Graphs Identified by Logics with Counting

We classify graphs and, more generally, finite relational structures that are identified by C2, that is, two-variable first-order logic with counting. Using this classification, we show that it can be decided in almost linear time whether a structure is identified by C2. Our classification implies that for every graph identified by this logic, all vertex-colored versions of it are also identified. A similar statement is true for finite relational structures. We provide constructions that solve the inversion problem for finite structures in linear time. This problem has previously been shown to be polynomial time solvable by Martin Otto. For graphs, we conclude that every C2-equivalence class contains a graph whose orbits are exactly the classes of the C2-partition of its vertex set and which has a single automorphism witnessing this fact. For general k, we show that such statements are not true by providing examples of graphs of size linear in k which are identified by C3 but for which the orbit partition is strictly finer than the Ck-partition. We also provide identified graphs which have vertex-colored versions that are not identified by Ck.Comment: 33 pages, 8 Figure

“…the point is to change it”: Critical realism and human geography

This paper picks up themes discussed in Cox’s (2013) ‘Notes on a brief encounter: critical realism, historical materialism and human geography’. I argue that perhaps the encounter was more complex than Cox allows. At core Cox underplays, or marginalises, the discussion of causality and dismisses the significance of ontology stressing instead epistemology. The paper makes a case for another reading of the debate, one that has continuing significance

Comparison of spontaneous with controlled mode of ventilation in tonsillectomy

Methods: This randomized study compares spontaneous versus controlled ventilation in 60 ASA I and II patients undergoing tonsillectomy as regards haemodynamic stability, recovery characteristics, intra- and immediate postoperative complications and surgical impressions.Results: The patients in the balanced anaesthesia (B) group showed less haemodynamic variability compared to baseline after tracheal intubation, mouth gag application and removal and incision. Two patients had dysrhythmias in the B group compared to six in the spontaneous breathing (S) group. Six patients in the S group had a rise in endtidal carbon dioxide concentration above 7.8 kPa (60 mmHg). Recovery scores were higher in the B group at 10 and 20 min into recovery. The surgical impression of bleeding and jaw relaxation was similar with both groups. The incidence of postoperative nausea and vomiting and agitation was higher in the S group but did not achieve statistical significance.CONCLUSION: Use of balanced anaesthesia offered more haemodynamic stability and a rapid recovery

Generating real-world evidence on the quality use, benefits and safety of medicines in australia: History, challenges and a roadmap for the future

Australia spends more than $20 billion annually on medicines, delivering significant health benefits for the population. However, inappropriate prescribing and medicine use also result in harm to individuals and populations, and waste of precious health resources. Medication data linked with other routine collections enable evidence generation in pharmacoepidemiology; the science of quantifying the use, effectiveness and safety of medicines in real-world clinical practice. This review details the history of medicines policy and data access in Australia, the strengths of existing data sources, and the infrastructure and governance enabling and impeding evidence generation in the field. Currently, substantial gaps persist with respect to cohesive, contemporary linked data sources supporting quality use of medicines, effectiveness and safety research; exemplified by Aus-tralia’s limited capacity to contribute to the global effort in real-world studies of vaccine and dis-ease-modifying treatments for COVID-19. We propose a roadmap to bolster the discipline, and population health more broadly, underpinned by a distinct capability governing and streamlining access to linked data assets for accredited researchers. Robust real-world evidence generation requires current data roadblocks to be remedied as a matter of urgency to deliver efficient and equitable health care and improve the health and well-being of all Australians

Generating Real-World Evidence on the Quality Use, Benefits and Safety of Medicines in Australia: History, Challenges and a Roadmap for the Future.

Australia spends more than $20 billion annually on medicines, delivering significant health benefits for the population. However, inappropriate prescribing and medicine use also result in harm to individuals and populations, and waste of precious health resources. Medication data linked with other routine collections enable evidence generation in pharmacoepidemiology; the science of quantifying the use, effectiveness and safety of medicines in real-world clinical practice. This review details the history of medicines policy and data access in Australia, the strengths of existing data sources, and the infrastructure and governance enabling and impeding evidence generation in the field. Currently, substantial gaps persist with respect to cohesive, contemporary linked data sources supporting quality use of medicines, effectiveness and safety research; exemplified by Australia's limited capacity to contribute to the global effort in real-world studies of vaccine and disease-modifying treatments for COVID-19. We propose a roadmap to bolster the discipline, and population health more broadly, underpinned by a distinct capability governing and streamlining access to linked data assets for accredited researchers. Robust real-world evidence generation requires current data roadblocks to be remedied as a matter of urgency to deliver efficient and equitable health care and improve the health and well-being of all Australians

NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models

INTRODUCTION:Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the post-translational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. HSP90 has emerged in recent years as a promising new target for anticancer therapies.METHODS:The concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50% (GI50 values) were established in a panel of breast cancer cell lines and patient-derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect, and dose regimen were established in a BT-474 breast cancer xenograft model. The effect on HSP90-p23 complexes, client protein degradation, and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis, and immunoprecipitation.RESULTS:We show that the novel small molecule HSP90 inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion � hallmarks of HSP90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels.CONCLUSION:NVP-AUY922 is a potent small molecule HSP90 inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, the compound recently has entered clinical phase I breast cancer trials

Alternating hemiplegia of childhood: evolution over time and mouse model corroboration

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder caused by ATP1A3 mutations. Some evidence for disease progression exists, but there are few systematic analyses. Here, we evaluate alternating hemiplegia of childhood progression in humans and in the D801N knock-in alternating hemiplegia of childhood mouse, Mashlool, model. This study performed an ambidirectional (prospective and retrospective data) analysis of an alternating hemiplegia of childhood patient cohort (n = 42, age 10.24 ± 1.48 years) seen at one US centre. To investigate potential disease progression, we used linear mixed effects models incorporating early and subsequent visits, and Wilcoxon Signed Rank test comparing first and last visits. Potential early-life clinical predictors were determined via multivariable regression. We also compared EEG background at first encounter and at last follow-up. We then performed a retrospective confirmation study on a multicentre cohort of alternating hemiplegia of childhood patients from France (n = 52). To investigate disease progression in the Mashlool mouse, we performed behavioural testing on a cohort of Mashlool- mice at prepubescent and adult ages (n = 11). Results: US patients, over time, demonstrated mild worsening of non-paroxysmal disability index scores, but not of paroxysmal disability index scores. Increasing age was a predictor of worse scores: P < 0.0001 for the non-paroxysmal disability index, intellectual disability scale and gross motor scores. Earliest non-paroxysmal disability index score was a predictor of last visit non-paroxysmal disability index score (P = 0.022), and earliest intellectual disability score was a predictor of last intellectual disability score (P = 0.035). More patients with EEG background slowing were noted at last follow-up as compared to initial (P = 0.015). Similar worsening of disease with age was also noted in the French cohort: age was a significant predictor of non-paroxysmal disability index score (P = 0.001) and first and last non-paroxysmal disability index score scores significantly differed (P = 0.002). In animal studies, adult Mashlool mice had, as compared to younger Mashlool mice, (i) worse balance beam performance; (ii) wider base of support; (iii) higher severity of seizures and resultant mortality; and (iv) no increased predisposition to hemiplegic or dystonic spells. In conclusion, (i) non-paroxysmal alternating hemiplegia of childhood manifestations show, on average over time, progression associated with severity of early-life non-paroxysmal disability and age. (ii) Progression also occurs in Mashlool mice, confirming that ATP1A3 disease can lead to age-related worsening. (iii) Clinical findings provide a basis for counselling patients and for designing therapeutic trials. Animal findings confirm a mouse model for investigation of underlying mechanisms of disease progression, and are also consistent with known mechanisms of ATP1A3-related neurodegeneration

Multi-photon ionisation spectroscopy for rotational state preparation of N+2

In this paper we investigate the 2 + 1′ resonance enhanced multi-photon ionisation (REMPI) of molecular nitrogen via the a1Πg(v = 6) intermediate state and analyse its feasibility to generate molecular nitrogen ions in a well defined ro-vibrational state. This is an important tool for high precision experiments based on trapped molecular ions, and is crucial for studying the time variation of the fundamental constant mp/me using N+2. The transition is not reported in the literature and detailed spectral analysis has been conducted to extract the molecular constants of the intermediate state. By carefully choosing the intermediate ro-vibrational state, the ionisation laser wavelength and controlling the excitation laser pulse energy, unwanted formation of rotationally excited molecular ions can be suppressed and ro-vibrational ground state ions can be generated with high purity

How victim age affects the context and timing of child sexual abuse: applying the routine activities approach to the first sexual abuse incident

The aim of this study was to examine from the routine activities approach how victim age might help to explain the timing, context and nature of offenders’ first known contact sexual abuse incident. One-hundred adult male child sexual abusers (M = 45.8 years, SD = 12.2; range = 20–84) were surveyed about the first time they had sexual contact with a child. Afternoon and early evening (between 3 pm and 9 pm) was the most common time in which sexual contact first occurred. Most incidents occurred in a home. Two-thirds of incidents occurred when another person was in close proximity, usually elsewhere in the home. Older victims were more likely to be sexually abused by someone outside their families and in the later hours of the day compared to younger victims. Proximity of another person (adult and/or child) appeared to have little effect on offenders’ decisions to abuse, although it had some impact on the level of intrusion and duration of these incidents. Overall, the findings lend support to the application of the routine activities approach for considering how contextual risk factors (i.e., the timing and relationship context) change as children age, and raise questions about how to best conceptualize guardianship in the context of child sexual abuse. These factors should be key considerations when devising and implementing sexual abuse prevention strategies and for informing theory development

The EpsE Flagellar Clutch Is Bifunctional and Synergizes with EPS Biosynthesis to Promote Bacillus subtilis Biofilm Formation

Many bacteria inhibit motility concomitant with the synthesis of an extracellular polysaccharide matrix and the formation of biofilm aggregates. In Bacillus subtilis biofilms, motility is inhibited by EpsE, which acts as a clutch on the flagella rotor to inhibit motility, and which is encoded within the 15 gene eps operon required for EPS production. EpsE shows sequence similarity to the glycosyltransferase family of enzymes, and we demonstrate that the conserved active site motif is required for EPS biosynthesis. We also screen for residues specifically required for either clutch or enzymatic activity and demonstrate that the two functions are genetically separable. Finally, we show that, whereas EPS synthesis activity is dominant for biofilm formation, both functions of EpsE synergize to stabilize cell aggregates and relieve selective pressure to abolish motility by genetic mutation. Thus, the transition from motility to biofilm formation may be governed by a single bifunctional enzyme