Cost-effectiveness analysis of empagliflozin treatment in people with Type 2 diabetes and established cardiovascular disease in the EMPA-REG OUTCOME trial.

AIM: In the EMPA-REG OUTCOME trial, empagliflozin therapy reduced cardiovascular death by 38% compared with placebo when added to standard of care. Using the trial results, we created a discrete-event simulation model to assess lifetime health economic outcomes in people with Type 2 diabetes and established cardiovascular disease. METHODS: Time-dependent survival regression analysis was performed on data from EMPA-REG OUTCOME for 10 cardiovascular and renal events (e.g. stroke, heart failure hospitalization, macroalbuminuria, cardiovascular mortality) to capture event rates over time, and interaction between events. Model performance was assessed by comparing predicted and observed outcomes at 3 years. Costs in the United Kingdom (UK) and health utilities were obtained from published literature. Outcomes included cumulative event rates, life-years, costs and quality-adjusted life-years (QALYs). RESULTS: The model predicted an 18% relative increase (by 2.1 life-years) in survival for empagliflozin (14.0 life-years) vs. standard of care (11.9 life-years), attributable to direct treatment effect on cardiovascular mortality, and to indirect effect via reductions in other events. Participants treated with empagliflozin may experience improved quality of life (1.0 QALY) and higher costs (£3737/participant), yielding an incremental cost-effectiveness ratio (ICER) of £4083/QALY. Sensitivity analyses confirmed the robustness of these results to changes in input parameters. CONCLUSIONS: Based on extrapolation of EMPA-REG OUTCOME trial data using a participant-level simulation model, empagliflozin in addition to standard of care is projected to be highly cost-effective using UK healthcare costs. The impact in other countries will vary due to differences in drug pricing and accrual of other costs. (Clinical Trial Registry No: NCT01131676).

Effect of gonadotropin-inhibitory hormone on luteinizing hormone secretion in humans.

BACKGROUND: Gonadotropin-inhibitory hormone (GnIH, human homologue of RFRP-3) suppresses gonadotropin secretion in animal models, but its effects have not been studied in the human. OBJECTIVE: We tested the hypotheses that exogenous GnIH inhibits LH secretion (i) in postmenopausal women and (ii) in men concurrently administered exogenous kisspeptin. DESIGN: Following in vitro and in vivo preclinical studies to functionally characterize the GnIH peptide, a dose-finding study (human GnIH: 1·5-150 µg/kg/h, iv for 3 h) was undertaken, and 50 µg/kg/h selected for further evaluation. Five postmenopausal women were administered 50 µg/kg/h iv infusion for 3 h or vehicle on two separate days. Four men were administered kisspeptin-10 (0·3 µg/kg iv bolus) with simultaneous infusion of GnIH (50 µg/kg/h, iv for 3 h) or vehicle. PARTICIPANTS: Healthy postmenopausal women (mean age 58 ± 2 years, LH: 30·8 ± 2·9 IU/l, FSH: 78·7 ± 6·4 IU/l, oestradiol: <50 pmol/l) and men (39·8 ± 2·1 years, mean total testosterone 12·1 ± 1·8 nmol/l, LH 2·2 ± 0·2 IU/l). PRIMARY OUTCOME: Change in area under curve (AUC) of LH during GnIHvs vehicle. RESULTS: During GnIH administration in postmenopausal women, LH secretion decreased (ΔAUC: -9·9 ± 1·8 IU/3 h) vs vehicle (ΔAUC: -0·5 ± 1·7 IU/3 h; P = 0·02). Kisspeptin-10-stimulated LH responses in men were not affected by GnIH co-administration (60-min AUC of LH 6·2 ± 0·8 IU/h with kisspeptin-10 alone, 6·3 ± 1·0 IU/h, kisspeptin-10 with GnIH, P = 0·72). Exogenous GnIH was well tolerated, with no adverse events reported. CONCLUSIONS: Gonadotropin-inhibitory hormone decreased LH secretion in postmenopausal women in this first-in-human study. Kisspeptin-stimulated LH secretion in men was not inhibited during concomitant administration of GnIH.

Kisspeptin-10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback.

STUDY QUESTION: Does sex-steroid feedback influence gonadotrophin responses to kisspeptin-10? SUMMARY ANSWER: Gonadotrophin response to kisspeptin-10 is enhanced in sex-steroid deficient post-menopausal women and suppressed in women taking pharmacological doses of exogenous estrogen and progestogen. WHAT IS KNOWN ALREADY: Kisspeptin, a novel hypothalamic neuropeptide, stimulates gonadotrophin secretion by stimulating GnRH secretion and has been shown in animal models to play a pivotal role in mediating sex steroid feedback. As estrogen feedback occurs at both the hypothalamus and the pituitary levels, we hypothesized that the stimulatory effect of kisspeptin-10 in women would be dependent on prevailing sex steroid milieu. STUDY DESIGN, SIZE, DURATION: An experimental study of a novel neuropeptide in women-10 in the early follicular phase, 6 post-menopausal and 8 taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Gonadotrophin secretion was followed for 60 min after kisspeptin administration. METHODS AND PARTICIPANTS: The gonadotrophin response to intravenous kisspeptin-10 (0.3 µg/kg) in women in the early follicular phase was compared with that in the presence of low endogenous sex steroids/high gonadotrophin secretion (post-menopausal women) and in women taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Area under the curve (AUC) of gonadotrophin secretion sampled at 15 min intervals over 60 min before and after kisspeptin-10 was analysed. MAIN RESULTS AND ROLE OF CHANCE: Kisspeptin-10 stimulated LH secretion in follicular (ΔAUC 2.3 ± 0.8 IU/l h, P = 0.009), post-menopausal (5.3 ± 0.9 IU/l h P 0.002) and progestogen (2.6 ± 0.8 IU/l h P 0.05) groups but not in women taking combined pill (0.9 ± 0.4 IU/l h P 0.13). FSH secretion was significantly increased only in post-menopausal women (ΔAUC 2.6 ± 0.8 IU/l h P = 0.03) with changes of <0.5 IU/l h observed in the other three groups. Both LH and FSH responses in post-menopausal women were significantly larger than the other groups (one-way ANOVA analysis of ΔAUC; LH (P = 0.012) and FSH (P = 0.001)]. LIMITATIONS, REASONS FOR CAUTION: This study only assessed acute responses to an intravenous bolus of kisspeptin-10 administration, and the impact of continuous exposure to kisspeptin-10 on LH pulse frequency in women remains to be studied to fully understand the translational potential. WIDER IMPLICATIONS OF THE FINDINGS: Gonadotrophin secretion in women is stimulated by kisspeptin-10. These results suggest that the pituitary gonadotrope is a functionally important locus of estrogen feedback in women and also inform potential translational applications of kisspeptin in reproductive endocrine disorders. STUDY FUNDING: Medical Research Council (UK). COMPETING INTERESTS: None.

Clinical effectiveness of a brief educational intervention in Type 1 diabetes: results from the BITES (Brief Intervention in Type 1 diabetes, Education for Self-efficacy) trial.

AIMS: Intensive 5-day educational interventions for people with Type 1 diabetes have shown improved outcomes in a number of European studies. The aim was to assess the effectiveness of a brief (2.5 days) psycho-educational intervention. METHODS: Our randomized trial in a secondary-care setting had 54 and 60 participants allocated to intervention and control groups, respectively. Primary outcomes were HbA1c and severe hypoglycaemia. Secondary outcomes were blood pressure, weight, height, lipids and psychometric profile. RESULTS: HbA1c showed no statistically significant change at 3 months [difference = 0.01, 95% confidence interval (CI) -0.23, 0.26, P = 0.92], 6 months (difference = -0.06, 95% CI -0.32, 0.20, P = 0.67) and 12 months (difference = 0.01, 95% CI -0.30, 0.32, P = 0.94). Incidence of severe hypoglycaemia (per patient per year) in the intervention group (0.41) and control group (0.48) was not statistically different. Treatment satisfaction improved at 3 months (difference = 9.4, 95% CI 5.2, 13.6, P = 0.0005), 6 months (difference = 10.4, 95% CI 6.0, 14.8, P = 0.0005) and 12 months (difference = 7.1, 95% CI 2.1, 12.1, P = 0.006). The 'Managing psychological aspects' and 'Setting and achieving goals' dimensions of the Diabetes Empowerment Scale also showed significant improvement at 3, 6 and 12 months. Diabetes Knowledge Test, Illness Perception Questionnaire, Hypoglycaemia Fear Scale and Short Form 36 showed no significant change. CONCLUSIONS: This brief intervention had no significant impact on HbA(1c) or severe hypoglycaemia, but improved diabetes treatment satisfaction and patient empowerment. Current Controlled Trials ISRCTN75807800.

Measurement of the bactericidal activity of fluoroquinolones against Streptococcus pneumoniae using the bactericidal index method.

Kill curve analysis alone showed trovafloxacin to be more bactericidal than levofloxacin, grepafloxacin and moxifloxacin against four isolates of Streptococcus pneumoniae. However, using the bactericidal index (BI) method, levofloxacin was the most bactericidal fluoroquinolone using serum or lung biopsy concentration levels against the ofloxacin-susceptible strains and trovafloxacin was the most bactericidal against the ofloxacin-intermediate strain. None of the fluoroquinolones was bactericidal against the ofloxacin-resistant strain. With BIs using epithelial lining fluid or alveolar macrophage concentration levels, trovafloxacin or grepafloxacin was most bactericidal, respectively. These data illustrate that simple analysis of traditional kill curves may not be adequate in the evaluation of fluoroquinolone bactericidal activity. The results of this study suggest a need for further investigation to assess the role of tissue concentration and bactericidal activity in antimicrobial efficacy.

Hypertension in sickle cell disease.

We report a young male with sickle cell trait who developed severe hypertension and splenic infarction soon after travel to a high altitude. Hypertension persisted for three days after a diagnostic laparotomy. His blood pressure then continued to be normal over the next one and a half years. Red cell sludging in the small vessels of the kidney possibly activated the renin angiotensin system.

Multiple effects of performance-contingent pay for wait-persons.

The owners of three restaurants requested help with the pay of waitpersons who were paid by the hour. The waitpersons asked for raises which the owners said they could not afford. This research changed the method of compensating waitpersons by making their pay contingent on dollars of food sold. Increased productivity and increased earnings per hour of work for all of the waitpersons followed the beginning of the performance-contingent pay. Most of the waitpersons also earned increased take-home pay when the performance-contingent pay began. There was little improvement in labor costs per dollar of food sold, a measure of benefit to the owners. The fact that benefits to workers occurred without benefits to owners is contrary to common views about the effects of performance-contingent pay.

Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men.

CONTEXT: Kisspeptins stimulate GnRH and thus gonadotropin secretion. Kisspeptin-10 is the minimal kisspeptin sequence with full intrinsic bioactivity, but it has not been studied in man. OBJECTIVE: We investigated our hypothesis that kisspeptin-10 increases GnRH and thus LH pulse frequency. DESIGN AND PARTICIPANTS: The dose response of kisspeptin-10 was investigated by administering iv bolus doses (0.01-3.0 µg/kg) and vehicle to healthy men. Effects on LH pulse frequency and size were determined by deconvolution analysis during infusion of kisspeptin-10 for up to 22.5 h. RESULTS: Intravenous bolus kisspeptin-10 resulted in a rapid and dose-dependent rise in serum LH concentration, with maximal stimulation at 1 µg/kg (4.1 ± 0.4 to 12.4 ± 1.7 IU/liter at 30 min, P < 0.001, n = 6). Administration of 3 µg/kg elicited a reduced response vs. 1 µg/kg (P < 0.05). Infusion of kisspeptin-10 at 4 µg/kg · h for 22.5 h elicited an increase in LH from a mean of 5.4 ± 0.7 to 20.8 ± 4.9 IU/liter (n = 4; P < 0.05) and serum testosterone increased from 16.6 ± 2.4 to 24.0 ± 2.5 nmol/liter (P < 0.001). LH pulses were obscured at this high rate of secretion, but a lower dose infusion of kisspeptin-10 (1.5 µg/kg · h) increased mean LH from 5.2 ± 0.8 to 14.1 ± 1.7 IU/liter (n = 4; P < 0.01) and increased LH pulse frequency from 0.7 ± 0.1 to 1.0 ± 0.2 pulses/h (P < 0.05) and secretory burst mass from 3.9 ± 0.4 to 12.8 ± 2.6 IU/liter (P < 0.05). CONCLUSIONS: Kisspeptin-10 boluses potently evoke LH secretion in men, and continuous infusion increases testosterone, LH pulse frequency, and pulse size. Kisspeptin analogues have therapeutic potential as regulators of LH and thus testosterone secretion.

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.

Outcomes of renal transplantation in patients with immunoglobulin A nephropathy in India.

BACKGROUND: There is a paucity of data on the course of renal transplant in patients with immunoglobulin A (IgA) nephropathy (IgAN) from India. While the natural history of IgAN in the Indian context is rapidly progressive, the post-transplant course remains speculative. AIM: To study the graft survival in renal transplant recipients whose native kidney disease was IgAN and the incidence and correlates of recurrent disease. SETTINGS AND DESIGNS: Retrospective case control study from a Nephrology unit of a large tertiary care center. MATERIALS AND METHODS: The outcomes of 56 transplant patients (58 grafts) with biopsy-proven IgAN and of 116 patients without IgAN or diabetic nephropathy, transplanted during the same period were analyzed. Correlates of biopsy-confirmed recurrent disease were determined. STATISTICAL ANALYSIS: Means were analyzed by Student's t test and Mann-Whitney test; proportions were determined by Chi-square analysis and graft survival curves were generated using the Kaplan-Meier. RESULTS: Five-year graft survival for IgA patients was not significantly different from that in the reference group (90% and 79%, P = 0.6). During a mean follow-up of 42 months (range, 1-144), 28 event graft biopsies were required in 20 grafts of IgAN. Histological recurrence was diagnosed in five of the 20 available biopsies (25%) after a mean duration of 28 months. Recurrence did not correlate with donor status, HLA B35 and A2, recipient age, gender or immunosuppression. CONCLUSIONS: Renal transplantation is an appropriate treatment modality for IgA nephropathy patients with end-stage renal disease in India, despite the potential for recurrent disease. The posttransplant course is an indolent one when compared to the malignant pretransplant phase.

Synthesis of spirohydantoins and spiro-2,5-diketopiperazines via resin-bound cyclic alpha,alpha-disubstituted alpha-amino esters.

A seven-step solid-phase synthesis of spirohydantoins and an eight-step solid-phase synthesis of spiro-2,5-diketopiperazines is reported. Key intermediate in the synthesis of both compound libraries is the resin-bound cyclic alpha,alpha-disubstituted alpha-amino ester, which can be obtained after selective homogeneous reduction of the aliphatic nitro ester using tin(II) chloride dihydrate. Nitro ester, in turn, is synthesized by a high-pressure-assisted [4 + 2] cycloaddition of resin-bound nitro alkene and butadiene, whereas nitro alkene is obtained by a Knoevenagel condensation of resin-bound nitro acetate with an imine. Novel spirohydantoins are obtained by isocyanate coupling with the resin-bound amino ester 5, followed by cyclization cleavage using a base. Novel spiro-2,5-diketopiperazines are obtained by PyBOP coupling of a Fmoc-protected amino acid with resin-bound amino ester, followed by Fmoc deprotection and an acid-assisted cyclization cleavage. After preparation of seven different resin-bound alpha,alpha-disubstituted alpha-amino esters, a 7 x 8 compound library of spirohydantoins was synthesized using eight different isocyanates, and a 7 x 8 compound library of spiro-2,5-diketopiperazines was synthesized using eight different Fmoc amino acids.

Purification of pneumococcal type II topoisomerases and inhibition by gemifloxacin and other quinolones.

Topoisomerase IV and DNA gyrase were purified from a ciprofloxacin-sensitive Streptococcus pneumoniae strain and from two clinical isolates of S. pneumoniae with high-level resistance to ciprofloxacin by means of a gene cloning method in Escherichia coli. All the quinolones tested (gemifloxacin, trovafloxacin, levofloxacin, ciprofloxacin and grepafloxacin) were able to inhibit topoisomerase IV at lower concentrations than those required for DNA gyrase, suggesting that topoisomerase IV is the primary target in the three pneumococci, in agreement with recently published enzyme data. Gemifloxacin (SB-265805) was found to be the most active agent against topoisomerase IV but, surprisingly, not against DNA gyrase. These findings indicate that the potent in vitro activity of gemifloxacin against S. pneumoniae, including ciprofloxacin-resistant strains, results from a strong affinity for pneumococcal topoisomerase IV.

Bactericidal activity of gemifloxacin and other quinolones against Streptococcus pneumoniae.

This study compared the bactericidal activity of gemifloxacin (SB-265805) and a panel of test quinolones against two ciprofloxacin-resistant pneumococcal strains (Streptococcus pneumoniae 502226 and 503244) and one ciprofloxacin-sensitive strain (S. pneumoniae C3LN4). Activities were compared by calculating the bactericidal index of these agents. Gemifloxacin was found to be the most bactericidal quinolone tested against these strains. This finding confirms previous data indicating the superior in vitro activity of gemifloxacin against pneumococci, including ciprofloxacin-resistant strains. Although both ciprofloxacin-resistant strains tested had similar quinolone MICs, they differed considerably in their susceptibility to the bactericidal action of these agents. S. pneumoniae 502226 was more readily killed by quinolones than S. pneumoniae 503244 but, as would be expected, both were less susceptible than the ciprofloxacin-sensitive strain. Of the quinolones tested, trovafloxacin showed disproportionally poor activity against the ciprofloxacin-resistant strains even though potent activity was present against the ciprofloxacin-sensitive strain. These data highlight the importance of assessing quinolone bactericidal activity in addition to the MIC when evaluating new members of this antimicrobial class.

Paratyphoid in man and cattle.

Salmonella paratyphi B, phage type Taunton, caused generalized subclinical infection of cows and cases of human enteric fever at a dairy farm. The cattle were probably infected from a stream receiving the sewage effluent of a village in which a chronic carrier lived. At the same time as the farm outbreak a water-borne outbreak of human paratyphoid fever occurred in villages several miles away. The water supply was chlorinated and no failure of its treatment had been detected. S. paratyphi B, type Taunton, was isolated from the septic tank of a cottage near the water source and from soil over a break in the effluent pipe. Several inhabitants of the cottage worked at the infected dairy farm and one showed serological evidence of infection.Attention is drawn to the lack of statutory powers which could be applied to prevent the spread of the disease from the dairy herd and to the hazards of simple chlorination in the absence of additional safeguards of a water supply liable to pollution by surface water.

High pressure: a promising tool for multicomponent reactions.

In this paper the application of high pressure in multicomponent reactions is discussed. Using high pressure the scope of certain multicomponent reactions can be increased. Reactions are described that can only be performed in a multicomponent fashion when high pressure catalysis is applied. An overview of high pressure catalysed multicomponent reactions is presented with special attention to the domino [4 + 2]/[3 + 2] cycloaddition reaction.