Prognostic stratification of HPV-associated oropharyngeal cancer based on CD103+ immune cell abundance in patients treated on TROG 12.01 and De-ESCALaTE randomized trials.

BACKGROUND: High CD103+ intratumoral immune cell (ITIC) abundance is associated with better prognosis in unselected patients with human papilloma virus-associated oropharyngeal squamous cell carcinoma (HPV-associated OPSCC) treated with cisplatin and radiotherapy (CIS/RT). Substituting cetuximab (CETUX) for CIS with RT in HPV-associated OPSCC resulted in inferior efficacy. Our aim was to determine whether quantification of CD103 ITIC could be used to identify a population of HPV-associated OPSCC with superior prognosis. PATIENTS AND METHODS: We pooled data from the TROG 12.01 and De-ESCALaTE randomized trials that compared CETUX/70GyRT with CIS/70GyRT in low-risk HPV-associated OPSCC: American Joint Committee on Cancer 7 stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history >10 pack-years and/or distant metastases), including all patients with available tumor samples. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/RT comparing CD103+ ITIC high (≥30%) versus low (<30%). High and low CD103 were compared using Cox regression adjusting for age, stage and trial. RESULTS: Tumor samples were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. CD103+ ITIC abundance was high in 27% of patients. The median follow-up was 3.2 years. The 3-year FFS in patients treated with CETUX/RT was 93% [95% confidence interval (CI) 79% to 98%] in high CD103 and 74% (95% CI 63% to 81%) in low CD103 [adjusted hazard ratio = 0.22 (95% CI 0.12-0.41), P < 0.001]. The 3-year overall survival in patients treated with CETUX/RT was 100% in high CD103 and 86% (95% CI 76% to 92%) in low CD103, P < 0.001. In patients treated with CIS/RT, there was no significant difference in FFS. CONCLUSIONS: CD103+ ITIC expression separates CETUX/RT-treated low-risk HPV-associated OPSCC into excellent and poor prognosis subgroups. The high CD103 population is a rational target for de-intensification trials.

Identification of an excellent prognosis subset of human papillomavirus-associated oropharyngeal cancer patients by quantification of intratumoral CD103+ immune cell abundance.

BACKGROUND: Accurate prognostic stratification of human papillomavirus-associated oropharyngeal cancers (HPV+OPSCC) is required to identify patients potentially suitable for treatment deintensification. We evaluated the prognostic significance of CD103, a surface marker associated with tissue-resident memory T cells (TRMs), in two independent cohorts of patients with HPV+OPSCC. PATIENTS AND METHODS: The abundance and distribution of CD103+ immune cells were quantified using immunohistochemistry in a cohort of 189 HPV+OPSCC patients treated with curative intent and correlated with outcome. Findings were then validated in an independent cohort comprising 177 HPV+OPSCCs using univariable and multivariable analysis. Intratumoral CD103+ immune cells were characterized by multispectral fluorescence immunohistochemistry and gene expression analysis. RESULTS: High intratumoral abundance of CD103+ immune cells using a ≥30% cut-off was found in 19.8% of tumors in the training cohort of HPV+OPSCC patients and associated with excellent prognosis for overall survival (OS) with adjusted hazard ratio (HR) of 0.13 [95% confidence interval (CI) 0.02-0.94, P = 0.004]. In the independent cohort of HPV+OPSCCs, 20.4% had high intratumoral CD103+ abundance and an adjusted HR for OS of 0.16 (95% CI 0.02-1.22, P = 0.02). Five year OS of patients with high intratumoral CD103 was 100% across both cohorts. The C-statistic for the multivariate prognostic model with stage and age was significantly improved in both cohorts with the addition of intratumoral CD103+ cell abundance. On the basis of spatial location, co-expression of CD8 and CD69, and gene expression profiles, intratumoral CD103+ cells were consistent with TRMs. CONCLUSION: Quantification of intratumoral CD103+ immune cell abundance provides prognostic information beyond that provided by clinical parameters such as TNM-staging, identifying a population of low risk HPV+OPSCC patients who are good candidates for trials of deintensification strategies.

Route to improving Type 1 diabetes mellitus glycaemic outcomes: real-world evidence taken from the National Diabetes Audit.

AIM: To use general practice-level data for England, available through the National Diabetes Audit, and primary care prescribing data to identify prescription treatment factors associated with variations in achieved glucose control (HbA1c ). METHODS: General practice-level National Diabetes Audit data on Type 1 diabetes, including details of population characteristics, services, proportion of people achieving target glycaemic control [HbA1c ≤58 mmol/mol (7.5%)] and proportion of people at high glycaemic risk [HbA1c >86 mmol/ml (10%)], were linked to 2013-2016 primary care diabetes prescribing data on insulin types and blood glucose monitoring for all people with diabetes. RESULTS: A wide variation was found between the 10th percentile and the 90th percentile of general practices in both target glycaemic control (15.6% to 44.8%, respectively) and high glycaemic risk (4.8% to 28.6%, respectively). Our analysis suggests that, given the extrapolated total of 280 000 people with Type 1 diabetes in the UK, there may be the potential to increase the number of those within target glycaemic control from 80 000 to 101 000; 53% of this increase (11 000 people) would result from service improvements and 47% (10 000 people) from medication and technology changes. The same improvements would also provide the opportunity to reduce the number of people at high glycaemic risk from 42 000 to 26 500. A key factor associated with practice-level target HbA1c achievement would be greater use of insulin pumps for up to an additional 56 000 people. CONCLUSION: If the HbA1c achievement rates in service provision, medication and use of technology currently seen in practices in the 90th percentile were to be matched with regard to HbA1c achievement rates in all general practices, glycaemic control might be improved for 36 500 people, with all the attendant health benefits.

Frequency and prognostic significance of p16(INK4A) protein overexpression and transcriptionally active human papillomavirus infection in laryngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV) infection is a powerful prognostic biomarker in a subset of head and neck squamous cell carcinomas, specifically oropharyngeal cancers. However, the role of HPV in non-oropharyngeal sites, such as the larynx, remains unconfirmed. METHODS: We evaluated a cohort of 324 laryngeal squamous cell carcinoma (LSCC) patients for the expression of p16(INK4A) (p16) protein by immunohistochemistry (IHC) and for high-risk HPV E6 and E7 mRNA transcripts by RNA in situ hybridisation (ISH). p16 expression and HPV status were correlated with clinicopathological features and outcomes. RESULTS: Of 307 patients assessable for p16 IHC, 20 (6.5%) were p16 positive. Females and node-positive patients were more likely to be p16 positive (P<0.05). There were no other significant clinical or demographic differences between p16-positive and -negative cases. There was no difference in overall survival (OS) between p16-positive and -negative patients with 2-year survival of 79% in each group (HR=0.83, 95% CI 0.36-1.89, P=0.65). There was no statistically significant difference in failure-free survival (FFS) with 2-year FFS of 79% and 66% for p16-positive and -negative patients, respectively (HR=0.60, 95% CI 0.26-1.36, P=0.22). Only seven cases were found to be HPV RNA ISH positive, all of which were p16 IHC positive. There was no statistically significant difference in OS between patients with HPV RNA ISH-positive tumours compared with -negative tumours with 2-year survival of 86% and 71%, respectively (HR=0.76, 95% CI 0.23-2.5, P=0.65). The 2-year FFS was 86% and 59%, respectively (HR=0.62, 95% CI 0.19-2.03, P=0.43). CONCLUSIONS: p16 overexpression is infrequent in LSCC and the proportion of cases with high-risk HPV transcripts is even lower. There are no statistically significant correlations between p16 IHC or HPV RNA ISH status and OS or disease outcomes.

A phase Ib/II translational study of sunitinib with neoadjuvant radiotherapy in soft-tissue sarcoma.

BACKGROUND: Preoperative radiotherapy (RT) is commonly used to treat localised soft-tissue sarcomas (STS). Hypoxia is an important determinant of radioresistance. Whether antiangiogenic therapy can 'normalise' tumour vasculature, thereby improving oxygenation, remains unknown. METHODS: Two cohorts were prospectively enrolled. Cohort A evaluated the implications of hypoxia in STS, using the hypoxic tracer (18)F-azomycin arabinoside (FAZA-PET). In cohort B, sunitinib was added to preoperative RT in a dose-finding phase 1b/2 design. RESULTS: In cohort A, 13 out of 23 tumours were hypoxic (FAZA-PET), correlating with metabolic activity (r(2)=0.85; P<0.001). Two-year progression-free (PFS) and overall (OS) survival were 61% (95% CI: 0.44-0.84) and 87% (95% CI: 0.74-1.00), respectively. Hypoxia was associated with radioresistance (P=0.012), higher local recurrence (Hazard ratio (HR): 10.2; P=0.02), PFS (HR: 8.4; P=0.02), and OS (HR: 41.4; P<0.04). In Cohort B, seven patients received sunitinib at dose level (DL): 0 (50 mg per day for 2 weeks before RT; 25 mg per day during RT) and two patients received DL: -1 (37.5 mg per day for entire period). Dose-limiting toxicities were observed in 4 out of 7 patients at DL 0 and 2 out of 2 patients at DL -1, resulting in premature study closure. Although there was no difference in PFS or OS, patients receiving sunitinib had higher local failure (HR: 8.1; P=0.004). CONCLUSION: In STS, hypoxia is associated with adverse outcomes. The combination of sunitinib with preoperative RT resulted in unacceptable toxicities, and higher local relapse rates.

Chronic kidney disease and diabetes in the national health service: a cross-sectional survey of the U.K. national diabetes audit.

AIMS: We investigated the prevalence of chronic kidney disease and attainment of therapeutic targets for HbA1c and blood pressure in a large U.K.-based diabetes population. METHODS: The U.K. National Diabetes Audit provided data from 1 January 2007 to 31 March 2008. Inclusion criteria were a documented urinary albumin:creatinine ratio and serum creatinine. Patients were stratified according to chronic kidney disease stage and albuminuria status. Chronic kidney disease was defined as an estimated glomerular filtration rate < 60 ml min(-1) 1.73 m(-2) , albuminuria or both. The proportions of patients achieving nationally defined glycaemic and systolic blood pressure targets were determined. RESULTS: The cohort comprised 1,423,669 patients, of whom 868,616 (61%) met inclusion criteria. Of the patients analysed, 92.2% had Type 2 diabetes. A higher proportion of people with Type 2 diabetes (42.3%) had renal dysfunction compared with those with Type 1 diabetes (32.4%). Achievement of systolic blood pressure and HbA1c targets was poor. Among people with Type 1 diabetes, 67.8% failed to achieve an HbA1c < 58 mmol/mol (7.5%). Of all people with diabetes, 37.8% failed to achieve a systolic blood pressure < 140 mmHg. Blood pressure control was poor in advanced chronic kidney disease. For example, mean (standard deviation) systolic blood pressure rose from 128.6 (15.4) mmHg among people with Type 1 diabetes and normal renal function to 141.0 (23.6) mmHg in those with chronic kidney disease stage 5 and macroalbuminuria. CONCLUSIONS: The high prevalence of chronic kidney disease and poor attainment of treatment targets highlights a large subset of the diabetes population at increased risk of cardiovascular mortality or progressive kidney disease.

Multimodal microscopy using 'half and half' contact mode and ultrasonic force microscopy.

Advances in the design and fabrication of multifunctional nanostructured materials require characterization techniques capable of simultaneously mapping multiple material properties with nanoscale resolution. We show that this can be achieved by combining nanomechanical information from ultrasonic force microscopy (UFM) with simultaneously acquired friction force and conductivity measurements from contact mode scanning. This utilizes a 'half and half' approach, where the AFM is operated alternatively in UFM and contact mode, with the switching rate sufficiently fast that simultaneous contact mode and UFM information is acquired at each pixel of an image. We demonstrate the potential of such a multimodal approach through its application to composite systems consisting of graphene islands on a copper surface, single-walled carbon nanotubes (SWNTs) on a silicon oxide substrate, and a graphene epoxy composite. The half and half approach enables the friction force to be measured without topographical cross-talk. Application to the SWNT sample reveals a further advantage; due to the superlubricity of UFM it enables standard contact mode imaging techniques to be applied to delicate samples.

Excess mortality during hospital stays among patients with recorded diabetes compared with those without diabetes.

AIM: To assess the additional mortality during hospital admissions among patients with recorded diabetes and identify the extent of variation in English provider trusts. METHODS: Inpatient admissions to all English hospitals between April 2010 and March 2012 were extracted from Hospital Episode Statistics. Binary logistic regression was used to standardize for age, sex, deprivation, method and reason for admission, co-morbidities and type of trust. Trust level standardized mortality ratios for inpatients with recorded diabetes were compared with those without recorded diabetes and with published measures of hospital mortality. RESULTS: Of the 10 169 003 hospital admissions analysed, 11.2% had recorded diabetes, but 21.5% of inpatient deaths occurred in this group. After adjustment for case mix, hospital admissions in patients with recorded diabetes had a 6.4% greater risk of dying (2052 more deaths over 2 years) than would be expected compared with similar patients without recorded diabetes. The additional risk of death was significantly greater in smaller trusts. The highest additional risk of death was found in hospital admissions of younger female patients admitted electively. At provider trust level, 37.4% of variation in adjusted mortality in patients with recorded diabetes was explained by the mortality in those without recorded diabetes. CONCLUSION: A diagnosis of diabetes has an adverse impact on hospital mortality that cannot be explained by usual case-mix adjustments, and the additional risk of dying is greatest among hospital admissions that would normally have a low risk of death. This implies that diabetes may override the usual risk factors for hospital mortality.

Phase IIa randomized, placebo-controlled study of antimicrobial photodynamic therapy in bacterially colonized, chronic leg ulcers and diabetic foot ulcers: a new approach to antimicrobial therapy.

BACKGROUND: With increasing problems of antibiotic resistance, photodynamic therapy (PDT) is being developed as a novel antimicrobial treatment. Following light activation, cationic photosensitizer PPA904 [3,7-bis(N,N-dibutylamino) phenothiazin-5-ium bromide] kills a broad spectrum of bacteria in vitro and this has a variety of potential clinical applications. OBJECTIVES: To determine if PDT in bacterially colonized chronic leg ulcers and chronic diabetic foot ulcers can reduce bacterial load, and potentially lead to accelerated wound healing. METHODS: Sixteen patients with chronic leg ulcers and 16 patients with diabetic foot ulcers (each eight active treatment/eight placebo) were recruited into a blinded, randomized, placebo-controlled, single-treatment, Phase IIa trial. All patients had ulcer duration > 3 months, bacterially colonized with > 10 colony-forming units cm . After quantitatively assessing pretreatment bacterial load via swabbing, PPA904 or placebo was applied topically to wounds for 15 min, followed immediately by 50 J cm of red light and the wound again sampled for quantitative microbiology. The wound area was measured for up to 3 months following treatment. RESULTS: Treatment was well tolerated with no reports of pain or other safety issues. In contrast to placebo, patients on active treatment showed a reduction in bacterial load immediately post-treatment (P < 0·001). After 3 months, 50% (four of eight) of patients with actively treated chronic leg ulcer showed complete healing, compared with 12% (one of eight) of patients on placebo. CONCLUSIONS: This first controlled study of PDT in chronic wounds demonstrated significant reduction in bacterial load. An apparent trend towards wound healing was observed; further study of this aspect with larger patient numbers is indicated.

Variation in the recorded incidence of amputation of the lower limb in England.

AIMS/HYPOTHESIS: The study aimed to explore the variation in recorded incidence of lower limb amputation in England. METHODS: The incidences of amputations in adults with and without diabetes were determined from hospital episode statistics over 3 years to 31 March 2010 and compared between the 151 Primary Care Trusts (PCTs) in England. RESULTS: There were 34,109 amputations, including 16,693 (48.9%) in people with diabetes. The incidence was 2.51 per 1,000 person-years in people with diabetes and 0.11 per 1,000 person-years in people without (relative diabetes risk 23.3). Incidence varied eightfold across PCTs in people both with diabetes (range 0.64-5.25 per 1,000 person-years) and without (0.03-0.24 per 1,000 person-years). Amputations in people with diabetes varied tenfold--both major (range 0.22-2.20 per 1,000 person-years) and minor (range 0.30-3.25 per 1,000 person-years). The incidences of minor and major amputations were positively correlated both in those with (r = 0.537, p < 0.0005) and without (r = 0.611, p < 0.0005) diabetes. Incidences of amputations were also correlated between people with and without diabetes (total amputations r = 0.433, p < 0.0005; major amputations r = 0.528, p < 0.0005). There was a negative correlation between the incidence of amputation and estimated prevalence of ethnic Asians. No association was found between the PCT incidence of either total amputations and general population prevalence of social deprivation (r = -0.138, p = 0.092) or smoking (r = 0.137, p = 0.096). CONCLUSIONS/INTERPRETATION: Variation in amputation incidence occurs across England. Because of the similarity in amputation variation between people with and without diabetes the variation may reflect generic differences in local healthcare delivery, although racial factors may also contribute.

Analysis of circulating angiogenic biomarkers from patients in two phase III trials in lung cancer of chemotherapy alone or chemotherapy and thalidomide.

BACKGROUND: Thalidomide has potent anti-inflammatory and anti-angiogenic properties. It was evaluated in combination with chemotherapy in two randomised placebo-controlled trials in patients with small cell lung cancer (SCLC, n=724) and advanced non-small cell lung cancer (NSCLC, n=722). Neither study demonstrated an improvement in overall survival with the addition of thalidomide to chemotherapy. This study investigated circulating angiogenic biomarkers in a subset of these patients. METHODS: Serial plasma samples were collected in a cohort of patients enrolled in these two trials (n=95). Vascular endothelial growth factor (VEGF), soluble truncated form of VEGF receptor-2 (sVEGFR-2), interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (sICAM-1) levels were measured by enzyme-linked immunosorbent assays. Results were correlated with patient clinical data including stage, response rate and progression-free survival (PFS). RESULTS: Baseline biomarker levels were not significantly different between SCLC and NSCLC. For pooled treatment groups, limited stage SCLC was associated with lower baseline VEGF (P=0.046), sICAM-1 (P=0.008) and IL-8 (P=0.070) than extensive stage disease. Low baseline IL-8 was associated with a significantly improved PFS in both SCLC and NSCLC (P=0.028), and a greater reduction in IL-8 was associated with a significantly improved tumour response (P=0.035). Baseline angiogenic factor levels, however, did not predict response to thalidomide. CONCLUSION: Circulating angiogenic biomarkers did not identify patients who benefited from thalidomide treatment.

A semiconductor source of triggered entangled photon pairs.

Entangled photon pairs are an important resource in quantum optics, and are essential for quantum information applications such as quantum key distribution and controlled quantum logic operations. The radiative decay of biexcitons-that is, states consisting of two bound electron-hole pairs-in a quantum dot has been proposed as a source of triggered polarization-entangled photon pairs. To date, however, experiments have indicated that a splitting of the intermediate exciton energy yields only classically correlated emission. Here we demonstrate triggered photon pair emission from single quantum dots suggestive of polarization entanglement. We achieve this by tuning the splitting to zero, through either application of an in-plane magnetic field or careful control of growth conditions. Entangled photon pairs generated 'on demand' have significant fundamental advantages over other schemes, which can suffer from multiple pair emission, or require post-selection techniques or the use of photon-number discriminating detectors. Furthermore, control over the pair generation time is essential for scaling many quantum information schemes beyond a few gates. Our results suggest that a triggered entangled photon pair source could be implemented by a simple semiconductor light-emitting diode.

Changes on soundscapes reveal impacts of wildfires in the fauna of a Brazilian savanna.

Wildfire is a natural process in Brazilian savannas, but human activities alter fire regimes and threaten biodiversity. In this study, we used an ecoacoustics approach to assess fauna responses and recovery after wildfire in a Brazilian savanna. Six passive acoustic monitoring devices were used to record soundscapes before and after a wildfire a at burned and non-burned sites for one year and one month (September 2012 to September 2013). Power Spectral Density and the Acoustic Complexity Index were used to track biophony. Before the fire, the two sites had similar biophonic patterns (PSD: T = 1136, Z = 1.52, P = 0.12; ACI: T = 1117, Z = 1.10, P = 0.26) and soniferous species richness (Site 1 = 52 and Site 2 = 49). However, in the first two sessions of recordings after the fire, biophony became higher at the burned site during the day (PSD: T = 211 and 233; Z = 4.13 and 6.41; ACI: T = 120 and 469, Z = 5.14 and 7.07; all P < 0.00). During the night, biophony was usually higher at the non-burned site until May 2013 (PSD: T = 0 to 453; Z = 3.30 to 5.90; ACI: T = 333 to 491, Z = 3.80 to 4.93; all P < 0.00). Biophony became similar (P = 0.17 to 0.38) at the two sites or higher (P = 0.00 to 0.01) at the burned site from July to September 2013 (PSD: T = 55 to 1167; Z = 1.35 to 6.89; ACI: T = 719 to 1365, Z = 0.87 to 3.04). After the fire, a reduction of soniferous species at the burned site was observed for insects and bats. Both biophonic activity and soniferous species showed a tendency to recover one year after the fire, but there were still less species in September 2013 (non-burned = 43 and burned = 37) when compared to September 2012 at both sites (Site 1 = 52 and Site 2 = 49). Our results showed that changes in the natural regimes of fire can negatively impact the biodiversity and reinforce the need for monitoring protocols and inspection of wildfires.

Priorities and preferences of advanced soft tissue sarcoma patients starting palliative chemotherapy: baseline results from the HOLISTIC study.

INTRODUCTION: Palliative chemotherapy is the principal treatment of patients with advanced soft tissue sarcomas (STS); however prognosis is limited (median overall survival 12-19 months). In this setting, patient values and priorities are central to personalised treatment decisions. PATIENTS AND METHODS: The prospective HOLISTIC study was conducted in the UK and the Netherlands assessing health-related quality of life in STS patients receiving palliative chemotherapy. Participants completed a questionnaire before starting chemotherapy, including attitudes towards quality of life (QoL) versus length of life (LoL), decisional control preferences, and decisional conflict. Chi-square and Fisher's exact tests were used to evaluate associations between patient characteristics and preferences. RESULTS: One hundred and thirty-seven patients with advanced STS participated (UK: n = 72, the Netherlands: n = 65). Median age was 62 (27-79) years. Preference for extended LoL (n = 66, 48%) was slightly more common than preference for QoL (n = 56, 41%); 12 patients (9%) valued LoL and QoL equally (missing: n = 3). Younger patients (age <40 years) prioritised LoL, whereas two-thirds of older patients (aged ≥65 years) felt that QoL was equally or more important than LoL (P = 0.020). Decisional conflict was most common in patients who prioritised QoL (P = 0.024). Most patients preferred an active (n = 45, 33%) or collaborative (n = 59, 44%) role in treatment decisions. Gender, performance status, and country were significantly associated with preferred role. Concordance between preferred and actual role in chemotherapy decision was high (n = 104, 76%). CONCLUSIONS: Heterogeneous priorities and preferences among advanced STS patients support personalised decisions about palliative treatment. Considering individual differences during treatment discussions may enhance communication and optimise patient-centred care.

Fishing for gaps in science: a bibliographic analysis of Brazilian freshwater ichthyology from 1986 to 2005.

To investigate Brazilian freshwater ichthyology, from 1986 to 2005, a bibliometric analysis was conducted using abstracts downloaded from The Web of Science database searching for the keywords 'fish', 'pisces', 'teleostei' and the address field having the word 'Brazil'. The results of this study showed that Brazilian freshwater ichthyology publications have been increasing during the study period. This process is a consequence of a series of investments that the Brazilian Government has made. Furthermore, data analyses identified scientific areas where there was a lack of scientific knowledge (e.g. studies of species threatened with extinction and certain hydrologic basins). Research institutions from the north-east and northern region of Brazil had the lowest participation in scientific productivity, which was a reflection of their regions poorer economic situation. This study showed that scientific productivity in Brazilian ichthyology was a direct reflection of state investment in research. Furthermore, data in this study follow expected statistical probabilities, for example, fishes from the most diverse families were the most studied. Thus, the study shows that great progress has been made by Brazilian ichthyologists in the last 20 years; however, due to the mega diversity of fishes in Brazil, much remains to be done if many species are to become known to science and to be saved from extinction. This it seems will depend on continued and further investment by Brazilian Government funding agencies, as Brazilian ichthyologists have demonstrated their capacity to generate high quality information about their study species.

Synthesis and Single-Crystal X-ray Structure of a Highly Symmetrical C60 Derivative, C60Br24.

C(60) and liquid bromine react to form C(60)Br(24), a crystalline compound isolated as a bromine solvate, C(60)Br(24)(Br(2))(x), The x-ray crystal structure defines a new pattern of addition to the carbon skeleton that imparts a rare high symmetry. The parent C(60) framework is recognizable in C(60)Br(24), but sp(3) carbons at sites of bromination distort the surface, affecting conformations of all of the hexagonal and pentagonal rings. Twenty-four bromine atoms envelop the carbon core, shielding the 18 remaining double bonds from addition. At 150 degrees to 200 degrees C there is effectively quantitative reversion of C(60)Br(24) to C(60) and Br(2).

Methicillin-resistant Staphylococcus aureus bacteraemia and mortality in a teaching hospital.

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for more than 40% of S. aureus bacteraemias in the UK and is associated with considerable morbidity and mortality. This retrospective audit examined the epidemiology of MRSA bacteraemia (MRSAB) at our institution, where the MRSAB rate has been high. A retrospective case note review was undertaken of all patients dying within 90 days of an episode of MRSAB during a 12-month period. A clinical panel classified deaths as having MRSAB as the main cause, contributing cause or having no bearing on the death. Sixty-two patients had one or more episodes of MRSAB and 30 died within 90 days. The mean age of those dying was 72 (43-96) years and of those surviving was 57 (21-87) years. MRSAB was judged to be the main or contributing cause of death in 24 cases, giving an associated mortality of 39%. All-cause mortality at 7, 30 and 90 days was 19, 40 and 48%, respectively. We investigated the minimum inhibitory contribution (MIC) to vancomycin for 79 MRSAB isolates, of which 70.8% of isolates had an MIC value of 2 mg/l. None of the isolates expressed heteroresistance to vancomycin. Five out of seven patients in whom MRSAB was the main cause of death had community onset of infection. It is unlikely that efforts to reduce delays in delivering effective antimicrobial therapy will have a major impact on mortality. Efforts to reduce the burden of MRSAB should focus on the primary prevention of bacteraemia.

The North West Diabetic Pregnancy Audit: a practical system for multi-centre diabetic pregnancy audit.

AIMS: Improving care for women with pre-gestational diabetic pregnancy is a core objective of the St Vincent Declaration and the Diabetes National Service Framework. The aim was to develop a practicable collaborative audit methodology for pre-gestational diabetic pregnancy. METHODS: In 1999, care professionals in the north-west of England agreed standards and a simple monthly data collection system. Annual reports are compiled to summarize compliance with the standards. Each hospital receives an individualized report comprising tables and funnel plots that allow between-hospital comparisons. RESULTS: Data on pre-gestational diabetic pregnancies are collated from 30 maternity units. Funnel plots and tables presented in the annual reports highlight any large differences between hospitals in booking and outcome measures for diabetic pregnancies. CONCLUSIONS: The annual audit reports allow the assessment of current management and outcomes for diabetic pregnancies at a regional and local level. These reports help to identify areas where diabetic pregnancy care requires further attention.

Response to Scheel et al.

Scheel et al.[1] highlight three types of methodological concern with the work reported in our recent paper [2], related to analytical decisions, fetal behavior, and how light interfaces with maternal tissue. Here we outline why the issues raised do not detract from our originally reported conclusions. In our view, the procedural and analytical decisions that we made in our study [2] were the most appropriate given the uncharted territory that we explored. The best test of methodological robustness of our approach would be replication by another laboratory.

Mining noise affects loud call structures and emission patterns of wild black-fronted titi monkeys.

Anthropogenic noise pollution is increasing and can constrain acoustic communication in animals. Our aim was to investigate if the acoustic parameters of loud calls and their diurnal pattern in the black-fronted titi monkey (Callicebus nigrifrons) are affected by noise produced by mining activity in a fragment of Atlantic Forest in Brazil. We installed two passive acoustic monitoring devices to record sound 24 h/day, 7 days every 2 months, for a year; one unit was close to an opencast mine and the other 2.5 km away from it. Both sites presented similar habitat structures and were inhabited by groups of black-fronted titi monkeys. We quantified the noise at both sites by measuring the equivalent continuous sound level every 2 months for 1 year and quantified the emission of loud calls by titi monkeys through visual inspection of the recordings. The close site presented higher ambient noise levels than the far site. The quantitative comparison of loud calls of black-fronted titi monkeys between the two sites showed less calling activity in the site close to the mine than in the site further away. Approximately 20 % of the calls detected at the site close to the mine were masked by noise from truck traffic. Loud calls were longer at the site far from the mine and the diurnal patterns of vocal activity differed in the amount of calling as well as in the timing of peak calling activity between the two sites. Our results indicate that mining noise may constrain titi monkeys' long-distance vocal communication. Loud calls occupy a similar frequency band to mining noise, and an increase in ambient noise may be triggering black-fronted titi monkeys to adjust their long-distance communication patterns to avoid masking of their calls. Given that vocalizations are an important means of social interaction in this species, there are concerns about the impact of mining noise on populations exposed to this human activity.