Short-term associations between outdoor air pollution and visits to accident and emergency departments in London for respiratory complaints.
Many epidemiological studies have shown positive short-term associations between health and current levels of outdoor air pollution. The aim of this study was to investigate the association between air pollution and the number of visits to accident and emergency (A&E) departments in London for respiratory complaints. A&E visits include the less severe cases of acute respiratory disease and are unrestricted by bed availability. Daily counts of visits to 12 London A&E departments for asthma, other respiratory complaints, and both combined for a number of age groups were constructed from manual registers of visits for the period 1992-1994. A Poisson regression allowing for seasonal patterns, meteorological conditions and influenza epidemics was used to assess the associations between the number of visits and six pollutants: nitrogen dioxide, ozone, sulphur dioxide, carbon monoxide, and particles measured as black smoke (BS) and particles with a median aerodynamic diameter of <10 microm (PM10). After making an allowance for the multiplicity of tests, there remained strong associations between visits for all respiratory complaints and increases in SO2: a 2.8% (95% confidence interval (CI) 0.7-4.9) increase in the number of visits for a 18 microg x (-3) increase (10th-90th percentile range) and a 3.0% (95% CI 0.8-5.2) increase for a 31 microg x m(-3) increase in PM10. There were also significant associations between visits for asthma and SO2, NO2 and PM10. No significant associations between O3 and any of the respiratory complaints investigated were found. Because of the strong correlation between pollutants, it was difficult to identify a single pollutant responsible for the associations found in the analyses. This study suggests that the levels of air pollution currently experienced in London are linked to short-term increases in the number of people visiting accident and emergency departments with respiratory complaints.


Envenomation by Trimeresurus stejnegeri stejnegeri: clinical manifestations, treatment and associated factors for wound necrosis.
Trimeresurus stejnegeri stejnegeri bite induces tissue swelling, pain, thrombocytopenia, rhabdomyolysis, and acute renal failure. However, the incidence of coagulopathy, factors associated with wound necrosis, and the appropriate management of this condition have not been well characterized yet. This study included patients bitten by T. s. stejnegeri that were admitted to the study hospitals from 2001 to 2016. Patient characteristics, laboratory data, and management approaches were compared in victims with and without wound necrosis. A total of 185 patients were evaluated: three patients (1.6%) were asymptomatic; whereas tissue swelling and pain, local ecchymosis, wound necrosis, coagulopathy, thrombocytopenia, rhabdomyolysis, and renal impairment were present in 182, 53, 13, 15, 10, 1, and 3 patients, respectively. One patient died from coagulopathy and hemorrhagic shock. Antivenom was administered to all envenomed patients at a median time of 1.8 h after the bite. The median total dose of antivenom was five vials. Chi-square analysis showed that bitten fingers, using cold packs during first aid, presence of bullae or blisters, lymphangitis or lymphadenitis, local numbness and suspected infection to be significantly associated with wound necrosis. After adjustment using a multivariate logistic regression model, only cold packs as first aid, bulla or blister formation, and wound infection remained significant. The main effects of T. s. stejnegeri envenomation are tissue swelling, pain, and local ecchymosis. We do not recommend the use of cold packs during first aid to reduce wound pain, as this may be a risk factor for wound necrosis. In addition, patients with bulla or blister formation should be carefully examined for subsequent wound necrosis. Antiplatelet use may worsen systemic bleeding. No severe rhabdomyolysis or renal failure was observed in this large case series, we therefore considered that they were not prominent effects of T. s. stejnegeri bite.


Targeted Memory Reactivation during Sleep Adaptively Promotes the Strengthening or Weakening of Overlapping Memories.
System memory consolidation is conceptualized as an active process whereby newly encoded memory representations are strengthened through selective memory reactivation during sleep. However, our learning experience is highly overlapping in content (i.e., shares common elements), and memories of these events are organized in an intricate network of overlapping associated events. It remains to be explored whether and how selective memory reactivation during sleep has an impact on these overlapping memories acquired during awake time. Here, we test in a group of adult women and men the prediction that selective memory reactivation during sleep entails the reactivation of associated events and that this may lead the brain to adaptively regulate whether these associated memories are strengthened or pruned from memory networks on the basis of their relative associative strength with the shared element. Our findings demonstrate the existence of efficient regulatory neural mechanisms governing how complex memory networks are shaped during sleep as a function of their associative memory strength.SIGNIFICANCE STATEMENT Numerous studies have demonstrated that system memory consolidation is an active, selective, and sleep-dependent process in which only subsets of new memories become stabilized through their reactivation. However, the learning experience is highly overlapping in content and thus events are encoded in an intricate network of related memories. It remains to be explored whether and how memory reactivation has an impact on overlapping memories acquired during awake time. Here, we show that sleep memory reactivation promotes strengthening and weakening of overlapping memories based on their associative memory strength. These results suggest the existence of an efficient regulatory neural mechanism that avoids the formation of cluttered memory representation of multiple events and promotes stabilization of complex memory networks.


Electron capture dissociation as structural probe for noncovalent gas-phase protein assemblies.
Electron capture dissociation (ECD) of proteins in Fourier transform ion cyclotron resonance mass spectrometry usually leads to charge reduction and backbone-bond cleavage, thereby mostly retaining labile, intramolecular noncovalent interactions. In this report, we evaluate ECD of the 84-kDa noncovalent heptameric gp31 complex and compare this with sustained off-resonance irradiation collisionally activated dissociation (SORI-CAD) of the same protein. Unexpectedly, the 21+ charge state of the gp31 oligomer exhibits a main ECD pathway resulting in a hexamer and monomer, disrupting labile, intermolecular noncovalent bonds and leaving the backbone intact. Unexpectedly, the charge separation over the two products is highly proportional to molecular weight. This indicates that a major charge redistribution over the subunits of the complex does not take place during ECD, in contrast to the behavior observed when using SORI-CAD. We speculate that the ejected monomer retains more of its original structure in ECD, when compared to SORI-CAD. ECD of lower charge states of gp31 does not lead to dissociation of noncovalent bonds. We hypothesize that the initial gas-phase structure of the 21+ charge state is significantly different from the lower charge states. These structural differences result in the different reaction pathways when using ECD.


[Comparative study of the perception of urban noise].
To comparatively analyze the perception of daily urban noise between residents of an acoustically and a non-acoustically controlled area. Two urban areas were selected through objective assessments of equivalent sound levels and defined as a non-acoustically and an acoustically controlled area. A random sample of each area was selected and a questionnaire was applied to its residents. Statistical indicators of urban noise perception were generated through factorial multivariate analysis. The average sound level (Leq) found in the downtown district (a non-acoustically controlled area) was 72.9 dB(A) and in the acoustically controlled area was 53.3 dB(A). Three statistical indicators were generated through factorial multivariate analysis: temporary perception, perception of atypical noises and sources and disturbances. Residents of the acoustically controlled area reported increased noise level. The sound level in the downtown district has remained practically constant and much above the standards established by local law. The generated indicators are useful parameters to characterize the perception to continuous noise exposure in the population.


Chemokine receptor-like 2 is involved in ischemic brain injury.
We examined the role of CCRL2 in ischemic brain injury using both in vitro and in vivo mouse stroke models. The expression of CCRL2 was enhanced at both the RNA and protein levels in cultured brain slices under ischemic conditions. Ischemia-induced cell death was reduced in brain slices derived from CCRL2 knockout (KO) mice in comparison with those from wild type (WT) mice. The infarct volume was smaller and neurological deficits were attenuated in CCRL2 KO mice when compared to WT mice subjected to a transient middle cerebral artery occlusion. Our data suggest that CCRL2 is involved in ischemia-induced brain injury in mice.


An insight into osteoarthritis susceptibility: Integration of immunological and genetic background.
Osteoarthritis (OA) is a progressive degenerative disease that affects all synovial joints, causing the disability of the main locomotor diarthrodial joints. OA pathogenesis is caused by a complex interplay between a number of genetic and environmental risk factors, involved in the early onset and progression of this chronic inflammatory joint disease. Uncovering the underlying immunological and genetic mechanisms will enable an insight into OA pathophysiology and lead to novel and integrative approaches in the treatment of OA patients, together with a reduction of the disease risk, or a delay of its onset in susceptible patients.


Modeling Lactococcus lactis using a genome-scale flux model.
Genome-scale flux models are useful tools to represent and analyze microbial metabolism. In this work we reconstructed the metabolic network of the lactic acid bacteria Lactococcus lactis and developed a genome-scale flux model able to simulate and analyze network capabilities and whole-cell function under aerobic and anaerobic continuous cultures. Flux balance analysis (FBA) and minimization of metabolic adjustment (MOMA) were used as modeling frameworks. The metabolic network was reconstructed using the annotated genome sequence from L. lactis ssp. lactis IL1403 together with physiological and biochemical information. The established network comprised a total of 621 reactions and 509 metabolites, representing the overall metabolism of L. lactis. Experimental data reported in the literature was used to fit the model to phenotypic observations. Regulatory constraints had to be included to simulate certain metabolic features, such as the shift from homo to heterolactic fermentation. A minimal medium for in silico growth was identified, indicating the requirement of four amino acids in addition to a sugar. Remarkably, de novo biosynthesis of four other amino acids was observed even when all amino acids were supplied, which is in good agreement with experimental observations. Additionally, enhanced metabolic engineering strategies for improved diacetyl producing strains were designed. The L. lactis metabolic network can now be used for a better understanding of lactococcal metabolic capabilities and potential, for the design of enhanced metabolic engineering strategies and for integration with other types of 'omic' data, to assist in finding new information on cellular organization and function.


Short interspersed transposable elements (SINEs) are excluded from imprinted regions in the human genome.
To test whether regions undergoing genomic imprinting have unique genomic characteristics, imprinted and nonimprinted human loci were compared for nucleotide and retroelement composition. Maternally and paternally expressed subgroups of imprinted genes were found to differ in terms of guanine and cytosine, CpG, and retroelement content, indicating a segregation into distinct genomic compartments. Imprinted regions have been normally permissive to L1 long interspersed transposable element retroposition during mammalian evolution but universally and significantly lack short interspersed transposable elements (SINEs). The primate-specific Alu SINEs, as well as the more ancient mammalian-wide interspersed repeat SINEs, are found at significantly low densities in imprinted regions. The latter paleogenomic signature indicates that the sequence characteristics of currently imprinted regions existed before the mammalian radiation. Transitions from imprinted to nonimprinted genomic regions in cis are characterized by a sharp inflection in SINE content, demonstrating that this genomic characteristic can help predict the presence and extent of regions undergoing imprinting. During primate evolution, SINE accumulation in imprinted regions occurred at a decreased rate compared with control loci. The constraint on SINE accumulation in imprinted regions may be mediated by an active selection process. This selection could be because of SINEs attracting and spreading methylation, as has been found at other loci. Methylation-induced silencing could lead to deleterious consequences at imprinted loci, where inactivation of one allele is already established, and expression is often essential for embryonic growth and survival.


Surgical closure of cleft palate defects in dogs using a modification of the traditional von Langenbeck technique: 12 cases (2015-2022).
To describe the author's surgical guidelines for the effective use of a modified von Langenbeck technique, utilizing bilateral bipedicle mucoperiosteal flaps in the dog. 12 client-owned dogs with cleft palate defects of the hard and soft palates. 12 dogs with cleft palate were presented to the Angell Animal Medical Center from May 20, 2015, to March 24, 2022. The patient's ages ranged from 5 months to 3 years. All 12 dogs had closure of the hard palate clefts by use of modifications of the original von Langenbeck technique in this prospective study. Successful closure of the cleft (hard and soft) palate defects was achieved in all 12 dogs in a single surgical procedure. A small residual opening was noted at the level of the incisive papilla in each dog; this was of no clinical consequence in this report. The von Langenbeck technique, using the simple closure modifications reported, was effective in closing both narrow and wide defects. Successful execution requires the complete elevation of each flap, which facilitates their tension-free advancement over the palatal cleft. Vertical mattress sutures evert the flap margins, allowing for direct collagen surface contact for proper healing. Placement of sutures in the rugal folds increases the tissue purchase to reduce the risk of suture cut-out. Fine interrupted sutures, placed between the vertical mattress sutures, maintains the proper alignment of the incisional margins. The author waits a minimum of 5 months before closing cleft palate defects, enabling the donor areas time to mature and improving their ability to retain sutures more effectively.


Dual-trap technique for reduction of low-frequency noise in force measuring optical tweezers.
High-resolution long-time force measurements by optical tweezers are often limited by low-frequency (1/f) noise. A dual-trap technique is presented that can reduce such noise in the force signal. It incorporates a second trap (a reference trap) that probes the noise in the system and it is based upon the assumption that the low-frequency parts of the noise from the two traps are correlated. A subtraction of the low-frequency signal from the reference trap from the signal from the force measuring trap will therefore yield a net signal that is significantly less influenced by noise. It is shown that this dual-trap technique can reduce the noise in the force signal up to 60% depending on detection bandwidth.


Optimization of dosing schedule of daily inhalant dexamethasone to minimize phase shifting of clock gene expression rhythm in the lungs of the asthma mouse model.
Glucocorticoid receptor agonists such as dexamethasone (DEXA) have been recommended for the treatment of asthma. An increased frequency of dosing with these drugs seems preferable for cases of severe or uncontrolled asthma. The purpose of this experiment was to find the appropriate dosing schedule (frequency and timing) for DEXA inhalation based on chronotherapeutic dosing to minimize phase shifts of clock function in the lungs of the ovalbumin-treated asthmatic mouse. The daily rhythm of clock gene expression was similar between control and ovalbumin-treated mice. Acute inhalation of DEXA significantly increased mPer1 gene expression in the lungs but not the liver of mice. Daily exposure of DEXA at zeitgeber time 0 (lights on) or at zeitgeber time 18 (6 h after lights off) for 6 d caused a phase advance or phase delay of bioluminescence rhythm in the lungs, respectively, similar to light-induced phase shifts in locomotor activity rhythm. Daily zeitgeber time 0 exposure to DEXA attenuated the expression level of the mClca3 gene, which is associated with mucus overproduction, and there was a phase-advancing peak time of the mClca3 rhythm. The present results denote the importance of selecting the most appropriate time of day for nebulizer administration of DEXA to minimize adverse effects such as the phase shifting of clock function in asthmatic lungs. This is the first report of a successful protocol that could obtain phase shifts of clock gene expression rhythm in isolated peripheral organs in vivo.


Molecular Oxygen Binding in the Mitochondrial Electron Transfer Flavoprotein.
Reactive oxygen species such as superoxide are potentially harmful byproducts of the aerobic metabolism in the inner mitochondrial membrane, and complexes I, II, III of the electron transport chain have been identified as primary sources. The mitochondrial fatty acid b-oxidation pathway may also play a yet uncharacterized role in reactive oxygen species generation, apparently at the level of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) and/or its redox partner electron-transfer flavoprotein (ETF). These enzymes comprise a key pathway through which electrons are sequentially shuttled from several dehydrogenases to the respiratory chain. The exact mechanisms of superoxide production have not been fully established, but a crucial starting point would be the binding of molecular oxygen within one of the protein complexes. The present investigation offers a comprehensive computational approach for the determination of binding modes and characteristic binding times of small molecules inside proteins, which is then used to reveal several O2 binding sites near the flavin adenine dinucleotide cofactor of the ETF enzyme. The binding sites are further characterized to extract the necessary parameters for further studies of possible electron transfer between flavin and O2 leading to radical pair formation and possible superoxide production.


Asymmetric interference between the perception of shape and the perception of surface properties.
We previously showed that the processing of shape and the processing of surface properties linked to material properties engage different regions of the ventral stream (J. S. Cant & M. A. Goodale, 2007). Moreover, we recently used Garner's speeded-classification task to show that varying the surface (material) properties of objects does not interfere with shape judgments and vice versa (J. S. Cant, M. E. Large, L. McCall, & M. A. Goodale, 2008). In the present study, we looked at Garner interference when surface cues contributed to the perception of object shape and hypothesized that this would interfere with judgments about the width and the length of the objects. In contrast, we predicted that varying the width and the length of the objects would not interfere with surface-property judgments. This is precisely what we found. These results suggest that the shape and the surface properties of an object cannot be processed independently when both these sets of cues are linked to the perception of the object's overall shape. These observations, together with our previous findings, suggest that the surface cues that contribute to object shape are processed quite separately from the surface cues that are linked to an object's material properties.


Fabrication of polycaprolactone-silanated β-tricalcium phosphate-heparan sulfate scaffolds for spinal fusion applications.
Interbody spinal fusion relies on the use of external fixation and the placement of a fusion cage filled with graft materials (scaffolds) without regard for their mechanical performance. Stability at the fusion site is instead reliant on fixation hardware combined with a selected cage. Ideally, scaffolds placed into the cage should both support the formation of new bone and contribute to the mechanical stability at the fusion site. We recently developed a scaffold consisting of silane-modified PCL-TCP (PCL-siTCP) with mechanical properties that can withstand the higher loads generated in the spine. To ensure the scaffold more closely mimicked the bone matrix, we incorporated collagen (Col) and a heparan sulfate glycosaminoglycan sugar (HS3) with increased affinity for heparin-binding proteins such as bone morphogenetic protein-2 (BMP-2). The osteostimulatory characteristic of this novel device delivering exogenous BMP2 was assessed in vitro and in vivo as a prelude to future spinal fusion studies with this device. A combination of cell-free assays (BMP2 release), progenitor cell-based assays (BMP2 bioactivity, cell proliferation and differentiation), and rodent ectopic bone formation assays was used to assess the osteostimulatory characteristics of the PCL-siTCP-based scaffolds. Freshly prepared rat mesenchymal stem cells were used to determine reparative cell proliferation and differentiation on the PCL-siTCP-based scaffolds over a 28-day period in vitro. The bioactivity of BMP2 released from the scaffolds was assessed on progenitor cells over a 28-day period using ALP activity assays and release kinetics as determined by enzyme-linked immunosorbent assay. For ectopic bone formation, intramuscular placement of scaffolds into Sprague Dawley rats (female, 4 weeks old, 120-150 g) was achieved in five animals, each receiving four treatments randomized for location along the limb. The four groups tested were (1) PCL-siTCP/Col (5-mm diameter×1-mm thickness), PCL-siTCP/Col/BMP2 (5 µg), (3) PCL-siTCP/Col/HS3 (25 µg), and (4) PCL-siTCP/Col/HS3/BMP2 (25 and 5 µg, respectively). Bone formation was evaluated at 8 weeks post implantation by microcomputed tomography (µCT) and histology. Progenitor cell-based assays (proliferation, mRNA transcripts, and ALP activity) confirmed that BMP2 released from PCL-siTCP/Col/HS3 scaffolds increased ALP expression and mRNA levels of the osteogenic biomarkers Runx2, Col1a2, ALP, and bone gla protein-osteocalcin compared with devices without HS3. When the PCL-siTCP/Col/HS3/BMP2 scaffolds were implanted into rat hamstring muscle, increased bone formation (as determined by two-dimensional and three-dimensional µCTs and histologic analyses) was observed compared with scaffolds lacking BMP2. More consistent increases in the amount of ectopic bone were observed for the PCL-siTCP/Col/HS3/BMP2 implants compared with PCL-siTCP/Col/BMP2. Also, increased mineralizing tissue within the pores of the scaffold was seen with modified-tetrachrome histology, a result confirmed by µCT, and a modest but detectable increase in both the number and the thickness of ectopic bone structures were observed with the PCL-siTCP/Col/HS3/BMP2 implants. The combination of PCL-siTCP/Col/HS3/BMP2 thus represents a promising avenue for further development as a bone graft alternative for spinal fusion surgery.


Dopant profiling and surface analysis of silicon nanowires using capacitance-voltage measurements.
Silicon nanowires are expected to have applications in transistors, sensors, resonators, solar cells and thermoelectric systems. Understanding the surface properties and dopant distribution will be critical for the fabrication of high-performance devices based on nanowires. At present, determination of the dopant concentration depends on a combination of experimental measurements of the mobility and threshold voltage in a nanowire field-effect transistor, a calculated value for the capacitance, and two assumptions--that the dopant distribution is uniform and that the surface (interface) charge density is known. These assumptions can be tested in planar devices with the capacitance-voltage technique. This technique has also been used to determine the mobility of nanowires, but it has not been used to measure surface properties and dopant distributions, despite their influence on the electronic properties of nanowires. Here, we measure the surface (interface) state density and the radial dopant profile of individual silicon nanowire field-effect transistors with the capacitance-voltage technique.


Systematic review of medical student willingness to volunteer and preparedness for pandemics and disasters.
This systematic review aimed to estimate the willingness of students to volunteer during a disaster, and how well-prepared medical students are for volunteering by assessing their knowledge and medical school curriculum of disaster and pandemic medicine. A total of 37 studies met inclusion criteria including 11 168 medical students and 91 medical schools. 24 studies evaluated knowledge (64.9%), 16 evaluated volunteering (43.2%) and 5 evaluated medical school curricula (13.5%). Weighted mean willingness to volunteer during a disaster was 68.4% (SD=21.7%, range=26.7%-87.8%, n=2911), and there was a significant difference between those planning to volunteer and those who actually volunteered (p<0.0001). We identified a number of modifiable barriers which may contribute to this heterogeneity. Overall, knowledge of disasters was poor with a weighted mean of 48.9% (SD=15.1%, range=37.1%-87.0%, n=2985). 36.8% of 76 medical schools curricula included teaching on disasters. However, students only received minimal teaching (2-6 hours). This study demonstrates that there is a large number of students who are willing to volunteer during pandemics. However, they are unlikely to be prepared for these roles as overall knowledge is poor, and this is likely due to minimal teaching on disasters at medical school. During the current COVID-19 pandemic and in future disasters, medical students may be required to volunteer as auxiliary staff. There is a need to develop infrastructure to facilitate this process as well as providing education and training to ensure students are adequately prepared to perform these roles safely.


Subjective life experiences of family caregivers of dependent older adults.
This study aimed to understand the subjective meanings attributed to home care by family caregivers of dependent older adults through a multicenter qualitative investigation that gathered 84 in-depth interviews with family caregivers from eight Brazilian locations. The hermeneutic-dialectic, theoretical, methodological framework was employed. The following categories emerged from the analysis: 1. Movements inhibiting emotions and feelings; 2. Presence of processes of symbiosis and emotional dependence in the older adult-relative relationship; 3. Contentment in caring for the dependent older adult; and 4. Giving up current and future life projects. The results reveal life experiences marked by symbiotic processes, emotional dependence, and psychic stress. Dependence causes suffering and feelings of despair, powerlessness, impatience, but also solidarity and empathy. Withdrawal from the job market, social depreciation of family caregiver's activity, social isolation, neglected self-care, and family conflicts impact caregivers' subjectivity. The elaboration of public policies must consider the social-affective life experiences of family caregivers of dependent older adults in order to include the care of those providing care.


Duration of biodynamic changes associated with water resistance therapy.
In current voice research, there is a growing interest in semi-occluded vocal tract exercises and their contribution to an increased vocal efficiency. However, there are only few studies on the lasting effects. Eight vocally healthy subjects were asked to sustain a phonation at a comfortable loudness on the vowel /i/, with a Fundamental Frequency of 250 Hz (females) or 125 Hz (males). During phonation the subjects were simultaneously recorded with transnasal High Speed Videoendoscopy (HSV, 20,000fps), electroglottography, and audio signals. The subjects then performed a water resistance therapy (WRT) for 10 min (tube: 30 cm length, 5 cm below water surface, diameter 9 mm). Repeated measurements of sustained phonation were performed 0, 5, 10, 20, and 30 min after exercising. From the HSV material the Glottal Area Waveform (GAW) was segmented and GAW parameters were computed. There were strong inter-individual differences concerning the changes of different measures over time after WRT. In general, directly after WRT there was a lowering of the GAW derived Period Perturbation Quotient, a lowering of the Closing Quotient and an increase of the Sound Pressure Level (SPL) in comparison to the pre-intervention measurement. However, only 5 min post WRT there was no longer a clear difference compared to baseline results before WRT. Other values such as Open Quotients exhibited no evident changes by WRT at any timepoint. WRT showed strong inter-individual effects concerning the changes in the evaluated measures post-intervention. General tendencies of some measures directly after the intervention showed a brief effect of only a few minutes.


Risk assessment in oncology clinical practice. From risk factors to risk models.
Myelosuppression and neutropenia represent the major dose-limiting toxicity of cancer chemotherapy. Chemotherapy-induced neutropenia may be accompanied by fever, presumably due to life-threatening infection, which generally requires hospitalization for evaluation and treatment with empiric broad-spectrum antibiotics. The resulting febrile neutropenia is a major cause of the morbidity, mortality, and costs associated with the treatment of patients with cancer. Furthermore, the threat of febrile neutropenia often results in chemotherapy dose reductions and delays, which can compromise long-term clinical outcomes. Prophylactic colony-stimulating factor (CSF) has been shown to reduce the incidence, severity, and duration of neutropenia and its complications. Guidelines from the American Society of Clinical Oncology recommend the use of CSF on the basis of the myelosuppressive potential of the chemotherapy regimen. The challenge in ensuring the appropriate and cost-effective use of prophylactic CSF is to determine which patients would be most likely to benefit from it. A number of patient-, disease-, and treatment-related factors are associated with an increased risk of neutropenia and its complications. A number of clinical predictive models have been developed from retrospective datasets to identify patients at greater risk for neutropenia and its complications. Early studies have demonstrated the potential of such models to guide the targeted use of CSF to those patients who are most likely to benefit from the early use of these supportive agents. Additional prospective research is needed to develop more accurate and valid risk models and to evaluate the efficacy and cost-effectiveness of model-targeted use of CSF in high-risk patients.


Excess of heme induces tissue factor-dependent activation of coagulation in mice.
An excess of free heme is present in the blood during many types of hemolytic anemia. This has been linked to organ damage caused by heme-mediated oxidative stress and vascular inflammation. We investigated the mechanism of heme-induced coagulation activation in vivo. Heme caused coagulation activation in wild-type mice that was attenuated by an anti-tissue factor antibody and in mice expressing low levels of tissue factor. In contrast, neither factor XI deletion nor inhibition of factor XIIa-mediated factor XI activation reduced heme-induced coagulation activation, suggesting that the intrinsic coagulation pathway is not involved. We investigated the source of tissue factor in heme-induced coagulation activation. Heme increased the procoagulant activity of mouse macrophages and human PBMCs. Tissue factor-positive staining was observed on leukocytes isolated from the blood of heme-treated mice but not on endothelial cells in the lungs. Furthermore, heme increased vascular permeability in the mouse lungs, kidney and heart. Deletion of tissue factor from either myeloid cells, hematopoietic or endothelial cells, or inhibition of tissue factor expressed by non-hematopoietic cells did not reduce heme-induced coagulation activation. However, heme-induced activation of coagulation was abolished when both non-hematopoietic and hematopoietic cell tissue factor was inhibited. Finally, we demonstrated that coagulation activation was partially attenuated in sickle cell mice treated with recombinant hemopexin to neutralize free heme. Our results indicate that heme promotes tissue factor-dependent coagulation activation and induces tissue factor expression on leukocytes in vivo. We also demonstrated that free heme may contribute to thrombin generation in a mouse model of sickle cell disease.


The effects on boar sperm quality of dietary supplementation with omega-3 polyunsaturated fatty acids differ among porcine breeds.
The present study was undertaken to shed light on the relationship between boar sperm quality and dietary supplementation with omega-3 polyunsaturated fatty acids, which has been reported inconsistently in the literature. With this aim, such effects were evaluated and compared among three different porcine breeds: Duroc, Large-White, and Pietrain. Animals were randomly separated into two groups and fed either with a control diet or with a diet supplemented with omega-3. Sperm quality of these boar (ejaculate volume, sperm concentration, sperm viability, acrosome and mitochondrial sheath integrity, sperm motility, sperm morphology, and osmotic resistance of spermatozoa) was assessed every week for a 26-week period. Supplementing boar's diet with omega-3 did not affect ejaculate volume, sperm concentration, sperm motility, sperm viability, and acrosome and mitochondrial sheath integrity. In contrast, supplemented diet positively affected both sperm morphology in Large-White and Pietrain breeds and the osmotic resistance of Pietrain spermatozoa. No effects were seen for the same sperm parameters in Duroc breed. These breed-differences in boar fed with the supplemented diet could explain the contradictions in literature and might be related with differences in the composition of plasma membrane among breeds reported by other authors. Because no harmful effects were observed in the three evaluated breeds, but positive effects in Large-White and Pietrain boar, we can conclude that omega-3 fatty acids may be added to boar's diet at the levels used in this study to improve their sperm quality. More research is, however, needed to determine how these fatty acids differently affect the morphology and the osmotic resistance of the spermatozoa in these breeds.


Adverse events in healthcare: learning from mistakes.
Large national reviews of patient charts estimate that approximately 10% of hospital admissions are associated with an adverse event (defined as an injury resulting in prolonged hospitalization, disability or death, caused by healthcare management). Apart from having a significant impact on patient morbidity and mortality, adverse events also result in increased healthcare costs due to longer hospital stays. Furthermore, a substantial proportion of adverse events are preventable. Through identifying the nature and rate of adverse events, initiatives to improve care can be developed. A variety of methods exist to gather adverse event data both retrospectively and prospectively but these do not necessarily capture the same events and there is variability in the definition of an adverse event. For example, hospital incident reporting collects only a very small fraction of the adverse events found in retrospective chart reviews. Until there are systematic methods to identify adverse events, progress in patient safety cannot be reliably measured. This review aims to discuss the need for a safety culture that can learn from adverse events, describe ways to measure adverse events, and comment on why current adverse event monitoring is unable to demonstrate trends in patient safety.


Human luminance pattern-vision mechanisms: masking experiments require a new model.
A widely used model of simultaneous luminance pattern masking is based on mechanisms that sum inputs linearly and produce a response that is an S-shaped function of that sum. This model makes two predictions about masking: (1) Changing the masker spatial waveform will shift the threshold-versus-masker contrast function horizontally by a multiplicative constant. (2) Adding a second fixed-contrast masker will shift this function horizontally by an additive constant. Experimental tests do not support these predictions. The results can be explained by a new model that incorporates broadband divisive inhibition, consistent with physiology.


Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism.
The oxytocin receptor gene (OXTR) has been studied in autism because of the role of oxytocin (OT) in social cognition. Linkage has also been demonstrated to the region of OXTR in a large sample. Two single nucleotide polymorphisms (SNPs) and a haplotype constructed from them in OXTR have been associated with autism in the Chinese Han population. We tested whether these associations replicated in a Caucasian sample with strictly defined autistic disorder. We genotyped the two previously associated SNPs (rs2254298, rs53576) in 57 Caucasian autism trios. Probands met clinical, ADI-R, and ADOS criteria for autistic disorder. Significant association was detected at rs2254298 (p=0.03) but not rs53576. For rs2254298, overtransmission of the G allele to probands with autistic disorder was found which contrasts with the overtransmission of A previously reported in the Chinese Han sample. In both samples, G was more frequent than A. However, in our Caucasian autism trios and the CEU Caucasian HapMap samples the frequency of A was less than that reported in the Chinese Han and Chinese in Bejing HapMap samples. The haplotype test of association did not reveal excess transmission from parents to affected offspring. These findings provide support for association of OXTR with autism in a Caucasian population. Overtransmission of different alleles in different populations may be due to a different pattern of linkage disequilibrium between the marker rs2254298 and an as yet undetermined susceptibility variant in OXTR.


Acupuncture and Neural Mechanism in the Management of Low Back Pain-An Update.
Within the last 10 years, the percentage of low back pain (LBP) prevalence increased by 18%. The management and high cost of LBP put a tremendous burden on the healthcare system. Many risk factors have been identified, such as lifestyle, trauma, degeneration, postural impairment, and occupational related factors; however, as high as 95% of the cases of LBP are non-specific. Currently, LBP is treated pharmacologically. Approximately 25 to 30% of the patients develop serious side effects, such as drowsiness and drug addiction. Spinal surgery often does not result in a massive improvement of pain relief. Therefore, complementary approaches are being integrated into the rehabilitation programs. These include chiropractic therapy, physiotherapy, massage, exercise, herbal medicine and acupuncture. Acupuncture for LBP is one of the most commonly used non-pharmacological pain-relieving techniques. This is due to its low adverse effects and cost-effectiveness. Currently, many randomized controlled trials and clinical research studies have produced promising results. In this article, the causes and incidence of LBP on global health care are reviewed. The importance of treatment by acupuncture is considered. The efforts to reveal the link between acupuncture points and anatomical features and the neurological mechanisms that lead to acupuncture-induced analgesic effect are reviewed.


Anti-inflammatory, Antipruritic and Mast Cell Stabilizing Activity of Aristolochia Indica.
Aristolochia indica has been widely used in the traditional medicine for the treatment of a variety of diseases. In the present study different extracts of roots of A. indica were evaluated for their anti-inflammatory, antipruritic and mast cell stabilizing activity. Anti-inflammatory activity was performed by compound 48/80 induced rat paw edema model and antipruritic activity by examining the incidence of scratching behavior. Mast cell stabilizing activity was performed by compound 48/80 and sheep serum induced mast cell degranulation methods. The ethanol extract (300 mg/kg) and petroleum ether extract (100 mg/kg) were found to inhibit mast cell degranulation significantly equivalent to that of standard drug ketotifen (69%) by compound 48/80 model. In sheep serum model the ethanol extracts (150 and 300 mg/kg) and petroleum ether extract (100 mg/kg) showed good mast cell stabilizing activity (66-67%). Ethanol extract at 150 mg/kg showed 70% reduction of rat paw oedema and also significantly reduced the scratching response. Results suggest A. indica has good mast cell stabilizing, anti-inflammatory and antipruritic activity.


Sleep-effects on implicit and explicit memory in repeated visual search.
In repeated visual search tasks, facilitation of reaction times (RTs) due to repetition of the spatial arrangement of items occurs independently of RT facilitation due to improvements in general task performance. Whereas the latter represents typical procedural learning, the former is a kind of implicit memory that depends on the medial temporal lobe (MTL) memory system and is impaired in patients with amnesia. A third type of memory that develops during visual search is the observers' explicit knowledge of repeated displays. Here, we used a visual search task to investigate whether procedural memory, implicit contextual cueing, and explicit knowledge of repeated configurations, which all arise independently from the same set of stimuli, are influenced by sleep. Observers participated in two experimental sessions, separated by either a nap or a controlled rest period. In each of the two sessions, they performed a visual search task in combination with an explicit recognition task. We found that (1) across sessions, MTL-independent procedural learning was more pronounced for the nap than rest group. This confirms earlier findings, albeit from different motor and perceptual tasks, showing that procedural memory can benefit from sleep. (2) Likewise, the sleep group compared with the rest group showed enhanced context-dependent configural learning in the second session. This is a novel finding, indicating that the MTL-dependent, implicit memory underlying contextual cueing is also sleep-dependent. (3) By contrast, sleep and wake groups displayed equivalent improvements in explicit recognition memory in the second session. Overall, the current study shows that sleep affects MTL-dependent as well as MTL-independent memory, but it affects different, albeit simultaneously acquired, forms of MTL-dependent memory differentially.


Screening for anabolic steroids in urine of forensic cases using fully automated solid phase extraction and LC-MS-MS.
A screening method for 18 frequently measured exogenous anabolic steroids and the testosterone/epitestosterone (T/E) ratio in forensic cases has been developed and validated. The method involves a fully automated sample preparation including enzyme treatment, addition of internal standards and solid phase extraction followed by analysis by liquid chromatography-tandem mass spectrometry (LC-MS-MS) using electrospray ionization with adduct formation for two compounds. Urine samples from 580 forensic cases were analyzed to determine the T/E ratio and occurrence of exogenous anabolic steroids. Extraction recoveries ranged from 77 to 95%, matrix effects from 48 to 78%, overall process efficiencies from 40 to 54% and the lower limit of identification ranged from 2 to 40 ng/mL. In the 580 urine samples analyzed from routine forensic cases, 17 (2.9%) were found positive for one or more anabolic steroids. Only seven different steroids including testosterone were found in the material, suggesting that only a small number of common steroids are likely to occur in a forensic context. The steroids were often in high concentrations (>100 ng/mL), and a combination of steroids and/or other drugs of abuse were seen in the majority of cases. The method presented serves as a fast and automated screening procedure, proving the suitability of LC-MS-MS for analyzing anabolic steroids.


Impact of Within-Tree Organ Distances on Floral Induction and Fruit Growth in Apple Tree: Implication of Carbohydrate and Gibberellin Organ Contents.
In plants, organs are inter-dependent for growth and development. Here, we aimed to investigate the distance at which interaction between organs operates and the relative contribution of within-tree variation in carbohydrate and hormonal contents on floral induction and fruit growth, in a fruit tree case study. Manipulations of leaf and fruit numbers were performed in two years on "Golden delicious" apple trees, at the shoot or branch scale or one side of Y-shape trees. For each treatment, floral induction proportion and mean fruit weight were recorded. Gibberellins content in shoot apical meristems, photosynthesis, and non-structural carbohydrate concentrations in organs were measured. Floral induction was promoted by leaf presence and fruit absence but was not associated with non-structural content in meristems. This suggests a combined action of promoting and inhibiting signals originating from leaves and fruit, and involving gibberellins. Nevertheless, these signals act at short distance only since leaf or fruit presence at long distances had no effect on floral induction. Conversely, fruit growth was affected by leaf presence even at long distances when sink demands were imbalanced within the tree, suggesting long distance transport of carbohydrates. We thus clarified the inter-dependence and distance effect among organs, therefore their degree of autonomy that appeared dependent on the process considered, floral induction or fruit growth.


Identification of multiple genetic susceptibility loci in Takayasu arteritis.
Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)).


Polymorphic populations of Dactylorhiza incarnata s.l. (Orchidaceae) on the Baltic island of Gotland: morphology, habitat preference and genetic differentiation.
Organisms may be polymorphic within natural populations, but often the significance and genetic background to such polymorphism is not known. To understand the colour polymorphism expressed in the diploid marsh-orchids Dactylorhiza incarnata, morphological, habitat and genetic differentiation was studied in mixed populations on the island of Gotland, supplemented with genetic marker data from adjacent areas. A total of 398 accessions was investigated for plastid haplotype and three nuclear microsatellites. Morphometric data and vegetation data were obtained from a subset of 104 plants. No clear pattern of habitat differentiation was found among the colour morphs. Within sites, the yellow-flowered morph (ochroleuca) was slightly larger than the others in some flower characters, whereas the purple-flowered morph with spotted leaves (cruenta) was on average smaller. However, populations of the same colour morph differed considerably between sites, and there was also considerable overlap between morphs. Morphs were often genetically differentiated but imperfectly separated within sites. Most populations were characterized by significant levels of inbreeding. The ochroleuca morph constitutes a coherent, highly homozygous sublineage, although introgression from purple-flowered morphs occurs at some sites. The cruenta morph was genetically variable, although Gotland populations formed a coherent group. Purple-flowered plants with unspotted leaves (incarnata in the strict sense) were even more variable and spanned the entire genetic diversity seen in the other morphs. Colour polymorphism in D. incarnata is maintained by inbreeding, but possibly also by other ecological factors. The yellow-flowered morph may best be recognized as a variety of D. incarnata, var. ochroleuca, and the lack of anthocyanins is probably due to a particular recessive allele in homozygous form. Presence of spotted leaves is an uncertain taxonomic character, and genetic differentiation within D. incarnata would be better described by other morphological characters such as leaf shape and stature and size and shape of lip and spur.


Energy Availability, Macronutrient Intake, and Nutritional Supplementation for Improving Exercise Performance in Endurance Athletes.
Endurance athletes use nutritional guidelines and supplements to improve exercise performance and recovery. However, use is not always based on scientific evidence of improved performance, which type of athlete would benefit most, or the optimal dose and timing of a particular supplement. Health professionals that give advice to athletes need to target their recommendations on the energy systems and muscle fiber types used for the athlete's sporting event, the goal of the training block, the time of the competitive season, and the characteristics and food preferences of the individual athlete. This review aims to summarize the most current research findings on the optimal calorie, carbohydrate, and protein intake for athlete health, performance, and recovery. We also summarized new findings on fluid intake and the optimal dose and timing of beetroot and caffeine supplementation on time trial performance in endurance athletes.


Infrared 7.6-microm lead-salt diode laser heterodyne radiometry of water vapor in a CH4-air premixed flat flame.
We deal with the design of a diode laser heterodyne radiometer and its application in a combustion process. We present some experimental results obtained with a CH4-air premised flat flame as the optical source. The goal is to prove that heterodyne detection techniques are relevant in remote detection and diagnostics of combustion and can have important applications in both civil and military fields. To the best of our knowledge, it is the first time that this demonstration is made. The radiometer, in spite of the low-power lead-salt diode laser used as a local oscillator, enables us to record high-temperature water-vapor emission spectra in the region of 1315 cm(-1).


Estimation of exposure durations for vitamin D production and sunburn risk in Switzerland.
Although overexposure to solar ultraviolet radiation (UVR) is responsible for cutaneous melanoma and epithelial skin cancer and can cause negative health effects such as sunburn, a "little and often" exposure regime is often suggested to produce naturally recommended vitamin D levels, being essential for skeletal health. This study aimed to quantify solar UV doses needed to trigger 1000 International Units (IU) vitamin D doses and, at the same time, producing sunburn in Switzerland. Solar UV erythema irradiance (in mW/m2) measured at four meteorological stations in Switzerland for the period 2005-2017 were used to evaluate effective solar UV radiation producing 1000 IU vitamin D doses in skin phototype II and III individuals. Daily solar UV exposure durations (in minutes) needed to produce vitamin D with limited sunburn risk were estimated while considering mean vitamin D food intake of the Swiss population and seasonal skin coverage. In summer and spring, with 22% of uncovered skin, 1000 IU vitamin D doses are synthesized in 10-15 min of sun exposure for adults. Exposure durations between erythema risk and 1000 IU vitamin D production vary between 9 and 46 min. In winter and autumn, the recommended vitamin D production without sunburn risks often unachievable, since up to 6.5 h of sun exposure might be necessary considering 8-10% of uncovered skin surface. The vitamin D food intake only represented 10% of the recommended vitamin D production and remained unchanged throughout the year. These findings might clarify why vitamin D deficiency is common in Switzerland. Moreover, exposure durations between recommended vitamin D and increased sunburn risk might only differ by few minutes. Without additional oral vitamin D supplementation, daily doses of vitamin D (1000 IU) are not reachable in autumn and winter months in Switzerland.


Graded-index fibers, Wigner-distribution functions, and the fractional Fourier transform.
Two definitions of a fractional Fourier transform have been proposed previously. One is based on the propagation of a wave field through a graded-index medium, and the other is based on rotating a function's Wigner distribution. It is shown that both definitions are equivalent. An important result of this equivalency is that the Wigner distribution of a wave field rotates as the wave field propagates through a quadratic graded-index medium. The relation with ray-optics phase space is discussed.


Integrating sex and attachment in emotionally focused couple therapy.
In this article, sexual functioning is placed in the context of love as an attachment bond. Attachment theory offers the most coherent and empirically validated theory of adult love and is summarized together with the implications of this theory for the practice of couple therapy in which sexual issues are often addressed. Recent research on attachment and sexuality is outlined and a model of healthy sexuality where attachment and sexuality are integrated is offered. The principles of an attachment-oriented approach to sex issues are set out and illustrated with reference to the process of emotionally focused couple therapy. Case descriptions and brief in-session transcripts are included.


Different Amounts of Physical Activity Measured by Pedometer and the Associations With Health Outcomes in Adults.
Physical activity level is an important tool to identify individuals predisposed to developing chronic diseases, which represent a major concern worldwide. To identify correlates of daily step counts measured using pedometers, as well as analyze the associations between health outcomes and 3 different amounts of daily physical activity. The sample comprised 278 participants (126 men and 153 women) with a mean age of 46.51 ± 9.02 years. Physical activity was assessed using pedometers for 7 consecutive days, and 3 amounts of daily physical activity were considered: ≥10,000 steps/day, ≥7500 steps/day, and <5000 steps/day. Sleep quality was assessed through a questionnaire, and dual-energy x-ray absorptiometry was used to measure body fat. Sociodemographic and anthropometric data were also collected. The percentages of adults achieving at least 10,000 and 7500 steps/day on a minimum of 5 days of the evaluated week were 12.9% and 30.9%, respectively. Adults who reached ≥7500 steps/day had a lower likelihood of being obese (odds ratio [OR] = 0.38, 95% confidence interval [CI], 0.17-0.85) and reporting worse sleep quality (OR = 0.58, 95% CI, 0.34-0.99). Adults who reached <5000 steps/day had a higher likelihood of reporting worse sleep quality (OR = 2.11, 95% CI, 1.17-3.82). Physical activity in adulthood, as measured by pedometer, constituted a behavior related to lower adiposity and better sleep quality.


Neuromedin U in the paraventricular and arcuate hypothalamic nuclei increases non-exercise activity thermogenesis.
Brain neuromedin U (NMU) has been associated with the regulation of both energy intake and expenditure. We hypothesized that NMU induces changes in spontaneous physical activity and nonexercise activity thermogenesis (NEAT) through its actions on hypothalamic nuclei. We applied increasing doses of NMU directly to the paraventricular (PVN) and arcuate hypothalamic nuclei using chronic unilateral guide cannulae. In both nuclei, NMU significantly and dose-dependently increased physical activity and NEAT. Moreover, NMU increased physical activity and NEAT during the first hour of the dark phase, indicating that the reduction of sleep is unlikely to account for the increased physical activity seen with NMU treatment. As a positive control, we demonstrated that paraventricular NMU also significantly decreased food intake, as well as body weight. These data demonstrate that NMU is positively associated with NEAT through its actions in the PVN and arcuate nucleus. In co-ordination with its suppressive effects on feeding, the NEAT-activating effects of NMU make it a potential candidate in the combat of obesity.


Effect of Ga incorporation on the structure and Li ion conductivity of La3Zr2Li7O12.
In this paper we examine the effect of Ga doping on the structure and conductivity of the high Li ion content garnet-related system, La(3)Zr(2)Li(7)O(12). Without Ga doping, La(3)Zr(2)Li(7)O(12) is tetragonal and has low Li ion conductivity. The introduction of Ga leads to a change to a cubic unit cell, and a large enhancement in the conductivity. Prior structural studies of La(3)Zr(2)Li(7)O(12) have shown the presence of both tetrahedral and distorted octahedral sites for Li, and the low conductivity can be explained by the ordered nature of the Li distribution. The present structural study of La(3)Zr(2)Ga(0.5)Li(5.5)O(12) shows that Ga substitutes onto the tetrahedral site. Despite the presence of non-mobile Ga(3+) on the Li sites, the conductivity is enhanced as a result of the introduction of vacancies in the Li sites, and consequent disorder on the Li sublattice. Further work has suggested that over time in air, there is some H(+)/Li(+) exchange, and consequently some variation in the conductivity.


Metabolomics of cerebrospinal fluid reveals changes in the central nervous system metabolism in a rat model of multiple sclerosis.
Experimental Autoimmune Encephalomyelitis (EAE) is the most commonly used animal model for Multiple Sclerosis (MScl). CSF metabolomics in an acute EAE rat model was investigated using targetted LC-MS and GC-MS. Acute EAE in Lewis rats was induced by co-injection of Myelin Basic Protein with Complete Freund's Adjuvant. CSF samples were collected at two time points: 10 days after inoculation, which was during the onset of the disease, and 14 days after inoculation, which was during the peak of the disease. The obtained metabolite profiles from the two time points of EAE development show profound differences between onset and the peak of the disease, suggesting significant changes in CNS metabolism over the course of MBP-induced neuroinflammation. Around the onset of EAE the metabolome profile shows significant decreases in arginine, alanine and branched amino acid levels, relative to controls. At the peak of the disease, significant increases in concentrations of multiple metabolites are observed, including glutamine, O-phosphoethanolamine, branched-chain amino acids and putrescine. Observed changes in metabolite levels suggest profound changes in CNS metabolism over the course of EAE. Affected pathways include nitric oxide synthesis, altered energy metabolism, polyamine synthesis and levels of endogenous antioxidants. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0306-3) contains supplementary material, which is available to authorized users.


2-D structure of the A region of Xist RNA and its implication for PRC2 association.
In placental mammals, inactivation of one of the X chromosomes in female cells ensures sex chromosome dosage compensation. The 17 kb non-coding Xist RNA is crucial to this process and accumulates on the future inactive X chromosome. The most conserved Xist RNA region, the A region, contains eight or nine repeats separated by U-rich spacers. It is implicated in the recruitment of late inactivated X genes to the silencing compartment and likely in the recruitment of complex PRC2. Little is known about the structure of the A region and more generally about Xist RNA structure. Knowledge of its structure is restricted to an NMR study of a single A repeat element. Our study is the first experimental analysis of the structure of the entire A region in solution. By the use of chemical and enzymatic probes and FRET experiments, using oligonucleotides carrying fluorescent dyes, we resolved problems linked to sequence redundancies and established a 2-D structure for the A region that contains two long stem-loop structures each including four repeats. Interactions formed between repeats and between repeats and spacers stabilize these structures. Conservation of the spacer terminal sequences allows formation of such structures in all sequenced Xist RNAs. By combination of RNP affinity chromatography, immunoprecipitation assays, mass spectrometry, and Western blot analysis, we demonstrate that the A region can associate with components of the PRC2 complex in mouse ES cell nuclear extracts. Whilst a single four-repeat motif is able to associate with components of this complex, recruitment of Suz12 is clearly more efficient when the entire A region is present. Our data with their emphasis on the importance of inter-repeat pairing change fundamentally our conception of the 2-D structure of the A region of Xist RNA and support its possible implication in recruitment of the PRC2 complex.


Vis-a-Vis: Visual Exploration of Visualization Source Code Evolution.
Developing an algorithm for a visualization prototype often involves the direct comparison of different development stages and design decisions, and even minor modifications may dramatically affect the results. While existing development tools provide visualizations for gaining general insight into performance and structural aspects of the source code, they neglect the central importance of result images unique to graphical algorithms. In this article, we present a novel approach that enables visualization programmers to simultaneously explore the evolution of their algorithm during the development phase together with its corresponding visual outcomes by providing an automatically updating meta visualization. Our interactive system allows for the direct comparison of all development states on both the visual and the source code level, by providing easy to use navigation and comparison tools. The on-the-fly construction of difference images, source code differences, and a visual representation of the source code structure further enhance the user's insight into the states' interconnected changes over time. Our solution is accessible via a web-based interface that provides GPU-accelerated live execution of C++ and GLSL code, as well as supporting a domain-specific programming language for scientific visualization.


JAKOB narrative analysis: the psychodynamic conflict as a narrative model.
When a patient tells a story during psychotherapy sessions, it is both a mutual interaction between patient and therapist and a presentation of personal experience. The patient calls up and re-creates a biographical occurrence and puts it before a listener for viewing, enacting it verbally in the perspective of wish fulfillment and anxiety coping. JAKOB narrative analysis, situated in the field of psychoanalytical and narrative analytical research, is an encoding-supported qualitative instrument for the systematic reconstruction of verbal everyday narratives in the context of psychotherapeutic processes. In this study, the JAKOB narrative analysis is described in detail with the aid of an example narrative, put in relation to the therapeutic process, and discussed critically from a methodological viewpoint.


Customizing survey instruments and data collection to reach Hispanic/Latino adults in border communities in Texas.
We sought to modify an instrument and to use it to collect information on smoking knowledge, attitudes, beliefs, and behaviors among Hispanics/Latinos, and to adapt survey methods to obtain high participation levels. Methods. Promotoras (outreach workers) conducted face-to-face interviews with 1485 Hispanic adults (July 2007-April 2008). The project team used GeoFrame field enumeration methods to develop a sampling frame from households in randomly selected colonias (residential areas along the Texas-Mexico border that may lack some basic necessities (e.g. portable water), in El Paso, Texas. The revised questionnaire included 36 unchanged items from the State Adult Tobacco Survey, 7 modified items, and 17 new items focusing on possible culturally specific quitting methods, secondhand smoke issues, and attitudes and knowledge about tobacco use that might be unique for Hispanic/Latino groups. The eligibility rate was 90.2%, and the conservative combined completed screener and interview response rate was 80.0%. Strategic, targeted, carefully designed methods and surveys can achieve high reach and response rates in hard-to-reach populations. Similar procedures could be used to obtain cooperation of groups who may not be accessible with traditional methods.


Ancient phylogenetic beginnings of immunoglobulin hypermutation.
Many structures and molecules closely related to those involved in the specific process of immunoglobulin (Ig) hypermutation existed before the appearance of primordial Ig genes. Consequently, these structures can be found even in animals and organisms distinct from vertebrates; likewise, homologues of hypermutation enzymes are present in a broad range of species, from bacteria to mammals. Our analysis, based predominantly on primary structure, demonstrates the existence of molecules similar to Ig domains, variable Ig domains (IGv), and antigen receptors (AR) in unicellular organisms, nonvertebrate metazoans, and nonvertebrate Coelomata, respectively. In addition, we deal here with some important structural properties of CDR1-like segments of the selected sponge adhesion molecule GCSAMS exhibiting chimerical Ig domain similarities, and demonstrate the occurrence of conserved regions corresponding to Ohno's modern intact primordial building block in the C-terminal part of IGv-related segments of nonvertebrate origin. The results of our analysis are also discussed with respect to the possible phylogeny of molecules preceding the hypothetical common antigen receptor ancestor.


Disabled persons and the labor market in Sweden.
Persons with disabilities have well-documented problems entering the labor market all over the world. Research reveals that legislation to assist such individuals has relatively less significance than the attitudes of individual employers. In Jonkoping, Sweden, a smaller town of about 120,000 inhabitants, about 100 openings for jobs are created annually for people with learning disabilities and reduced employment capacity. Despite difficulties, local labor market agencies succeed to a relatively great extent, to find real and lasting jobs. An intervention often used for these individuals in Sweden is called Special Introduction and Follow-up Support (SIUS). The purpose of this paper is to provide balance to the somewhat biased but dominant view of persons with disabilities and unemployability. This is contradicted by Swedish data showing that it is possible to find jobs for people with disabilities with the support by trained of SIUS advisers.


Tildrakizumab in moderate-to-severe plaque psoriasis: A multicenter, retrospective, real-life study.
New biologic agents targeting interleukin (IL)23/T-helper17 axis, such as tildrakizumab, have been developed for the treatment of plaque psoriasis. To analyze the efficacy and safety of tildrakizumab in a real life setting of patients affected by moderate-to-severe psoriasis over a 28-week treatment period. A multicentric retrospective study was conducted in patients who initiated tildrakizumab between February 2020 and March 2021. Psoriasis Area and Severity Index-PASI was measured at baseline and after 4, 16 and 28 weeks. The percentage change in PASI value from baseline to the considered time-points, proportion of patients with absolute PASI <3 at week 28 and the percentages of achieving a PASI75 or PASI90 response were assessed. Data about potential safety issues and adverse events (AEs) were collected. Statistical analysis were performed for establish clinical efficacy and for variables predicting clinical response. Fifty nine patients with psoriasis were included. Overall mean PASI percentage reduction was of 88% from baseline to week 28 and 47 out of 59 patients (79.7%) at week 28 had an absolute PASI <3. PASI75 and PASI90 responses at week 28 were achieved by 48 (81.40%) patients and 38 (64.4.0%) patients, respectively. No substantial associations between gender, body mass index - BMI, PASI at baseline and prior exposition to biological therapies and the efficacy endpoints were retrieved. No serious safety issues or discontinuations related to adverse events were reported. In our real-life study, tildrakizumab showed high efficacy and a favorable safety profile, regardless of patient- and disease-related factors.


Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis.
Janus kinases (Jaks) play an important role in signal transduction via cytokine and growth factor receptors. A targeted inactivation of Jak2 was performed. Jak2-/- embryos are anemic and die around day 12.5 postcoitum. Primitive erythrocytes are found, but definitive erythropoiesis is absent. Compared to erythropoietin receptor-deficient mice, the phenotype of Jak2 deficiency is more severe. Fetal liver BFU-E and CFU-E colonies are completely absent. However, multilineage hematopoietic stem cells (CD34low, c-kit(pos)) can be found, and B lymphopoiesis appears intact. In contrast to IFNalpha stimulation, Jak2-/- cells do not respond to IFNgamma. Jak2-/- embryonic stem cells are competent for LIF signaling. The data provided demonstrate that Jak2 has pivotal functions for signal transduction of a set of cytokine receptors required in definitive erythropoiesis.


Morphological and phylogenetic data do not support the split of Alexandrium into four genera.
A recently published study analyzed the phylogenetic relationship between the genera Centrodinium and Alexandrium, confirming an earlier publication showing the genus Alexandrium as paraphyletic. This most recent manuscript retained the genus Alexandrium, introduced a new genus Episemicolon, resurrected two genera, Gessnerium and Protogonyaulax, and stated that: "The polyphyly [sic] of Alexandrium is solved with the split into four genera". However, these reintroduced taxa were not based on monophyletic groups. Therefore this work, if accepted, would result in replacing a single paraphyletic taxon with several non-monophyletic ones. The morphological data presented for genus characterization also do not convincingly support taxa delimitations. The combination of weak molecular phylogenetics and the lack of diagnostic traits (i.e., autapomorphies) render the applicability of the concept of limited use. The proposal to split the genus Alexandrium on the basis of our current knowledge is rejected herein. The aim here is not to present an alternative analysis and revision, but to maintain Alexandrium. A better constructed and more phylogenetically accurate revision can and should wait until more complete evidence becomes available and there is a strong reason to revise the genus Alexandrium. The reasons are explained in detail by a review of the available molecular and morphological data for species of the genera Alexandrium and Centrodinium. In addition, cyst morphology and chemotaxonomy are discussed, and the need for integrative taxonomy is highlighted.


Associations between microRNA expression and mesenchymal marker gene expression in glioblastoma.
The subclassification of glioblastoma (GBM) into clinically relevant subtypes using microRNA (miRNA)- and messenger RNA (mRNA)-based integrated analysis has been attempted. Because miRNAs regulate multiple gene-signaling pathways, understanding miRNA-mRNA interactions is a prerequisite for understanding glioma biology. However, such associations have not been thoroughly examined using high-throughput integrated analysis. To identify significant miRNA-mRNA correlations, we selected and quantified signature miRNAs and mRNAs in 82 gliomas (grade II: 14, III: 16, IV: 52) using real-time reverse-transcriptase polymerase chain reaction. Quantitative expression data were integrated into a single analysis platform that evaluated the expression relationship between miRNAs and mRNAs. The 21 miRNAs include miR-15b, -21, -34a, -105, -124a, -128a, -135b, -184, -196a-b, -200a-c, -203, -302a-d, -363, -367, and -504. In addition, we examined 23 genes, including proneural markers (DLL3, BCAN, and OLIG2), mesenchymal markers (YKL-40, CD44, and Vimentin), cancer stem cell-related markers, and receptor tyrosine kinase genes. Primary GBM was characterized exclusively by upregulation of mesenchymal markers, whereas secondary GBM was characterized by significant downregulation of mesenchymal markers, miR-21, and -34a, and by upregulation of proneural markers and miR-504. Statistical analysis showed that expression of miR-128a, -504, -124a, and -184 each negatively correlated with the expression of mesenchymal markers in GBM. Our functional analysis of miR-128a and -504 as inhibitors demonstrated that suppression of miR-128a and -504 increased the expression of mesenchymal markers in glioblastoma cell lines. Mesenchymal signaling in GBM may be negatively regulated by miR-128a and -504.


Comparing acoustic and radar deterrence methods as mitigation measures to reduce human-bat impacts and conservation conflicts.
Where humans and wildlife co-exist, mitigation is often needed to alleviate potential conflicts and impacts. Deterrence methods can be used to reduce impacts of human structures or activities on wildlife, or to resolve conservation conflicts in areas where animals may be regarded as a nuisance or pose a health hazard. Here we test two methods (acoustic and radar) that have shown potential for deterring bats away from areas where they forage and/or roost. Using both infrared video and acoustic methods for counting bat passes, we show that ultrasonic speakers were effective as bat deterrents at foraging sites, but radar was not. Ultrasonic deterrents decreased overall bat activity (filmed on infrared cameras) by ~80% when deployed alone and in combination with radar. However, radar alone had no effect on bat activity when video or acoustic data were analysed using generalised linear mixed effect models. Feeding buzzes of all species were reduced by 79% and 69% in the ultrasound only treatment when compared to the control and radar treatments, but only the ultrasound treatment was significant in post-hoc tests. Species responded differently to the ultrasound treatments and we recorded a deterrent effect on both Pipistrellus pipistrellus (~40-80% reduction in activity) and P. pygmaeus (~30-60% reduction), but not on Myotis species. However, only the ultrasound and radar treatment was significant (when compared to control and radar) in post-hoc tests for P. pipistrellus. Deterrent treatment was marginally non-significant for P. pygmaeus, but the ultrasound only treatment was significant when compared to radar in post-hoc tests. We therefore suggest that acoustic, but not radar methods are explored further as deterrents for bats. The use of acoustic deterrence should always be assessed on a case-by-case basis, with a focus on bat conservation.


DNA base excision repair in human malaria parasites is predominantly by a long-patch pathway.
Mammalian cells repair apurinic/apyrimidinic (AP) sites in DNA by two distinct pathways: a polymerase beta (pol beta)-dependent, short- (one nucleotide) patch base excision repair (BER) pathway, which is the major route, and a PCNA-dependent, long- (several nucleotide) patch BER pathway. The ability of a cell-free lysate prepared from asexual Plasmodium falciparum malaria parasites to remove uracil and repair AP sites in a variety of DNA substrates was investigated. We found that the lysate contained uracil DNA glycosylase, AP endonuclease, DNA polymerase, flap endonuclease, and DNA ligase activities. This cell-free lysate effectively repaired a regular or synthetic AP site on a covalently closed circular (ccc) duplex plasmid molecule or a long (382 bp), linear duplex DNA fragment, or a regular or reduced AP site in short (28 bp), duplex oligonucleotides. Repair of the AP sites in the various DNA substrates involved a long-patch BER pathway. This biology is different from mammalian cells, yeast, Xenopus, and Escherichia coli, which predominantly repair AP sites by a one-nucleotide patch BER pathway. The apparent absence of a short-patch BER pathway in P. falciparum may provide opportunities to develop antimalarial chemotherapeutic strategies for selectively damaging the parasites in vivo and will allow the characterization of the long-patch BER pathway without having to knock-out or inactivate a short-patch BER pathway, which is necessary in mammalian cells.


Integrating interactive computational modeling in biology curricula.
While the use of computer tools to simulate complex processes such as computer circuits is normal practice in fields like engineering, the majority of life sciences/biological sciences courses continue to rely on the traditional textbook and memorization approach. To address this issue, we explored the use of the Cell Collective platform as a novel, interactive, and evolving pedagogical tool to foster student engagement, creativity, and higher-level thinking. Cell Collective is a Web-based platform used to create and simulate dynamical models of various biological processes. Students can create models of cells, diseases, or pathways themselves or explore existing models. This technology was implemented in both undergraduate and graduate courses as a pilot study to determine the feasibility of such software at the university level. First, a new (In Silico Biology) class was developed to enable students to learn biology by "building and breaking it" via computer models and their simulations. This class and technology also provide a non-intimidating way to incorporate mathematical and computational concepts into a class with students who have a limited mathematical background. Second, we used the technology to mediate the use of simulations and modeling modules as a learning tool for traditional biological concepts, such as T cell differentiation or cell cycle regulation, in existing biology courses. Results of this pilot application suggest that there is promise in the use of computational modeling and software tools such as Cell Collective to provide new teaching methods in biology and contribute to the implementation of the "Vision and Change" call to action in undergraduate biology education by providing a hands-on approach to biology.


Frequent detection of human adenovirus from the lower gastrointestinal tract in men who have sex with men.
The association between baseline seropositivity to human adenovirus (HAdV) type 5 and increased HIV acquisition in the Step HIV Vaccine Study has raised questions concerning frequency of acquired and/or persistent Adenovirus infections among adults at high risk of HIV-1 infection. To evaluate the frequency and pattern of HAdV shedding from the lower GI tract, we retrospectively tested rectal swabs for HAdVs in a cohort of 20 HSV-2 positive HIV-positive Peruvian men who have sex with men (MSM) undergoing rectal swabbing three times/week for 18 consecutive weeks, in a prospective study of HSV-2 suppression in HIV infection. Viral DNA was extracted and amplified using a sensitive multiplex PCR assay that detects all currently recognized HAdV types. Molecular typing of viruses was performed on selected samples by hexon gene sequencing. Baseline neutralizing antibody titers to HAdVs -5, -26, -35 and -48 were also assessed. 15/20 individuals had HAdV detected during follow up. The median frequency of HAdV detection was 30% of samples (range 2.0% to 64.7%). HAdV shedding typically occurred on consecutive days in clustered episodes lasting a median of 4 days (range 1 to 9 days) separated by periods without shedding, suggesting frequent new infections or reactivation of latent infections over time. 8 of the 15 shedders had more than one type detected in follow-up. 20 HAdV types from species B, C, and D were identified, including HAdV-5, -26 and -48, HAdV types under development as potential vaccine candidates. 14/20 subjects were seropositive for HAdV-5; 15/20 for HAdV-26; 3/20 for HAdV-35; and 2/20 for HAdV-48. HAdV shedding did not correlate with CD4 count, plasma HIV-1 viral load, or titers to HAdV-5 or HAdV-35. The sole individual with HAdV-5 shedding was HAdV-5 seropositive. HAdV shedding was highly prevalent and diverse, including types presently under consideration as HIV vaccine vectors. Subclinical HAdV infection of the GI tract is common among MSM in Peru; the prevalence of HAdV in the enteric tract should be evaluated in other populations. The association between ongoing recent enteric HAdV and the immune response to recombinant HAdV vaccines should be evaluated.


The Future of Axial Spondyloarthritis Rehabilitation: Lessons Learned From COVID-19.
Supervised physical therapy and rehabilitation are vital for effective long-term management of axial spondyloarthritis (SpA). However, the unprecedented year of 2020 and the COVID-19 pandemic has prompted a drastic change in health care provision across all disease areas. In this review, we summarize changes that have been introduced to support rehabilitation in axial SpA during the pandemic and considerations for the future of axial SpA rehabilitation in the wake of COVID-19. We have witnessed the launch of online virtual physical therapy and education, in addition to an emphasis on remote monitoring. We have been propelled into a new era of digital service provision; not only providing a temporary stop-gap in treatment for some patients, but in the future, potentially allowing for a wider reach and provision of care and resilience of vital services. Unique collaboration between patients, health care professionals, and researchers will be key to fostering relationships and trust and facilitating wider evaluation and implementation of digital services at each stage in a patient's journey, which is imperative for relieving pressure from health care providers. Despite the potential of such digital interventions, it is important to highlight the maintained critical need for face-to-face services, particularly for vulnerable patients or during diagnosis or a flare of symptoms. It is also vital that we remain vigilant regarding digital exclusion to avoid further widening of existing health inequalities. Optimization of digital infrastructure, staff skills, and digital education alongside promoting accessibility and engagement and building trust among communities will be vital as we enter this new age of blended in-person and digital service provision.


CD4+ T Cells of Myasthenia Gravis Patients Are Characterized by Increased IL-21, IL-4, and IL-17A Productions and Higher Presence of PD-1 and ICOS.
Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies predominantly against the acetylcholine receptor (AChR). Specific T cell subsets are required for long-term antibody responses, and cytokines secreted mainly from CD4+ T cells regulate B cell antibody production. The aim of this study was to assess the differences in the cytokine expressions of CD4+ T cells in MG patients with AChR antibodies (AChR-MG) and the effect of immunosuppressive (IS) therapy on cytokine activity and to test these findings also in MG patients without detectable antibodies (SN-MG). Clinically diagnosed AChR-MG and SN-MG patients were included. The AChR-MG patients were grouped as IS-positive and -negative and compared with age- and sex-matched healthy controls. Peripheral blood mononuclear cells were used for ex vivo intracellular cytokine production, and subsets of CD4+ T cells and circulating follicular helper T (cTfh) cells were detected phenotypically by the expression of the chemokine and the costimulatory receptors. Thymocytes obtained from patients who had thymectomy were also analyzed. IL-21, IL-4, IL-10, and IL-17A productions in CD4+ T cells were increased in AChR-MG compared to those in healthy controls. IS treatment enhanced IL-10 and reduced IFN-γ production in AChR-MG patients compared to those in IS-negative patients. Increased IL-21 and IL-4 productions were also demonstrated in SN-MG patients. Among CD4+ T cells, Th17 cells were increased in both disease subgroups. Treatment induced higher proportions of Th2 cells in AChR-MG patients. Both CXCR5+ and CXCR5- CD4+ T cells expressed higher programmed cell death protein 1 (PD-1) and inducible costimulatory (ICOS) in AChR-MG and SN-MG groups, mostly irrespective of the treatment. Based on chemokine receptors on CXCR5+PD-1+ in CD4+ T (cTfh) cells, in AChR-MG patients without treatment, the proportions of Tfh17 cells were higher than those in the treated group, whereas the Tfh1 cells were decreased compared with those in the controls. The relevance of CXCR5 and PD-1 in the pathogenesis of AChR-MG was also suggested by the increased presence of these molecules on mature CD4 single-positive thymocytes from the thymic samples. The study provides further evidence for the importance of IL-21, IL-17A, IL-4, and IL-10 in AChR-MG. Disease-related CD4+T cells are identified mainly as PD-1+ or ICOS+ with or without CXCR5, resembling cTfh cells in the circulation or probably in the thymus. AChR-MG and SN-MG seem to have some similar characteristics. IS treatment has distinctive effects on cytokine expression.


Improving patient access to cancer drugs in India: Using economic modeling to estimate a more affordable drug cost based on measures of societal value.
Using multiples of India's per capita gross domestic product (GDP) as the threshold for economic value as suggested by the World Health Organization (WHO), decision analysis modeling was used to estimate a more affordable monthly cost in India for a hypothetical new cancer drug that provides a 3-month survival benefit to Indian patients with metastatic colorectal cancer (mCRC). A decision model was developed to simulate progression-free and overall survival in mCRC patients receiving chemotherapy with and without the new drug. Costs for chemotherapy and side-effects management were obtained from both public and private hospitals in India. Utility estimates measured as quality-adjusted life-years (QALY) were determined by interviewing twenty-four oncology nurses using the Time Trade-Off technique. The monthly cost of the new drug was then estimated using a target threshold of US$9,300 per QALY gained, which is three times the Indian per capita GDP. The base-case analysis suggested that a price of US$98.00 per dose would be considered cost-effective from the Indian public healthcare perspective. If the drug were able to improve patient quality of life above the standard of care or survival from 3 to 6 months, the price per dose could increase to US$170 and US$253 and offer the same value. The use of the WHO criteria for estimating the cost of a new drug based on economic value for a developing country like India is feasible and can be used to estimate a more affordable cost based on societal value thresholds.


Mitigation of monocyte driven thrombosis on cobalt chrome surfaces in contact with whole blood by thin film polar/hydrophobic/ionic polyurethane coatings.
Monocytes are active at the crossroads between inflammation and coagulation processes since they can secrete pro-inflammatory cytokines and express tissue factor (TF), a major initiator of coagulation. Cobalt-chrome (CoCr), a metal alloy, used as a biomaterial for vascular stents, has been shown to be potentially pro-thrombotic and pro-inflammatory. Research work with a polymer from a family of degradable-polar hydrophobic ionic polyurethanes (D-PHI), called HHHI, has been shown to exhibit anti-inflammatory responses from human monocytes. We have generated multifunctional polyurethane thin films (MPTF) based on the HHHI chemistry, as a thin coating for CoCr and have evaluated the reactivity of blood with MPTF-coated CoCr. The results showed that the coating of CoCr with MPTF derived from HHHI prevents thrombin generation, reduces coagulation activation, and suppresses fibrin formation in whole blood. Activation of monocytes was also suppressed at the surface of MPTF-coated CoCr and specifically the decrease in thrombin generation was accompanied by a significant decrease in TF and pro-inflammatory cytokine levels. Mass spectroscopy of the adsorbed proteins showed lower levels of fibrinogen, fibronectin and complement C3, C4, and C8 when compared to CoCr. We can conclude that MPTFs reduce the pro-thrombotic and pro-inflammatory phenotype of monocytes and macrophages on CoCr, and prevent clotting in whole blood.


Randomized controlled trial of a cognitive-behavioral therapy plus hypnosis intervention to control fatigue in patients undergoing radiotherapy for breast cancer.
The objective of this study was to test the efficacy of cognitive-behavioral therapy plus hypnosis (CBTH) to control fatigue in patients with breast cancer undergoing radiotherapy. We hypothesized that patients in the CBTH group receiving radiotherapy would have lower levels of fatigue than patients in an attention control group. Patients (n = 200) were randomly assigned to either the CBTH (n = 100; mean age, 55.59 years) or attention control (n = 100; mean age, 55.97 years) group. Fatigue was measured at four time points (baseline, end of radiotherapy, 4 weeks, and 6 months after radiotherapy). Fatigue was measured using the Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue subscale and Visual Analog Scales (VASs; Fatigue and Muscle Weakness). The CBTH group had significantly lower levels of fatigue (FACIT) at the end of radiotherapy (z, 6.73; P < .001), 4-week follow-up (z, 6.98; P < .001), and 6-month follow-up (z, 7.99; P < .001) assessments. Fatigue VAS scores were significantly lower in the CBTH group at the end of treatment (z, 5.81; P < .001) and at the 6-month follow-up (z, 4.56; P < .001), but not at the 4-week follow-up (P < .07). Muscle Weakness VAS scores were significantly lower in the CBTH group at the end of treatment (z, 9.30; P < .001) and at the 6-month follow-up (z, 3.10; P < .02), but not at the 4-week follow-up (P < .13). The results support CBTH as an evidence-based intervention to control fatigue in patients undergoing radiotherapy for breast cancer. CBTH is noninvasive, has no adverse effects, and its beneficial effects persist long after the last intervention session. CBTH seems to be a candidate for future dissemination and implementation.


Magnetic and electrical stimulation of the auditory cortex for intractable tinnitus. Case report.
Tinnitus is a distressing symptom that affects up to 15% of the population for whom no satisfactory treatment exists. The authors present a novel surgical approach for the treatment of intractable tinnitus, based on cortical stimulation of the auditory cortex. Tinnitus can be considered an auditory phantom phenomenon similar to deafferentation pain, which is observed in the somatosensory system. Tinnitus is accompanied by a change in the tonotopic map of the auditory cortex. Furthermore, there is a highly positive association between the subjective intensity of the tinnitus and the amount of shift in tinnitus frequency in the auditory cortex, that is, the amount of cortical reorganization. This cortical reorganization can be demonstrated by functional magnetic resonance (fMR) imaging. Transcranial magnetic stimulation (TMS) is a noninvasive method of activating or deactivating focal areas of the human brain. Linked to a navigation system that is guided by fMR images of the auditory system, TMS can suppress areas of cortical plasticity. If it is successful in suppressing a patient's tinnitus, this focal and temporary effect can be perpetualized by implanting a cortical electrode. A neuronavigation-based auditory fMR imaging-guided TMS session was performed in a patient who suffered from tinnitus due to a cochlear nerve lesion. Complete suppression of the tinnitus was obtained. At a later time an extradural electrode was implanted with the guidance of auditory fMR imaging navigation. Postoperatively, the patient's tinnitus disappeared and remains absent 10 months later. Focal extradural electrical stimulation of the primary auditory cortex at the area of cortical plasticity is capable of suppressing contralateral tinnitus completely. Transcranial magnetic stimulation may be an ideal method for noninvasive studies of surgical candidates in whom stimulating electrodes might be implanted for tinnitus suppression.


Oral Health Status, Oral Health Behaviours and Oral Health Care Utilisation Among Migrants Residing in Europe: A Systematic Review.
As the reported data on oral health status among the migrants in Europe is fragmented, we systematically reviewed the published literature on the oral health status, behaviours and care utilisation among migrants residing in Europe. For this, we retrieved publications from PubMed and EMBASE, supplemented by manual citation screening and grey literature search on Google scholars. Two independent reviewers screened the studies, extracted data and critically appraised the publications. A total of 69 studies included showed higher dental caries among migrant children. But some studies on adolescents and adults reported similar or even better oral health among migrants compared to the host population, while other reported the opposite. Poor oral health behaviours were generally reported among the migrants and they frequently made use of emergency service utilisation compared to the host population. We shed light on the gaps in dental literature and make some recommendations for the future.


Optima TB: A tool to help optimally allocate tuberculosis spending.
Approximately 85% of tuberculosis (TB) related deaths occur in low- and middle-income countries where health resources are scarce. Effective priority setting is required to maximise the impact of limited budgets. The Optima TB tool has been developed to support analytical capacity and inform evidence-based priority setting processes for TB health benefits package design. This paper outlines the Optima TB framework and how it was applied in Belarus, an upper-middle income country in Eastern Europe with a relatively high burden of TB. Optima TB is a population-based disease transmission model, with programmatic cost functions and an optimisation algorithm. Modelled populations include age-differentiated general populations and higher-risk populations such as people living with HIV. Populations and prospective interventions are defined in consultation with local stakeholders. In partnership with the latter, demographic, epidemiological, programmatic, as well as cost and spending data for these populations and interventions are then collated. An optimisation analysis of TB spending was conducted in Belarus, using program objectives and constraints defined in collaboration with local stakeholders, which included experts, decision makers, funders and organisations involved in service delivery, support and technical assistance. These analyses show that it is possible to improve health impact by redistributing current TB spending in Belarus. Specifically, shifting funding from inpatient- to outpatient-focused care models, and from mass screening to active case finding strategies, could reduce TB prevalence and mortality by up to 45% and 50%, respectively, by 2035. In addition, an optimised allocation of TB spending could lead to a reduction in drug-resistant TB infections by 40% over this period. This would support progress towards national TB targets without additional financial resources. The case study in Belarus demonstrates how reallocations of spending across existing and new interventions could have a substantial impact on TB outcomes. This highlights the potential for Optima TB and similar modelling tools to support evidence-based priority setting.