Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis.
Chromosomal instability is believed to be a common feature of most human tumors, but the stage at which such instability originates has not been defined. At the molecular level, chromosomal instability is characterized by allelic imbalance (AI), representing losses or gains of defined chromosomal regions. We have assessed AI in early colorectal tumors using newly developed methods for assessing AI in complex cell populations. A total of 32 adenomas of average size (2 mm; range, 1-3 mm) were studied. AI of chromosome 5q markers occurred in 55% of tumors analyzed, consistent with a gatekeeping role of the adenomatous polyposis coli tumor suppressor gene located at chromosomal position 5q21. AI was also detected in each of the other four chromosomes tested. The fractions of adenomas with AI of chromosomes 1p, 8p, 15q, and 18q were 10,19, 28, and 28%, respectively. Over 90% of the tumors exhibited AI of at least one chromosome, and 67% had allelic imbalance of a chromosome other than 5q. These findings demonstrate that AI is a common event, even in very small tumors, and suggest that chromosomal instability occurs very early during colorectal neoplasia.


Sources of variation in spinal indentation testing: indentation site relocation, intraabdominal pressure, subject movement, muscular response, and stiffness estimation.
Force-displacement properties of spinal tissues assessed by blunt indentation are thought to have clinical relevance; however, numerous variables with respect to spinal indentation have yet to be identified or characterized completely. To identify and quantify, where possible, previously unidentified or incompletely characterized variables with respect to spinal indentation. Multiprotocol design. Four experiments were performed: (1) Twelve asymptomatic subjects were indented with concurrent electromyography during conditions of rest, held inspiration, increased intraabdominal pressure and lumbar extension. (2) Changes in the recumbent position of 12 subjects were measured while a series of movements was performed in restrained and unrestrained conditions. (3) Ten clinicians attempted to locate, and to relocate, a subcutaneous anatomical landmark through visualization/palpation and ultrasonic imaging. (4) Performances of 3 methods of force-displacement curve modeling were compared with respect to stiffness estimation. (1) Spinal stiffness increased significantly in a minority of subjects awaiting indentation and in a majority of subjects during increases in intraabdominal pressure. (2) Changes in subject position were significantly reduced by a restraint system. (3) With respect to interclinician error in locating and relocating an indentation site, there was significant improvement with the use of ultrasonic visualization. (4) The error associated with linear techniques used to model curvilinear force-displacement data plots increased with increasing linear intervals. Several sources of variation in spinal indentation were identified: indentation site relocation, intraabdominal pressure, subject movement, muscular response, and stiffness estimation. These variables, which have been unaccounted for in previous indentation studies, might be responsible for the change or lack of change in force-displacement properties between preintervention and postintervention indentation trials.


Expression of IFN-gamma in cerebrovascular endothelial cells from aged mice.
Recently, it has become clear that interferon-gamma (IFN-gamma) plays a role in the central nervous system (CNS) as well as in the immune system. However, the reason for the alteration in IFN-gamma production in the brain with aging remains unknown. In this study, we investigated the expression of IFN-gamma in the brain in terms of both mRNA and protein and compared the expression in young adult brain with that in aged mice. The cerebrum and cerebellum were collected from young adult (8-10 weeks old) and aged (24-26 months old) BALB/c mice, and the expressions of IFN-gamma and IFN-gamma receptor-1 (IFNGR-1) mRNA were examined by RT-PCR. Expression of IFN-gamma mRNA was detected in the brains from aged mice but not in those from young adult mice. However, IFNGR-1 mRNA was expressed in the brains from both young adult and aged mice. Moreover, IFN-gamma levels in the cerebrum and cerebellum from aged mice were detectable by ELISA, but IFN-gamma was undetectable in these tissues from young adult mice. To identify the cellular source of IFN-gamma in the brain of aged mice, immunostaining using antimouse IFN-gamma monoclonal antibody (mAb) was done. Immunoreactivity of IFN-gamma appeared to be located in cerebrovascular endothelial cells, including the choroid plexus of the cerebellum from aged mice. Expression of IFN-gamma and IFNGR-1 was also identified in isolated microvessels from brains. These results suggest that IFN-gamma plays a role in age-associated changes.


Human monoclonal antibodies that recognize conserved epitopes in the core-lipid A region of lipopolysaccharides.
Epstein-Barr virus (EBV)-transformed human B lymphocytes were fused with a murine-human heteromyeloma to produce stable hybrid cell lines that secreted human monoclonal antibodies (mAbs) of the IgM class that recognized conserved epitopes in the core-lipid A region of lipopolysaccharides (LPS). Three of the mAbs reacted with epitopes on the lipid A moiety, while a fourth recognized a determinant in the core oligosaccharide. The lipid A-specific mAbs cross-reacted with heterologous rough LPS and with lipid As released by acid hydrolysis of different intact (smooth) LPS. Carbohydrate groups in the O-side chain and core oligosaccharide of isolated, smooth LPS restricted antibody access to antigenic sites on lipid A. Yet, one lipid A-reactive mAb recognized its epitope on the surfaces of a variety of intact bacteria. These findings confirm the presence of highly conserved epitopes in the core-lipid A complex and prove the existence of human B cell clones with the potential for secreting high avidity IgM antibodies that react with these widely shared determinants. Such human mAbs might provide protective activity against disease caused by diverse gram-negative bacteria.


Pharmacologic pupillary constriction after dilated fundus examination for ectopia lentis to prevent further subluxation.
To describe two cases of ectopia lentis with different preoperative management strategies following the initial diagnostic dilated exam. In both cases, the patients presented with bilateral subluxation of the crystalline lens. Neither patient had a known history of Marfan's disease, homocystinuria or other systemic disorders that affect the body's connective tissue possibly leading to lens subluxation. Patient 1 was sent home after dilated fundus examination with no special precautions. That same night, he developed severe right eye pain and further decreased vision. He was found to have complete dislocation of his right crystalline lens into the anterior chamber with corneal edema and an elevated pressure, requiring an urgent pars plana lensectomy. In our second case of ectopia lentis, patient 2 was examined prior to dilation and noted to have bilateral subluxation of the lens into the vitreous. Twenty minutes after dilation, the crystalline lens was noted to be in the anterior chamber in the right eye. The patient was laid supine for several minutes and once the lens was in the posterior cavity, she was given 1% pilocarpine in both eyes to constrict the pupil to prevent dislocation in the anterior chamber. Patient 2 had an uneventful perioperative period and did not suffer worsening subluxation after her initial visit. Unlike patient 1, patient 2 did not suffer further subluxation after her initial dilated eye exam, therefore avoiding a more arduous clinical and surgical course. Patients presenting with completely dislocated lenses may benefit from the reversal of pupillary dilation by being placed in the supine position and given reversal drops such as 1% pilocarpine prior to leaving the office. This method may help prevent complications from anterior lens subluxation and pupillary block glaucoma until definitive surgical managment.


Depression and chronic heart failure in the elderly: an intriguing relationship.
Chronic heart failure and depressive disorders have a high prevalence and incidence in the elderly. Several studies have shown how depression tends to exacerbate coexisting chronic heart failure and its clinical outcomes and vice versa, especially in the elderly. The negative synergism between chronic heart failure and depression in the elderly may be approached only taking into account the multifaceted pathophysiological characteristics underlying both these conditions, such as behavioural factors, neurohormonal activation, inflammatory mediators, hypercoagulability and vascular damage. Nevertheless, the pathophysiological link between these two conditions is not well established yet. Despite the high prevalence of depression in chronic heart failure elderly patients and its negative prognostic value, it is often unrecognized especially because of shared symptoms. So the screening of mood disorders, using reliable questionnaires, is recommended in elderly patients with chronic heart failure, even if cannot substitute a diagnostic interview by mental health professionals. In this setting, treatment of depression requires a multidisciplinary approach including: psychotherapy, antidepressants, exercise training and electroconvulsive therapy. Pharmacological therapy with selective serotonin reuptake inhibitors, despite conflicting results, improves quality of life but does not guarantee better outcomes. Exercise training is effective in improving quality of life and prognosis but at the same time cardiac rehabilitation services are vastly underutilized.


High-Affinity Functional Fluorescent Ligands for Human β-Adrenoceptors.
Visualization of the G-protein coupled receptor (GPCR) is of great importance for studying its function in a native cell. We have synthesized a series of red-emitting fluorescent probes targeting β-adrenergic receptor (βAR) that are compatible with confocal and Stimulated Emission Depletion (STED) microscopy as well as with Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assay in living cells. The probe based on the agonist BI-167107 and fluorescent dye KK114 demonstrates nanomolar binding affinity and up to nine-fold β2AR selectivity over β1AR. Carazolol-derived probes are fluorogenic and allow no-wash imaging experiments. STED microscopy of β2ARs stained at the native expression level on pancreatic CAPAN cells provides two-fold improvement in lateral optical resolution over confocal mode and reveals the formation of receptor microdomains. These probes retain their functional (agonist or antagonist) properties, allowing simultaneous modulation of cyclic adenosine monophosphate (cAMP) levels and receptor internalization as well as imaging receptor localization.


Epigenome-wide studies of antipsychotics: a systematic review and pathway meta-analysis.
Background & methods: Researchers have aimed to understand the mechanisms of antipsychotics through epigenetics to inform interindividual response rates. However, findings have widely varied across studies, making advancement in the field difficult. Materials & methods: A systematic review was performed to include all epigenome-wide studies of antipsychotic treatment in humans. Methylation sites were used for a pathway and enrichment map analysis was conducted. Results & conclusion: Seven studies were included and 82 methylation sites were used for the exploratory pathway meta-analysis that identified six pathway clusters. The findings here demonstrate that studies of the epigenome and antipsychotic treatment are highly heterogeneous in nature and could inform future work to target cross-cutting gene sets and pathways.


Site-restricted plasminogen activation mediated by group A streptococcal streptokinase variants.
SK (streptokinase) is a secreted plasminogen activator and virulence factor of GAS (group A Streptococcus). Among GAS isolates, SK gene sequences are polymorphic and are grouped into two sequence clusters (cluster type-1 and cluster type-2) with cluster type-2 being further classified into subclusters (type-2a and type-2b). In the present study, we examined the role of bacterial and host-derived cofactors in SK-mediated plasminogen activation. All SK variants, apart from type-2b, can form an activator complex with Glu-Plg (Glu-plasminogen). Specific ligand-binding-induced conformational changes in Glu-Plg mediated by fibrinogen, PAM (plasminogen-binding group A streptococcal M protein), fibrinogen fragment D or fibrin, were required for type-2b SK to form a functional activator complex with Glu-Plg. In contrast with type-1 and type-2a SK, type-2b SK activator complexes were inhibited by α2-antiplasmin unless bound to fibrin or to the GAS cell-surface via PAM in combination with fibrinogen. Taken together, these data suggest that type-2b SK plasminogen activation may be restricted to specific microenvironments within the host such as fibrin deposits or the bacterial cell surface through the action of α2-antiplasmin. We conclude that phenotypic SK variation functionally underpins a pathogenic mechanism whereby SK variants differentially focus plasminogen activation, leading to specific niche adaption within the host.


Compatibilization of Poly(Lactic Acid) (PLA) and Bio-Based Ethylene-Propylene-Diene-Rubber (EPDM) via Reactive Extrusion with Different Coagents.
Much effort has been made to enhance the toughness of poly (lactic acid) (PLA) to broaden its possible range of usage in technical applications. In this work, the compatibility of PLA with a partly bio-based ethylene-propylene-diene-rubber (EPDM) through reactive extrusion was investigated. The concentration of EPDM in the PLA matrix was in the range of up to 20%. The reactive extrusion was carried out in a conventional twin-screw extruder. Contact angle measurements were performed to calculate the interfacial tension and thus the compatibility between the phases. The thermal and mechanical properties as well as the phase morphology of the blends were characterized. A copolymer of poly (ethylene-co-methyl acrylate-co-glycidyl methacrylate) (EMAGMA) was used as compatibilizer, which leads to a significant reduction in the particle size of the dispersed rubber phase when compared with the blends without this copolymer. The use of EMAGMA combined with soybean oil (SBO) and a radical initiator enhances the elongation at break of the compound. The results indicate that the reduction of the particle size of the dispersed phase obtained with the compatibilizer alone is not sufficient to improve the mechanical properties of the blend system. The induced radical reactions also influenced the mechanical properties of the blend significantly.


Bioaerosols in the landfill environment: an overview of microbial diversity and potential health hazards.
Landfilling is one of the indispensable parts of solid waste management in various countries. Solid waste disposed of in landfill sites provides nutrients for the proliferation of pathogenic microbes which are aerosolized into the atmosphere due to the local meteorology and various waste disposal activities. Bioaerosols released from landfill sites can create health issues for employees and adjoining public. The present study offers an overview of the microbial diversity reported in the air samples collected from various landfill sites worldwide. This paper also discusses other aspects, including effect of meteorological conditions on the bioaerosol concentrations, sampling techniques, bioaerosol exposure and potential health impacts. Analysis of literature concluded that landfill air is dominated by microbial dust or various pathogenic microbes like Enterobacteriaceae, Staphylococcus aureus, Clostridium perfringens, Acinetobacter calcoaceticus and Aspergillus fumigatus. The bioaerosols present in the landfill environment are of respirable sizes and can penetrate deep into lower respiratory systems and trigger respiratory symptoms and chronic pulmonary diseases. Most studies reported higher bioaerosol concentrations in spring and summer as higher temperature and relative humidity provide a favourable environment for survival and multiplication of microbes. Landfill workers involved in solid waste disposal activities are at the highest risk of exposure to these bioaerosols due to their proximity to solid waste and as they practise minimum personal safety and hygiene measures during working hours. Workers are recommended to use personal protective equipment and practise hygiene to reduce the impact of occupational exposure to bioaerosols.


Diabetes prevention among American Indians: the role of self-efficacy, risk perception, numeracy and cultural identity.
According to the Risk Perception Attitude (RPA) framework, classifying people according to their perceptions of disease risk and their self-efficacy beliefs allows us to predict their likelihood for engaging in preventive behaviors. Health interventions can then be targeted according to RPA group. We applied the framework to type 2 diabetes prevention behaviors among American Indians and expanded it to include culture and numeracy. Using a cross-sectional study design, we surveyed a sample of Northern Plains American Indians in a reservation community setting on self-reported perceptions of diabetes risk, objective diabetes risk, self-efficacy, engagement in healthy behaviors, knowledge of diabetes risk factors, and covariates including demographics, numeracy, and cultural identity. We used the RPA framework to classify participants into four groups based on their perceptions of risk and self-efficacy. Analyses of variance and covariance estimated inter-group differences in behaviors associated with type 2 diabetes prevention. Among 128 participants, our only finding consistent with the RPA framework was that self-efficacy and risk perception predicted knowledge about diabetes risk factors. We found limited evidence for the influence of cultural identity within the RPA framework. Overall, participants had lower numeracy skills which tended to be associated with inaccurate perceptions of higher levels of risk. The theoretical framework may benefit from inclusion of further contextual factors that influence these behaviors. Attention to numeracy skills stands out in our study as an important influence on the RPA framework, highlighting the importance of attending to numeracy when targeting and tailoring risk information to participants segmented by the RPA framework.


Untangling the functional potential of PSA-NCAM-expressing cells in CNS development and brain repair strategies.
Central nervous system (CNS) neural stem cells (NSCs), which are mostly defined by their ability to self-renew and to generate the three main cell lineages of the CNS, were isolated from discrete regions of the adult mammalian CNS including the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus in the hippocampus. At early stages of CNS cell fate determination, NSCs give rise to progenitors that express the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). PSA-NCAM(+) cells persist in adult brain regions where neuronal plasticity and sustained formation of new neurons occur. PSA-NCAM has been shown to be involved in the regulation of CNS myelination as well as in changes of cell morphology that are necessary for motility, axonal guidance, synapse formation, and functional plasticity in the CNS. Although being preferentially committed to a restricted either glial or neuronal fate, cultured PSA-NCAM(plus) progenitors do preserve a relative degree of multipotentiality. Considering that PSA-NCAM(+) cells can be neatly used for brain repair purposes, there is much interest for studying signaling factors regulating their development. With this regard, it is noteworthy that neurotransmitters, which belong to the micro-environment of neural cells in vivo, regulate morphogenetic events preceding synaptogenesis such as cell proliferation, migration, differentiation and death. Consistently, several ionotropic but also G-protein-coupled neurotransmitter receptors were found to be expressed in CNS embryonic and postnatal progenitors. In the present review, we outlined the ins and outs of PSA-NCAM(plus) cells addressing to what extent our understanding of extrinsic and in particular neurotransmitter-mediated signaling in these CNS precursor cells might represent a new leading track to develop alternative strategies to stimulate brain repair.


Correlations of demographical and clinicopathological features with patient outcome of pancreatic ductal adenocarcinoma: A retrospective study (2010-2018) from a Libyan Cohort.
The aim of the study was to study the correlations of demographical and clinicopathological variables of patients with pancreatic ductal adenocarcinoma (PDAC) and evaluate the association of these variables with patients' survival outcomes. A retrospective analysis of 123 patients with PDAC were diagnosed and treated at the National Cancer Institute, Misurata, Libya during the 2010-2108 period. Data for demographics, clinicopathological, biological variables, risk factors, presentation, treatment, and survival-related data were collected from the patients' medical records. The mean age of patient was 61.2 years (range: 19-90 years) and most of patients (80.5%) were aged >50 years. For gender distribution, PDAC was more frequent in males (59.3%). Abdominal pain was the most frequent presenting symptom (84.6%) and 78% (96 patients) among them had head tumors. Most patients (80.5%) presented with unresectable tumor at diagnosis. Disease-free survival was better in patients with early stage (P < 0.0001), low-grade tumor (P = 0.001), resectable tumor (P < 0.0001), and with carcinoembryonic antigen levels <5 ng/ml (P = 0.004). Multivariate Cox's regression analysis showed that tumor stage is an independent poor survival factor (P = 0.002). Age at diagnosis, gender, family history, and position of tumor did not show any significant associations with patient outcome. Libyan patients with PDAC had different demographics, clinicopathological, and biological variables. Typically, they presented with unresectable tumor, advanced stages, and had very short survival times. These results urge us to conduct in-depth biomolecular research studies to identify effective early diagnostics and therapeutics biomarkers in order to fight this disease before it escalates.


Integrated Care Models: HIV and Substance Use.
Behaviors and practices associated with substance use contribute to lack of HIV virologic suppression and onward transmission. In the USA, many recent HIV outbreaks have been connected with substance use. Evidence-based strategies for integrating care of those at risk for and living with HIV and who use substances continue to evolve. This review, based on scientific and medical literature through March 2023, provides an overview and evaluation of initiatives for integrated care aimed to serve patients at risk for and with HIV and a substance use disorder. Integrated care services can improve health outcomes for patients at risk for and with HIV and a substance use disorder; for instance, treatment for an opioid use disorder can help improve HIV viral suppression. Brick-and-mortar facilities can provide successful care integration with appropriate clinic leadership to support multidisciplinary care teams, up-to-date provider training, and sufficient pharmacy stock for substance use treatment. Delivering healthcare services to communities (e.g., mobile healthcare clinics and pharmacies, telehealth) may prove to be an effective way to provide integrated services for those with or at risk of HIV and substance use disorders. Incorporating technology (e.g., mobile phone applications) may facilitate integrated care. Other venues, including harm reduction programs and carceral settings, should be targets for integrated services. Venues providing healthcare should invest in integrated care and support legislation that increases access to services related to HIV and substance use.


Controlling methacryloyl substitution of chondroitin sulfate: injectable hydrogels with tunable long-term drug release profiles.
Drug delivery systems capable of local sustained release of small molecule therapeutics remain a critical need in many fields, including oncology. Here, a system to create tunable hydrogels capable of modulating the loading and release of cationic small molecule therapeutics was developed. Chondroitin sulfate (CS) is a sulfated glycosaminoglycan that has many promising properties, including biocompatibility, biodegradation and chemically modifiable groups for both covalent and non-covalent bonding. CS was covalently modified with photocrosslinkable methacryloyl groups (CSMA) to develop an injectable hydrogel fabrication. Utilizing anionic groups, cationic drugs can be adsorbed and released from the hydrogels. This study demonstrates the synthesis of CSMA with a varying degree of substitution (DS) to generate hydrogels with varying swelling properties, maximum injection force, and drug release kinetics. The DS of the synthesized CSMA ranged from 0.05 ± 0.02 (2 h reaction) to 0.28 ± 0.02 (24 h reaction) with a DS of 1 representing 100% modification. The altered DS resulted in changes in hydrogel properties with the swelling of 20% CSMA hydrogels ranging from 42 (2 h reaction) to 13 (24 h reaction) and injection forces ranging from 18 N (2 h reaction) to 94 N (24 h reaction). The release of sunitinib, an oncology therapeutic that inhibits intracellular signaling by targeting multiple receptor tyrosine kinases, ranged from 18 μg per day (2 h reaction) to 9 μg per day (24 h reaction). While decreasing the DS increased the hydrogel swelling and rate of therapeutic release, it also limited the hydrogel fabrication range to only those containing 10% or higher CSMA. Blended polymer systems with poly(vinyl alcohol)-methacrylate (PVAMA) were fabricated to stabilize the resulting hydrogels via attenuating the swelling properties. Release profiles previously unattainable with the pure CSMA hydrogels were achieved with the blended hydrogel formulations. Overall, these studies identify a method to formulate tunable CSMA and blended CSMA/PVAMA hydrogels capable of sustained release of cationic therapeutics over six weeks with applications in oncology therapeutics.


[Molecular mechanisms of stress adaptation: immediate early genes].
Immediate early gene (IEG) expression is the important part of adaptive reactions caused by short-term high-intensity physical activities. IEG leads to activation of transcription, protein neo-synthesis and form-specific stress response. We were looking for human body physical exercise adaptation leukocytes IEG expression markers. Gene expression profiles were measured using microarray technology and validated by real time PCR. In this study, we describe several cell stress adaptation regulators groups: stress response, splicing and cell signaling.


A Prospective Study Assessing Complication Rates and Patient-Reported Outcomes in Breast Reconstructions Using a Novel, Deep Dermal Human Acellular Dermal Matrix.
The value proposition of an acellular dermal matrix (ADM) taken from the deep dermis is that the allograft may be more porous, allowing for enhanced integration and revascularization. In turn, this characteristic may attenuate complications related to foreign body reactions, seromas, and infection. However, this is juxtaposed against the potential loss of allograft structural integrity, with subsequent risk of malposition and extrusion. Despite the active use of novel, deep dermal ADMs, the clinical outcomes of this new technology has not been well studied. This is a prospective study to evaluate surgical and patient-reported outcomes using a deep dermal ADM, FlexHD Pliable. Surgical outcomes and BREAST-Q patient-reported outcomes were evaluated postoperatively at 2- and 6-month time points. Seventy-two breasts (41 patients) underwent reconstruction. Complication rate was 12.5%, including 2 hematomas and 7 flap necroses. One case of flap necrosis led to reconstructive failure. Notably, there were no cases of infection, seroma, or implant extrusion or malposition. Average BREAST-Q scores were satisfaction with outcome (70.13 ± 23.87), satisfaction with breasts (58.53 ± 20.00), psychosocial well being (67.97 ± 20.93), sexual well being (54.11 ± 27.72), and physical well being (70.45 ± 15.44). Two-month postoperative BREAST-Q scores decreased compared with baseline and returned to baseline by 6 months. Postoperative radiation therapy had a negative effect on satisfaction with breasts (P = 0.004) and sexual well being (P = 0.006). Deep dermal ADM is a novel modification of traditional allograft technology. Use of the deep dermal ADM yielded acceptably low complication rates and satisfactory patient-reported outcomes.


Blood plasma traits associated with genetic merit for feed utilization in Holstein cows.
The objective of this study was to evaluate the potential of selection for feed utilization on associated blood plasma metabolite and hormone traits. Dry matter intake (DMI) was recorded in 970 Holsteins from 11 commercial farms in Pennsylvania and used to derive dry matter efficiency (DME; fat-corrected milk yield/DMI), crude protein efficiency (CPE; protein yield/crude protein intake), and residual feed intake (RFI, defined as actual feed intake minus expected feed intake for maintenance and milk production, based on calculation of DMI adjusted for yield, body weight, and body condition score). Estimated breeding values for the 4 feed utilization traits (DMI, DME, CPE, and RFI), yield traits, body traits, and days open were standardized according to their respective genetic standard deviations. Up to 631 blood samples from 393 cows from 0 to 60 d in milk (DIM) were evaluated for blood plasma concentrations of glucose, nonesterified fatty acids (NEFA), β-hydroxybutyrate (BHB), creatinine, urea, growth hormone (GH), 3,5,3'-triiodothyronine (T3), and other parameters. Blood plasma traits were regressed on DIM, lactation number, herd, and standardized genetic merit. Cows with higher genetic merit for yield had significantly higher concentrations of GH, NEFA (milk and protein yield), and BHB (fat yield) from 31 to 60 DIM, but lower concentrations of glucose from 0 to 30 DIM, and T3 (milk yield, 0-60 DIM). The high GH-low glucose-low T3 concentration pattern was further accentuated for cows with genetic merit for enhanced feed efficiency (higher DME and lower RFI). Cows with a genetic tendency to be thin (low body condition score) also had elevated GH concentrations, but lower blood glucose, creatinine, and T3 concentrations. Those characteristics associated with enhanced feed efficiency (higher GH and lower glucose and T3 concentrations) were unfavorably associated with fertility, as indicated by elevated days open. Elevated NEFA and BHB concentrations were also associated with extended days open. Consideration of metabolic profiles when evaluating feed efficiency might be a method of maintaining high levels of health and reproductive fitness when selecting for feed efficiency.


Precipitation-dependent flowering of Globularia alypum and Erica multiflora in Mediterranean shrubland under experimental drought and warming, and its inter-annual variability.
Relationships between autumn flowering, precipitation and temperature of plant species of Mediterranean coastal shrublands have been described, but not analysed experimentally. These relationships were analysed for two species of co-occurring, dominant, autumn-flowering shrubs, Globularia alypum and Erica multiflora, over 4 years and in experimentally generated drought and warming conditions. The aim was to improve predictions about the responses and adaptations of flowering of Mediterranean vegetation to climate change. Beginning of anthesis and date of maximum flowering intensity ('peak date') were monitored over 4 years (2001-2004) on a garrigue land type in the noth-east of the Iberian Peninsula. Two experimental treatments were applied, increased temperature (+0.73 degrees C) and reduced soil moisture (-17%) relative to untreated plots. Flowering of Globularia alypum and Erica multiflora differed greatly between years depending on the precipitation of the previous months and the date of the last substantial rainfall (>10 mm). Globularia alypum flowered once or twice (unimodal or bimodal) as the result of differences in the distribution and magnitude of precipitation in late-spring and summer (when floral buds develop). The drought treatment delayed and decreased flowering of Globularia alypum in 2001 and delayed flowering in 2002. Warming extended the period between the beginning of flowering and the end of the second peak for autumn flowering in 2001 and also increased peak intensity in 2002. Flowering of Erica multiflora was unaffected by either treatment. Autumn flowering of Globularia alypum and Erica multiflora is more dependent on water availability than on temperature. Considerable inter-annual plasticity in the beginning of anthesis and peak date and on unimodal or bimodal flowering constitutes a 'safe strategy' for both species in relation to varying precipitation and temperature. However, severe changes in precipitation in spring and summer may severely affect flowering of Globularia alypum but not Erica multiflora, thus affecting development/structure of the ecosystem if such conditions persist.


Exploring Disparities in Awarding VA Service-Connected Disability for Post-Traumatic Stress Disorder for Active Duty Military Service Members from Recent Conflicts in Iraq and Afghanistan.
We explore disparities in awarding post-traumatic stress disorder (PTSD) service-connected disability benefits (SCDB) to veterans based on gender, race/ethnicity, and misconduct separation. Department of Defense data on service members who separated from October 1, 2001 to May 2017 were linked to Veterans Administration (VA) administrative data. Using adjusted logistic regression models, we determined the odds of receiving a PTSD SCDB conditional on a VA diagnosis of PTSD. A total of 1,558,449 (79% of separating service members) had at least one encounter in VA during the study period (12% female, 4.5% misconduct separations). Females (OR 0.72) and Blacks (OR 0.93) were less likely to receive a PTSD award and were nearly equally likely to receive a PTSD diagnosis (OR 0.97, 1.01). Other racial/ethnic minorities were more likely to receive an award and diagnosis, as were those with misconduct separations (award OR 1.3, diagnosis 2.17). Despite being diagnosed with PTSD at similar rates to their referent categories, females and Black veterans are less likely to receive PTSD disability awards. Other racial/ethnic minorities and those with misconduct separations were more likely to receive PTSD diagnoses and awards. Further study is merited to explore variation in awarding SCDB.


Leveraging the E-commerce footprint for the surveillance of healthcare utilization.
The utilization of healthcare services serves as a barometer for current and future health outcomes. Even in countries with modern healthcare IT infrastructure, however, fragmentation and interoperability issues hinder the (short-term) monitoring of utilization, forcing policymakers to rely on secondary data sources, such as surveys. This deficiency may be particularly problematic during public health crises, when ensuring proper and timely access to healthcare acquires special importance. We show that, in specific contexts, online pharmacies' digital footprint data may contain a strong signal of healthcare utilization. As such, online pharmacy data may enable utilization surveillance, i.e., the monitoring of short-term changes in utilization levels in the population. Our analysis takes advantage of the scenario created by the first wave of the Covid-19 pandemic in Mainland China, where the virus' spread lead to pervasive and deep reductions of healthcare service utilization. Relying on a large sample of online pharmacy transactions with full national coverage, we first detect variation that is strongly consistent with utilization reductions across geographies and over time. We then validate our claims by contrasting online pharmacy variation against credit-card transactions for medical services. Using machine learning methods, we show that incorporating online pharmacy data into the models significantly improves the accuracy of utilization surveillance estimates.


1H magnetic resonance spectroscopy in dementia.
Present data support the concept that (1)H magnetic resonance spectroscopy ((1)H MRS) may become an adjunct to clinical evaluation for differential diagnosis of dementia in the future. The value of (1)H MRS in monitoring the disease progression in dementia is expected to be in areas where group effects are sought such as monitoring effectiveness of therapies in drug trials. Elevation of myoinositol to creatine (mI/Cr) and choline to creatine (Cho/Cr) and reduction in the neuronal integrity marker N-acetylaspartate to creatine (NAA/Cr) levels in individuals with mild cognitive impairment and pre-symptomatic Alzheimer's disease suggests that (1)H MRS may also be valuable in predicting future development of dementia and monitoring early disease progression for preventive therapies. Investigations of in vivo (1)H MRS as a marker for differential diagnosis and progression of dementia, however, has been limited to clinically confirmed cohorts and remains to be validated by histopathology at autopsy. Overall, MRS is a promising investigational technique in ageing and dementia at this time. The potential clinical application of MRS in ageing and dementia, however, is growing with technical advances in the field.


Isodesacetyluvaricin, an Annonaceous acetogenin, specifically inhibits gene expression of cyclooxygenase-2.
Cyclooxygenase-2 (COX-2) is an inducible isoform of the enzyme responsible for the synthesis of several inflammatory mediators. In a search for phytochemicals with anti-inflammatory activity, the COX-2 inhibitory activity of 15 typical Annonaceous acetogenins was examined. Isodesacetyluvaricin (1), from the Formosan tropical fruit tree Annona glabra, exhibited the most potent activity. Reverse transcription PCR was used to test the effect of 1 on epidermal growth factor-stimulated expression of COX-2 in cultures of A431 human epidermoid carcinoma cells. Three hours after exposure to 1 (5 μM), A431 cells had barely detectable levels of COX-2 mRNA. A corresponding but smaller decline in the COX-2 protein appeared on using Western blots. Lipopolysaccharide-stimulated expression of COX-2 in Raw 264.7 mouse leukemic monocyte-macrophages showed a similar decrease. Luciferase assays revealed that cells exposed to 1 had reduced activities of two COX-2 promoter-transcription factors: cAMP response element-binding factor and nuclear factor of activated T-cells. Compound 1 did not affect cell proliferation, as measured by a colorimetric assay, or intracellular store-operated calcium influx, as determined by fluorescence imaging. Thus, 1 may serve as a lead compound for targeting inflammatory diseases as well as angiogenesis and cancer metastasis.


[Chloditane therapy of adrenocortical cancer].
Adrenocortical cancer (ACC) is a rare and aggressive tumor often diagnosed at the late stage of its development. Treatment with adrenocorticotoxic drug chloditane has been applied decades, but in spite of this we see scrupulous investigations of using chloditane in a complex treatment of ACC be carried out. The author has analyzed the following schemes of chloditane use: in preoperative period, after the potentially radical and non-potentially radical surgery, for symptomatic treatment. The most effective scheme of chloditane use was shown to be that of using maximal tolerance dose of the medication constantly after a conducted radical operation. The use of chloditane is not obligatory after potentially radical operation in case the tumor is less than 7-8 cm.


Performing without a net: transitioning away from a health information technology-rich training environment.
In many academic medical centers (AMCs), health information technology (HIT) has become a foundational component of patient care. Medical training in these environments generates dependence on HIT. The authors conducted this study to determine how transitioning from an HIT-rich environment affects practitioners' self-perceptions of competence, practice efficiency, and patient safety. In 2004 and 2005, the authors performed a cross-sectional survey study involving medical students and residents who had graduated from Vanderbilt University Medical Center (VUMC), an HIT-rich AMC. The authors distributed surveys to 679 graduates from 2001 to 2003 who transferred to other institutions. Although 128 surveys were returned undelivered because of wrong addresses, 328 (60%) were returned complete and analyzed. Among respondents, 255 (78%) reported transitioning to environments with less HIT than VUMC. The authors compared responses from this group with those of peers who transitioned to environments with the same or greater HIT penetration. After controlling for confounding effects, the authors found that graduates who transitioned to lower-HIT institutions reported feeling less able to practice safe patient care (P = .02), to utilize evidence at the point of care (P = .05), to work efficiently (P < .001), to share and communicate information (P = .03), and to work effectively within the local system (P = .007). Providers who transition away from HIT-rich environments may perceive their care as less safe and less efficient. These results support greater adoption of HIT and underscore the need for formal education for new trainees, faculty, and staff transitioning to a new system of care.


Intraocular lens subluxation in marfan syndrome.
Ectopia lentis (EL) is a major criteria for the diagnosis of Marfan syndrome, it may vary from an asymptomatic mild displacement to a significant subluxation that places the equator of the lens in the pupillary axis. The purpose of this work is to present the case of a patient with Marfan syndrome who received treatment for subluxation at our institution. A 51-year-old female diagnosed with Marfan syndrome presented to the emergency department with bilateral eye redness, foreign body sensation and crusting around the eyes on awakening. She had the following history of cardiac and ophthalmologic complications, including: 1. Lens subluxation 2. High myopia 3. Aortic root dilation, 4. Mitral valve prolapse and 5. Tricuspid insufficiency. The ophthalmological management of Marfan patients is challenging and periodical follow-up is needed. Surgical versus conservative management is controversial, each case needs to be evaluated individually to analyze the risks and benefits of the procedures.


Implementation of Integrated Learning Program in neurosciences during first year of traditional medical course: perception of students and faculty.
Our college introduced an integrated learning program (ILP) for first year undergraduates with an aim to develop, implement and evaluate a module for CNS in basic sciences and to assess the feasibility of an ILP in phase I of medical education in a college following traditional medical curriculum. The idea of implementing ILP for Central Nervous System (CNS) in phase one was conceived by curriculum development committee drawn from faculty of all phases. After a series of meetings of curriculum development committee, inputs from basic science and clinical departments, a time table was constructed. Various teaching learning methods, themes for integrated didactic lectures, case based learning and clinical exposure were decided. Basic science faculty were made to participate actively in both case based learning and hospital visits along with clinical experts. The completed program was evaluated based on structured questionnaire. Sixty percent students rated the program good to excellent with reference to appreciation, understanding and application of basic science knowledge in health and disease. Seventy eight percent felt that this program will help them perform better in later days of clinical training. However sixty percent students felt that ILP will not help them perform better at the first professional examination. Seventy two per cent of faculty agreed that this program improved understanding and application of basic science knowledge of students. Ninety percent of faculty felt that this program will help them perform better in later days of clinical training. The adoption of present integrated module for CNS and the use of multiple teaching learning methods have been proven to be useful in acquisition of knowledge from the student satisfaction point of view. Students and faculty expressed an overall satisfaction towards ILP for CNS. The study showed that it is possible to adopt an integrated learning module in the first year of medical course under a conventional curriculum.


Treatment of Marmoset Intracerebral Hemorrhage with Humanized Anti-HMGB1 mAb.
Intracerebral hemorrhage (ICH) is recognized as a severe clinical problem lacking effective treatment. High mobility group box-1 (HMGB1) exhibits inflammatory cytokine-like activity once released into the extracellular space from the nuclei. We previously demonstrated that intravenous injection of rat anti-HMGB1 monoclonal antibody (mAb) remarkably ameliorated brain injury in a rat ICH model. Therefore, we developed a humanized anti-HMGB1 mAb (OKY001) for clinical use. The present study examined whether and how the humanized anti-HMGB1 mAb ameliorates ICH injury in common marmosets. The results show that administration of humanized anti-HMGB1 mAb inhibited HMGB1 release from the brain into plasma, in association with a decrease of 4-hydroxynonenal (4-HNE) accumulation and a decrease in cerebral iron deposition. In addition, humanized anti-HMGB1 mAb treatment resulted in a reduction in brain injury volume at 12 d after ICH induction. Our in vitro experiment showed that recombinant HMGB1 inhibited hemoglobin uptake by macrophages through CD163 in the presence of haptoglobin, suggesting that the release of excess HMGB1 from the brain may induce a delay in hemoglobin scavenging, thereby allowing the toxic effects of hemoglobin, heme, and Fe2+ to persist. Finally, humanized anti-HMGB1 mAb reduced body weight loss and improved behavioral performance after ICH. Taken together, these results suggest that intravenous injection of humanized anti-HMGB1 mAb has potential as a novel therapeutic strategy for ICH.


Characteristics of ageing pets and their owners: dogs v. cats.
The purpose of the present cross-sectional, convenience sampled study was to ascertain differences in diet and lifestyle between cat (n 155) and dog (n 318) owners and their pets. Average cat ownership was 6.1 (SD 5) years and average cat's age was 6.9 (SD 5) years. Cats were reported to be overweight (14 %), fed ad libitum (87 %), given medication (11 %) and had health conditions (24 %). Cat's age was significantly and positively related to cat's weight, duration of illness, owner's BMI and some owners' dietary characteristics. Overweight in cats was significantly associated with overweight in older owners ( ≥ 60 years). Younger cat owners ( < 60 years) showed non-statistically significant trends between the owner's BMI and cat's overweight. Cat's age was inversely correlated with cat's and owner's activity levels. Dogs were owned for 5.5 (SD 4) years and mean dog's age was 5.9 (SD 4) years. Dogs were reported to be overweight (18 %), fed ad libitum (49 %), given medication (31 %) and had health conditions (34 %). Dog's age was positively associated with duration of illness. Dog's age was inversely correlated with amount of food fed, dog's activity and owner's exercise and intake of fruit, vegetables and whole grains. Dog's age was positively correlated with the owner's BMI and frequency of added fat consumption. Overweight in dogs was associated with overweight in older owners ( ≥ 60 years) and was correlated with poorer health in both the dog and the owner. Younger dog owners were more likely to have an overweight dog if they themselves were obese. Similarities were found in owner's and pet's diet and lifestyle issues with ageing. Overweight was associated with ageing, dietary, lifestyle and health issues in this sample. Older owners who were overweight had overweight pets. Strategies should be targeted towards decreasing both owner's and pet's overweight. The use of exercise and dietary interventions should be encouraged.


The prolonged postoperative analgesic effect when dexamethasone is added to a nonsteroidal antiinflammatory drug (rofecoxib) before breast surgery.
Glucocorticoids provide analgesia. In this study, we evaluated the effects of adding dexamethasone to a multimodal postoperative analgesic regimen, including a long-acting nonsteroidal antiinflammatory drug. One-hundred patients admitted for ambulatory breast cancer surgery were studied. They received paracetamol 2 g and rofecoxib 50 mg orally 1 h before start of general anesthesia with propofol and remifentanil. The patients were then randomized to receive, in a double-blind manner, either dexamethasone 16 mg IV or placebo. Both groups received fentanyl 1 mug/kg IV and 20-40 mL bupivacaine 2.5 mg/mL wound infiltration before the end of surgery. There was no difference in pain scores or rescue medication between the groups during the first 4 h after surgery. After discharge, the median pain score during coughing or shoulder movement was 3 on a 0-10 scale in patients receiving placebo, and 1 in the patients receiving dexamethasone, which did not reach statistical significance (P = 0.06). From 24 to 72 h, the median pain with coughing or shoulder movement in patients receiving placebo was 2, and 1 in patients receiving dexamethasone, which did reach statistical significance (P < 0.05). Forty percent of patients receiving dexamethasone were pain free from 4 to 24 h, compared with 24% of patients receiving placebo, a difference that did not reach statistical significance (P = 0.09). Similarly, 46% of patients receiving dexamethasone were pain free from 24 to 72 h, compared with 28% of patients receiving placebo (P = 0.06). More patients had slept poorly on the first night in the dexamethasone group than in the control group, 68% vs 44%, (P < 0.05). Dexamethasone 16 mg provides prolonged postoperative analgesia from 24 to 72 h after surgery when added to a multimodal regimen including nonsteroidal antiinflammatory drug (rofecoxib).


Molecular epidemiology of cross-species Giardia duodenalis transmission in western Uganda.
Giardia duodenalis is prevalent in tropical settings where diverse opportunities exist for transmission between people and animals. We conducted a cross-sectional study of G. duodenalis in people, livestock, and wild primates near Kibale National Park, Uganda, where human-livestock-wildlife interaction is high due to habitat disturbance. Our goal was to infer the cross-species transmission potential of G. duodenalis using molecular methods and to investigate clinical consequences of infection. Real-time PCR on DNA extracted from fecal samples revealed a combined prevalence of G. duodenalis in people from three villages of 44/108 (40.7%), with prevalence reaching 67.5% in one village. Prevalence rates in livestock and primates were 12.4% and 11.1%, respectively. Age was associated with G. duodenalis infection in people (higher prevalence in individuals <or=15 years) and livestock (higher prevalence in subadult versus adult animals), but other potential risk factors in people (gender, contact with domestic animals, working in fields, working in forests, source of drinking water, and medication use) were not. G. duodenalis infection was not associated with gastrointestinal symptoms in people, nor was clinical disease noted in livestock or primates. Sequence analysis of four G. duodenalis genes identified assemblage AII in humans, assemblage BIV in humans and endangered red colobus monkeys, and assemblage E in livestock and red colobus, representing the first documentation of assemblage E in a non-human primate. In addition, genetic relationships within the BIV assemblage revealed sub-clades of identical G. duodenalis sequences from humans and red colobus. Our finding of G. duodenalis in people and primates (assemblage BIV) and livestock and primates (assemblage E) underscores that cross-species transmission of multiple G. duodenalis assemblages may occur in locations such as western Uganda where people, livestock, and primates overlap in their use of habitat. Our data also demonstrate a high but locally variable prevalence of G. duodenalis in people from western Uganda, but little evidence of associated clinical disease. Reverse zoonotic G. duodenalis transmission may be particularly frequent in tropical settings where anthropogenic habitat disturbance forces people and livestock to interact at high rates with wildlife, and this could have negative consequences for wildlife conservation.


Histone deacetylase III as a potential therapeutic target for the treatment of lethal sepsis.
We have recently demonstrated that inhibition of histone deacetylase (HDAC) Class I, II, and IV with nonspecific HDAC inhibitors improves survival in a mouse model of lethal cecal ligation and puncture (CLP). However, the consequence of HDAC Class III inhibition is unknown in this model. The aims of the present study were to explore the effect of EX-527, a selective Sirtuin 1 (SIRT1) inhibitor, on survival in the lethal model of CLP-sepsis and to assess the impact of the treatment on inflammatory cytokine production, coagulopathy, and bone marrow atrophy during severe sepsis. For Experiment I, C57BL/6J mice were subjected to CLP and, 1 hour later, intraperitoneally injected with either EX-527 dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Survival was monitored for 10 days. For Experiment II, 1 hour after CLP animals were randomly treated with (1) DMSO vehicle and (2) EX-527. Peritoneal fluid and blood samples were collected for measurement of cytokines, and blood was also used to evaluate coagulation status using thrombelastography. In addition, long bones (femurs and tibias) were examined to determine morphologic changes in the marrow by hematoxylin and eosin staining. For Experiment III, normal primary splenocytes were cultured and treated with lipopolysaccharide in the presence or absence of EX-527 to assess cytokine production. EX-527 significantly improved survival (50% vs. 0% survival as compared to vehicle, p = 0.0007) and attenuated levels of cytokines tumor necrosis factor α and interleukin 6 in the blood and the peritoneal fluid compared with the vehicle control. It also decreased tumor necrosis factor α and interleukin 6 production by splenocytes in vitro. Selective inhibition of SIRT1 was associated with significant improvements in fibrin cross-linkage, platelet function, and clot rigidity but had no significant impact on the clot initiation parameters. Moreover, inhibition of SIRT1 was associated with a significant decrease in bone marrow atrophy. Selective inhibition of Class III HDAC SIRT1 significantly improves survival, attenuates cytokine levels and sepsis-associated coagulopathy, and decreases bone marrow atrophy in a lethal mouse septic model.


Mobile phones in the orthopedic operating room: Microbial colonization and antimicrobial resistance.
Surgical site infections are a major cause of morbidity and mortality following orthopedic surgery. Recent efforts to identify sources of contamination in the operating rooms have implicated mobile phones. To investigate microbial colonization on the mobile phones of health care professionals in the orthopedic operating room. We conducted a cross-sectional study involving culture and sensitivity analysis of swabs taken from the mobile phones of orthopedic and anesthesia attendings, residents, technicians and nurses working in the orthopedic operating rooms over a period of two months. Demographic and cell phone related factors were recorded using a questionnaire and the factors associated with contamination were analyzed. Ninety-three of 100 mobile phones were contaminated. Species isolated were Coagulase-negative Staphylococcus (62%), Micrococcus (41%) and Bacillus (26%). The risk of contamination was increased with mobile covers and cracked screens and decreased by cell phone cleaning. Mobile phones belonging to health care workers are frequently contaminated with pathogenic bacteria with the potential of transferring drug resistance to nosocomial pathogens. Studies investigating the relationship to surgical site infections need to be conducted. The concept of "mobile hygiene" involving the change of mobile covers, replacement of cracked screens or even wiping the phone with an alcohol swab could yield the cost-effective balance that contaminated cell phones deserve until they are established as a direct cause of surgical site infections.


Stabilization of proximal interphalangeal joint in lesser toe deformities with an angulated intramedullary implant.
Hammertoe and claw toe are among the most common foot deformities. Proximal interphalangeal (PIP) joint realignment can be performed using specifically designed intramedullary implants. The aim of this study was to assess the clinical outcome of patients with lesser toes deformities undergoing PIP joint realignment using an intramedullary implant. Patients requiring PIP joint realignment were included in this prospective multicenter observational study and followed for 12 months. A total of 156 toes, in 117 patients were implanted with the implants. Complications and radiological and functional outcome were assessed. The proportion of joints fused on X-rays was 83.8% (95% CI: 77.8, 89.7) after 1 year. American Orthopaedic Foot and Ankle Society lesser metatarsophalangeal-interphalangeal scale (AOFAS-LMIS) improved from 40.4 (SD = 18.3) preoperatively to 85.5 (SD = 9.2) after 1 year. The proportion of patients with pain was 15.5% after 6 weeks and decreased to 4.7% after 1 year. Of the patients, 98% were satisfied about the operation. In patients with incomplete fusion of the PIP joint after 1 year, AOFAS-LMIS improved from 36.7 (SD = 18.9) preoperatively to 84.2 (SD = 10.1) 1 year postoperatively, while pain was reported by 2 patients (8.3%) after 1 year. Toe malalignment and lack of toe pulp-contact were reported slightly more frequently than for the whole group of patients, but not for the majority of the cases. Overall, complications were reported intraoperatively in 1.3% of the patients (2 cases) and postoperatively in 3.2% (5 cases). Revision was required in 1 case. Mallet toe deformity was found in 2.0% of the patients after 1 year. This study showed that the use of an intramedullary implant for PIP realignment led to a high rate of fusion and a good outcome. No need of reoperation was reported for patients with incomplete joint fusion who had a stable joint with no pain. Level IV, prospective case series.


Vascular cognitive deterioration and stroke.
Vascular cognitive impairment, the recent modification of the terminology related to vascular burden of the brain, reflects the all-encompassing effects of vascular disease or lesions on cognition. It incorporates the complex interactions between vascular aetiologies, risk factors and cellular changes within the brain and cognition. The concept covers the frequent poststroke cognitive impairment and dementia, as well as cerebrovascular disease (CVD) as the second most common factor related to dementia. CVD as well as vascular risk factors including arterial hypertension, history of high cholesterol, diabetes or forms of heart disease are independently associated with an increased risk of cognitive impairment and dementia. Traditional vascular risk factors and stroke are also independent factors for the clinical presentation of Alzheimer's disease (AD). In addition to these vascular factors, CVD/strokes, infarcts and white-matter lesions may trigger and modify the progression of AD as the most common cause of neurodegenerative dementia. The main subtypes of previously defined vascular dementia (VaD) include the cortical VaD or multi-infarct dementia also referred as poststroke VaD, subcortical ischaemic vascular disease and dementia or small-vessel dementia and strategic-infarct dementia. Whilst CVD is preventable and treatable, it is clearly a major factor in the prevalence of cognitive impairment in the elderly worldwide.


Healthcare staff's evaluation of a walk-in centre at a healthcare centre in an immigrant-dense area.
To evaluate a walk-in centre at a healthcare centre in an immigrant-dense area where a high proportion of the patients have limited language ability in Swedish, from the perspective of healthcare personnel. Increased global migration results in higher vulnerability in migrants, with the risk of increased morbidity and mortality. Migrants' health often deteriorates, which can be attributed to an increased level of stress and adaptation to a new lifestyle. Therefore, immigrants are at higher risk of being affected by, for example, cardiovascular diseases and diabetes. This requires access to good health care. A qualitative exploratory study was conducted, using semi-structured interviews. Content analysis was used in the analysis process. Semi-structured interviews were held with 15 purposively sampled doctors and nurses, working at a healthcare centre in Sweden. Data were collected during autumn 2017. The study was performed in accordance with COREQ. Working at the walk-in centre involved caring for everything from basic to advanced health problems and meant a high pace that required stress-resistant personnel. The walk-in centre was described as both promoting and threatening patient safety. The personnel had several ideas on how to develop the walk-in centre. A walk-in centre can be seen as a necessity related to issues of ensuring patient safety and delivering care for everyone in an immigrant-dense area. However, it cannot be the only form of care offered, as it seems not be adapted to certain groups, such as people with disabilities and the elderly. The findings emphasise that a walk-in centre is a way to increase accessibility for the entire population and offer equal care for all, even if it involves challenges that need to be addressed.


A technique for hepaticodochojejunostomy with transhepatic stent.
A technique for the placement of a transhepatic stent at the time of biliary-enteric anastomosis, which prevents the stent from interfering with the performance of the anastomosis is described herein. This technique obivates the need to pass the transhepatic catheter after the posterior portion of the hepaticojejunostomy has been completed.


Endothelial cells in the context of brain arteriovenous malformations.
A subset of brain arteriovenous malformations (AVM) cannot be treated using today's treatment paradigms. Novel therapies may be developed, however, as the underlying pathophysiology of these lesions becomes better understood. Endothelial cells (EC) are the subject of new biological therapies, such as radiosensitisation and vascular targeting. This work reviews the current research surrounding EC in the context of brain AVM, including both in vitro and AVM specimen analysis, with a particular focus on the effect of radiation on EC. EC are heterogeneous with no recognised common phenotype, which leads to difficulties in applying the results of the common studies using human umbilical vein endothelial cells to AVM research. Human brain EC are observed to have a high rate of proliferation and also have a reduced apoptotic response to inflammatory mediators such as transforming growth factor-beta. The angiogenic factors vascular endothelial growth factor and endothelin-1 (ET-1) are not normally produced by quiescent brain vasculature, but are produced by AVM EC. Radiation causes EC to separate and become disrupted. Leucocyte and platelet adherence is increased for several days post-irradiation due to increased E-selectin and P-selectin and intercellular adhesion molecule-1 expression. ET-1 is highly expressed in irradiated AVM EC. Radiosurgery produces local radiation-induced changes in EC, which may allow these changes to be harnessed in conjunction with other techniques such as vascular targeting.


Exploring a Mitochondria Targeting, Dinuclear Cyclometalated Iridium (III) Complex for Image-Guided Photodynamic Therapy in Triple-Negative Breast Cancer Cells.
Photodynamic therapy (PDT) has emerged as an efficient and noninvasive treatment approach utilizing laser-triggered photosensitizers for combating cancer. Within this rapidly advancing field, iridium-based photosensitizers with their dual functionality as both imaging probes and PDT agents exhibit a potential for precise and targeted therapeutic interventions. However, most reported classes of Ir(III)-based photosensitizers comprise mononuclear iridium(III), with very few examples of dinuclear systems. Exploring the full potential of iridium-based dinuclear systems for PDT applications remains a challenge. Herein, we report a dinuclear Ir(III) complex (IRDI) along with a structurally similar monomer complex (IRMO) having 2-(2,4-difluorophenyl)pyridine and 4'-methyl-2,2'-bipyridine ligands. The comparative investigation of the mononuclear and dinuclear Ir(III) complexes showed similar absorption profiles, but the dinuclear derivative IRDI exhibited a higher photoluminescence quantum yield (Φp) of 0.70 compared to that of IRMO (Φp = 0.47). Further, IRDI showed a higher singlet oxygen generation quantum yield (Φs) of 0.49 compared to IRMO (Φs = 0.28), signifying the enhanced potential of the dinuclear derivative for image-guided photodynamic therapy. In vitro assessments indicate that IRDI shows efficient cellular uptake and significant photocytotoxicity in the triple-negative breast cancer cell line MDA-MB-231. In addition, the presence of a dual positive charge on the dinuclear system facilitates the inherent mitochondria-targeting ability without the need for a specific targeting group. Subcellular singlet oxygen generation by IRDI was confirmed using Si-DMA, and light-activated cellular apoptosis via ROS-mediated PDT was verified through various live-dead assays performed in the presence and absence of the singlet oxygen scavenger NaN3. Further, the mechanism of cell death was elucidated by an annexin V-FITC/PI flow cytometric assay and by investigating the cytochrome c release from mitochondria using Western blot analysis. Thus, the dinuclear complex designed to enhance spin-orbit coupling with minimal excitonic coupling represents a promising strategy for efficient image-guided PDT using iridium complexes.


Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer.
It remains undetermined whether cisplatin and carboplatin are equally effective for advanced non-small-cell lung cancer (NSCLC). We therefore did a meta-analysis of trials that compared cisplatin-based chemotherapy with carboplatin-based chemotherapy. We performed a literature search to identify trials that had investigated the substitution of carboplatin for cisplatin in the treatment of advanced NSCLC. We evaluated these trials for inclusion, rated methodologic quality, and abstracted relevant data. Of 1,191 reports, eight trials (2,948 patients) were identified, five of which investigated drug regimens containing platinum plus a new agent. Cisplatin-based chemotherapy produced a higher response rate, but the survival advantage was not significant (hazard ratio = 1.050; 95% CI, 0.907 to 1.216; P =.515). Subgroup analysis revealed that combination chemotherapy consisting of cisplatin plus a new agent yields 11% longer survival than carboplatin plus the same new agent (hazard ratio = 1.106; 95% CI, 1.005 to 1.218; P =.039). Patients on cisplatin-based chemotherapy frequently developed nausea and vomiting; thrombocytopenia was more frequent during carboplatin-based chemotherapy. No significant difference in treatment-related mortality was observed. We found that combination chemotherapy consisting of cisplatin plus a new agent yields a substantial survival advantage compared with carboplatin plus a new agent in patients with advanced NSCLC, although we failed to find any survival difference in an analysis that included both new and old agents. The strength of our conclusion is limited because we used abstracted data, and careful interpretation is thus required. Nevertheless, our results raise a critical point that needs to be evaluated in future studies.


A new proposal for a principal component-based test for high-dimensional data applied to the analysis of PhyloChip data.
A modification of the principal component test is presented. It uses a weighted combination of the sums of squares for different principal components and is thus more powerful in high-dimensional settings with small sample sizes. Under usual normality assumptions, a rotation test is proposed which enables an exact conditional parametric test. The procedure is demonstrated with microarray data for the bacterial composition in the rhizosphere of different potato cultivars. In simulation studies, the power of the proposed statistic is compared with the competing multivariate parametric tests.


Cost-effectiveness analysis of a supported employment intervention for people with mood and anxiety disorders in Denmark - the IPS-MA intervention.
We aimed to investigate the cost-utility and cost-effectiveness of a modified Individual Placement and Support intervention for people with mood and anxiety disorders (IPS-MA). Costs were assessed from a societal perspective. Health care costs were derived from registers and combined with data on use of IPS-MA services, municipal social care, and labour market services. EQ-5D was used to compute QALY. Missing data were imputed in a sensitivity analysis. We also computed the cost per gain in hours worked. Incremental cost-effectiveness ratios (ICER) were computed and bootstrapped to obtain confidence intervals for QALY and gain in hours worked. We found no difference in overall costs between groups. A significant saving was found in use of labour market services in the IPS-MA group. But the IPS-MA group had significantly lower wage earnings compared to the control group. The intervention group had a higher, though statistically in-significant, increase in QALYs than the control group. The ICER did not show statistically significant results, but there was a tendency, that IPS-MA could have a positive effect on health-related quality of life without any additional costs. However, participants in the IPS-MA group had a significantly lower gain in hours worked compared to the control group. Despite a significant saving in use of labour market services, IPS-MA was not cost-effective. Participants in the IPS-MA group worked significantly fewer hours and earned significantly less than participants in the control group at 1-year follow-up.


Measuring stress in Australia: validation of the perceived stress scale (PSS-14) in a national sample.
In Australia, the stress levels have increased over the years, impacting on the physical and mental health of the general population. The aim of the present study was to evaluate the validity and reliability of the PSS-14 in an Australian population. The PSS-14 was applied to a large national sample comprising 3857 Australians in the population-based cross-sectional study Australia's National Survey of Adult Oral Health 2004-2006. The psychometric properties analyzed with the Rasch model and Graphical Log-linear Rasch models were: model fit, item fit, local dependence, differential item functioning, unidimensionality, reliability, targeting and criterion validity. The PSS-14 did not fit the pure RM (χ2 (55) = 3828.3, p = < 0.001) and the unidimensionality of the whole scale was rejected (p = < 0.001). The Perceived Stress (χ2 (27) = 1409.7, p = < 0.001) and Perceived Control (χ2 (27) = 713.4, p = < 0.001) subscales did not fit the pure RM. After the deletion of two items, the Perceived Stress subscale (χ2 (96) = 94.4, p = 0.440) fitted a GLLRM, while the Perceived Control scale (χ2 (55) = 62.50, p = 0.224) fitted a GLLRM after the exclusion of four misfitting items. The Perceived Stress subscale displayed adequate psychometric properties after the deletion of two items; however, the majority of problems centered around the Perceived Control subscale. The presence of differential item functioning among four items indicates that adjustment of total scores is required to avoid measurement bias. Recommendations for future applications in Australia are provided.


Late complications due to thoracic traumas.
A total of 412 patients who applied to our clinic after a thoracic trauma between March 2010 and December 2019 were examined retrospectively In this study, late complications that developed as a result of blunt and penetrating thoracic traumas were evaluated and it was aimed to present a prediction for the management of these complications to physicians who are dealing with trauma. Among the 412 thoracic trauma cases, 62 cases (15.04%) who developed late-term complications which constituted the main theme of this study were evaluated in terms of age, gender, the type of trauma, the cause of trauma, thorax, and concomitant organ pathologies that developed when the trauma first occurred, the late-term complications, and the treatment methods for them while considering mortality. Of 62 patients with late complications due to thoracic trauma, 47 (75.80%) were male, 15 (24.20%) were female, and the average age was 56.98±21.22. When the trauma type of the patients who developed posttraumatic late-term complications was evaluated, blunt traumas were seen in 90.33% (n=56) of the cases, whereas penetrating traumas were seen in 9.47% (n=6). Traffic accidents were the most common cause in blunt trauma cases (66.07%), whereas pointed and sharp-edged weapon injuries were the most common in penetrating traumas (83.33%). The most common thorax pathology is pulmonary contusion (75%) in blunt traumas and hemopneumothorax in penetrating traumas (66.66%). When the groups were analyzed separately, the most common late-term complication for penetrating traumas was retained hemothorax (66.66%), while pneumonia was the most common (41.07%) in blunt trauma cases. Video-assisted thoracoscopic surgery was performed in seventeen patients with retained post-traumatic hemothorax and thoracotomy was performed in eight cases. Seven patients with post-traumatic empyema underwent thoracoscopy, and four patients underwent decortication with thoracotomy. Six of the patients who developed late-term complications died. The mortality rate is 9.67%. Pneumonia was detected as a late complication type in 83.33% of cases with mortality. It will be appropriate for the physicians who are interested in trauma to determine the treatment modalities of the patients by considering many factors such as the age of the patient and the trauma type in terms of the late complications that they will not be able to detect at first glance.


Attachment security and disorganization in maltreating and high-risk families: a series of meta-analyses.
The current meta-analytic study examined the differential impact of maltreatment and various socioeconomic risks on attachment security and disorganization. Fifty-five studies with 4,792 children were traced, yielding 59 samples with nonmaltreated high-risk children (n = 4,336) and 10 samples with maltreated children (n = 456). We tested whether proportions of secure versus insecure (avoidant, resistant, and disorganized) and organized versus disorganized attachments varied as a function of risks. Results showed that children living under high-risk conditions (including maltreatment studies) showed fewer secure (d = 0.67) and more disorganized (d = 0.77) attachments than children living in low-risk families. Large effects sizes were found for the set of maltreatment studies: maltreated children were less secure (d = 2.10) and more disorganized (d = 2.19) than other high-risk children (d = 0.48 and d = 0.48, respectively). However, children exposed to five socioeconomic risks (k = 8 studies, d = 1.20) were not significantly less likely to be disorganized than maltreated children. Overall, these meta-analyses show the destructive impact of maltreatment for attachment security as well as disorganization, but the accumulation of socioeconomic risks appears to have a similar impact on attachment disorganization.


Boosting the oxygen reduction reaction activity of dual-atom catalysts on N-doped graphene by regulating the N coordination environment.
Development of low-cost and high-efficiency oxygen reduction reaction (ORR) catalysts is of significance for fuel cells and metal-air batteries. Here, by regulating the N environment, a series of dual-atom embedded N5-coordinated graphene catalysts, namely M1M2N5 (M1, M2 = Fe, Co, and Ni), were constructed and systematically investigated by DFT calculations. The results reveal that all M1M2N5 configurations are structurally and thermodynamically stable. The strong adsorption of *OH hinders the proceeding of ORR on the surface of M1M2N5, but M1M2N5(OH2) complexes are formed to improve their catalytic activity. In particular, FeNiN5(OH2) and CoNiN5(OH2) with the overpotentials of 0.33 and 0.41 V, respectively, possess superior ORR catalytic activity. This superiority should be attributed to the reduced occupation of d-orbitals of Fe and Co atoms in the Fermi level and the apparent shift of dyz and dz2 orbitals of Ni atoms towards the Fermi level after adsorbing *OH, thus regulating the active sites and exhibiting appropriate adsorption strength for reaction intermediates. This work provides significant insight into the ORR mechanism and theoretical guidance for the discovery and design of low-cost and high-efficiency graphene-based dual-atom ORR catalysts.


Differential regulation of Listeria monocytogenes internalin and internalin-like genes by sigmaB and PrfA as revealed by subgenomic microarray analyses.
The Listeria monocytogenes genome contains more than 20 genes that encode cell surface-associated internalins. To determine the contributions of the alternative sigma factor sigma(B) and the virulence gene regulator PrfA to internalin gene expression, a subgenomic microarray was designed to contain two probes for each of 24 internalin-like genes identified in the L. monocytogenes 10403S genome. Competitive microarray hybridization was performed on RNA extracted from (i) the 10403S parent strain and an isogenic Delta sigB strain; (ii) 10403S and an isogenic Delta prfA strain; (iii) a (G155S) 10403S derivative that expresses the constitutively active PrfA (PrfA*) and the Delta prfA strain; and (iv) 10403S and an isogenic Delta sigB Delta prfA strain. Sigma(B)- and PrfA-dependent transcription of selected genes was further confirmed by quantitative reverse-transcriptase polymerase chain reaction. For the 24 internalin-like genes examined, (i) both sigma(B) and PrfA contributed to transcription of inlA and inlB, (ii) only sigma(B) contributed to transcription of inlC2, inlD, lmo0331, and lmo0610; (iii) only PrfA contributed to transcription of inlC and lmo2445; and (iv) neither sigma(B) nor PrfA contributed to transcription of the remaining 16 internalin-like genes under the conditions tested.


Urban Disadvantage, Obesity, and Underweight in 31 Lower-Income Countries.
Although some studies have shown that obesity and other non-communicable diseases are more common in more disadvantaged areas, no publications to date have examined the interaction of obesity with urban and rural disadvantage in lower-income countries. This study analyzed the rates of obesity and underweight in disadvantaged urban women and disadvantaged rural women in 31 lower-income countries, and calculated the age-adjusted odds ratios of urban vs. rural obesity and underweight. The odds of obesity were significantly (p<0.05) higher for urban populations in 16 of the 31 countries and in all aggregated regions; the evidence that underweight is also associated more with urban populations was mixed. Because obesity is a rapidly-growing threat to the public health and financial strength of lower-income countries, and urban disadvantage is associated with more obesity than rural disadvantage, policymakers should work to understand, predict, and prevent obesity in urban populations specifically.


Audiologic management of bilateral external auditory canal atresia with the bone conducting implantable hearing device.
The hearing impairment associated with congenital external auditory canal atresia has been managed with early bone conduction hearing aid placement and surgical reconstruction in selected patients. However, many patients do not wear a bone conduction hearing aid because of physical or social considerations and surgical reconstruction of the external auditory canal and middle ear may be difficult or contraindicated. This report details the use of implantable bone conducting hearing devices in five children with bilateral external auditory canal atresia. Each patient had bilateral conductive hearing impairment with normal bone conduction thresholds. Four of the five patients had associated craniofacial anomalies including three cases of microtia. The average preoperative sound field speech reception threshold improved from 63 dB to 13 dB with the implant. Patients experienced a definite preference for the implanted hearing device over the bone conduction hearing aid.


How often are male mosquitoes attracted to humans?
Many mosquito species live close to humans where females feed on human blood. While male mosquitoes do not feed on blood, it has long been recognized that males of some species can be attracted to human hosts. To investigate the frequency of male mosquito attraction to humans, we conducted a literature review and human-baited field trials, as well as laboratory experiments involving males and females of three common Aedes species. Our literature review indicated that male attraction to humans is limited to a small number of species, including Ae. aegypti and Ae. albopictus. In our human-baited field collections, only 4 out of 13 species captured included males. In laboratory experiments, we found that male Ae. notoscriptus and Ae. vigilax showed no attraction to humans, while male Ae. aegypti exhibited persistent attraction for up to 30 min. Both male and female Ae. aegypti displayed similar preferences for different human subjects, suggesting that male Ae. aegypti respond to similar cues as females. Additionally, we found that mosquito repellents applied to human skin effectively repelled male mosquitoes. These findings shed light on mosquito behaviour and have implications for mosquito control programmes, particularly those involving the release or monitoring of the male mosquito population.


Quality of life in chronic haemodialysis and peritoneal dialysis patients in Turkey and related factors.
Turkey is the fifth country in Europe with regard to the number of patients receiving haemodialysis (HD). However, only a limited number of studies have comparatively investigated the factors that affect quality of life in haemodialysis and peritoneal dialysis (PD) patients in Turkey. The purpose of the study was to investigate the factors that affect quality of life in haemodialysis and peritoneal dialysis patients, as well as providing a comparison of quality of life between these groups. In this cross-sectional study, Quality of Life Scale and a data form was completed by 300 dialysis patients who received treatment at five hospital-based dialysis units in Istanbul, Turkey. The data were evaluated using arithmetic mean values, standard deviations, minimums, maximums, percentages, independent groups t-tests, Spearman correlation analyses and one-way variance analyses. The quality of life values in peritoneal dialysis patients were found to be higher than those of haemodialysis patients (P < 0.05). It was concluded that the quality of life in chronic dialysis patients was affected by various factors.


A comparison of hazard perception and hazard prediction tests across China, Spain and the UK.
Hazard perception (HP) is the ability to spot on-road hazards in time to avoid a collision. This skill is traditionally measured by recording response times to hazards in video clips of driving, with safer, experienced drivers often out-performing inexperienced drivers. This study assessed whether HP test performance is culturally specific by comparing Chinese, Spanish and UK drivers who watched clips filmed in all three countries. Two test-variants were created: a traditional HP test (requiring timed hazard responses), and a hazard prediction test, where the film is occluded at hazard-onset and participants predict what happens next. More than 300 participants, across the 3 countries, were divided into experienced and inexperienced-driver groups. The traditional HP test did not discriminate between experienced and inexperienced drivers, though participant nationality influenced the results with UK drivers reporting more hazards than Chinese drivers. The hazard prediction test, however, found experienced drivers to out-perform inexperienced drivers. No differences were found for nationality, with all nationalities being equally skilled at predicting hazards. The results suggest that drivers' criterion level for responding to hazards is culturally sensitive, though their ability to predict hazards is not. We argue that the more robust, culturally-agnostic, hazard prediction test appears better suited for global export.


[Clinical picture of isolated retinal vasculitis].
Clinical picture of isolated retinal vasculitis (IRV) in 43 patients (25 men and 18 women) aged 22-42 years is analyzed. IRV was bilateral in 88.4% cases and involved the veins. Two forms of disease were distinguished: peripheral (in 75%) and central-peripheral (25%). Both forms were characterized by a high hemorrhagic activity, occlusion of vessels, ischemic zones and neovascularization of the retina and optic disk, but these signs were more frequent in central peripheral form of IRV. IRV is a grave disease leading to poor vision or blindness in 18% cases. The onset is poorly manifest with floating spots and blurred vision; the main symptom is vitreous hemorrhage. Visual acuity was significantly decreased in patients with occlusive IRV in comparison with those without occlusions (0.32 +/- 0.37 vs. 0.77 +/- 0.28). The earliest changes can be detected mainly in the peripheral parts of the retina. This necessitates special attention of ophthalmologist to seemingly negligible complaints of patients and thorough examination of the fundus oculi, particularly of its peripheral sections, which can be performed only on condition of adequate mydriasis. Only timely diagnosis and early pathogenetic therapy can decrease the probability of such complications as hemophthalmos, retinal neovascularization, detachment of retina, and neovascular glaucoma, and prevent disability.


Giant primary retroperitoneal seminoma: A case report.
Primary extragonadal seminomas are rare tumors. There have been only a few cases of the primary retroperitoneal seminomas reported in the literature up to date. We reported a 56-year-old man with giant primary retroperitoneal seminoma presented with the enlargement of the left side of the abdomen and deep venous thrombosis of the left leg. Computed tomography of the abdomen showed a large tumor occupying the left part of the retroperitoneal space with 23 x 13 cm in diameter. Firm tumor mass having 25 x 15 cm in diameter was surgically removed from the left retroperitoneum. The tumor adhered the tunica adventitia of the aorta and it was carefully resected from the aortic wall. The diagnosis of seminoma was made during histopathological examination. The patient underwent chemotherapy. Two years after finished chemotherapy the patient accepted left orchiectomy with the aim of eliminating the possibility of the occult malignancy of the testicle. Histopathological analysis of the testicular tissue was normal and the diagnosis of primary retroperitoneal seminoma was confirmed. CONCLUSION. Despite its small incidence in general population, the diagnosis of retroperitoneal seminoma should be considered in male patients with nonspecific symptoms and with retroperitoneal tumor mass.


NET-RMDs study: networks of fatigue and pain in rheumatic and musculoskeletal diseases - protocol for an international cross-sectional study.
Fatigue and pain are the main symptoms of rheumatic and musculoskeletal diseases (RMDs). Healthcare professionals have a primary role in helping patients to manage both these symptoms, which are part of a complex network of co-occurring factors including sleep problems, psychological distress, social support, body weight, diet, inactive lifestyle and disease activity. The patterns of relationships (networks) between these factors and these symptoms, fatigue and pain, are largely unknown. The current proposal aims to reveal them using network estimation techniques. We will also consider differences in networks for subgroups of people with (1) different RMDs and (2) different clusters (profiles) of biopsychosocial factors. Adults with at least one RMD will be recruited to this online cross-sectional observational project. To provide a complete overview, a large sample size from different countries will be included. A brief online survey, using 0-10 numeric rating scales will measure, for the past month, levels of fatigue and pain as well as scores on seven biopsychosocial factors. These factors were derived from literature and identified by interviews with patients, health professionals and rheumatologists. Using this input, the steering committee of the project decided the factors to be measured giving priority to those that can be modified in self-management support in community health centres worldwide. Network estimation techniques are used to detect the complex patterns of relationships between these biopsychosocial factors, fatigue and pain; and how these differ for subgroups of people with different RMDs and profiles. Ethical approval of national Institutional Review Boards was obtained. The online survey includes an information letter and informed consent form. The findings will be disseminated via conferences and publications in peer-reviewed scientific journals, while public media channels will be used to inform people with RMDs and other interested parties.


Intravenous mecillinam compared with other β-lactams as targeted treatment for Escherichia coli or Klebsiella spp. bacteraemia with urinary tract focus.
Mecillinam (amdinocillin) is active against Gram-negative bacteria. Clinical data on the efficacy of IV mecillinam for severe urinary tract infections is sparse. To assess the effectiveness of targeted IV mecillinam compared with other β-lactams for bacteraemia with Escherichia coli and Klebsiella spp. and a urinary tract focus. We performed a retrospective cohort study at five university hospitals in the Capital Region of Denmark from 1 January 2012 to 31 December 2017. We used Cox proportional hazard regression to compare the primary composite endpoint (all-cause mortality or bacteraemia recurrence within 30 days) between patients treated with mecillinam versus ampicillin, cefuroxime, piperacillin/tazobactam and meropenem. We included 1129 patients in the primary analysis, of which 146 were given IV mecillinam as targeted treatment. We found no significant difference in the primary endpoint between patients treated with mecillinam versus ampicillin and cefuroxime, but found a higher risk for the primary endpoint in the piperacillin/tazobactam and meropenem groups, with adjusted HRs of 2.22 (95% CI 1.24-3.97, P < 0.01) and 2.48 (95% CI 1.04-5.93, P = 0.04), respectively, compared with mecillinam. The results of this study suggest that IV mecillinam may be a suitable targeted treatment for bacteraemia with a urinary tract focus. However, these results need confirmation by randomized controlled studies.


Visualization of inhomogeneous current distribution on ZrO2-coated LiCoO2 thin-film electrodes using scanning electrochemical cell microscopy.
Cathode surface coating with metal-oxide thin layers has been intensively studied to improve the cycle durability of lithium-ion batteries. A comprehensive understanding of the metal-oxide morphology and the local electrochemical properties is essential for figuring out the metal-oxide coating effect. In this study, scanning electrochemical cell microscopy (SECCM) is used to analyze the surface morphology with high spatial resolution, together with the local electrochemical properties.


[Metabolism of organic nitrogen compounds by carboxydobacteria].
The capability to hydrolyze and assimilate creatinine, uric and hippuric acids as sources of nitrogen, carbon and energy was studied in Comamonas compransoris Z-1155, Seliberia carboxydohydrogena Z-1062 and Pseudomonas gazotropha Z-1156. The organisms effectively hydrolyzed these compounds and assimilated their nitrogen under the conditions of autotrophic growth. The carboxydobacteria were also capable of growing in media containing creatinine, uric and hippuric acids and assimilated these compounds as carbon sources. In the absence of extraneous energy sources, none of the organisms grew in media with organic nitrogen compounds though the latter were hydrolyzed.


Yusho patients show increased serum IL-17, IL-23, IL-1β, and TNFα levels more than 40 years after accidental polychlorinated biphenyl poisoning.
The Yusho poisoning incident, caused by rice oil contaminated with polychlorinated biphenyls (PCBs), polychlorinated quarterphenyls (PCQs), and polychlorinated dibenzofurans (PCDFs) generated by heat-denatured PCBs, occurred in 1968 in western Japan. Although severe symptoms are rarely observed today, the levels of PCBs and PCDFs in the sera of Yusho patients remain high. The aryl hydrocarbon receptor (AhR), which also acts as a dioxin receptor, is a transcriptional regulator that mediates dioxin toxicity. Recent studies show that dioxin mediates its immune toxic effects via AhR and that AhR activation induces dysregulation of interleukin (IL)-17- producing T (TH17) cells. This study therefore hypothesized that Yusho patients would show dysregulated TH17 cell-mediated immune responses. To validate the hypothesis, levels of IL-17 and IL-22, each secreted by TH17 cells, along with IL-1β and IL-23 were measured in serum samples from 40 Yusho patients and 40 age-matched controls. Levels of tumor necrosis factor (TNF)-α potentially secreted by TH17 cell-stimulated neutrophils and macrophages were also measured. The results indicated that serum IL-17 levels, as well as those of IL-1β, IL-23, and TNFα, were significantly higher in Yusho patients than in controls. In contrast, serum IL-22 levels were significantly lower in the Yusho patients. These results suggest that Yusho patients have dysregulated TH17 cell-mediated immune responses that may be linked to inflammation.


Alterations in helper-specific circulating T lymphocytes and in the autologous mixed lymphocyte reaction in chronic hepatitis B.
Defects in T lymphocyte subpopulations and in the functional characteristics of such cells have been thought to play a role in the evolution of chronic hepatitis B, but the precise nature of the alterations and their significance remains unresolved. We studied lymphocyte subsets in 27 patients with chronic hepatitis B utilizing standard monoclonal antibodies including Leu 1,2a,3a,7 and D1/12 (against the common determinant of the Dr molecule), as well as a newly described monoclonal antibody, "5/9," which is thought to characterize a unique subpopulation of T4 cells with specific helper/inducer function. These results were compared with those obtained using the autologous mixed lymphocyte reaction assay for the same patients in order to further delineate the lymphocyte alterations in chronic hepatitis B. A significant reduction in the mean number of Leu 3a (T4) positive cells was observed as well as a reduction in the number of 5/9 positive cells. These changes were most evident in those positive for HBeAg in serum. Reduction in Leu 3a cells was associated with a reduced autologous mixed lymphocyte reaction assay response, and was most marked in the HBeAg-positive individuals. These findings suggest that HBeAg-positive patients in whom active viral replication is occurring have a defect in T lymphocyte number and function, which may be due in part to reduced 5/9 positive cells. These alterations may be related to the persistence of virus in chronic active hepatitis B patients.


[Detection of synthesized microsomal hemoproteins (cytochrome P-448) using autofluorography].
Simple and informative method for the elucidation of de novo synthesized forms of microsomal cytochrome P-448 induced by 3-methylcholanthrene and 2,3,7,8-tetrachlordibenzo-p-dioxine has been developed. The method is based on gel fluorography upon electrophoretic separation of microsomal proteins obtained from the liver of rats pre-treated with the inducers of monooxygenase system components and then with 14C-leucine. At least two forms of cytochrome P-448 (with molecular weight of 56000 and 53000) were shown to be de novo synthesized under the influence of 3-methylcholanthrene and 2,3,7,8-tetrachlodbibenzo-p-dioxine.