Royal College of Psychiatrists Liaison Faculty & Joint British Diabetes Societies (JBDS): guidelines for the management of diabetes in adults and children with psychiatric disorders in inpatient settings.

The Royal College of Psychiatrists Liaison Faculty & Joint British Diabetes Societies (JBDS) for Inpatient Care guidelines for the management of diabetes in adults and children with psychiatric disorders in inpatient settings are available in full at: www.diabetes.org.uk/joint-british-diabetes-society and https://abcd.care/joint-british-diabetes-societies-jbds-inpatient-care-group. This article summarizes the guidelines and recommendations. Commissioners are urged to ensure that the needs of people with diabetes and severe mental illness are specifically addressed in contracts with providers of inpatient care, and to avoid financial or other barriers to cross-organizational working and to ensure that patient-structured education is commissioned to meets the complex needs of people with diabetes and severe mental illness. Acute trusts are asked to develop joint pathways with mental health providers and facilitate multidisciplinary working and to screen for mental ill health in those admitted with acute complications of diabetes whose aetiology is unclear or not medically explained. Mental health trusts should create a diabetes register, screen for diabetes, particularly in those prescribed second-generation antipsychotics and ensure that staff are trained in managing and avoiding hypoglycaemia, and the safe use of insulin. Finally, clinical teams should ensure that all staff can access training in diabetes and mental health to support them to care for people with both diabetes and severe mental illness, develop local pathways for joint working and ensure best practice tariff criteria are met for diabetic ketoacidosis and hypoglycaemia, and for children and young people with diabetes.

Immunohistochemical Characterization of Sarcomas in Trp53+/- Haploinsufficient Mice.

The use of immunohistochemical (IHC) staining in determining and/or confirming the cellular origin of poorly differentiated sarcomas was evaluated in this study. Sarcomatous neoplasms were evaluated in a research study conducted in 2 strains of p53+/- haploinsufficient mice. The most common neoplasms were undifferentiated sarcomas, followed by osteosarcomas and rhabdomyosarcomas (RMSs). The RMSs were poorly differentiated and appeared similar to the pleomorphic, or adult type, RMS of humans. All sarcomas stained positive by IHC for the mesenchymal cell intermediate filament vimentin. The RMSs were identified by positive IHC staining for myogenin, a transcription factor specific to skeletal muscle. Osteosarcomas were easily identifiable on hematoxylin and eosin-stained slides; no generally accepted IHC stain specific for bone is presently available. Some of the undifferentiated sarcomas contained numerous macrophages that stained positive for F4/80, a macrophage marker; the positive-staining cells were considered to be infiltrating macrophages. One-third of the neoplasms observed in this study were associated with subcutaneous implanted electronic microchips used for animal identification. Based upon histopathologic evaluation and IHC staining, it was not possible to distinguish neoplasms associated with subcutaneous microchips from neoplasms not associated with microchips.

Impact of personalized cardiovascular disease risk estimates on physical activity-a randomized controlled trial.

AIM: Informing a person of their individual risk of developing a disease in the future may be sufficient to provide the person with the impetus to adopt risk reducing behaviours. The aim of this study was to determine if a personalised 10-year cardiovascular disease (CVD) risk estimate can increase physical activity and other risk reduction behaviours in adults at high risk of CVD. METHODS: Pilot 2 × 2 factorial randomised controlled trial conducted in Oxfordshire, UK including 194 adults at increased CVD risk (10-year CVD risk ≥ 20%) recruited from four general practices. Main outcome measure at one month was physical activity measured by accelerometer. RESULTS: Median (IQR) age was 62.3 (54.9, 66.1) years, 67% were men and 19% had known diabetes. Mean (SD) total accelerometer counts per day was 297 × 10(-3) (110 × 10(-3) ) and activity of moderate or greater intensity was undertaken for 53 (22) minutes per day. In the 185 (95%) participants attending follow-up an increase in physical activity was not seen. There was a non-significant 0.5% (p = 0.56) greater increase in accelerometer counts in those receiving personalised CVD risk estimates. No significant within or between group changes were seen at one month in estimated 10-year CVD risk. A net 7% decrease in mean LDL cholesterol (p = 0.004) was seen in the intervention group despite similar increases in new prescriptions for lipid lowering therapies. CONCLUSION: In adults at increased risk of CVD provision of personalised 10-year CVD risk estimates did not appear to increase physical activity or estimated CVD risk over a one-month period.

Taking training into your own hands.

The Young Diabetologists' Forum (YDF) is a group designed and run by specialist trainees in endocrinology and diabetes that aims to provide high quality educational events. The YDF recognised that not all trainees in the specialty had equitable access to training opportunities and resolved to try and remedy the situation. This article describes the history and evolution of the YDF into an organisation representing over 400 trainees in endocrinology and diabetes, providing up to seven training events per year and with a budget of over pounds 200,000. As well as offering education and training another key purpose of the YDF is to give trainees from around the country the opportunity to meet up and exchange thoughts and ideas. The overall aim of the organisation is to improve the lives of people with diabetes by helping to ensure that future specialists are fully equipped for their role.

Efficacy and safety of once-weekly semaglutide 1.0mg vs once-daily liraglutide 1.2mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10).

AIMS: SUSTAIN 10 compared the efficacy and safety of the anticipated most frequent semaglutide dose (1.0mg) with the current most frequently prescribed liraglutide dose in Europe (1.2mg), reflecting clinical practice. METHODS: In this phase 3b, open-label trial, 577 adults with type 2 diabetes (HbA1c 7.0-11.0%) on 1-3 oral antidiabetic drugs were randomized 1:1 to subcutaneous once-weekly semaglutide 1.0mg or subcutaneous once-daily liraglutide 1.2mg. Primary and confirmatory secondary endpoints were changes in HbA1c and body weight from baseline to week 30, respectively. RESULTS: Mean HbA1c (baseline 8.2%) decreased by 1.7% with semaglutide and 1.0% with liraglutide (estimated treatment difference [ETD] -0.69%; 95% confidence interval [CI] -0.82 to -0.56, P<0.0001). Mean body weight (baseline 96.9kg) decreased by 5.8kg with semaglutide and 1.9kg with liraglutide (ETD -3.83kg; 95% CI -4.57 to -3.09, P<0.0001). The proportions of subjects achieving glycaemic targets of<7.0% and=6.5%, weight loss of=5% and=10%, and a composite endpoint of HbA1c<7.0% without severe or blood glucose-confirmed symptomatic hypoglycaemia and no weight gain were greater with semaglutide vs liraglutide (all P<0.0001). Both treatments had similar safety profiles, except for more frequent gastrointestinal disorders (the most common adverse events [AEs]) and AEs leading to premature treatment discontinuation with semaglutide vs liraglutide (43.9% vs 38.3% and 11.4% vs 6.6%, respectively). CONCLUSION: Semaglutide was superior to liraglutide in reducing HbA1c and body weight. Safety profiles were generally similar, except for higher rates of gastrointestinal AEs with semaglutide vs liraglutide.

Impact of using a non-diabetes-specific risk calculator on eligibility for statin therapy in type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to investigate the impact of using a non-diabetes-specific cardiovascular disease (CVD) risk calculator to determine eligibility for statin therapy according to current UK National Institute for Health and Clinical Excellence (NICE) guidelines for those patients with type 2 diabetes who are at an increased risk of CVD (10 year risk >or=20%). METHODS: The 10 year CVD risks were estimated using the UK Prospective Diabetes Study (UKPDS) Risk Engine and the Framingham equation for 4,025 patients enrolled in the Lipids in Diabetes Study who had established type 2 diabetes and LDL-cholesterol <4.1 mmol/l. RESULTS: The mean (SD) age of the patients was 60.7 (8.6) years, blood pressure 141/83 (17/10) mmHg and the total cholesterol:HDL-cholesterol ratio was 3.9 (1.0). The median (interquartile range) diabetes duration was 6 (3-11) years and the HbA(1c) level was 8.0% (7.2-9.0%). The cohort comprised 65% men, 91% whites, 4% Afro-Caribbeans, 5% Asian Indians and 15% current smokers. More patients were classified as being at high risk by the UKPDS Risk Engine (65%) than by the Framingham CVD equation (63%) (p < 0.0001). The Framingham CVD equation classified fewer men and people aged <50 years old as high risk (p < 0.0001). There was no difference between the UKPDS Risk Engine and Framingham classification of women at high risk (p = 0.834). CONCLUSIONS/INTERPRETATION: These results suggest that the use of Framingham-derived rather than UKPDS Risk Engine-derived CVD risk estimates would deny about one in 25 patients statin therapy when applying current NICE guidelines. Thus, under these guidelines the choice of CVD risk calculator is important when assessing CVD risk in patients with type 2 diabetes, particularly for the identification of the relatively small proportion of younger people who require statin therapy.

The relevance of nanoscale biological fragments for ice nucleation in clouds.

Most studies of the role of biological entities as atmospheric ice-nucleating particles have focused on relatively rare supermicron particles such as bacterial cells, fungal spores and pollen grains. However, it is not clear that there are sufficient numbers of these particles in the atmosphere to strongly influence clouds. Here we show that the ice-nucleating activity of a fungus from the ubiquitous genus Fusarium is related to the presence of nanometre-scale particles which are far more numerous, and therefore potentially far more important for cloud glaciation than whole intact spores or hyphae. In addition, we quantify the ice-nucleating activity of nano-ice nucleating particles (nano-INPs) washed off pollen and also show that nano-INPs are present in a soil sample. Based on these results, we suggest that there is a reservoir of biological nano-INPs present in the environment which may, for example, become aerosolised in association with fertile soil dust particles.

Characterization of hepatocellular resistance and susceptibility to styrene toxicity in B6C3F1 mice.

Short-term inhalation exposure of B6C3F1 mice to styrene causes necrosis of centrilobular (CL) hepatocytes. However, in spite of continued exposure, the necrotic parenchyma is rapidly regenerated, indicating resistance by regenerated cells to styrene toxicity. These studies were conducted to test the hypothesis that resistance to repeated styrene exposure is due to sustained cell proliferation, with production of hepatocytes that have reduced metabolic capacity. Male mice were exposed to air or 500 ppm styrene (6 h/day); hepatotoxicity was evaluated by microscopic examination, serum liver enzyme levels, and bromodeoxyuridine (BrdU)-labeling index (LI). Metabolism was assessed by measurement of blood styrene and styrene oxide. Both single and repeated exposures to styrene resulted in mortality by Day 2; in mice that survived, there was CL necrosis with elevated BrdU LI at Day 6, and complete restoration of the necrotic parenchyma by Day 15. The BrdU LI in mice given a single exposure had returned to control levels by Day 15. Re-exposure of these mice on Day 15 resulted in additional mortality and hepatocellular necrosis, indicating that regenerated CL cells were again susceptible to the cytolethal effect of styrene following a 14-day recovery. However, in mice repeatedly exposed to styrene for 14 days, the BrdU LI remained significantly increased on Day 15, with preferential labeling of CL hepatocytes with enlarged nuclei (karyomegaly). If repeated exposures were followed by a 10-day recovery period, CL karyomegaly persisted, but the BrdU LI returned to control level and CL hepatocytes became susceptible again to styrene toxicity as demonstrated by additional mortality and acute necrosis after a challenge exposure. These findings indicated a requirement for continued styrene exposure and DNA synthesis in order to maintain this resistant phenotype. Analyses of proliferating-cell nuclear-antigen (PCNA) labeling were conducted to further characterize the cell cycle kinetics of these hepatocytes. The proportion of cells in S-phase was increased by repeated exposure. However, PCNA analysis also revealed an even larger increase in the G1 cell compartment with repeated exposures, without a concurrent increase in G2 phase or in mitotic cell numbers. These data indicate that resistance to styrene-induced necrosis under conditions of repeated exposure is not due to sustained cell turnover and production of new, metabolically inactive cells, but rather is due to some other, as yet unknown, protective phenotype of the regenerated cells.

Mercury vapor and female reproductive toxicity.

Epidemiological studies finding menstrual cycle abnormalities among women occupationally exposed to Hg degrees prompted us to investigate the mechanisms of reproductive toxicity of Hg degrees in the female rat. Nose-only Hg degrees vapor inhalation exposures were conducted on regularly cycling rats 80-90 days of age in dose-response and acute time-course studies, which have previously proven useful as a model to identify ovarian toxicants. Vaginal smears were evaluated daily and serum hormone levels were correlated with cycle and with ovarian morphology at necropsy. Exposure concentration-related effects of Hg degrees were evaluated by exposing rats to 0, 1, 2, or 4 mg/m3 Hg degrees vapor 2 h/day for 11 consecutive days. Tissue Hg levels correlated with exposure concentration and duration. Exposure of rats to 4 mg/m3 (but not 1 or 2 mg/m3) Hg vapor for 11 days resulted in significant decreases in body weights relative to controls. Estrous cycles were slightly prolonged in the 2 and 4 mg/m3 dose groups, and serum estradiol and progesterone levels were significantly different in the 4 mg/m3 group compared to controls. The alterations in cycle and hormones at the 4 mg/m3 exposure concentration were attributed to body weight loss and generalized toxicity. In the time-course study, rats were exposed to 2 mg/m3 Hg degrees or air beginning in metestrus and evaluated daily for 8 days. A lengthening of the cycle was detected and morphological changes were observed in the corpora lutea (CL) after exposure for 6 days. To determine if changes in the CL and cyclicity correlated with a functional defect, rats were exposed to Hg degrees vapor and evaluated for pregnancy outcome. There were no significant effects on pregnancy rate or numbers of implantation sites when rats were exposed to 1 or 2 mg/m3 Hg degrees for 8 days prior to breeding, or when exposed for 8 days after breeding. These studies indicate that exposure to Hg degrees vapor altered estrous cyclicity, but had no significant effect on ovulation, implantation, or maintenance of first pregnancy during exposure of short duration in female rats.

Characterization of inhaled alpha-methylstyrene vapor toxicity for B6C3F1 mice and F344 rats.

alpha-Methylstyrene (AMS) is a chemical intermediate used in the synthesis of specialty polymers and copolymers. Inhalation studies of AMS were conducted because of the lack of toxicity data and the structural similarity of AMS to styrene, a toxic and potentially carcinogenic chemical. Male and female B6C3F1 mice were exposed to 0, 600, 800, or 1000 ppm AMS 6 h/day, 5 days/week, for 12 days. After 1 exposure, 21% (5/24) of female mice were found dead in the 1000-ppm group, 56% (10/18) in the 800-ppm group, and 6% (1/18) in the 600-ppm concentration group. After 12 exposures, relative liver weights were significantly increased and relative spleen weights were significantly decreased in both male and female mice at all concentrations. No microscopic treatment-related lesions were observed. A decrease in hepatic glutathione (GSH) was associated with AMS exposure for 1 and 5 days. Male and female F344 rats were exposed to 0, 600 or 1000 ppm AMS for 12 days. No mortality or sedation occurred in AMS-exposed rats. Relative liver weights were significantly increased in both males and females after 12 exposures to 600 or 1000 ppm. An increased hyaline droplet accumulation was detected in male rats in both concentration groups; no significant microscopic lesions were observed in other tissues examined. Exposure of male and female F344 rats and male NBR rats to 0, 125, 250 or 500 ppm AMS, 6 h/day for 9 days resulted in increased accumulation of hyaline droplets in the renal tubules of male F344 rats in the 250 and 500 ppm concentration groups. Although AMS and styrene are structurally very similar, AMS was considerably less toxic for mice and more toxic for male rats than styrene.

Disposition of inhaled mercury vapor in pregnant rats: maternal toxicity and effects on developmental outcome.

The disposition and toxicity of inhaled elemental mercury (Hg0) vapor for pregnant Long-Evans rats, and potential adverse effects on reproductive outcome were investigated. Rats were exposed to 0, 1, 2, 4, or 8 mg Hg0/m(3) for 2 h/day from gestation day (GD) 6 through GD 15. Maternal toxicity occurred primarily in rats exposed to 4 and 8 mg/m(3) and was manifested as a concentration-related decrease in body weight gain and mild nephrotoxicity. Control rats gained about 13% of their initial body weight during the 10-day exposure. Rats exposed to 4 mg/m(3) Hg0 gained about 7% less than controls, and rats exposed to 8 mg/m(3) Hg0 lost about 17% of their initial body weight during the 10-day exposure period. Maternal kidney weights were significantly increased in the 4 and 8 mg/m(3) concentration groups, and urinalysis revealed increased levels of protein and alkaline phosphatase activity in urine of all Hg0-exposed rats. Dams exposed to 8 mg/m(3) were euthanized in moribund condition on postnatal day (PND) 1. There was no histopathological evidence of toxicity in maternal lung, liver, or kidney of exposed rats at GD 6, GD 15, or PND 1. The incidence of resorptions was significantly increased, litter size and PND 1 neonatal body weights were significantly decreased only in the 8-mg/m(3) group. Total Hg concentrations in maternal tissues increased with increasing number of exposure days and concentration. In general, approximately 70% of Hg was eliminated from maternal tissues during the week following the last exposure (GD 15 to PND 1). Elimination of Hg from maternal brain and kidney was slower than in other tissues, possibly due to higher levels of metallothionein. Total Hg concentrations in fetal tissues increased with increasing number of exposure days and concentration, demonstrating that a significant amount of Hg crossed the placenta. One week after the last exposure, significant amounts of Hg were still present in brain, liver, and kidney of PND 1 neonates. Metallothionein levels in neonatal tissues were not significantly increased by exposure to 4 mg/m(3) Hg0. The total amount of Hg in neonatal brain (ng/brain) continued to increase after termination of inhalation exposure, suggesting a redistribution of Hg from the dam to neonatal brain. These data demonstrate that inhaled Hg0 vapor is distributed to all maternal and fetal tissues in a dose-dependent manner. Adverse effects of Hg on developmental outcome occurred only at a concentration that caused maternal toxicity.

Upper respiratory tract toxicity of inhaled methylvinyl ketone in F344 rats and B6C3F1 mice.

The National Toxicology Program is conducting a chemical class study to investigate the structure-activity relationships for the toxicity of alpha,beta-unsaturated ketones. Methylvinyl ketone (MVK) was selected for study because it is a representative straight-chain aliphatic alpha,beta-unsaturated ketone and because of its extensive use and widespread exposure. Short-term inhalation studies of MVK were conducted to provide toxicity data for comparison with other alpha,beta-unsaturated ketones and for use in designing chronic toxicity and carcinogenicity studies. In 2-week studies, rats and mice were exposed to 0, 0.25, 0.5, 1, 2, 4, or 8 ppm MVK 6 h/day, 5 days/week for 12 exposures. Morbidity and early deaths occurred in all male and female rats after 1 exposure and in 2 male mice after 10 exposures to 8 ppm. Rats exhibited nasal cavity toxicity and lung necrosis at 4 ppm. No toxicity was observed in animals exposed to less than 2 ppm. Based on these results a 13-week study was conducted at 0, 0.5, 1, and 2 ppm MVK. As observed in the 2-week study, the nasal cavity was the main target organ and rats were more sensitive than mice. Respiratory and olfactory epithelial necrosis were prominent by day 21 in the rat. At study termination these lesions were still evident but not as severe as noted earlier. Additionally, changes such as olfactory epithelial regeneration and metaplasia (respiratory) as well as respiratory epithelial hyperplasia and metaplasia (squamous) were clearly evident. Nasal lesions in mice were limited to a subtle squamous metaplasia of transitional and/or respiratory epithelium covering predominantly the tips of naso- and maxilloturbinates in Levels I and II. A transient, leukopenia was observed in rats exposed to 2 ppm, however, this effect was not present after 13 weeks of exposure. In mice, leukocyte counts were significantly decreased at all exposure concentrations after 13 weeks of exposure. Absolute testicular and epididymal weights and sperm counts were decreased at the high dose only. MVK can be characterized as a reactive, direct-acting gaseous irritant. MVK exposure causes the same nasal cavity lesions as the cyclic alpha,beta-unsaturated ketone, 2-cyclohexen-1-one, although at lower exposure concentrations.

Cytogenetic and germ cell effects of phosphine inhalation by rodents: II. Subacute exposures to rats and mice.

Phosphine (PH3) is a highly toxic grain fumigant to which there is significant human workplace exposure. To determine the in vivo cytogenetic effects of inhalation of PH3, male F344/N rats and B6C3F1 mice were exposed to target concentrations of 0, 1.25, 2.5, or 5 ppm PH3 for 6 hr/day for 9 days over an 11-day period. Approximately 20 hr after the termination of exposures, blood was removed from the mice and rats by cardiac puncture and the lymphocytes cultured for analyses of sister chromatid exchanges and chromosome aberrations in rats and mice, and micronuclei (MN) in cytochalasin B-induced binucleated lymphocytes from mice. In addition, bone marrow (rats) and peripheral blood (mice) smears were made for the analysis of MN in polychromatic and normochromatic erythrocytes. No significant increase in any of the cytogenetic endpoints was found at any of the concentrations examined. These results indicate that concentrations of PH3 up to 5 ppm are not genotoxic to rodents when administered by inhalation for 9 days during an 11-day period as measured by several cytogenetic assays. To evaluate the effects of PH3 on male germ cells, a dominant lethal test was conducted in male mice exposed to 5 ppm PH3 for 10 days over a 12-day period and mated to groups of untreated females (2 females/male) on each of 6 consecutive 4-day mating intervals. None of the 6 groups of females exhibited a significant increase in percent resorptions. These results indicate that exposure to 5 ppm PH3 by inhalation does not induce dominant lethality in male mouse germ cells at steps in spermatogenesis ranging from late differentiating spermatogonia/early primary spermatocytes through mature sperm.

Primary tumors of the facial nerve: diagnosis and management.

Benign primary tumors of the facial nerve are frequently misdiagnosed because of variable and subtle clinical manifestations. Three such cases of facial nerve neuroma seen in the past 3 years will be presented. Difficulties in patient assessment including the lack of specificity for topographic testing, as well as the capricious behavior of the facial nerve in these patients will be discussed. The efficacy of diagnostic techniques presently available and in use including computerized tomography and electrodiagnostic studies will be discussed. Diagnosis of these tumors might generally be thought to be straightforward and easier with the advent of new diagnostic techniques, but this has, in fact, not been the case. Techniques for removal and repair will be presented. The combined approach utilizing the mastoid and middle fossa will be presented.

Trial of an oral antigen against upper respiratory-tract infection. Results in the second year (1973-74).

A double-blind trial in two randomly structured groups of boarders (44 girls and 66 boys) aged 7 to 13 years was undertaken in two Bristrol schools. Dosage was 1 ml a day of fluid (antigen or placebo) orally for the first four weeks of the autumn term, absenteeism being the main parameter measured, using a structured recording code. There was a highly significant difference in the number of days lost from upper respiratory-tract infection in the treated as opposed to the placebo group (x2 = 40-00 P less than 0-001 (v = 1). The number of colds was also significantly lower in the treated group (x2 = 8-05 P less than 0-005 (V less than i)).

Lack of confidence among trainee doctors in the management of diabetes: the Trainees Own Perception of Delivery of Care (TOPDOC) Diabetes Study.

BACKGROUND: There is an increased prevalence of diabetes. Doctors in training, irrespective of specialty, will have patients with diabetes under their care. AIM: To determine levels of confidence of doctors in training in the management of diabetes and establish their training needs in this area of clinical practice. DESIGN: A national online survey of trainee doctors in the UK using a pre-validated questionnaire. METHODS: A four-point confidence rating scale was used to rate confidence in the management of diabetes and comparators. A six-point scale was used to quantify how often trainees would contribute to the management of patients with diabetes and trainees were asked about their training in managing diabetes. RESULTS: A total of 2149 doctors completed the survey. The percentage 'fully confident' in diagnosing diabetes was 27%, diagnosing and managing hypoglycaemia 55%, diagnosing and managing diabetic ketoacidosis 43%, managing intravenous (IV) insulin 27%, prescribing IV fluids for patients with diabetes 39% and altering diabetes therapy prior to surgery/other procedure 18%. In comparison, 66% and 65% were 'fully confident' in the management of angina and asthma, respectively (P < 0.05). Forty-one percent would take the initiative to optimize glycaemic control for patients under their care >80% of the time. Respectively, 19% and 35% of respondents reported that their undergraduate and postgraduate training had prepared them adequately to optimize treatment of diabetes. The majority (>70%) wanted further training in managing all aspects of diabetes care. CONCLUSIONS: Trainee doctors in the UK lack confidence in the management of diabetes, are unlikely to take the initiative to optimize glycaemic control and report a need for further training.