Guidelines for the management of diabetes in care homes during the Covid-19 pandemic.

The National Diabetes Stakeholders Covid-19 Response Group was formed in early April 2020 as a rapid action by the Joint British Diabetes Societies for Inpatient Care, Diabetes UK, the Association of British Clinical Diabetologists, and Diabetes Frail to address and support the special needs of residents with diabetes in UK care homes during Covid-19. It was obvious that the care home sector was becoming a second wave of Covid-19 infection and that those with diabetes residing in care homes were at increased risk not only of susceptibility to infection but also to poorer outcomes. Its key purposes included minimising the morbidity and mortality associated with Covid-19 and assisting care staff to identify those residents with diabetes at highest risk of Covid-19 infection. The guidance was particularly created for care home managers, other care home staff, and specialist and non-specialist community nursing teams. The guidance covers the management of hyperglycaemia by discussion of various clinical scenarios that could arise, the management of hypoglycaemia, foot care and end of life care. In addition, it outlines the conditions where hospital admission is required. The guidance should be regarded as interim and will be updated as further medical and scientific evidence becomes available.

Language matters. Addressing the use of language in the care of people with diabetes: position statement of the English Advisory Group.

The language used by healthcare professionals can have a profound impact on how people living with diabetes, and those who care for them, experience their condition and feel about living with it day-to-day. At its best, good use of language, both verbal and written, can lower anxiety, build confidence, educate and help to improve self-care. Conversely, poor communication can be stigmatizing, hurtful and undermining of self-care and can have a detrimental effect on clinical outcomes. The language used in the care of those with diabetes has the power to reinforce negative stereotypes, but it also has the power to promote positive ones. The use of language is controversial and has many perspectives. The development of this position statement aimed to take account of these as well as the current evidence base. A working group, representing people with diabetes and key organizations with an interest in the care of people with diabetes, was established to review the use of language. The work of this group has culminated in this position statement for England. It follows the contribution of Australia and the USA to this important international debate. The group has set out practical examples of language that will encourage positive interactions with those living with diabetes and subsequently promote positive outcomes. These examples are based on a review of the evidence and are supported by a simple set of principles.

European molecular epidemiology and strain diversity of feline calicivirus.

Feline calicivirus (FCV) causes a variable syndrome of upper respiratory tract disease, mouth ulcers and lameness. A convenience-based prospective sample of oropharyngeal swabs (n=426) was obtained from five countries (France, Germany, Greece, Portugal and the UK). The prevalence of FCV by virus isolation was 22.2 per cent. Multivariable analysis found that animals presenting with lymphoplasmacytic gingivitis stomatitis complex were more likely to test positive for FCV infection. Furthermore, vaccinated cats up to 48 months of age were significantly less likely to be infected with FCV than unvaccinated animals of similar ages. Phylogenetic analysis based on consensus sequences for the immunodominant region of the capsid gene from 72 FCV isolates identified 46 strains. Thirteen of the 14 strains with more than one sequence were restricted to individual regions or sites in individual countries; the exception was a strain present in two sites close to each other in France. Four strains were present in more than one household. Five colonies, four of which were rescue shelters, had multiple strains within them. Polymerase sequence suggested possible rare recombination events. These locally, nationally and internationally diverse FCV populations maintain a continuous challenge to the control of FCV infection and disease.

Respiratory syncytial virus infection of airway epithelial cells, in vivo and in vitro, supports pulmonary antibody responses by inducing expression of the B cell differentiation factor BAFF.

BACKGROUND: The mechanisms regulating antibody expression within the human lung during airway infection are largely unknown. In this study, our objectives were to determine if infection with respiratory syncytial virus (RSV) upregulates expression of the B cell differentiation factors A proliferation inducing ligand (APRIL) and B cell activating factor of the TNF family (BAFF), if this is a common feature of viral airway infection, and how this is regulated in human airway epithelial cells. METHODS: We measured BAFF and APRIL protein expression in bronchoalveolar lavage (BAL) fluid from infants with severe RSV disease, and healthy control children, and in nasopharyngeal aspirates from preschool children with other single respiratory viral infections. We also measured mRNA expression in bronchial brushings from RSV-infected infants, and in RSV-infected paediatric primary airway epithelial cell cultures (pAEC). Beas-2B cell cultures were used to examine mechanisms regulating BAFF expression. RESULTS: BAFF protein and mRNA were elevated (in marked contrast with APRIL) in BAL and bronchial brushings, respectively, from RSV-infected infants. BAFF protein was also found in upper airway secretions from children with human metapneumovirus, H1N1, bocavirus, rhinovirus, RSV and Mycoplasma pneumoniae infection. BAFF mRNA and protein were expressed following in vitro RSV infection of both pAEC and Beas-2B cultures, with mRNA expression peaking 12-h postinfection. BAFF induction was blocked by addition of a neutralising anti-interferon-ß antibody or palivizumab. CONCLUSIONS: BAFF, produced through an interferon-ß-dependent process, is a consistent feature of airway infection, and suggests a role for the airway epithelia in supporting protective antibody and B cell responses in the lung.

Neutrophil TLR4 expression is reduced in the airways of infants with severe bronchiolitis.

BACKGROUND: In respiratory syncytial virus (RSV) bronchiolitis, neutrophils account for >80% of cells recovered from the airways in bronchoalveolar lavage (BAL) fluid. This study investigated neutrophil activation and Toll-like receptor (TLR) expression in the blood and lungs of infants with severe RSV bronchiolitis. METHODS: BAL fluid and (blood) samples were collected from 24 (16) preterm and 23 (15) term infants ventilated with RSV bronchiolitis, and 12 (8) control infants. Protein levels and mRNA expression of CD11b, myeloperoxidase (MPO) and TLRs 2, 4, 7, 8 and 9 were measured in neutrophils. RESULTS: Blood neutrophils had more CD11b in preterm and term infants with RSV bronchiolitis than control infants (p<0.025) but similar amounts of MPO. BAL fluid neutrophils from infants with RSV bronchiolitis had greater amounts of CD11b and MPO than blood neutrophils and BAL fluid neutrophils from controls (p<0.01). Blood neutrophils from term infants with RSV bronchiolitis had less total TLR4 protein than preterm infants with RSV bronchiolitis (p = 0.005), and both had less than controls (p<0.04). Total TLR4 for each group was greater in BAL fluid neutrophils than in blood neutrophils. Blood neutrophils from preterm infants with RSV bronchiolitis had greater TLR4 mRNA expression than term infants with RSV bronchiolitis (p = 0.005) who had similar expression to controls (p = 0.625). CONCLUSIONS: In infants with severe RSV bronchiolitis, neutrophil activation starts in the blood and progresses as they are recruited into the airways. Total neutrophil TLR4 remains low in both compartments. TLR4 mRNA expression is unimpaired. This suggests that neutrophil TLR4 expression is deficient in these infants, which may explain why they develop severe RSV bronchiolitis.

Diagnosis of pulmonary embolus using ventilation/perfusion lung scintigraphy: more than 0.5 segment of ventilation/perfusion mismatch is sufficient.

BACKGROUND: To determine the optimal diagnostic cut-off point using a simplified criterion for the detection of pulmonary embolus (PE) and to evaluate the criterion's utility and reporter reproducibility. METHODS: Lung scintigraphy was carried out in 924 patients for the diagnosis of PE. This group consisted of 316 men and 608 women with median age of 63 years (range 18-94 years). Ventilation imaging was carried out with Tc-99m Technegas followed by perfusion imaging using 190 MBq Tc-99m macroaggregated albumin. Studies were classified using a 6-category probability criterion of incremental ventilation/perfusion (V/Q) mismatch: A, normal; B, low (minor matched V/Q defects or segmental matched V/Q defects without opacity on chest X-ray); C, low-moderate (a partial segment of V/Q mismatch); D, moderate (1 segment of mismatch); E, moderate-high (1-2 segments of V/Q mismatch) and F, high probability (=2 segments of V/Q mismatch). Clinical end-points at 3 and 6 months were death by PE or PE treated with anticoagulation therapy. Three-reporter reproducibility was determined by kappa statistic on a subgroup of patients (53/924). RESULTS: A total of 122 patients (13%) had a confirmed diagnosis of PE at 3 months and no additional cases were registered at 6 months. The lung scintigraphy probability classification showed: normal 152 (16%), low 620 (67%), low-moderate 20 (2%), moderate 28 (3%), moderate-high 24 (3%) and high 80 (9%). The respective sensitivities and specificities, where the diagnostic cut-offs were established at F, high; E, moderate-high; D, moderate and C, low-moderate probability, were F, 64 and 100%; E, 82 and 99%; D, 95 and 98% and C, 98 and 96%. The respective false-negative cases for F, E, D and C cut-offs were 44, 22, 7 and 3. Using the revised Prospective Investigation of Pulmonary Embolism Diagnosis reporting classification reporter agreement showed kappa values of 0.31-0.48. Using a simplified 2-category (>0.5 segment of V/Q mismatch positive, all others negative) criterion resulted in a higher reporting agreement (kappa 0.74-0.83). There were only 3% of indeterminate cases if this was defined by the D category and a maximum of 8% if categories C, D and E were included. CONCLUSIONS: Using a simplified diagnostic criterion where all studies showing >0.5 segments of V/Q mismatch are regarded as positive and all others as negative, lung scintigraphy, incorporating Tc-99m Technegas ventilation imaging or its equivalent, can achieve a very high diagnostic accuracy for the detection of PE. Using this technique, less than 5% of scans are indeterminate. A simplified, unambiguous approach to reporting is recommended.

Complementary role of adjunctive breast magnetic resonance imaging and scintimammography in patients of all ages undergoing breast cancer surgery.

The aims of this study were to assess breast MRI and scintimammography (SMM) for the detection of breast cancer, and to determine any complementary role of these tests to each other and conventional imaging. Seventy-two patients (age 35-81 years) with a suspicious breast mass were investigated by mammography, breast ultrasound, breast MRI and SMM before undergoing surgical excision of the breast mass. Sensitivity, specificity and area under receiver operator characteristic curves were calculated for each test. Of the 72 patients, there were 66 proven malignant tumours, including two patients with bilateral breast cancer. When comparing the diagnostic sensitivity of breast MRI and SMM for lesion size, both tests showed higher sensitivities for lesions >25 mm in size, particularly for SMM. When these tests were compared for patient age, patients less than 51 years showed higher sensitivities for both tests. This was statistically significant for breast MRI. The overall respective diagnostic sensitivities for mammography, mammography with breast ultrasound, breast MRI and SMM were 56, 67, 86 and 85%. The differences were significant between mammography, mammography/ultrasound and both breast MRI and SMM. Breast MRI and SMM offer incremental diagnostic advantage in the diagnosis of breast cancer. Although improved diagnostic accuracy is seen in patients of all ages, those patients less than 51 years of age receive the greatest diagnostic benefit.

Increased incidence of neoplasia of the digestive tract in men with persistent activation of the coagulant pathway.

BACKGROUND: Thrombin promotes angiogenesis and cell proliferation in cancer. Whether thrombin turnover influences cancer incidence is unknown. OBJECTIVES: To explore the relation between the status of the coagulant pathway and cancer incidence by population survey. METHODS: Of 4,009 middle-aged men clinically free of malignancy, 3052 (76.1%) were recruited. Measurements of hemostatic status were made annually for 4 years, and follow-up for morbidity and mortality was maintained thereafter. Persistent activation of the coagulant pathway was diagnosed when prothrombin fragment 1+2 and fibrinopeptide A concentrations exceeded the upper quartiles of the population distribution in two consecutive annual examinations. Cancer incidence rates in men developing persistent activation (taking the time of onset of activation as baseline) were compared with those in men remaining free of this condition. RESULTS: Persistent activation of the hemostatic pathway was a distinct entity found in 111 men [43 expected by chance alone (P <0.001)], and associated with activation throughout the coagulation pathway. Total mortality (/1000 person-years) was higher in those with persistent activation than in others (17.1 and 9.7, respectively, P=0.015), owing to a higher mortality from all cancers (11.3 and 5.1, respectively, P=0.01), due in turn largely to a higher mortality from cancers of the digestive tract (6.3 and 1.9, respectively, P=0.004). Trends were similar for non-fatal cancers. CONCLUSIONS: Persistent activation of the coagulant pathway plays a role in the preclinical phase of cancer and is associated with an increased incidence of clinical malignancy, especially of the digestive tract.

A modified Kleihauer technique for the quantification of foetomaternal haemorrhage.

The Kleihauer technique, based on acid elution of maternal red cells, is the mostly widely used technique in the UK to screen for, and estimate the volume of, foetomaternal haemorrhage (FMH) and for determining the need for additional doses of anti-D immunoglobulin to prevent maternal alloimmunization. However, technicians often report difficulties in identifying and accurately counting maternal red cells in the blood film, leading to imprecision in the calculated FMH. In this report, we describe a simple modification of the standard Kleihauer technique, based on performing acid elution of only half of the film. Compared to the standard method, the modified technique showed improved accuracy and reduced interobserver variability across a range of simulated FMH volumes. There was a high degree of correlation between the new technique and FMH estimated by flow cytometry (r2 = 0.916, P < 0.001). Technicians found the new technique easy to incorporate into routine practice in a busy teaching hospital laboratory and were impressed by the relative ease of counting maternal ghost cells. The modified technique has been used routinely in our laboratory for 3 years, during which time our performance in the UK National External Quality Assurance Scheme for FMH has been uniformly satisfactory.

A performance evaluation of commercial fibrinogen reference preparations and assays for Clauss and PT-derived fibrinogen.

The wide availability of fibrinogen estimations based on the prothrombin time (PT-Fg) has caused concern about the variability and clinical utility of fibrinogen assays. In a multi-centre study, we investigated fibrinogen assays using various reagents and analysers. Clauss assays generally gave good agreement, although one reagent gave 15-30% higher values in DIC and thrombolysis. Two commercial reference preparations had much lower potencies than the manufacturers declared, and plasma turbidity influenced parallelism in some Clauss assays. PT-Fg assays gave higher values than Clauss and showed calibrant dependent effects, the degree of disparity correlating with calibrant and test sample turbidity. Analyser and thromboplastin dependent differences were noted. The relationship between Clauss and PT-Fg assays was sigmoid, and the plateau of maximal PT-Fg differed by about 2 g/l between reagents. ELISA and immunonephelometric assays correlated well, but with a high degree of scatter. Antigen levels were higher than Clauss, but slightly lower than PT-Fg assays, which appeared to be influenced by degraded fibrinogen. Clauss assays are generally reproducible between centres, analysers and reagents, but PT-Fg assays are not reliable in clinical settings.

The clinical utility of nuclear medicine imaging for the detection of occult gastrointestinal haemorrhage.

Acute gastrointestinal bleeding is often intermittent and the bleeding source may be difficult to locate, resulting in delay of potentially life-saving treatment. The aim of this study was to determine the clinical utility of 99mTc labelled red blood cell imaging and [99mTc]pertechnetate (Meckel's scan) imaging in a series of 137 patients admitted over a 5 year period to hospital for management of acute gastrointestinal bleeding. Of the 137 patients, 70 had positive 99mTc red blood cell studies. Eleven of 24 patients who had imaging performed beyond 3 h had positive scans that would otherwise have been missed. Only 47 patients had a definite final diagnosis at the time of hospital discharge, of which six were negative on 99mTc red blood cell imaging. The correct site of bleeding was localized in seven of 21 patients with foregut bleeding, and 15 of 20 patients with colonic bleeding. Endoscopy yielded a diagnosis in 13 of the 47 patients (28%). Eleven patients had Meckel's scans but all were negative. Angiography was diagnostic in one of 17 patients studied. 99mTc red blood cell imaging is a useful test in the management of acute gastrointestinal bleeding. Imaging beyond 3 h may further improve the bleeding detection rate. This test, however, may be an unreliable means of localization of bleeding, particularly in the foregut.

Does inflammatory proteolytic activity contribute to the increased factor IX activation peptide in men at high risk of coronary heart disease? A preliminary study.

In the Second Northwick Park Heart Study, the activation peptides of factor IX (FIXpep) and factor X (FXpep) were measured in 1261 middle-aged men by double-antibody radioimmunoassay. During follow-up 147 men who had a first coronary heart disease (CHD) event were found to have had an increased FIXpep (p = 0.003) and a reduced FXpep (p = 0.05) at baseline compared with those remaining CHD-free (controls). Plasma FIXpep and FXpep were positively associated, but the rate of rise in FIXpep with increasing FXpep was higher in cases than controls (p for interaction = 0.01). In a sample of 87 controls, FIXpep was positively and independently related to the concentrations of a polymorphonuclear-specific fibrinogen degradation product (p = 0.036) and FXpep (p = 0.004), but in larger samples no statistically significant associations were found either with C-reactive protein or with fibrinogen concentration. The findings suggested that the increased FIXpep in men at high CHD-risk may have been partly due to the generation of factor IX inactivation peptides by inflammatory proteolysis and their recognition together with true FIXpep in the radioimmunoassay. Direct evidence for this hypothesis requires development of assays for human elastase-specific factor IX inactivation peptides.

Factor VII activation, apolipoprotein A-I and reverse cholesterol transport: possible relevance for postprandial lipaemia.

Postprandial lipaemia is associated with activation of factor VII (FVII) and efflux of cholesterol from tissues to nascent plasma high density lipoproteins (HDL) containing apolipoprotein A-I (apo A-I). To determine whether FVII activation and cholesterol efflux occur together in other situations, the responses to intravenous infusion of HDL-like apo A-I/phosphatidylcholine discs were measured in 10 healthy men. Disc infusion (40 mg apo A-I/kg body weight) over 4 h was followed by increases in HDL cholesteryl ester and plasma apo A-I (p <0.0001). Significant activation of FVII was apparent during infusion in fasting subjects (p = 0.03), activated FVII averaging 123% of baseline value by 12 h (p <0.0001). Plasma thrombin-antithrombin (TAT) complex increased to 156% of baseline level by 12 h (p >0.05) but individual responses differed considerably. Peak TAT post-infusion was associated inversely with peak HDL triglyceride concentration (p = 0.004). The coagulation responses to disc-infusion may be due to transfer of phosphatidylserine to cell surfaces during cholesterol efflux.

Determination of the optimal minimum radioiodine dose in patients with Graves' disease: a clinical outcome study.

The study was performed under the auspices of the International Atomic Energy Commission, Vienna, Austria, with the aim of determining the optimal minimum therapeutic dose of iodine-131 for Graves' disease. The study was designed as a single-blinded randomised prospective outcome trial. Fifty-eight patients were enrolled, consisting of 50 females and 8 males aged from 17 to 75 years. Each patient was investigated by clinical assessment, biochemical and immunological assessment, thyroid ultrasound, technetium-99m thyroid scintigraphy and 24-h thyroid 131I uptake. Patients were then randomised into two treatment groups, one receiving 60 Gy and the other receiving 90 Gy thyroid tissue absorbed dose of radioiodine. The end-point markers were clinical and biochemical response to treatment. The median follow-up period was 37.5 months (range, 24-48 months). Among the 57 patients who completed final follow-up, a euthyroid state was achieved in 26 patients (46%), 27 patients (47%) were rendered hypothyroid and four patients (7%) remained hyperthyroid. Thirty-four patients (60%) remained hyperthyroid at 6 months after the initial radioiodine dose (median dose 126 MBq), and a total of 21 patients required additional radioiodine therapy (median total dose 640 MBq; range 370-1,485 MBq). At 6-month follow-up, of the 29 patients who received a thyroid tissue dose of 90 Gy, 17 (59%) remained hyperthyroid. By comparison, of the 28 patients who received a thyroid tissue dose of 60 Gy, 17 (61%) remained hyperthyroid. No significant difference in treatment response was found (P=0.881). At 6 months, five patients in the 90-Gy group were hypothyroid, compared to two patients in the 60-Gy group (P=0.246). Overall at 6 months, non-responders to low-dose therapy had a significantly larger thyroid gland mass (respective means: 35.9 ml vs 21.9 ml) and significantly higher levels of serum thyroglobulin (respective means: 597.6 microg/l vs 96.9 microg/l). Where low-dose radioiodine treatment of Graves' disease is considered, a dose of 60 Gy will yield a 39% response rate at 6 months while minimising early hypothyroidism. No significant advantage in response rate is gained by using a dose of 90 Gy. For more rapid therapeutic effect at the expense of an increased rate of hypothyroidism, doses in excess of 120 Gy may be required. Ultrasound determination of thyroid mass and measurement of serum thyroglobulin levels may be predictive of those patients who will be less responsive to low-dose therapy.