice to treat bipolar disorder (BD) and treatment-resistant major depressive disorder (MDD) among older adults, little is known about its efficacy and tolerability in this population, which is generally excluded from randomized clinical trials. The objective of this study was to evaluate the efficacy and tolerability of long-term use of lithium among older adults with BD and MDD.Data from the Cohort of individuals with Schizophrenia and mood disorders Aged 55 years or more (CSA) were used. Two groups of patients with BD and MDD were compared: those who were currently receiving lithium versus those who were not. The effects of lithium on psychiatric (i.e., depressive symptoms severity, perceived clinical severity, rates of psychiatric admissions in the past-year), geriatric (overall and cognitive functioning) and physical outcomes (i.e., rates of non-psychiatric medical comorbidities and general hospital admissions in the past-year) were evaluated. All analyses were adjusted for age, sex, duration of disorder, diagnosis, smoking status, alcohol use, and use of antipsychotics, antiepileptics or antidepressants.Among the 281 older participants with BD or MDD, 15.7% were taking lithium for a mean duration of 12.5(SD = 11.6) years. Lithium use was associated with lower intensity of depressive symptoms, reduced perceived clinical global severity and lower benzodiazepine use (all p 0.05), without being linked to greater rates of medical comorbidities, except for hypothyroidism.Data were cross-sectional and data on lifetime history of psychotropic medications was not assessed.Our results suggest that long-term lithium use may be efficient and relatively well-tolerated in older adults with BD or treatment-resistant MDD.

To demonstrate safety of a developed intranasal dexamethasone-infused in situ gelling formulation, quantification of a validated clinical biomarker indicative of cytotoxic potential using a human sinonasal explant model was first confirmed. Systematic cytotoxicity studies using the lactate dehydrogenase (LDH) detection assay revealed no elevation from baseline, in LDH levels, with tissue integrity of explanted human nasal mucosa also maintained; this was further corroborated using tissue histopathological examination. Next, with safety confirmed ex vivo, freshly excised human nasal tissue was utilised to quantify dexamethasone release from the lead sol–gel systems; this being achieved through development and validation of a HPLC-UV analytical method, which reliably quantified controlled therapeutic release and deposition into mucosal tissue. Collectively, these findings indicate promise in the safety of each excipient within the concentrations employed in the functional sol–gel system, complemented by successful and reliable drug release and deposition into human nasal mucosal tissue. These findings pave the way for application of the dexamethasone-based sol–gel system to the extended delivery of corticosteroids to nasal mucosa in the management of localised inflammatory conditions of an acute and chronic nature, such as chronic rhinosinusitis, which can be expected to benefit from controlled and extended drug delivery characteristics imparted by appropriately engineered in situ gelling systems. Keywords: Intranasal soluble gels, Sinusitis, Explant human nasal mucosa, Tissue toxicity, LDH assay, Drug deposition in human nasal mucosa

A specific treatment protocol for managing scapular spine fractures does not currently exist. The purpose of our report is to describe this type of injury and detail our treatment management in order to better elucidate this rare pathology. We present a case of a 26-year-old female with an acute scapular spine and base fracture after a motor vehicle collision. Successful treatment of an acute free-floating scapular spine fracture was achieved with open reduction and internal fixation utilizing an elbow plate. Since scapular spine fractures are an unfortunate, rare injury, it may impose difficult challenges to the treating surgeon. With our case report, we hope to contribute to the overall knowledge of scapular spine fractures and offer our experience with a successful and appropriate treatment option in our patient.

ObjectivesTo evaluate the correlation of O-antigen serotypes with resistance profiles and high-risk clones in a Spanish nationwide survey.MethodsUp to 30 consecutive healthcare-associated Pseudomonas aeruginosa isolates were collected during October 2017 from each of 51 hospitals (covering all Spanish regions) with a total of 1445 isolates studied. MICs of 13 antipseudomonal agents and MDR/XDR profiles had been previously determined, as well as whole-genome sequences of 185 representative XDR isolates. O-antigen serotypes (O1–O16) were determined by agglutination using serotype-specific antisera (BioRad). The Pseudomonas aeruginosa serotyper (PAst) program was used for in silico serotyping.ResultsThe most frequent serotypes were O6 (17.8%), O1 (15.4%) and O11 (13.3%). In contrast, the most frequent serotype among XDR isolates (17.3%) was O4 (34.1%), distantly followed by O11 (15.9%). Within serotypes, XDR phenotypes were more frequent for O12 (60.0%) and O4 (57.3%). The most frequent clone among the XDR isolates was ST175 (40.9%), followed by CC235 (10.7%), ST308 (5.2%) and CC111 (3.6%). Up to 81.6% of XDR ST175 isolates typed O4, whereas 18.4% were non-typeable. O4 genotype was detected in all sequenced (n=55) ST175 isolates. On the other hand, CC235 and ST308 were associated with O11, whereas CC111 was linked to serotype O12.ConclusionsO4 serotype is linked to the MDR/XDR profile of widespread ST175 (typically only susceptible to colistin, amikacin and the novel combinations ceftolozane/tazobactam and ceftazidime/avibactam) and therefore, after local validation, its detection in the microbiology laboratory might be useful for guiding semi-empirical antipseudomonal therapies and infection control measures in Spanish hospitals.

The Virtual Population (ViP) phantoms have been used in many dosimetry studies, yet, to date, anatomical phantom uncertainty in radiofrequency (RF) research has largely been neglected. The objective of this study is to gain insight, for the first time, regarding the uncertainty in RF-induced fields during magnetic resonance imaging associated with tissue assignment and segmentation quality and consistency in anatomical phantoms by evaluating the differences between two generations of ViP phantoms, ViP1.x and ViP3.0. The RF-induced 10g-average electric (E-) fields, tangential E-fields distribution along active implantable medical devices (AIMD) routings, and estimated AIMD heating were compared for five phantoms that are part of both ViP1.x and ViP3.0. The results demonstrated that differences exceeded 3 dB (-29%, +41%) for local quantities and 1 dB (±12% for field, ±25% for power) for integrated and volume-averaged quantities (e.g., estimated AIMD-heating and 10 g-average E-fields), while the variation across different ViP phantoms of the same generation can exceed 10 dB (-68% and +217% for field, -90% and +900% for power). In conclusion, the anatomical phantom uncertainty associated with tissue assignment and segmentation quality/consistency is larger than previously assumed, i.e., 0.6 dB or ±15% (k = 1) for AIMD heating. Further, multiple phantoms based on different volunteers covering the target population are required for quantitative analysis of dosimetric endpoints, e.g., AIMD heating, which depend on patient anatomy. Phantoms with the highest fidelity in tissue assignment and segmentation should be used, as these ensure the lowest uncertainty and possible underestimation of exposure. To verify that the uncertainty decreases monotonically with improved phantom quality, the evaluation of differences between phantom generations should be repeated for any improvement in segmentation. Bioelectromagnetics. 2019;40:458-471. © 2019 Bioelectromagnetics Society.

Acute myelogenous leukemia (AML) is a hematological malignancy marked by the accumulation of large numbers of immature myeloblasts in bone marrow. The overall prognosis in AML is poor; hence, there is a pressing need to improve treatment. Although the sphingolipid (SL) ceramide demonstrates known cancer suppressor properties, it’s mechanism of action is multifaceted. Our studies in leukemia and other cancers have demonstrated that when combined with the antiestrogen, tamoxifen, the apoptosis-inducting effect of ceramide is greatly enhanced. The goal of the present study was to establish whether a ceramide-tamoxifen regimen also affects autophagic-driven cellular responses in leukemia. Using the human AML cell line KG-1, we demonstrate that, unlike exposure to the single agents, combination C6-ceramide-tamoxifen upregulated LC3-II expression, inhibited the mTOR signaling pathway, and synergistically induced KG-1 cell death in an Atg5-dependent manner. In addition, colocalization of autophagosome and mitochondria, indicative of mitophagosome formation and mitophagy, was observed. Versatility of the drug regimen was confirmed by experiments in MV4-11 cells, a FLT3-ITD AML mutant. These results indicate that the C6-ceramide-tamoxifen regimen plays a pivotal role inducing autophagy in AML, and thus constitutes a novel therapeutic design.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of older AML patients fail to respond to cytotoxic chemotherapy, and most responders relapse with drug-resistant disease. Failure to achieve complete remission can be partly attributed to the drug resistance advantage of AML blasts that frequently express P-glycoprotein (P-gp), an ATP-binding cassette transporter. Our previous work showed that elevated acid ceramidase (AC) levels in AML contribute to blast survival. Here, we investigated P-gp expression levels in AML relative to AC. Using parental HL-60 cells and drug-resistant derivatives as our model, we found that P-gp expression and efflux activity were highly upregulated in resistant derivatives. AC overexpression in HL-60 conferred resistance to the AML chemotherapeutic drugs, cytarabine, mitoxantrone, and daunorubicin, and was linked to P-gp upregulation. Furthermore, targeting AC through pharmacologic or genetic approaches decreased P-gp levels and increased sensitivity to chemotherapeutic drugs. Mechanistically, AC overexpression increased NF-κB activation whereas NF-kB inhibitors reduced P-gp levels, indicating that the NF-kappaB pathway contributes to AC-mediated modulation of P-gp expression. Hence, our data support an important role for AC in drug resistance as well as survival and suggest that sphingolipid targeting approaches may also impact drug resistance in AML.

The distribution of key chemicals in mainstream cigarette smoke (MCS) particles of different sizes have implications for respiratory dose. In this study, a differential mobility spectrometer (DMS) ...

BACKGROUND For small molecules such as teriflunomide, used to treat relapsing multiple sclerosis (MS), that are potentially embryotoxic, there is a theoretical risk of transmission of the medication from males on the drug to female sexual partners. However, that risk has been undefined up to now. METHODS Teriflunomide concentrations were assayed concomitantly in ten sexually active couples, not using barrier methods of contraception, in whom the male partner with MS was on treatment with teriflunomide 14 mg daily for at least two months. These results were compared by male and female age, teriflunomide concentrations and reported average number of incidences of sexual intercourse per month. The threshold level of detection of teriflunomide was 0.020 µg/ml in females. RESULTS The average age of the cohort was 46.70 for males and 47.10 for females. Four of ten females had detectible teriflunomide concentrations (mean 0.046µg/ml (range 0.22-0.077, standard deviation 0.025). Male age and both female teriflunomide positive threshold and female teriflunomide concentration were inversely correlated (r=0.67, R2=0.45, p=0.034) for the former and (r=0.62, R2=0.39, p=.05, ns) for the latter. No significant correlations were observed for female age, male teriflunomide concentrations, or reported mean monthly episodes of sexual intercourse. CONCLUSION This limited study suggests that the small risk that low levels of teriflunomide can be transmitted from male to female partners via sexual intercourse is related to male age. This supports the recommendations found in the United States Product Insert (USPI) stating that men taking teriflunomide who do not wish to father a child, and their female partners, should use reliable contraception. Men wishing to father a child should discontinue use of teriflunomide and undergo an accelerated elimination procedure to reduce the plasma concentrations of the medication to less than 0.02 mg/L (0.02 µg/ml1.

Laser-induced incandescence (LII) is an optical technique that is widely used for the in situ measurement of the soot volume fraction in flames. The low intensity of LII signals in low-sooting turbulent flames means that long camera acquisition times are needed to achieve sufficiently high signal-to-noise ratios. The direct application of auto-compensating LII (AC-LII) to infer the soot volume fraction from the measured LII signals can lead to large errors due to the significant decrease in the temperature of the soot particles over the duration of the camera gate. In order to reduce the measurement errors from AC-LII, we propose an improved approach in which the cooling of soot particles during the camera acquisition of LII signals is considered. The proposed methodology is applied to planar AC-LII measurements for the determination of soot volume fraction and primary particle diameter in a low-sooting turbulent flame, with the help of the open source LII software LIISim. This study represents the first application of planar AC-LII to a turbulent flame. A sensitivity analysis is also conducted in order to determine the main factors affecting the uncertainty of the proposed approach. Copyright © 2021 American Association for Aerosol Research

We have combined an anterior segment (AS) optical coherence tomography (OCT) system and a wavefront-based aberrometer with an approach that senses ocular wavefront aberrations using the OCT beam. Temporal interlacing of the OCT and aberrometer channels allows for OCT images and refractive error measurements to be acquired continuously and in real-time. The system measures refractive error with accuracy and precision comparable to that of clinical autorefractors. The proposed approach provides a compact modular design that is suitable for integrating OCT and wavefront-based autorefraction within the optical head of the ophthalmic surgical microscope for guiding cataract surgery or table-top devices for simultaneous autorefraction and ocular biometry.

Multiple sclerosis (MS) is a "3C" (complex, chronic, costly) condition that is a common and disabling neurological illness affecting approximately 1 million adults in the United States. MS has been studied at the basic science, individual, and population levels, but not at the system level to assess small-area variation effects on MS population health outcomes. System-level effects have been observed in other 3C conditions including cystic fibrosis, rheumatoid arthritis, and inflammatory bowel disease. The authors report here on system-level variation findings from the baseline period during the first year of the Multiple Sclerosis Continuous Quality Improvement (MS-CQI) study. Stepwise binary logistic regression analyses were conducted to investigate system-level (small-area variation) effects on MS relapses (exacerbations), disease-modifying therapy (DMT) utilization, and brain MRI utilization, controlling for demographics (age and sex) and other potential confounders. Significant differences were observed in people with MS (PwMS) between centers for a number of demographic and disease characteristics, including sex, age, and MS subtype. Controlling for these factors, significant system-level effects were observed on outcomes, including DMT utilization, MRI utilization, and relapses. Significant relationships also were observed between outcomes and urgent care utilization, including emergency department visits and hospitalizations. This initial study provides evidence establishing the presence of system-level variation effects on MS outcomes in a multicenter population study - where PwMS get their care can influence their outcomes. Results support continued systems-level research and improvement initiatives to optimize MS population health outcomes in this challenging and costly complex chronic condition.

PURPOSE To evaluate if income status affects the timing of presentation to orthopaedic care, surgical treatment, or continuity of care following a closed ankle fracture. METHODS Th is retrospective study identified 434 patients with closed ankle fractures treated with operative fixation from 2014 to 2016. Median income data were extracted using the patients' ZIP codes and data from the U.S. Census Bureau. RESULTS Lower-income patients presented to the hospital and received surgical treatment significantly later than others. They were also more often uninsured and nonadherent with postoperative weightbearing precautions. Additionally, these patients less frequently sought care on the day of their injury, and they had both shorter inpatient stays and duration of overall follow-up in comparison with others. CONCLUSION Socioeconomic status is a vital consideration for improving patient access to acute orthopaedic surgical care. Lower-income patients are more susceptible to multiple time-sensitive delays in their care, and these patients frequently encounter difficulties maintaining appropriate follow-up carex.

Currently there is great interest in targeting mitochondrial oxidative phosphorylation (OXPHOS) in cancer. However, notwithstanding the targeting of mutant dehydrogenases, nearly all hopeful ‘mito-therapeutics’ cannot discriminate cancerous from non-cancerous OXPHOS and thus suffer from a limited therapeutic index. Using acute myeloid leukemia (AML) as a model, herein, we leveraged an in-house diagnostic biochemical workflow to identify ‘actionable’ bioenergetic vulnerabilities intrinsic to cancerous mitochondria. Consistent with prior reports, AML growth and proliferation was associated with a hyper-metabolic phenotype which included increases in basal and maximal respiration. However, despite having nearly 2-fold more mitochondria per cell, clonally expanding hematopoietic stem cells, leukemic blasts, as well as chemoresistant AML were all consistently hallmarked by intrinsic OXPHOS limitations. Remarkably, by performing experiments across a physiological span of ATP free energy, we provide direct evidence that leukemic mitochondria are particularly poised to consume ATP. Relevant to AML biology, acute restoration of oxidative ATP synthesis proved highly cytotoxic to leukemic blasts, suggesting that active OXPHOS repression supports aggressive disease dissemination in AML. Together, these findings argue against ATP being the primary output of leukemic mitochondria and provide proof-of-principle that restoring, rather than disrupting, OXPHOS may represent an untapped therapeutic avenue for combatting hematological malignancy and chemoresistance.

Background: Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. Vinca alkaloids such as vincristine (VCR), widely used in cancer treatment, are no exception, as their beneficial actions are often supplanted by resistance. In the present work we utilized HL-60 human leukemia cells and a VCR-resistant counterpart, HL-60/VCR cells, to determine potential interplay between SL metabolism and mitochondrial bioenergetics supportive of VCR resistance. Methods: Cellular SL alterations were assessed via a combination of enzyme immunoblot analysis and lipidomics. Mitochondrial function was evaluated in intact cells, permeabilized cells and isolated mitochondria using a comprehensive diagnostic assay system designed to directly interrogate oxidative phosphorylation (OXPHOS) kinetics. Informed by SL and bioenergetic readouts, experiments were designed to assess the therapeutic efficacy of co-targeting SL metabolism and mitochondrial flux to combat VCR resistance. Results: Relative to wild-type cells, HL-60/VCR presented with global alterations in SL composition, typified by upregulated expression of sphingosine kinase (SPHK1), which catalyzes formation of sphingosine 1-phosphate (S1P), glucosylceramide synthase (GCS), which catalyzes formation of glucosylceramides (GC), and acid ceramidase, responsible for ceramide hydrolysis. In support of these changes, VCR resistance was also characterized by increases in S1P, several molecular species of ceramide and GC, and changes in sphingomyelin (SM) molecular species. With respect to mitochondria, despite increased basal respiration in HL-60/VCR cells, direct interrogation of the mitochondrial network revealed intrinsic respiratory complex insufficiency, largely localized to complex I (CI). Importantly, forced ceramide accumulation in wild-type cells phenocopied the respiratory insufficiency observed in HL-60/VCR, and co-targeting SL metabolism and CI induced synergistic cytotoxicity in HL-60/VCR. Conclusions: Together, these data underscore the intimate connection between cellular sphingolipids and mitochondrial metabolism and suggest that pharmacological intervention across both pathways may represent a novel treatment strategy against VCR resistance.

Background The workflow of breast cancer screening programs could be improved given the high workload and the high number of false-positive and false-negative assessments. Purpose To evaluate if using an artificial intelligence (AI) system could reduce workload without reducing cancer detection in breast cancer screening with digital mammography (DM) or digital breast tomosynthesis (DBT). Materials and Methods Consecutive screening-paired and independently read DM and DBT images acquired from January 2015 to December 2016 were retrospectively collected from the Córdoba Tomosynthesis Screening Trial. The original reading settings were single or double reading of DM or DBT images. An AI system computed a cancer risk score for DM and DBT examinations independently. Each original setting was compared with a simulated autonomous AI triaging strategy (the least suspicious examinations for AI are not human-read; the rest are read in the same setting as the original, and examinations not recalled by radiologists but graded as very suspicious by AI are recalled) in terms of workload, sensitivity, and recall rate. The McNemar test with Bonferroni correction was used for statistical analysis. Results A total of 15 987 DM and DBT examinations (which included 98 screening-detected and 15 interval cancers) from 15 986 women (mean age ± standard deviation, 58 years ± 6) were evaluated. In comparison with double reading of DBT images (568 hours needed, 92 of 113 cancers detected, 706 recalls in 15 987 examinations), AI with DBT would result in 72.5% less workload (P