Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

Improved outcomes of large B-cell lymphoma patients treated with CD19 CAR T in the UK over time.

The success of CD19 Chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off-the-shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the 'standard-of-care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020-2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression-free survival (1-year PFS 50% vs. 32%, p < 0.001) and overall survival (1-year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high-grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up-to-date clinical data when comparing CAR T against new treatment options for r/r LBCL.

CAR T in patients with large B-cell lymphoma not fit for autologous transplant.

Large B-cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa-cel versus axi-cel (52% vs. 48%) compared to 20% versus 80% in ASCT-fit patients; p < 0.0001. The drop-out rate from approval to infusion was significantly higher in the ASCT-unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression-free and overall survival were similar in both cohorts. CAR T was well-tolerated in ASCT-unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real-world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant.

Do we all walk the walk? A comparison of walking behaviors across tetrapods.

A walking gait has been identified in a range of vertebrate species with different body plans, habitats, and life histories. With increased application of this broad umbrella term, it has become necessary to assess the physical characteristics, analytical approaches, definitions, and diction used to describe walks. To do this, we reviewed studies of slow speed locomotion across a range of vertebrates to refine the parameters used to define walking, evaluate analytical techniques, and propose approaches to maximize consistency across subdisciplines. We summarize nine key parameters used to characterize walking behaviors in mammals, birds, reptiles, amphibians, and fishes. After identifying consistent patterns across groups, we propose a comprehensive definition for a walking gait. A walk is a form of locomotion where the majority of the forward propulsion of the animal comes from forces generated by the appendages interacting with the ground. During a walk, an appendage must be out of phase with the opposing limb in the same girdle and there is always at least one limb acting as ground-support (no suspension phase). Additionally, walking occurs at dimensionless speeds <1 v* and the duty factor of the limbs is always >0.5. Relative to other gaits used by the same species, the stance duration of a walk is long, the cycle frequency is low, and the cycle distance is small. Unfortunately, some of these biomechanical parameters, while effectively describing walks, may also characterize other, non-walking gaits. Inconsistent methodology likely contributes to difficulties in comparing data across many groups of animals; consistent application of data collection and analytical techniques in research methodology can improve these comparisons. Finally, we note that the kinetics of quadrupedal movements are still poorly understood and much work remains to be done to understand the movements of small, exothermic tetrapods.

Scale Thickness Predicts Skin Puncture-Force Resistance in Three Pleuronectiform Fishes.

In fishes, the skin and scales provide a physical barrier to the external environment and must withstand direct physical insult from biotic and abiotic features of the habitat. Flatfishes likely rely heavily on their scales for physical defense because they rest directly on the substrate. Using a flatfish model, we asked: what are the effects of scale type and scale morphology on puncture force resistance? We also asked: are there morphological and functional differences between the eyed and blind sides in flatfishes and do the morphological and functional properties of scales vary with organism size? Using a large size range of three species of Pleuronectid flatfish (Isopsetta isolepis, n = 10; Parophrys vetulus, n = 10; and Platichthys stellatus, n = 12), we measured the force required to puncture the integument using a sample of skin+scales taken from the eyed and blind side of each individual. We also measured the diameter, area, and thickness of the scales of each individual. Scaling relationships (body length vs. variable of interest) were derived for each species and compared with a priori expectations of geometric similarity. We found no relationship between scale type and puncture resistance and no differences in morphological parameters or puncture resistance between the eyed and blind side within a given species. These flatfish species do vary in their ability to withstand puncture forces; however, once scale thickness is taken into account, species differences disappear. Thus, the ability of a flatfish to withstand mechanical insult from puncture-forces varies depending on the thickness of the scale.

El Grosor de la escala Predice la Resistencia a la Punción de la Piel en Tres Peces Pleuronectiformes (Scale Thickness Predicts Skin Puncture-Force Resistance in Three Pleuronectiform Fishes) En los peces, la piel y las escamas proporcionan una barrera física al ambiente externo y deben resistir la injuria física directa de las características bióticas y abióticas del hábitat. Los peces planos probablemente dependen mucho de sus escamas para la defensa física porque descansan directamente sobre el sustrato. Usando un modelo de peces planos, preguntamos: ¿cuáles son los efectos del tipo y la morfología de la escama en la resistencia a la fuerza de punción? También preguntamos: ¿hay diferencias morfológicas y funcionales entre los lados ciego y ocular en los peces planos y si las propiedades morfológicas y funcionales de las escamas varían con el tamaño del organismo? Usando un amplio rango de tamaño de tres especies de peces planos Pleuronectidos (Isopsetta isolepis, n = 10; Parophrys vetulus, n = 10; y Platichthys stellatus, n = 12), medimos la fuerza requerida para perforar el integumento utilizando una muestra de escamas de la piel tomada del lado ocular y ciego de cada individuo. También medimos el diámetro, el área y el grosor de las escamas de cada individuo. Se derivaron relaciones escalares (longitud corporal vs. variable de interés) para cada especie y se compararon con las expectativas a priori de similitud geométrica. No encontramos ninguna relación entre el tipo de escama y la resistencia a la punción, y no hay diferencias en los parámetros morfológicos o la resistencia a la punción entre el lado ciego y ocular dentro de una especie dada. Estas especies de peces planos varían en su capacidad para soportar las fuerzas de punción; sin embargo, una vez que se toma en cuenta el grosor de la escama, las diferencias entre especies desaparecen. Por lo tanto, la capacidad de un pez plano para soportar la injuria mecánica de las fuerzas de punción varía según el grosor de la escama. Translated to Spanish by C.A. Alfonso (calfonsoc@vt.edu).

Espessura da Escama Prevê a Resistência à Força de Punção Cutânea em Três Peixes Pleuronectiformes (Scale Thickness Predicts Skin Puncture-Force Resistance in Three Pleuronectiform Fishes) A pele e as escamas dos peixes fornecem uma barreira física ao ambiente externo, devendo aguentar injúrias provenientes dos aspectos bióticos e abióticos do seu habitat. Os linguados provavelmente dependem muito de suas escamas para defesa porque eles estão em contato direto com o substrato. Usando um modelo de linguado, perguntamos quais os efeitos do tipo de escama e da morfologia da mesma na resistência à punção. Nós também perguntamos se existem diferenças morfológicas e funcionais entre os lados dos olhos e os lados cegos em linguados e se as propriedades morfológicas e funcionais das escamas variam com o tamanho do organismo. Usando uma extensa faixa de tamanho de três espécies de linguados pleuronectídeos (Isopsetta isolepis, n = 10; Parophrys vetulus, n = 10; e Platichthys stellatus, n = 12), medimos a força necessária para perfurar o tegumento em uma amostra de pele+escamas tirada de ambos os lados de cada indivíduo. Também medimos o diâmetro, área e espessura das escamas deles. As relações de escalonamento (comprimento do corpo vs. variável de interesse) foram derivadas para cada espécie e comparadas às expectativas de similaridade geométrica determinadas a priori. Não encontramos relação entre o tipo de escama e a resistência à perfuração e não houve diferenças nos parâmetros morfológicos ou na resistência à perfuração entre o lado dos olhos e o lado cego em uma dada espécie. Essas espécies de linguado variam em sua capacidade de aguentar forças de punção; no entanto, uma vez que a espessura da escama é levada em conta, as diferenças entre as espécies desaparecem. Assim, a capacidade de um linguado de suportar injúrias mecânicas causadas por perfuração varia dependendo da espessura da escama. Translated to Portuguese by G. Sobral (gabisobral@gmail.com).

Benthic walking, bounding, and maneuvering in flatfishes (Pleuronectiformes: Pleuronectidae): New vertebrate gaits.

Video-based observations of voluntary movements reveal that six species of pleuronectid flatfishes use sequential portions of long-based dorsal and anal fins as "feet" (hereafter, fin-feet) to move on the substrate. All six species used a gait that we term "walking," which produced constant forward movement, and several of these species also used a second gait that we call "bounding" for intermittent movements over the substrate. We selected Pacific Sand Sole, Psettichthys melanostictus, and English Sole, Parophrys vetulus, for kinematic analyses of these two gaits. Psettichthys melanostictus consistently used walking for benthic locomotion; Parophrys vetulus primarily used a bounding gait. During forward walking, a fin ray swings up off the substrate, protracts and converges with neighboring fin rays to contribute to a fin-foot. The fin-foot pushes down on the substrate and rotates posteriorly by sequential recruitment of fin rays, a pattern known as a metachronal wave. As one fin-foot passes off the posterior end of the fin, a new fin-foot forms anteriorly. During bounding, undulations of the body and tail assist one or two waves of fin-feet, producing rapid but intermittent forward acceleration of the body. Flatfishes also use fin-feet to maneuver on the substrate. The Starry Flounder, Platichthys stellatus, performs near zero displacement rotation by running waves of fin-feet in opposing directions along the dorsal and anal fins. Although other teleosts use specialized pectoral fin rays for bottom walking (e.g., Sea Robins: Triglidae), the duplication of structures and patterns of movement in the median fins of flatfishes more closely resembles metachronal motions of millipede feet or the parapodia of polychaete worms. Sequential use of median fin rays in flatfishes resembles that of other teleosts that swim with elongate median fins, including Amiiformes, Gymnotiformes, and some Tetraodontiformes, but flatfishes offer a novel form of substrate locomotion based on dorsal and anal fins.

Can members of the south-western Gila robusta species complex be distinguished by morphological features?

The goal for this project was to re-examine key morphological characters hypothesized to differentiate Gila intermedia, Gila robusta and Gila nigra and outline methods better suited for making species designations based on morphology. Using a combination of meristic counts, morphological measurements and geometric morphometrics, morphological dissimilarities were quantified among these three putative species. Traditional meristic counts and morphological measurements (i.e. distances between landmarks) were not useful for species identification. Geometric morphometrics, however, identified differences among species, while also suggesting an effect of geographic location on morphological variation. Using canonical variate analysis for the 441 fish sampled in this study, geometric morphometrics accurately predicted true group membership 100% of the time for G. nigra, 97% of the time for G. intermedia and 91% of the time for G. robusta. These results suggest that geometric morphometric analysis is necessary to identify morphological differences among the three species. Geometric morphometric analysis used in this study can be adopted by management officials as a tool to classify unidentified individuals.

Building healthy construction workers: Their views on health, wellbeing and better workplace design.

Construction is a heavy manual industry where working into later life can be a challenge. An interview study was conducted to explore workers' understanding of their health at work and ways of making their jobs easier, safer or more comfortable. Using purposive sampling, 80 trades' workers were selected from construction sites in the UK. The Nordic Musculoskeletal Questionnaire and Work Ability Index were used to explore aches and pains and reducing strain on the body. A high prevalence of symptoms was reported and ratings of work ability were high. Workers were aware of the physical demands of their work and had over 250 ideas around health and wellbeing e.g. rucksacks for tools, bespoke benches, adapting PPE, and higher cost solutions e.g. mechanical lifting aids. Engagement of the workforce should be encouraged and feed into change processes in the industry to enable all workers stay fit for work for longer.

Sustained periodic terrestrial locomotion in air-breathing fishes.

While emergent behaviours have long been reported for air-breathing osteichthyians, only recently have researchers undertaken quantitative analyses of terrestrial locomotion. This review summarizes studies of sustained periodic terrestrial movements by air-breathing fishes and quantifies the contributions of the paired appendages and the axial body to forward propulsion. Elongate fishes with axial-based locomotion, e.g. the ropefish Erpetoichthys calabaricus, generate an anterior-to-posterior wave of undulation that travels down the axial musculoskeletal system and pushes the body against the substratum at multiple points. In contrast, appendage-based locomotors, e.g. the barred mudskipper Periophthalmus argentilineatus, produce no axial bending during sustained locomotion, but instead use repeated protraction-retraction cycles of the pectoral fins to elevate the centre of mass and propel the entire body anteriorly. Fishes that use an axial-appendage-based mechanism, e.g. walking catfishes Clarias spp., produce side-to-side, whole-body bending in co-ordination with protraction-retraction cycles of the pectoral fins. Once the body is maximally bent to one side, the tail is pressed against the substratum and drawn back through the mid-sagittal plane, which elevates the centre of mass and rotates it about a fulcrum formed by the pectoral fin and the ground. Although appendage-based terrestrial locomotion appears to be rare in osteichthyians, many different species appear to have converged upon functionally similar axial-based and axial-appendage-based movements. Based on common forms observed across divergent taxa, it appears that dorsoventral compression of the body, elongation of the axial skeleton or the presence of robust pectoral fins can facilitate effective terrestrial movement by air-breathing fishes.

A study to investigate dose escalation of doxorubicin in ABVD chemotherapy for Hodgkin lymphoma incorporating biomarkers of response and toxicity.

BACKGROUND: Myelotoxicity during initial cycles of chemotherapy for Hodgkin lymphoma is associated with better outcome, supporting the concept of individualised dosing based on pharmacodynamic end points to optimise results. This study was performed to identify the maximum tolerated dose (MTD) of doxorubicin within cycles 1-3 ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Circulating biomarkers of response (nucleosomal DNA, nDNA) and epithelial toxicity (Cytokeratin 18, CK18) were also measured. METHODS: Dose escalation of doxorubicin in cycles 1-3 ABVD supported by pegfilgrastim was performed on a six-patient cohort basis (35, 45 and 55 mg m(-2)) with doxorubicin reduced to 25 mg m(-2) or omitted in cycles 4-6 to maintain cumulative exposure of 103-130% standard ABVD. BVD was given at standard doses throughout. Six additional subjects were recruited at the MTD. RESULTS: Twenty-four subjects were recruited. Dose-limiting toxicities (DLTs) of grade 3 neuropathy, pneumonitis, palmar-plantar erythema and neutropenic infection were observed at 55 mg m(-2), so 45 mg m(-2) was declared the MTD. In patients who subsequently experienced DLT at any time, large increases in CK18 were seen on day 3 of cycle 1 ABVD. CONCLUSION: Escalated ABVD incorporating doxorubicin at 45 mg m(-2) in cycles 1-3 can be delivered safely with pegfilgrastim support. Circulating cell death biomarkers may assist in the development of future individualised dosing strategies.

Memantine block depends on agonist presentation at the NMDA receptor in substantia nigra pars compacta dopamine neurones.

NMDA glutamate receptors (NMDARs) have critical functional roles in the nervous system but NMDAR over-activity can contribute to neuronal damage. The open channel NMDAR blocker, memantine is used to treat certain neurodegenerative diseases, including Parkinson's disease (PD) and is well tolerated clinically. We have investigated memantine block of NMDARs in substantia nigra pars compacta (SNc) dopamine neurones, which show severe pathology in PD. Memantine (10 µM) caused robust inhibition of whole-cell (synaptic and extrasynaptic) NMDARs activated by NMDA at a high concentration or a long duration, low concentration. Less memantine block of NMDAR-EPSCs was seen in response to low frequency synaptic stimulation, while responses to high frequency synaptic stimulation were robustly inhibited by memantine; thus memantine inhibition of NMDAR-EPSCs showed frequency-dependence. By contrast, MK-801 (10 µM) inhibition of NMDAR-EPSCs was not significantly different at low versus high frequencies of synaptic stimulation. Using immunohistochemistry, confocal imaging and stereological analysis, NMDA was found to reduce the density of cells expressing tyrosine hydroxylase, a marker of viable dopamine neurones; memantine prevented the NMDA-evoked decrease. In conclusion, memantine blocked NMDAR populations in different subcellular locations in SNc dopamine neurones but the degree of block depended on the intensity of agonist presentation at the NMDAR. This profile may contribute to the beneficial effects of memantine in PD, as glutamatergic activity is reported to increase, and memantine could preferentially reduce over-activity while leaving some physiological signalling intact.

Medical grade sterilization affects synthetic polymer film properties intended for peripheral nerve repair: an in vitro study.

In vitro characterization of synthetic scaffolds in the laboratory commonly employs sterilization techniques, such as, ultraviolet light or ethanol (EtOH) soaking. These sterilization methods are not sufficient, however, to gain Regulatory approval for therapeutic use. Neglecting the effects medical grade sterilization may have on material properties could lead to years of research never translating to the clinic. The objective of this study was to ascertain whether medical grade gamma irradiation affected the properties of solvent-cast poly(ε-caprolactone)/poly(D, L-lactic acid) blend films for peripheral nerve repair. Scaffolds were sterilized at eight incremental doses of Gamma radiation (0-45 kGy). With increasing radiation dose, tensile testing identified significant reductions in both maximum tensile strength (>40 %) and strain (>90 %); gel permeation chromatography showed a dose-dependent reduction in polymer molecular weight (>46 %) and differential scanning calorimetry highlighted an increase in crystallinity. NG108-15 nerve cells were cultured up to 7 days on gamma irradiated and EtOH soaked films (control). Scanning electron microscopy showed cells proliferated on all films during this time and confirmed cell morphology was unaffected by sterilization method. However, cellular proliferation and number were greater for gamma irradiated films compared to EtOH soaked. Despite material properties being significantly altered, the in vitro response was encouraging and gamma irradiation may prove effective for medical grade sterilization of films intended for peripheral nerve repair.

Volatiles from apple trees infested with light brown apple moth larvae attract the parasitoid Dolichogenidia tasmanica.

The volatile compounds emitted from uninfested apple seedlings, cv. Royal Gala, and apple seedlings infested with generalist herbivore Epiphyas postvittana larvae were sampled using headspace collection and analyzed by gas chromatography-mass spectrometry. Nine additional compounds were only detected in infested apple seedlings [including benzyl alcohol, (E)-ß-ocimene, benzyl cyanide, indole, (E)-nerolidol, and four unidentified compounds]. Infested apple seedlings produced larger amounts of (Z)-3-hexenyl acetate, linalool, 4,8-dimethyl-1,3(E),7-nonatriene, methyl salicylate, ß-caryophyllene, germacrene D, (E,E)-α-farnesene, and (Z)-3-hexenyl benzoate than uninfested plants. Female parasitoids flew exclusively upwind to infested and not to uninfested apple seedlings in wind tunnel choice tests and preferred infested leaflets in still air, even after the removal of larvae. The attraction of a parasitoid to infested apple seedlings in the laboratory and in the field to apple and many other plants in at least six families supports considerable generality of the tritrophic signaling process.

Knowledge of Clostridium difficile infection among UK health-care workers: development of a knowledge assessment tool.

Doctors' knowledge provides the basis to support good practice in infection prevention and control. However, there exists a paucity of validated knowledge assessment tools that can be reliably employed to identify poor knowledge levels of Clostridium difficile infection (CDI) within populations of doctors, preventing the effective identification of knowledge deficiencies and focused targeting of educational interventions. Here, we describe a development process to validate a novel CDI knowledge assessment tool for doctors. Two previously published CDI knowledge questionnaires were amalgamated to produce a combined questionnaire. Content was further evaluated by a panel of CDI experts, producing the 'Lothian' questionnaire. These questionnaires were tested in control populations comprising either infection control nurse (ICN) specialists or non-clinically trained individuals, and a cohort of medical staff. We compared the efficacy of the 'Lothian' questionnaire against that of previous questionnaire reports. We found that all of the questionnaires studied significantly discriminated between non-clinical and clinical populations (ICNs and medical staff) (P < 0.001) and had similar levels of sensitivity and specificity in discrimination between these targeted populations. This study describes the development of a robust CDI knowledge assessment tool that can be used to evaluate knowledge levels among doctors, compare populations and assist the targeting of educational interventions and plot trends following such interventions.

P2Y1 receptor modulation of Ca2+-activated K+ currents in medium-sized neurons from neonatal rat striatal slices.

ATP signaling to neurons and glia in the nervous system occurs via activation of both P2Y and P2X receptors. Here, we investigated the effects of P2Y(1) receptor stimulation in developing striatal medium-sized neurons using patch-clamp recordings from acute brain slices of 7- and 28-day-old rats. Application of the selective P2Y(1) receptor agonist 2-(Methylthio) ADP trisodium salt (2-MeSADP; 250 nM) increased outward K(+) currents evoked by a ramp depolarization protocol in voltage-clamp recordings. This effect was observed in 59 out of 82 cells (72%) and was blocked completely by the P2Y(1) antagonist, 2'-deoxy-N(6)-methyl adenosine 3',5'-diphosphate. The averaged 2-MeSADP-sensitive conductance was fitted by the sum of a linear conductance and a Boltzmann relation, giving one-half activation voltage of -14.2 mV and an equivalent charge of 2.91. The 2MeSADP-mediated effect was sensitive to submillimolar concentrations of tetraethylammonium (TEA; 200 µM), to 200 nM iberiotoxin and to 100 nM apamin, suggesting the involvement of both big and small potassium (BK and SK, respectively) calcium-activated channels. In current-clamp experiments, 2-MeSADP decreased depolarization-evoked action potential (AP) firing in all 26 cells investigated, and this effect was reversed by TEA and by apamin but not by iberiotoxin. We conclude that the stimulation of P2Y(1) receptors in developing striatal neurons leads to activation of calcium-activated potassium channels [I(K(Ca))] of both BK and SK subtypes, the latter responsible for decreasing the frequency of AP firing in response to current injection. Therefore, P2Y(1) signaling leading to activation of I(K(Ca)) may be important in regulating the activity of medium-sized neurons in the striatum.

Patterning small-molecule biocapture surfaces: microcontact insertion printing vs. photolithography.

Chemical patterns prepared by self-assembly, combined with soft lithography or photolithography, are directly compared. Pattern fidelity can be controlled in both cases but patterning at the low densities necessary for small-molecule probe capture of large biomolecule targets is better accomplished using microcontact insertion printing (µCIP). Surfaces patterned by µCIP are used to capture biomolecule binding partners for the small molecules dopamine and biotin.

Mobile phone technology and hospitalized patients: a cross-sectional surveillance study of bacterial colonization, and patient opinions and behaviours.

Healthcare workers' mobile phones provide a reservoir of bacteria known to cause nosocomial infections. UK National Health Service restrictions on the utilization of mobile phones within hospitals have been relaxed; however, utilization of these devices by inpatients and the risk of cross-contamination are currently unknown. Here, we examine demographics and characteristics of mobile phone utilization by inpatients and phone surface microbial contamination. One hundred and two out of 145 (70.3%) inpatients who completed a questionnaire detailing their opinions and utilization of mobile phones, also provided their mobile phones for bacteriological analysis and comparative bacteriological swabs from their nasal cavities; 92.4% of patients support utilization of mobile phones by inpatients; indeed, 24.5% of patients stated that mobile phones were vital to their inpatient stay. Patients in younger age categories were more likely to possess a mobile phone both inside and outside hospital (p <0.01) but there was no gender association. Eighty-six out of 102 (84.3%) patients' mobile phone swabs were positive for microbial contamination. Twelve (11.8%) phones grew bacteria known to cause nosocomial infection. Seven (6.9%) phones and 32 (31.4%) nasal swabs demonstrated Staphylococcus aureus contamination. MSSA/MRSA contamination of phones was associated with concomitant nasal colonization. Patient utilization of mobile phones in the clinical setting is popular and common; however, we recommend that patients are educated by clear guidelines and advice on inpatient mobile phone etiquette, power charging safety, regular cleaning of phones and hand hygiene, and advised not to share phones or related equipment with other inpatients in order to prevent transmission of bacteria.

Functional heterogeneity of NMDA receptors in rat substantia nigra pars compacta and reticulata neurones.

The nigra substantia nigra pars compacta (SNc) and substantia pars reticulata (SNr) form two major basal ganglia components with different functional roles. SNc dopaminergic (DA) neurones are vulnerable to cell death in Parkinson's disease, and NMDA receptor activation is a potential contributing mechanism. We have investigated the sensitivity of whole-cell and synaptic NMDA responses to intracellular ATP and GTP application in the SNc and SNr from rats on postnatal day (P) 7 and P28. Both NMDA current density (pA/pF) and desensitization to prolonged or repeated NMDA application were greater in the SNr than in the SNc. When ATP levels were not supplemented, responses to prolonged NMDA administration desensitized in P7 SNc DA neurones but not at P28. At P28, SNr neurones desensitized more than SNc neurones, with or without added ATP. Responses to brief NMDA applications and synaptic NMDA currents were not sensitive to inclusion of ATP in the pipette solution. To investigate these differences between the SNc and SNr, NR2 subunit-selective antagonists were tested. NMDA currents were inhibited by ifenprodil (10 microM) and UBP141 (4 microM), but not by Zn(2+) (100 nm), in both the SNr and SNc, suggesting that SNc and SNr neurones express similar receptor subunits; NR2B and NR2D, but not NR2A. The different NMDA response properties in the SNc and SNr may be caused by differences in receptor modulation and/or trafficking. The vulnerability of SNc DA neurones to cell death is not correlated with NMDA current density or receptor subtypes, but could in part be related to inadequate NMDA receptor desensitization.

Clostridium difficile infection in general surgery patients; identification of high-risk populations.

BACKGROUND: Risk factors associated with Clostridium difficile infection (CDI) in general surgical patients are poorly characterised. This study aimed to characterise the incidence and associations of C. difficile positivity (CDP) in general surgical inpatients to aid in the design of future policies regarding focused screening and risk-stratification mechanisms in this patient subpopulation. MATERIALS AND METHODS: Discharge, laboratory and coding data from all general surgery inpatients admitted to a large tertiary referral general surgical unit, between March 2005 and May 2007, were examined. RESULTS: 21,371 patient records were interrogated. 101 (0.47%) CDP cases were identified from laboratory records and compared with non-CDP controls for age, gender, length of stay (LOS), admission to intensive care unit or high dependency unit (ICU/HDU), co-morbidities and surgical procedures. Univariate analysis identified a range of risk factors associated with positivity. Multivariate analysis identified malignancy, gastrointestinal disease, anaemia, respiratory disease, circulatory disease, diabetes mellitus, those undergoing gastrointestinal surgery and increasing age to be independently associated with CDP status. CONCLUSIONS: This study identifies incidence and risk factor associations of those who tested CDP in a large contemporary general surgery inpatient population. Focused screening programmes based on high-risk populations may provide information on further risk factors and allow risk-stratification. Further healthcare worker education regarding risk factors may reduce the clinical impact of CDI by encouraging increased vigilance and therefore earlier detection.