'Factors influencing future career choices of Queen's University Belfast Medical students.'

INTRODUCTION: Decisions made by medical students on future career choice have demonstrated concordance with subsequent postgraduate career path. This study aimed to understand the factors that impact undergraduate career decision making. METHODS: An anonymous voluntary survey consisting of binominal, Likert and free text responses was distributed to all medical students registered at Queen's University Belfast (QUB). Data was collected over 6 weeks in April-May 2021. The primary outcome was future career aspirations. The secondary outcomes were the impact of mentorship on career choice, the likelihood of students completing their medical degree and practicing medicine upon graduation. Local ethical approval was obtained. RESULTS: 202 responses were received (response rate 15%). 67% (n = 135) were female. One third of respondents remained undecided about their future career choice. Surgery was both the most popular definite career choice (16.3%) of respondents, butalsothespecialtymarkedmostoftenas'Least preferred Specialty' (33%). Factors positively influencing career choice were academic interest and flexibility in working hours. Negative predictors of career choice were lack of interest in the area, perceived workload, and duration of training schemes. 71% (n=144) of respondents reported that a subspecialty mentor would positively influence their career choice and two-thirds of respondents reported that financial factors would influence their career decision. 11% (n= 22) of respondents were unsure or undecided if they would continue medicine as a career upon graduation. CONCLUSION: Uncertainty over future career intention remains common with surgery the least popular speciality. Mentorship, integrating flexibility in training and enhancing academic interest should be considered by educational stakeholders as mechanisms to generating undergraduate interest in a subspecialty. Furthermore, the reported rate of students intention to leave their medical degree prior to graduation by this cohort is concerning, warranting further investigation.

Femtosecond pulse laser cleaning of spray paint from heritage stone surfaces.

We explore the use of femtosecond laser pulses to clean a variety of colors of spray paint from the Moruya granite, a stone with high heritage value that is widely used for monuments and sculptures in Sydney and New South Wales (Australia). The efficiency of the cleaning treatment and the effects on the stone substrate are evaluated using optical microscopy, optical profilometry, Raman spectroscopy, energy-dispersive X-ray spectroscopy, and colorimetry. We demonstrate that femtosecond laser cleans granite without damaging it and without discoloration when the laser fluence is set below the damage threshold of the stone.

The impact of COVID-19 on organ donation and transplantation in the UK: lessons learned from the first year of the pandemic.

The COVID-19 pandemic had a major impact on UK deceased organ donation and transplantation activity. We used national audit data from NHS Blood and Transplant to explore in detail the effects of the pandemic in comparison with 12 months pre-pandemic, and to consider the impact of the mitigating strategies and challenges placed on ICU by 'waves' of patients with COVID-19. Between 11 March 2020 and 10 March 2021, referrals to NHS Blood and Transplant of potential organ donors were initially inversely related to the number of people with COVID-19 undergoing mechanical ventilation in intensive care (incident rate ratio (95%CI) per 1000 patients 0.93 (0.88-0.99), p = 0.018), although this pattern reversed during the second wave (additional incident rate ratio (95%CI) 1.12 (1.05-1.19), p < 0.001). Adjusted numbers of donors (incident rate ratio (95%CI) 0.71 (0.61-0.81), p < 0.001) and organs retrieved (incident rate ratio (95%CI) 0.89 (0.82-0.97), p = 0.007) were inversely dependent on COVID-19 workload, though weekly numbers of transplants were unrelated (incident rate ratio (95%CI) 0.95 (0.86-1.04), p = 0.235). Non-COVID-19 mortality fell from 15,007 to 14,087 during the first wave (rate ratio (95%CI) 0.94 (0.92-0.96), p < 0.001) but climbed from 18,907 to 19,372 during the second wave (rate ratio (95%CI) 1.02 (1.00-1.05), p = 0.018). There were fewer in-hospital deaths from cardiac arrest and intracranial catastrophes throughout (rate ratio (95%CI) 0.83 (0.81-0.86), p < 0.001 and rate ratio (95%CI) 0.88 (0.85-0.91), p < 0.001, respectively). There were overall fewer eligible donors (n = 4282) when compared with pre-pandemic levels (n = 6038); OR (95%CI) 0.58 (0.51-0.66), p < 0.001. The total number of donations during the year fell from 1620 to 1140 (rate ratio (95%CI) 0.70 (0.65-0.76), p < 0.001), but the proportion of eligible donors who proceeded to donation (27%) was unchanged (OR (95%CI) 0.99 (0.91-1.08), p = 0.821). The reduction in donations and transplantation during the pandemic was multifactorial, but these data highlight the impact in the UK of a fall in eligible donors and an inverse relationship of referrals to COVID-19 workload. Despite the challenges faced, the foundations underpinning the UK deceased organ donation programme remained strong.

Contact chemoreception in multi-modal sensing of prey by Octopus.

Octopuses have keen vision and are generally considered visual predators, yet octopuses predominantly forage blindly in nature, inserting their arms into crevices to search and detect hidden prey. The extent to which octopuses discriminate prey using chemo- versus mechano-tactile sensing is unknown. We developed a whole-animal behavioral assay that takes advantage of octopuses' natural searching behavior to test their ability to discriminate prey from non-prey tastes solely via contact chemoreception. This methodology eliminated vision, mechano-tactile sensing and distance chemoreception while testing the contact chemosensory discriminatory abilities of the octopus arm suckers. Extracts from two types of prey (crab, shrimp) and three types of non-prey (sea star, algae, seawater) were embedded in agarose (to control for mechano-tactile discrimination) and presented to octopuses inside an artificial rock dome; octopuses reached their arms inside to explore its contents - imitating natural prey-searching behavior. Results revealed that octopuses are capable of discriminating between potential prey items using only contact chemoreception, as measured by an increased amount of sucker contact time and arm curls when presented with prey extracts versus non-prey extracts. These results highlight the importance of contact chemoreception in the multi-modal sensing involved in a complex foraging behavior.

The role of infiltrating lymphocytes in the neo-adjuvant treatment of women with HER2-positive breast cancer.

BACKGROUND: Pre-treatment tumour-associated lymphocytes (TILs) and stromal lymphocytes (SLs) are independent predictive markers of future pathological complete response (pCR) in HER2-positive breast cancer. Whilst studies have correlated baseline lymphocyte levels with subsequent pCR, few have studied the impact of neoadjuvant therapy on the immune environment. METHODS: We performed TIL analysis and T-cell analysis by IHC on the pretreatment and 'On-treatment' samples from patients recruited on the Phase-II TCHL (NCT01485926) clinical trial. Data were analysed using the Wilcoxon signed-rank test and the Spearman rank correlation. RESULTS: In our sample cohort (n = 66), patients who achieved a pCR at surgery, post-chemotherapy, had significantly higher counts of TILs (p = 0.05) but not SLs (p = 0.08) in their pre-treatment tumour samples. Patients who achieved a subsequent pCR after completing neo-adjuvant chemotherapy had significantly higher SLs (p = 9.09 × 10-3) but not TILs (p = 0.1) in their 'On-treatment' tumour biopsies. In a small cohort of samples (n = 16), infiltrating lymphocyte counts increased after 1 cycle of neo-adjuvant chemotherapy only in those tumours of patients who did not achieve a subsequent pCR. Finally, reduced CD3 + (p = 0.04, rho = 0.60) and CD4 + (p = 0.01, rho = 0.72) T-cell counts in 'On-treatment' biopsies were associated with decreased residual tumour content post-1 cycle of treatment; the latter being significantly associated with increased likelihood of subsequent pCR (p < 0.01). CONCLUSIONS: The immune system may be 'primed' prior to neoadjuvant treatment in those patients who subsequently achieve a pCR. In those patients who achieve a pCR, their immune response may return to baseline after only 1 cycle of treatment. However, in those who did not achieve a pCR, neo-adjuvant treatment may stimulate lymphocyte influx into the tumour.

Validation of the factors influencing family consent for organ donation in the UK.

Between 2013 and 2019, there was an increase in the consent rate for organ donation in the UK from 61% to 67%, but this remains lower than many European countries. Data on all family approaches (16,896) for donation in UK intensive care units or emergency departments between April 2014 and March 2019 were extracted from the referral records and the national potential donor audit held by NHS Blood and Transplant. Complete data were available for 15,465 approaches. Consent for donation after brain death was significantly higher than for donation after circulatory death, 70% (4260/6060) vs. 60% (5645/9405), (OR 1.58, 95%CI 1.47-1.69). Patient ethnicity, religious beliefs, sex and socio-economic status, and knowledge of a patient's donation decision were strongly associated with consent (p < 0.001). These factors should be addressed by medium- to long-term strategies to increase community interventions, encouraging family discussions regarding donation decisions and increasing registration on the organ donor register. The most readily modifiable factor was the involvement of an organ donation specialist nurse at all stages leading up to the approach and the approach itself. If no organ donation specialist nurse was present, the consent rates were significantly lower for donation after brain death (OR 0.31, 95%CI 0.23-0.42) and donation after cardiac death (OR 0.26, 95%CI 0.22-0.31) compared with if a collaborative approach was employed. Other modifiable factors that significantly improved consent rates included less than six relatives present during the formal approach; the time from intensive care unit admission to the approach (less for donation after brain death, more for donation after cardiac death); family not witnessing neurological death tests; and the relationship of the primary consenter to the patient. These modifiable factors should be taken into consideration when planning the best bespoke approach to an individual family to discuss the option of organ donation as an end-of-life care choice for the patient.

The rise of organ donation after circulatory death: a narrative review.

Solid organ transplantation saves and transforms lives. The original type of organ donation from deceased patients was controlled donation after circulatory death, previously referred to as non-heart beating organ donation. The rise of donation after circulatory death in the UK came about through advances in critical care and transplant medicine and support from several key organisations in developing a robust ethical, legal and professional framework. The transplant waiting list reached a historic peak in 2009-2010 of 8000 patients, but fell by 25% to 6000 in 2017-2018. There has also been a steady rise in the number of deceased donors and the number of donations after circulatory death. The contribution of donation after circulatory death to the total number of donations rose steadily between 2000 and 2012 and has remained about 40% since. Although the situation has improved for patients waiting for a transplant, deaths and long waits remain common. Changes to legislative, technical and peri-mortem procedures may greatly change future practices in donation after circulatory death in the UK.

The effect on consent rates for deceased organ donation in Wales after the introduction of an opt-out system.

Organ transplantation saves and transforms lives. Failure to secure consent for organ retrieval is widely regarded as the single most important obstacle to transplantation. A soft opt-out system of consent for deceased organ donation was introduced into Wales in December 2015, whilst England maintained the existing opt-in system. Cumulative data on consent rates in Wales were compared with those in England, using a two-sided sequential procedure that was powered to detect an absolute difference in consent rates between England and Wales of 10%. Supplementary risk-adjusted logistic regression analysis examined whether any difference in consent rates between the two nations could be attributed to variations in factors known to influence UK consent rates. Between 1 January 2016 and 31 December 2018, 8192 families of eligible donors in England and 474 in Wales were approached regarding organ donation, with overall consent rates of 65% and 68%, respectively. There was a steady upward trend in the proportion of families consenting to donation after brain death in Wales as compared with England and after 33 months, this reached statistical significance. No evidence of any change in the donation after circulatory death consent rate was observed. Risk-adjusted logistic regression analysis revealed that by the end of the study period the probability of consent to organ donation in Wales was higher than in England (OR [95%CI] 2.1 [1.26-3.41]). The introduction of a soft opt-out system of consent in Wales significantly increased organ donation consent though the impact was not immediate.

Expression of anaesthetic and analgesic drug target genes in excised breast tumour tissue: Association with clinical disease recurrence or metastasis.

BACKGROUND: Retrospective analyses suggest anaesthetic-analgesics technique during cancer surgery may affect recurrence/metastasis. This could involve direct effects of anaesthetic-analgesic drugs on cancer cells. While µ-opioid receptor over-expression in lung tumours is associated with greater metastasis, other anaesthetic-analgesic receptor targets in cancer recurrence/metastasis remain unexplored. Therefore, we evaluated the association between genetic expression of anaesthetic-analgesic receptor targets and recurrence/metastasis, using a repository of breast cancer gene expression and matching clinical data. METHODS: A list of 23 genes encoding for the most prominent anaesthetic-analgesic receptor targets was compiled. This was processed through BreastMark- an algorithm integrating gene expression data from ~17,000 samples and clinical data from >4,500 breast cancer samples. Gene expression data was dichotomized using disease-free survival (survival without recurrence) and distant disease-free survival (survival without metastasis) as end points. Hazard ratios were calculated by Cox-regression analysis. Enrichment for prognostic markers was determined by randomly choosing 23-member gene lists from all available genes, calculating how often >5 significant markers were observed and adjusting p-values for multiple testing. This was repeated 10,000 times and an empirical p-value calculated. RESULTS: Of 23 selected genes, 9 were significantly associated with altered rates of metastasis and 4 with recurrence on univariate analysis. Adjusting for multiple testing, 5 of these 9 genes remained significantly associated with metastasis, non with recurrence. This ratio of genes (5/23) was not significantly enriched for markers of metastasis (p = 0.07). CONCLUSION: Several anaesthetic-analgesic receptor genes were associated with metastatic spread in breast cancer. Overall there was no significant enrichment in prognostic markers of metastasis, although a trend was observed.

The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation.

BACKGROUND: Docetaxel based therapy is one of the first line chemotherapeutic agents for the treatment of metastatic castrate-resistant prostate cancer. However, one of the major obstacles in the treatment of these patients is docetaxel-resistance. Defining the mechanisms of resistance so as to inform subsequent treatment options and combinations represents a challenge for clinicians and scientists. Previous work by our group has shown complex changes in pro and anti-apoptotic proteins in the development of resistance to docetaxel. Targeting these changes individually does not significantly impact on the resistant phenotype but understanding the central signalling pathways and transcription factors (TFs) which control these could represent a more appropriate therapeutic targeting approach. METHODS: Using a number of docetaxel-resistant sublines of PC-3 cells, we have undertaken a transcriptomic analysis by expression microarray using the Affymetrix Human Gene 1.0 ST Array and in conjunction with bioinformatic analyses undertook to predict dysregulated TFs in docetaxel resistant prostate cancer. The clinical significance of this prediction was ascertained by performing immunohistochemical (IHC) analysis of an identified TF (SRF) in the metastatic sites from men who died of advanced CRPC. Investigation of the functional role of SRF was examined by manipulating SRF using SiRNA in a docetaxel-resistant PC-3 cell line model. RESULTS: The transcription factors identified include serum response factor (SRF), nuclear factor kappa-B (NFκB), heat shock factor protein 1 (HSF1), testicular receptor 2 & 4 (TR2 &4), vitamin-D and retinoid x receptor (VDR-RXR) and oestrogen-receptor 1 (ESR1), which are predicted to be responsible for the differential gene expression observed in docetaxel-resistance. IHC analysis to quantify nuclear expression of the identified TF SRF correlates with both survival from date of bone metastasis (p = 0.003), survival from androgen independence (p = 0.00002), and overall survival from prostate cancer (p = 0.0044). Functional knockdown of SRF by siRNA demonstrated a reversal of apoptotic resistance to docetaxel treatment in the docetaxel-resistant PC-3 cell line model. CONCLUSIONS: Our results suggest that SRF could aid in treatment stratification of prostate cancer, and may also represent a therapeutic target in the treatment of men afflicted with advanced prostate cancer.

Correction: Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein.

[This corrects the article DOI: 10.1371/journal.pone.0159449.].

Mid-infrared nonlinear optical response of Si-Ge waveguides with ultra-short optical pulses.

We characterize the nonlinear optical response of low loss Si(0.6)Ge(0.4) / Si waveguides in the mid-infrared between 3.3 µm and 4 µm using femtosecond optical pulses. We estimate the three and four-photon absorption coefficients as well as the Kerr nonlinear refractive index from the experimental measurements. The effect of multiphoton absorption on the optical nonlinear Kerr response is evaluated and the nonlinear figure of merit estimated providing some guidelines for designing nonlinear optical devices in the mid-IR. Finally, we compare the impact of free-carrier absorption at mid-infrared wavelengths versus near-infrared wavelengths for these ultra-short pulses.

Nonlinear optical response of low loss silicon germanium waveguides in the mid-infrared.

We have investigated the nonlinear optical response of low loss Si(0.6)Ge(0.4) / Si waveguides in the mid-infrared wavelength range from 3.25- 4.75µm using picosecond optical pulses. We observed and measured the three and four-photon absorption coefficients as well as the Kerr nonlinear refractive index. The dynamics of the spectral broadening suggests that, in addition to multiphoton absorption, the corresponding higher order nonlinear refractive phenomena also needs to be included when high optical pulse intensities are used at mid-infrared wavelengths in this material.

A randomized controlled trial of in-patient treatment for anorexia nervosa in medically unstable adolescents.

BACKGROUND: Anorexia nervosa (AN) is a serious disorder incurring high costs due to hospitalization. International treatments vary, with prolonged hospitalizations in Europe and shorter hospitalizations in the USA. Uncontrolled studies suggest that longer initial hospitalizations that normalize weight produce better outcomes and fewer admissions than shorter hospitalizations with lower discharge weights. This study aimed to compare the effectiveness of hospitalization for weight restoration (WR) to medical stabilization (MS) in adolescent AN. METHOD: We performed a randomized controlled trial (RCT) with 82 adolescents, aged 12-18 years, with a DSM-IV diagnosis of AN and medical instability, admitted to two pediatric units in Australia. Participants were randomized to shorter hospitalization for MS or longer hospitalization for WR to 90% expected body weight (EBW) for gender, age and height, both followed by 20 sessions of out-patient, manualized family-based treatment (FBT). RESULTS: The primary outcome was the number of hospital days, following initial admission, at the 12-month follow-up. Secondary outcomes were the total number of hospital days used up to 12 months and full remission, defined as healthy weight (>95% EBW) and a global Eating Disorder Examination (EDE) score within 1 standard deviation (s.d.) of published means. There was no significant difference between groups in hospital days following initial admission. There were significantly more total hospital days used and post-protocol FBT sessions in the WR group. There were no moderators of primary outcome but participants with higher eating psychopathology and compulsive features reported better clinical outcomes in the MS group. CONCLUSIONS: Outcomes are similar with hospitalizations for MS or WR when combined with FBT. Cost savings would result from combining shorter hospitalization with FBT.

Low loss coupling to sub-micron thick rib and nanowire waveguides by vertical tapering.

Highly nonlinear planar glass waveguides have been shown to be useful for all optical signal processing. However, the typical SMF-28 fiber to waveguide coupling loss of ~5dB/end remains a barrier to practical implementation. Low loss coupling to a fiber using vertical tapering of the waveguide film is analyzed for rib and nanowire waveguides and experimentally demonstrated for ribs showing polarization and wavelength independence over >300nm bandwidth. Tapers with essentially zero excess loss led to total losses from the waveguide to fiber core of 1.1dB per facet comprising only material absorption (0.75dB) and mode overlap loss (0.36dB), both of which can be eliminated with improvements to processing and materials.

ADAM-17: a novel therapeutic target for triple negative breast cancer.

BACKGROUND: Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR/HER family of receptors. PATIENTS AND METHODS: Expression of ADAM-17 was measured in 86 triple-negative and 96 non-triple-negative breast cancers. The ADAM-17 specific inhibitor, PF-5480090 (TMI-002, Pfizer) was tested in a panel of breast cancer cell lines for effects on functional outputs. RESULTS: In this study we show using both Western blotting and immunohistochemistry that ADAM-17 is expressed at significantly higher levels in TN than non-TN breast cancers. Using a panel of breast cancer cell lines in culture, PF-5480090 was found to decrease release of the EGFR ligand, TGF-alpha, decrease levels of phosphorylated EGFR and block cell proliferation in a cell-type-dependent manner. Potentially important was the finding of a significant and moderately strong correlation between ADAM-17 activity and extent of proliferation inhibition by PF-5480090 (r = 0.809; p = 0.003; n = 11). Pretreatment of cell lines with PF-5480090 enhanced response to several different cytotoxic and anti-EGFR/HER agents. CONCLUSION: It is concluded that inhibition of ADAM-17, especially in combination with chemotherapy or anti-EGFR/HER inhibitors, may be a new approach for treating breast cancer, including patients with TN disease.

An evaluation of statistical process control techniques applied to blood component quality monitoring with particular reference to CUSUM.

BACKGROUND: Statistical process control (SPC) is used to monitor the performance of blood component collection and production processes in the UK and elsewhere. The sensitivity of the applied technique(s) needs to be matched to the clinical importance of the parameter being monitored such that significant deviations in the process mean and/or variability of critical parameters (e.g. the leucocyte content of leucodepleted components) are detected and investigated immediately. AIMS: This study assessed the sensitivity and specificity of a range of techniques for variable and attribute (proportion non-conforming) data. MATERIALS AND METHODS: Comparison was based on a range of simulated and 'live' blood component quality monitoring data including X/R, cumulative sum (CUSUM) procedures, the scan statistic and np charts. RESULTS: X/R and CUSUM could detect shifts of two standard deviations in the process mean within 5 days. Current leucocyte count data (substantially skewed even after log transformation) was found to be better suited to attribute analysis. CUSUM alone was able to detect shifts on the same day when based on 20 or more samples and achieved acceptable specificity. CONCLUSIONS: CUSUM procedures for proportion non-conforming can usefully augment existing X/R techniques for leucodepletion monitoring, provide valid control limits and the required sensitivity. The scan statistic and 'np' charts offered no obvious advantages.

Transcriptional response to GAA deficiency (Pompe disease) in infantile-onset patients.

Pompe disease is a genetic disorder resulting from a deficiency of lysosomal acid alpha-glucosidase (GAA) that manifests as a clinical spectrum with regard to symptom severity and rate of progression. In this study, we used microarrays to examine gene expression from the muscle of two cohorts of infantile-onset Pompe patients to identify transcriptional differences that may contribute to the disease phenotype. We found strong similarities among the gene expression profiles generated from biceps and quadriceps, and identified a number of signaling pathways altered in both cohorts. We also found that infantile-onset Pompe patient muscle had a gene expression pattern characteristic of immature or regenerating muscle, and exhibited many transcriptional markers of inflammation, despite having few overt signs of inflammatory infiltrate. Further, we identified genes exhibiting correlation between expression at baseline and response to therapy. This combined dataset can serve as a foundation for biological discovery and biomarker development to improve the treatment of Pompe disease.

The suppression of star formation by powerful active galactic nuclei.

The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight correlation between the mass of the black hole and the mass of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming galaxies are usually dust-obscured and are brightest at infrared and submillimetre wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expelling the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.

Cavity enhanced stimulated Brillouin scattering in an optical chip for multiorder Stokes generation.

We report the first demonstration of on-chip cascaded stimulated Brillouin scattering (SBS). Cascaded SBS is characterized in a 4 cm long chalcogenide (As2S3) rib waveguide where the end facet reflections provide a monolithic Fabry-Perot (FP) resonator. The presence of the FP cavity reduces the Brillouin gain threshold, which enables observation of cascaded SBS at reduced pump powers. We observe up to three orders of Stokes waves in the backscattered signal at a coupled peak power of 1.34 W. Anti-Stokes waves due to four-wave mixing between the pump and the Stokes wave were observed in the forward spectrum.