Depth-resolved water temperature measurements using Raman LiDAR.

We present the retrieval of depth-resolved temperature measurements in water using Raman LiDAR. Using a 5 m pipe of laboratory water, we recover non-homogeneous temperature profiles with a temperature accuracy ranging between 0.35°C and 0.85°C, and a position resolution of 28 cm.

Effectiveness of an online module: climate-change and sustainability in clinical practice.

BACKGROUND: Climate change has significant implications for health, yet healthcare provision itself contributes significant greenhouse gas emission. Medical students need to be prepared to address impacts of the changing environment and fulfil a key role in climate mitigation. Here we evaluate the effectiveness of an online module on climate-change and sustainability in clinical practice designed to achieve learning objectives adapted from previously established sustainable healthcare priority learning outcomes. METHODS: A multi-media, online module was developed, and 3rd and 4th year medical students at Brighton and Sussex Medical School were invited to enrol. Students completed pre- and post-module questionnaires consisting of Likert scale and white space answer questions. Quantitative and qualitative analysis of responses was performed. RESULTS: Forty students enrolled and 33 students completed the module (83% completion rate). There was a significant increase in reported understanding of key concepts related to climate change and sustainability in clinical practice (p < 0.001), with proportion of students indicating good or excellent understanding increasing from between 2 - 21% students to between 91 - 97% students. The majority (97%) of students completed the module within 90 min. All students reported the module was relevant to their training. Thematic analysis of white space responses found students commonly reported they wanted access to more resources related to health and healthcare sustainability, as well as further guidance on how to make practical steps towards reducing the environmental impact within a clinical setting. CONCLUSION: This is the first study to evaluate learner outcomes of an online module in the field of sustainable health and healthcare. Our results suggest that completion of the module was associated with significant improvement in self-assessed knowledge of key concepts in climate health and sustainability. We hope this approach is followed elsewhere to prepare healthcare staff for impacts of climate change and to support improving the environmental sustainability of healthcare delivery. TRIAL REGISTRATION: Study registered with Brighton and Sussex Medical School Research Governance and Ethics Committee (BSMS RGEC). Reference: ER/BSMS3576/8, Date: 4/3/2020.

The effect of mental fatigue on the performance of Australian football specific skills amongst amateur athletes.

OBJECTIVES: This study investigated the effects of induced mental fatigue on the performance of Australian football (AF) specific skills amongst amateur AF players. DESIGN: Randomised cross over trial. METHODS: Twenty-five amateur AF players performed a series of standardised tests from the Australian Football League (AFL) Draft Combine after completing a 30-min Stroop test (mental fatigue condition) or 30-min control condition. The AFL Draft Combine tests included the standing vertical jump test, running vertical jump test, agility test, 20m sprint, Matthew Lloyd clean hands test, Brad Johnson goal kicking test and a Yo-Yo Intermittent Recovery Level 1 (Yo-Yo IR1) test. RESULTS: The Stroop test score decreased during the Stroop test (first five trials: mean=84.7, SD=3.5; last five trials: mean=82.2, SD=5.0, p=0.03). The Yo-Yo IR1 test (mental fatigue: median=920m, IQR=400; control: median=1040m, IQR=760; p=0.03) and Brad Johnson goalkicking test (mental fatigue: median=19.0, IQR=5.0; control: median=25.0, IQR=10.0, p=0.048) were negatively affected by mental fatigue. No other Draft Combine tests demonstrated a negative affect from mental fatigue. CONCLUSIONS: Mental fatigue had a detrimental influence on the performance of AF specific skills. The findings may have implications for AF players who are required to sustain attention and concentration for prolonged periods before and during matches.

Adaptive treatment and robust control.

A control theory perspective on determination of optimal dynamic treatment regimes is considered. The aim is to adapt statistical methodology that has been developed for medical or other biostatistical applications to incorporate powerful control techniques that have been designed for engineering or other technological problems. Data tend to be sparse and noisy in the biostatistical area and interest has tended to be in statistical inference for treatment effects. In engineering fields, experimental data can be more easily obtained and reproduced and interest is more often in performance and stability of proposed controllers rather than modeling and inference per se. We propose that modeling and estimation should be based on standard statistical techniques but subsequent treatment policy should be obtained from robust control. To bring focus, we concentrate on A-learning methodology as developed in the biostatistical literature and H∞ -synthesis from control theory. Simulations and two applications demonstrate robustness of the H∞ strategy compared to standard A-learning in the presence of model misspecification or measurement error.

Radiative Double-Electron Capture by Bare and One-Electron Ions on Gas Targets.

Radiative double-electron capture (RDEC) involves the transfer of two electrons with the simultaneous emission of a single photon. This process, which can be viewed as the inverse of double photoionzation, has been studied for 2.11 MeV/u F^{9+} and F^{8+} ions striking gas targets of N_{2} and Ne. The existence of RDEC is conclusively shown for both targets and the results are compared with earlier O^{8+} and F^{9+} findings for thin-foil carbon and with theory. The data for the carbon target showed some evidence for the existence of RDEC, but the interpretation was clouded by high-probability, unavoidable multiple collisions causing the exiting charge state to be increased.

Characterization of isolated liver sinusoidal endothelial cells for liver bioengineering.

BACKGROUND: The liver sinusoidal capillaries play a pivotal role in liver regeneration, suggesting they may be beneficial in liver bioengineering. This study isolated mouse liver sinusoidal endothelial cells (LSECs) and determined their ability to form capillary networks in vitro and in vivo for liver tissue engineering purposes. METHODS AND RESULTS: In vitro LSECs were isolated from adult C57BL/6 mouse livers. Immunofluorescence labelling indicated they were LYVE-1+/CD32b+/FactorVIII+/CD31-. Scanning electron microscopy of LSECs revealed the presence of characteristic sieve plates at 2 days. LSECs formed tubes and sprouts in the tubulogenesis assay, similar to human microvascular endothelial cells (HMEC); and formed capillaries with lumens when implanted in a porous collagen scaffold in vitro. LSECs were able to form spheroids, and in the spheroid gel sandwich assay produced significantly increased numbers (p = 0.0011) of capillary-like sprouts at 24 h compared to HMEC spheroids. Supernatant from LSEC spheroids demonstrated significantly greater levels of vascular endothelial growth factor-A and C (VEGF-A, VEGF-C) and hepatocyte growth factor (HGF) compared to LSEC monolayers (p = 0.0167; p = 0.0017; and p < 0.0001, respectively), at 2 days, which was maintained to 4 days for HGF (p = 0.0017) and VEGF-A (p = 0.0051). In vivo isolated mouse LSECs were prepared as single cell suspensions of 500,000 cells, or as spheroids of 5000 cells (100 spheroids) and implanted in SCID mouse bilateral vascularized tissue engineering chambers for 2 weeks. Immunohistochemistry identified implanted LSECs forming LYVE-1+/CD31- vessels. In LSEC implanted constructs, overall lymphatic vessel growth was increased (not significantly), whilst host-derived CD31+ blood vessel growth increased significantly (p = 0.0127) compared to non-implanted controls. LSEC labelled with the fluorescent tag DiI prior to implantation formed capillaries in vivo and maintained LYVE-1 and CD32b markers to 2 weeks. CONCLUSION: Isolated mouse LSECs express a panel of vascular-related cell markers and demonstrate substantial vascular capillary-forming ability in vitro and in vivo. Their production of liver growth factors VEGF-A, VEGF-C and HGF enable these cells to exert a growth stimulus post-transplantation on the in vivo host-derived capillary bed, reinforcing their pro-regenerative capabilities for liver tissue engineering studies.

Hypoxic preconditioning of myoblasts implanted in a tissue engineering chamber significantly increases local angiogenesis via upregulation of myoblast vascular endothelial growth factor-A expression and downregulation of miRNA-1, miRNA-206 and angiopoietin-1.

Vascularization is a major hurdle for growing three-dimensional tissue engineered constructs. This study investigated the mechanisms involved in hypoxic preconditioning of primary rat myoblasts in vitro and their influence on local angiogenesis postimplantation. Primary rat myoblast cultures were exposed to 90 min hypoxia at <1% oxygen followed by normoxia for 24 h. Real time (RT) polymerase chain reaction evaluation indicated that 90 min hypoxia resulted in significant downregulation of miR-1 and miR-206 (p < 0.05) and angiopoietin-1 (p < 0.05) with upregulation of vascular endothelial growth factor-A (VEGF-A; p < 0.05). The miR-1 and angiopoietin-1 responses remained significantly downregulated after a 24 h rest phase. In addition, direct inhibition of miR-206 in L6 myoblasts caused a significant increase in VEGF-A expression (p < 0.05), further establishing that changes in VEGF-A expression are influenced by miR-206. Of the myogenic genes examined, MyoD was significantly upregulated, only after 24 h rest (p < 0.05). Preconditioned or control myoblasts were implanted with Matrigel™ into isolated bilateral tissue engineering chambers incorporating a flow-through epigastric vascular pedicle in severe combined immunodeficiency mice and the chamber tissue harvested 14 days later. Chambers implanted with preconditioned myoblasts had a significantly increased percentage volume of blood vessels (p = 0.0325) compared with chambers implanted with control myoblasts. Hypoxic preconditioned myoblasts promote vascularization of constructs via VEGF upregulation and downregulation of angiopoietin-1, miR-1 and miR-206. The relatively simple strategy of hypoxic preconditioning of implanted cells - including non-stem cell types - has broad, future applications in tissue engineering of skeletal muscle and other tissues, as a technique to significantly increase implant site angiogenesis.

From breathless to failure: symptom onset and diagnostic meaning in patients with heart failure-a qualitative study.

OBJECTIVES: To explore 2 key points in the heart failure diagnostic pathway-symptom onset and diagnostic meaning-from the patient perspective. DESIGN: Qualitative interview study. SETTING: Participants were recruited from a secondary care clinic in central England following referral from primary care. PARTICIPANTS: Over age 55 years with a recent (<1 year) diagnosis of heart failure confirmed by a cardiologist following initial presentation to primary care. METHODS: Semistructured interviews were carried out with 16 participants (11 men and 5 women, median age 78.5 years) in their own homes. Data were audio-recorded and transcribed. Participants were asked to describe their diagnostic journey from when they first noticed something wrong up to and including the point of diagnosis. Data were analysed using the framework method. RESULTS: Participants initially normalised symptoms and only sought medical help when daily activities were affected. Failure to realise that anything was wrong led to a delay in help-seeking. Participants' understanding of the term 'heart failure' was variable and 1 participant did not know he had the condition. The term itself caused great anxiety initially but participants learnt to cope with and accept their diagnosis over time. CONCLUSIONS: Greater public awareness of symptoms and adequate explanation of 'heart failure' as a diagnostic label, or reconsideration of its use, are potential areas of service improvement.

Changes in the severity and subtype of Guillain-Barré syndrome admitted to a specialist Neuromedical ICU over a 25 year period.

We report a retrospective review of 110 patients with acute Guillain-Barré syndrome (GBS) admitted to a specialised intensive care unit (ICU) in a tertiary referral centre over a 25 year period, the start of which coincided with the widespread introduction of plasma exchange (PE) and intravenous immunoglobulin (IVIG). The results were analysed by comparing 52 patients admitted in the first decade (1991-2000; Group 1) with 58 patients admitted between 2001-2014 (Group 2). Patients in both groups were comparable with respect to age and sex, and had a similar incidence and range of ICU complications. They received a comparable range of immunomodulatory treatments including IVIG and PE. However, the delay from presentation to referral to the tertiary ICU was longer in patients in Group 2. They also required mechanical ventilation for a longer duration, and had longer ICU and hospital stays. In Group 2, there was a higher incidence of axonal neuropathy (51%, compared to 24% in Group 1). Despite the longer delay to referral, the prevalence of axonal neuropathy and the duration of ventilation, overall mortality showed a downward trend (Group 1: 13.5%; Group 2: 5.2%). There was no late mortality in either group after step-down to neuro-rehabilitation or following discharge home or to the referring hospital. The rehabilitation outcomes were similar. This data show a shift in the pattern of referral to a tertiary referral ICU between the first and second decades following the wider availability of IVIG and PE for the treatment of GBS. The possible causes and implications of these findings are discussed.

Comparison of two pancreatic enzyme products for exocrine insufficiency in patients with cystic fibrosis.

BACKGROUND: Zenpep (APT-1008) is a pancreatic enzyme product for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF). METHODS: Zenpep and Kreon, both containing 25,000 lipase units, were compared in a randomised, double-blind, crossover, non-inferiority study for CF-associated EPI in patients aged ≥12years. Patients on a standardised diet and stabilised treatment were randomised to two treatment sequences: Zenpep/Kreon or Kreon/Zenpep. The primary efficacy endpoint was the coefficient of fat absorption over 72h (CFA-72h). RESULTS: 96 patients (mean age 19.2years, 60.4% males) were randomised with 83 completers of both sequences comprising the efficacy population. Zenpep demonstrated non-inferiority and equivalence to Kreon in fat absorption (LS mean CFA-72h: Zenpep, 84.1% [SE 1.1] vs. Kreon, 85.3% [SE 1.1]; p=0.297). Safety and tolerability were similar. CONCLUSIONS: Zenpep is comparable with Kreon in efficacy and safety for the treatment of adolescents and adults with CF-associated EPI. NCT01641393.

Alloantibody Responses After Renal Transplant Failure Can Be Better Predicted by Donor-Recipient HLA Amino Acid Sequence and Physicochemical Disparities Than Conventional HLA Matching.

We have assessed whether HLA immunogenicity as defined by differences in donor-recipient HLA amino-acid sequence (amino-acid mismatch score, AMS; and eplet mismatch score, EpMS) and physicochemical properties (electrostatic mismatch score, EMS) enables prediction of allosensitization to HLA, and also prediction of the risk of an individual donor-recipient HLA mismatch to induce donor-specific antibody (DSA). HLA antibody screening was undertaken using single-antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The effect of AMS, EpMS, and EMS on the development of allosensitization (calculated reaction frequency [cRF]) and DSA was determined. Multivariate analyses, adjusting for time on the waiting list, maintenance on immunosuppression after transplant failure, and graft nephrectomy, showed that AMS (odds ratio [OR]: 1.44 per 10 units, 95% CI: 1.02-2.10, p = 0.04) and EMS (OR: 1.27 per 10 units, 95% CI: 1.02-1.62, p = 0.04) were independently associated with the risk of developing sensitization to HLA (cRF > 15%). AMS, EpMS, and EMS were independently associated with the development of HLA-DR and HLA-DQ DSA, but only EMS correlated with the risk of HLA-A and -B DSA development. Differences in donor-recipient HLA amino-acid sequence and physicochemical properties enable better assessment of the risk of HLA-specific sensitization than conventional HLA matching.

Transfer of HLA-Specific Allosensitization From a Highly Sensitized Deceased Organ Donor to the Recipients of Each Kidney.

We report for the first time the adoptive transfer of donor HLA-specific allosensitization in two recipients following kidney transplantation from a highly sensitized donor. Kidneys from a donation after circulatory death donor were transplanted into two nontransfused, HLA-specific antibody negative males receiving their first transplant. Antibody screening 7 days after transplant showed high level de novo IgG HLA class I- and class II-specific antibodies in both recipients, with largely overlapping antibody profiles but no antibodies to donor HLA. The unusually rapid appearance of de novo alloantibodies in immunosuppressed nonsensitized recipients and absence of donor HLA-specific antibody prompted testing of stored donor serum that revealed high antibody levels with specificities very similar to those seen in both recipients, but in addition the presence of strong antibodies to each recipient HLA. Alloantibody levels gradually declined but were still detectable at 3 months. These findings suggest that alloreactive passenger B cells/plasma cells within the kidneys of highly sensitized donors may give rise to rapid development of posttransplant de novo HLA-specific alloantibodies. While the clinical significance of this phenomenon is uncertain it provides one explanation for the appearance of de novo HLA-specific antibodies directed against third party but not donor HLA.

Should HLA mismatch acceptability for sensitized transplant candidates be determined at the high-resolution rather than the antigen level?

Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals.

The predictive value of obstructive sleep apnoea severity on clinical outcomes following maxillomandibular advancement surgery.

We aimed to evaluate whether the severity of preoperative obstructive sleep apnoea (OSA) has potential predictive value for the clinician assessing patients referred for maxillomandibular advancment surgery. We performed a retrospective analysis of consecutive patients who underwent maxillofacial operations for OSA at our institution. We stratified them into 2 groups according to apnoea/hypopnoea index (AHI) scores calculated from a preoperative sleep study: mild-moderate OSA (AHI less than 30) and severe OSA (AHI 30 and above). Both groups were matched for baseline demographic and clinical characteristics. We compared postoperative scores for the AHI and Epworth sleepiness scale (ESS), and lowest recorded oxygen saturation between groups. We identified 51 patients of whom 39 had complete data available for inclusion in our analysis. We found no statistically significant difference in the postoperative AHI scores between the two groups. The reduction in the mean ESS after operation was greater in the severe group than in the mild-moderate group (mean (SD) ESS 4 (3) compared with 9 (6), p<0.05). There were high rates of surgical success (postoperative AHI less than 15) in both groups, and results were comparable (mild-moderate group 82%, severe group 86%). The preoperative AHI does not appear to be a good predictor of surgical success after maxillomandibular advancement surgery. Patients with severe OSA postoperatively demonstrated a greater improvement in their subjective symptoms, when compared to subjects with mild-moderate OSA.

Physiochemical disparity of mismatched HLA class I alloantigens and risk of acute GVHD following HSCT.

We determined whether assessment of the immunogenicity of individual donor-recipient HLA mismatches based on differences in their amino-acid sequence and physiochemical properties predicts clinical outcome following haematopoietic SCT (HSCT). We examined patients transplanted with 9/10 single HLA class I-mismatched grafts (n=171) and 10/10 HLA-A-, -B-, -C-, -DRB1- and -DQB1-matched grafts (n=168). A computer algorithm was used to determine the physiochemical disparity (electrostatic mismatch score (EMS) and hydrophobic mismatch score (HMS)) of mismatched HLA class I specificities in the graft-versus-host direction. Patients transplanted with HLA-mismatched grafts with high EMS/HMS had increased incidence of ⩾grade II acute GVHD (aGVHD) compared with patients transplanted with low EMS/HMS grafts; patients transplanted with low and medium EMS/HMS grafts had similar incidence of aGVHD to patients transplanted with 10/10 HLA-matched grafts. Mortality was higher following single HLA-mismatched HSCT but was not correlated with HLA physiochemical disparity. Assessment of donor-recipient HLA incompatibility based on physiochemical HLA disparity may enable better selection of HLA-mismatched donors in HSCT.

Killer immunoglobulin-like receptor gene repertoire influences viral load of primary human cytomegalovirus infection in renal transplant patients.

Killer cell immunoglobulin-like receptors (KIR) are highly polymorphic members of the immunoglobulin superfamily, which influence the response of natural killer cells and some T-lymphocyte subsets. Analysis of a cohort of previously human cytomegalovirus (HCMV)-negative patients, who developed primary HCMV infection following HCMV-positive renal transplant (n=76), revealed an increase in the frequency of KIR genes located on the telomeric region of B haplotypes (Tel B). The presence of Tel B in combination with the KIR ligand HLA-C2 was significantly more frequent in this subgroup. These genetic factors were associated with resistance to HCMV infection in a second cohort (n=65), where the Tel B genes KIR2DL5, -2DS1, 2DS5 and -3DS1 were all significantly associated with high viral loads. Furthermore, the KIR haplotype Tel A when in combination with the KIR ligand HLA-C1 was significantly protective against the development of severe infection. Our results suggest that KIR are a significant factor in the control of primary HCMV infection, and that determination of KIR gene repertoire may help in detection of renal transplant patients who were most at risk.

The potential role of NT-proBNP in screening for and predicting prognosis in heart failure: a survival analysis.

OBJECTIVE: To determine the potential role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in screening for and predicting prognosis in heart failure by examining diagnosis and survival of patients with a raised NT-proBNP at screening. DESIGN: Survival analysis. SETTING: Prospective substudy of the Echocardiographic Heart of England Screening study (ECHOES) to investigate 10-year survival in participants with an NT-proBNP level at baseline. PARTICIPANTS: 594 participants took part in the substudy. Records of all participants in the ECHOES cohort were flagged during the screening phase which ended on 25 February 1999. All deaths until 25 February 2009 were coded. OUTCOME MEASURES: Logistic regression was used to examine whether NT-proBNP is useful in predicting heart failure at screening after adjustment for age, sex and cohort. Kaplan-Meier curves and log rank tests were used to compare survival times of participants according to NT-proBNP level. Cox regression was carried out to assess the prognostic effect of NT-proBNP after allowing for significant covariates and receiver operator curves were used to determine test reliability. RESULTS: The risk of heart failure increased almost 18-fold when NT-proBNP was 150 pg/mL or above (adjusted OR=17.7, 95% CI 4.9 to 63.5). 10-year survival in the general population cohort was 61% (95% CI 48% to 71%) for those with NT-proBNP ≥150 pg/mL and 89% (95% CI 84% to 92%) for those below the cut-off at the time of the initial study. After adjustment for age, sex and risk factors for heart failure, NT-proBNP level ≥150 pg/mL was associated with a 58% increase in the risk of death within 10 years (adjusted HR=1.58, 95% CI 1.09 to 2.30). CONCLUSIONS: Raised NT-proBNP levels, when screening the general population, are predictive of a diagnosis of heart failure (at a lower threshold than guidelines for diagnosing symptomatic patients) and also predicted reduced survival at 10 years.