Like Frying Multiple Eggs in One Pan: a Qualitative Study Exploring the Understanding of Inter-speciality Training in Cancer Care.

H igh-quality cancer care is a key priority worldwide. Caring for people affected by cancer requires a range of specific knowledge, skills and experience to deliver the complex care regimens both within the hospital and within the community environment. In June 2022, the European Cancer Organisation along with 33 European cancer societies began working together to develop a curriculum for inter-speciality training for healthcare professionals across Europe. As part of the project, this research consisted of a qualitative survey distributed to the European Union societies via email. The aim of this paper is to disseminate the qualitative findings from healthcare professionals across Europe. Questionnaires were sent out to a convenience sample of 219 healthcare professionals and patient advocates with a response rate of 55% (n = 115). The findings identified that there were four key themes: 'What is inter-speciality training?', 'Barriers and challenges', 'Support throughout the cancer journey' and 'New ways of working'. These results are part of a larger needs analysis and scoping review to inform the development of a core competency framework which will be part of an inter-speciality curriculum for specialist cancer doctors, nurses and other healthcare professionals across Europe. Healthcare professionals will be able to access education and training through the virtual learning environment and workshops and by clinical rotations to other specialties.

Neural correlates of perceptual switching while listening to bistable auditory streaming stimuli.

Understanding the neural underpinning of conscious perception remains one of the primary challenges of cognitive neuroscience. Theories based mostly on studies of the visual system differ according to whether the neural activity giving rise to conscious perception occurs in modality-specific sensory cortex or in associative areas, such as the frontal and parietal cortices. Here, we search for modality-specific conscious processing in the auditory cortex using a bistable stream segregation paradigm that presents a constant stimulus without the confounding influence of physical changes to sound properties. ABA_ triplets (i.e., alternating low, A, and high, B, tones, and _ gap) with a 700 ms silent response period after every third triplet were presented repeatedly, and human participants reported nearly equivalent proportions of 1- and 2-stream percepts. The pattern of behavioral responses was consistent with previous studies of visual and auditory bistable perception. The intermittent response paradigm has the benefit of evoking spontaneous perceptual switches that can be attributed to a well-defined stimulus event, enabling precise identification of the timing of perception-related neural events with event-related potentials (ERPs). Significantly more negative ERPs were observed for 2-streams compared to 1-stream, and for switches compared to non-switches during the sustained potential (500-1000 ms post-stimulus onset). Further analyses revealed that the negativity associated with switching was independent of switch direction, suggesting that spontaneous changes in perception have a unique neural signature separate from the observation that 2-stream percepts evoke more negative ERPs than 1-stream. Source analysis of the sustained potential showed activity associated with these differences originating in anterior superior temporal gyrus, indicating involvement of the ventral auditory pathway that is important for processing auditory objects.

Efficient, ultra-high-affinity chromatography in a one-step purification of complex proteins.

Protein purification is an essential primary step in numerous biological studies. It is particularly significant for the rapidly emerging high-throughput fields, such as proteomics, interactomics, and drug discovery. Moreover, purifications for structural and industrial applications should meet the requirement of high yield, high purity, and high activity (HHH). It is, therefore, highly desirable to have an efficient purification system with a potential to meet the HHH benchmark in a single step. Here, we report a chromatographic technology based on the ultra-high-affinity (Kd ∼ 10-14-10-17 M) complex between the Colicin E7 DNase (CE7) and its inhibitor, Immunity protein 7 (Im7). For this application, we mutated CE7 to create a CL7 tag, which retained the full binding affinity to Im7 but was inactivated as a DNase. To achieve high capacity, we developed a protocol for a large-scale production and highly specific immobilization of Im7 to a solid support. We demonstrated its utility with one-step HHH purification of a wide range of traditionally challenging biological molecules, including eukaryotic, membrane, toxic, and multisubunit DNA/RNA-binding proteins. The system is simple, reusable, and also applicable to pulldown and kinetic activity/binding assays.

Effect of Treatment With Tabalumab, a B Cell-Activating Factor Inhibitor, on Highly Sensitized Patients With End-Stage Renal Disease Awaiting Transplantation.

B cell-activation factor (BAFF) is critical for B cell maturation. Inhibition of BAFF represents an appealing target for desensitization of sensitized end-stage renal disease (ESRD) patients. We conducted a Phase 2a, single-arm, open-label exploratory study investigating the effect of tabalumab (BAFF inhibitor) in patients with ESRD and calculated panel reactive antibodies (cPRAs) >50%. The treatment period duration was 24 weeks. Eighteen patients received tabalumab, at doses of 240-mg subcutaneous (SC) at Week 0 followed by 120-mg SC monthly for 5 additional months. Patients were followed for an additional 52 weeks. Immunopharmacologic effects were characterized through analysis of blood for HLA antibodies, BAFF concentrations, immunoglobulins, T and B cell subsets, as well as pre- and posttreatment tonsil and bone marrow biopsies. Significant reductions in cPRAs were observed at Weeks 16 (p = 0.043) and 36 (p = 0.004); however, absolute reductions were small (<5%). Expected pharmacologic changes in B cell subsets and immunoglobulin reductions were observed. Two tabalumab-related serious adverse events occurred (pneumonia, worsening of peripheral neuropathy), while the most common other adverse events were injection-site pain and hypotension. Three patients received matched deceased donor transplants during follow-up. Treatment with a BAFF inhibitor resulted in statistically significant, but not clinically meaningful reduction in the cPRA from baseline (NCT01200290, Clinicaltrials.gov).

Rates of gyrase supercoiling and transcription elongation control supercoil density in a bacterial chromosome.

Gyrase catalyzes negative supercoiling of DNA in an ATP-dependent reaction that helps condense bacterial chromosomes into a compact interwound "nucleoid." The supercoil density (σ) of prokaryotic DNA occurs in two forms. Diffusible supercoil density (σ(D)) moves freely around the chromosome in 10 kb domains, and constrained supercoil density (σ(C)) results from binding abundant proteins that bend, loop, or unwind DNA at many sites. Diffusible and constrained supercoils contribute roughly equally to the total in vivo negative supercoil density of WT cells, so σ = σ(C)+σ(D). Unexpectedly, Escherichia coli chromosomes have a 15% higher level of σ compared to Salmonella enterica. To decipher critical mechanisms that can change diffusible supercoil density of chromosomes, we analyzed strains of Salmonella using a 9 kb "supercoil sensor" inserted at ten positions around the genome. The sensor contains a complete Lac operon flanked by directly repeated resolvase binding sites, and the sensor can monitor both supercoil density and transcription elongation rates in WT and mutant strains. RNA transcription caused (-) supercoiling to increase upstream and decrease downstream of highly expressed genes. Excess upstream supercoiling was relaxed by Topo I, and gyrase replenished downstream supercoil losses to maintain an equilibrium state. Strains with TS gyrase mutations growing at permissive temperature exhibited significant supercoil losses varying from 30% of WT levels to a total loss of σ(D) at most chromosome locations. Supercoil losses were influenced by transcription because addition of rifampicin (Rif) caused supercoil density to rebound throughout the chromosome. Gyrase mutants that caused dramatic supercoil losses also reduced the transcription elongation rates throughout the genome. The observed link between RNA polymerase elongation speed and gyrase turnover suggests that bacteria with fast growth rates may generate higher supercoil densities than slow growing species.

Prophylactic cosyntropin after unintentional dural puncture and incidence of post-dural puncture headache and epidural blood patch use: A retrospective cohort study (2019-2022).

BACKGROUND: Cosyntropin has been suggested to decrease the incidence of post-dural puncture headache (PDPH) by increasing the production of cerebrospinal fluid. This study examined the association of prophylactic cosyntropin administration with the incidence of PDPH and its management with an epidural blood patch after an unintentional dural puncture (UDP). METHODS: We conducted a retrospective cohort study of cases with UDP during placement of neuraxial labor analgesia. Per institutional practice and at the discretion of the anesthesiologist, intravenous cosyntropin 1 mg may be administered for PDPH prophylaxis. PDPH, time from UDP to cosyntropin administration, time to development of PDPH, and management with epidural blood patch(es) were recorded. RESULTS: Cosyntropin was administered in 164 of 234 (70%) cases with UDP. PDPH occurred 98/164 (60%) with cosyntropin and 45/70 (64%) without cosyntropin (p = 0.66). The PDPH adjusted incidence was 53% with cosyntropin and 62% without cosyntropin, difference 9% (95% CI -6% to 24%, p = 0.25). The adjusted epidural blood patch rate was 66% with cosyntropin and 78% without cosyntropin, difference of 12% (95% CI -5% to 28%, p = 0.17). CONCLUSIONS: Prophylactic cosyntropin following UDP was not associated with a significant decrease in PDPH rate or use of epidural blood patch for management of PDPH. There was no significant difference in the rate of adverse hyperglycemic or hypertensive events amongst those who did or did not receive cosyntropin.

Twenty Years of Collaboration to Sort out Phage Mu Replication and Its Dependence on the Mu Central Gyrase Binding Site.

For 20 years, the intricacies in bacteriophage Mu replication and its regulation were elucidated in collaboration between Ariane Toussaint and her co-workers in the Laboratory of Genetics at the Université Libre de Bruxelles, and the groups of Martin Pato and N. Patrick Higgins in the US. Here, to honor Martin Pato's scientific passion and rigor, we tell the history of this long-term sharing of results, ideas and experiments between the three groups, and Martin's final discovery of a very unexpected step in the initiation of Mu replication, the joining of Mu DNA ends separated by 38 kB with the assistance of the host DNA gyrase.

DNA topology of highly transcribed operons in Salmonella enterica serovar Typhimurium.

Bacteria differ from eukaryotes by having the enzyme DNA gyrase, which catalyses the ATP-dependent negative supercoiling of DNA. Negative supercoils are essential for condensing chromosomes into an interwound (plectonemic) and branched structure known as the nucleoid. Topo-1 removes excess supercoiling in an ATP-independent reaction and works with gyrase to establish a topological equilibrium where supercoils move within 10 kb domains bounded by stochastic barriers along the sequence. However, transcription changes the stochastic pattern by generating supercoil diffusion barriers near the sites of gene expression. Using supercoil-dependent Tn3 and γδ resolution assays, we studied DNA topology upstream, downstream and across highly transcribed operons. Whenever two Res sites flanked efficiently transcribed genes, resolution was inhibited and the loss in recombination efficiency was proportional to transcription level. Ribosomal RNA operons have the highest transcription rates, and resolution assays at the rrnG and rrnH operons showed inhibitory levels 40-100 times those measured in low-transcription zones. Yet, immediately upstream and downstream of RNA polymerase (RNAP) initiation and termination sites, supercoiling characteristics were similar to poorly transcribed zones. We present a model that explains why RNAP blocks plectonemic supercoil movement in the transcribed track and suggests how gyrase and TopA control upstream and downstream transcription-driven supercoiling.

An evaluation of a video magnification-based system for respiratory rate monitoring in an acute mental health setting.

CONTEXT: One of the most important goals of inpatient psychiatric care is to provide a safe and therapeutic environment for both patients and staff. A small number of aggressive or agitated patients are difficult to sedate, even after multiple doses of sedating antipsychotics. Adverse effects can result in harm to the patient and staff and that observations are conducted without touching the patient. AIM: This study aims to determine if motion magnification can improve the feasibility of non-contact respirations monitoring over a video feed. METHODS: Registered nurses were invited to view seven pairs of pre-recorded footage of healthy volunteers and count the number of breaths that they observe over a period of one minute for each. One of the paired videos was unprocessed and the other magnified the motion of chest rise and fall. RESULTS: Nursing observation of respirations showed an improvement in reduction of count error from 15.7 % to 1.5 % after video magnification of respiratory movement. Nurses also stated that viewing the processed video was much easier to make their observations from. CONCLUSION: It is possible to use magnified video to monitor respirations of patients during circumstances where it is potentially difficult to obtain. Further observational studies should be conducted on a larger scale with this type of technique and is urgently needed to inform practice.

Successful implementation of a national HLA-B*5701 genetic testing service in Canada.

Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) that is used in combination antiretroviral therapy in HIV-infected patients. It is currently recommended as a preferred or an alternative NRTI in antiretroviral-naïve patients. The major toxicity of abacavir is a hypersensitivity reaction (HSR), which occurs in approximately 5% of treated patients. There is a strong association between the human leukocyte antigen (HLA)-B*5701 allele and abacavir HSR, which has allowed for rapid acceptance of genetic screening for HLA-B*5701 in clinical use. Canadian clinicians working in hospital centers with HLA typing capacity opted to launch a pilot project in 2006 to offer the screening test as standard of care to HIV-infected patients. Currently, more than 11,000 HLA-B*5701 tests have been performed, among which 6.3% are positive. Continued efforts have been made to ensure that testing is available to all HIV-infected patients to widen the patients' therapeutic options. HLA-B*5701 screening shows clinical use and preliminary data suggest cost-effectiveness.

High flow extra-cranial to intra-cranial bypass for complex internal carotid aneurysms.

Cerebral revascularisation with extracranial - intracranial (EC-IC) bypass is generally indicated in patients with complex anterior circulation aneurysms who have failed parent artery occlusion. We report on the process and outcome of our early experience of performing high flow bypass in patients with complex anterior circulation aneurysms. We have reviewed patients who have undergone an EC-IC bypass for treatment of complex anterior circulation aneurysms, and report our outcome on graft patency, surgical complications, discharge destination, and obliteration rates. Nine patients that underwent 11 bypasses are described. Seven patients had a giant saccular aneurysm of the carotid, and these were all obliterated on post-operative imaging. Two patients presenting with an intracranial carotid dissection required trapping of the diseased segment following the bypass. The overall graft patency rate was 88%. One patient developed a post operative subdural collection (managed conservatively), and one patient required early graft revision. Discharge destination was home in 8/9 patients. There was no mortality. Although EC-IC bypass is a technically challenging procedure, it provides a valuable treatment option for patients with complex anterior circulation aneurysms. Good graft patency rates can be achieved with low surgical morbidity in patients with a disease process that otherwise attracts a highly unfavourable natural history.

Anaesthetic management of emergency caesarean section with isolated cortical vein thrombosis and subacute intracerebral haemorrhage.

We report the case of an emergency caesarean section 5 days following the onset of a right-sided hemiparesis due to an intracerebral haemorrhage. Computerised tomography imaging in the postoperative period revealed an isolated cortical vein thrombosis as the likely cause. The caesarean section was conducted under general anaesthesia following consideration of the risks and benefits and discussion of these with the patient. No peri-operative complications occurred and neuro-rehabilitation was commenced as an inpatient. This case highlights the importance of maintaining a targeted systolic blood pressure whilst avoiding increased intracranial pressure in the obstetric patient with an intracerebral haemorrhage, and that the mode and conduct of anaesthesia can have a profound impact on these measurements. To our knowledge, this is the first reported case of a patient having an emergency caesarean section after subacute intracerebral haemorrhage caused by an isolated cortical vein thrombosis and it demonstrates that general anaesthesia can be used safely in this context. In this complex obstetric case, the role of multidisciplinary team collaboration in the peri-operative period was essential to optimising the patient's outcome.

Estrogen receptor-beta mRNA is associated with adverse outcome in patients with breast cancer.

BACKGROUND/AIMS: Estrogen receptor (ER) is the prototype therapy predictive marker in oncology. The ER is now known to exist in two main forms with similar overall structure: ER-alpha and ER-beta. Both forms may be expressed in breast cancer. The aim of this study was to examine breast cancer outcome in relation to expression of ER-beta. METHODS: In this investigation, we measured the expression of ER-alpha protein and ER-beta mRNA in 121 extracts of invasive breast cancer. Association of expression with clinical outcome was examined using Kaplan-Meier and Cox regression analyses. RESULTS: While ER-alpha expression was associated with good patient outcome [hazard ratio (HR) for death from breast cancer 0.37; 95% confidence interval (CI) 0.17-0.84; p = 0.017], ER-beta predicted poor outcome (HR for death from breast cancer 2.49; 95% CI 1.10-5.63; p = 0.028). CONCLUSION: Based on these findings, we conclude that ER-beta may have a different biological role from that of ER-alpha in breast cancer.

Pandemic H1N1 influenza surveillance in Victoria, Australia, April - September, 2009.

Victoria was the first Australian state to report widespread transmission of pandemic H1N1 2009 influenza. Notifiable laboratory-confirmed influenza and a general practitioner sentinel surveillance system measuring influenza-like illness (ILI), including laboratory confirmation of influenza as the cause of ILI, were used to assess the pandemic. The pandemic influenza A(H1N1)v virus quickly became the dominant circulating strain and notification rates were highest in children and young adults. Despite a high number of notified cases, comparison of ILI rates suggested the season peaked in late June, was similar in magnitude to 2003 and 2007 and less severe than 1997. The majority of clinical presentations were mild, but one quarter of hospitalised cases required admission to intensive care. Given the low proportion of imported cases in the Victorian pandemic, the rapid increase in cases with no travel history and the low median age of cases notified during the phases of intense surveillance, we suggest there may have been silent importations of pandemic virus into Victoria before the first case was recognised. The usefulness of a general practitioner sentinel surveillance system to provide a comparable assessment of influenza and ILI activity over time was clearly demonstrated, and the need for similar hospital and mortality surveillance systems for influenza in Victoria was highlighted.

Acute colonic obstruction due to benign prostatic hypertrophy.

A seventy two year old man presented to the Emergency Department with clinical features of colonic obstruction. Subsequent radiological investigations confirmed this impression and revealed the aetiology to be compression of the sigmoid colon against the sacrum by a massively distended urinary bladder. Chronic urinary retention due to benign prostatic hypertrophy is an extremely unusual cause of large bowel obstruction. Little in this patient's clinical findings suggested this aetiology. We reviewed the literature in this area and highlight the benefits of CT scanning over contrast studies.

Death and transfiguration among bacteria.

When bacteria are placed in sub-optimal environments, they can respond by increasing the frequency of mutants created by base substitution, frame-shift and transposition mutations. Also, during periods of restrictive growth, 'dead' bacterial cells may transfer genetic material to neighboring colony-forming cells. This can be beneficial, resulting in a heterogeneous population that may exhibit differentiation and even produce killer cells. These discoveries reveal several conundrums about the control of an organism over mutations and the supposed randomness of genetic variation.

Supercoil Levels in E. coli and Salmonella Chromosomes Are Regulated by the C-Terminal 35⁻38 Amino Acids of GyrA.

Prokaryotes have an essential gene-gyrase-that catalyzes negative supercoiling of plasmid and chromosomal DNA. Negative supercoils influence DNA replication, transcription, homologous recombination, site-specific recombination, genetic transposition and sister chromosome segregation. Although E. coli and Salmonella Typhimurium are close relatives with a conserved set of essential genes, E. coli DNA has a supercoil density 15% higher than Salmonella, and E. coli cannot grow at the supercoil density maintained by wild type (WT) Salmonella. E. coli is addicted to high supercoiling levels for efficient chromosomal folding. In vitro experiments were performed with four gyrase isoforms of the tetrameric enzyme (GyrA2:GyrB2). E. coli gyrase was more processive and faster than the Salmonella enzyme, but Salmonella strains with chromosomal swaps of E. coli GyrA lost 40% of the chromosomal supercoil density. Reciprocal experiments in E. coli showed chromosomal dysfunction for strains harboring Salmonella GyrA. One GyrA segment responsible for dis-regulation was uncovered by constructing and testing GyrA chimeras in vivo. The six pinwheel elements and the C-terminal 35⁻38 acidic residues of GyrA controlled WT chromosome-wide supercoiling density in both species. A model of enzyme processivity modulated by competition between DNA and the GyrA acidic tail for access to ß-pinwheel elements is presented.