Interrogation of a longitudinal, national pharmacy claims dataset to explore factors that predict the need for add-on therapy in older and socioeconomically disadvantaged Australians with type 2 diabetes mellitus patients (T2DM).

PURPOSE: The management of type 2 diabetes mellitus (T2DM) is complex. The aim of this work is to explore factors that predict the need for add-on therapy in patients with T2DM in the community. METHODS: We accessed longitudinal, pharmacy payment claim records from the national Pharmaceutical Benefits Scheme (PBS) (Subsidises costs of medicines: government pays difference between patient co-payments, lower in concessional patients, and additional cost of drug.) for the period January 2006 to September 2014 (EREC/MI3127) from a 10% random sample of the Australian population validated to be representative of the population by the Australian Bureau of Statistics (ABS). Likely, T2DM patients were identified as those having been dispensed a single anti-hyperglycaemic drug (monotherapy). The time taken and possible factors that might lead to the addition of a second therapy were examined. An examination was made of trends in the co-prescription of either antihypertensive or anti-hyperlipidaemic agents in relation to the time (± 3 years) of initiating an anti-hyperglycaemic agent. RESULTS: Most (83%) presumed T2DM patients were initiated with metformin. The average time until the second agent was added was 4.8 years (95% CI 4.7-4.9). Satisfactory adherence, age, male gender, initiating therapy after 2012 and initiating with a sulphonylurea drug all were significant risks for add-on therapy. There was no overall trend in the initiation of antihypertensive and/or anti-hyperlipidaemic agents with respect to the time of anti-hyperglycaemic initiation. CONCLUSION: The usefulness of a longitudinal dataset of pharmacy-claim records is demonstrated. Over half of all older and socioeconmically disadvantaged T2DM patients captured in this longitudinal claims database will be prescribed a second anti-hyperglycaemic agent within 5 years of their first drug therapy. Several factors can predict the risk of prescription of add-on therapy, and these should be considered when prescribing medications to treat T2DM.

A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function.

PURPOSE: The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CLR), and apparent non-renal clearance of metformin (CLNR/F) in patients with varying degrees of kidney function and to develop dosing recommendations. METHODS: Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CLCR; range, 14-112 mL/min). A population pharmacokinetic model was built (NONMEM) in which the oral availability (F) was fixed to 0.55 with an estimated inter-individual variability (IIV). Simulations were performed to estimate AUC0-τ, CLR, and CLNR/F. RESULTS: The data (66 patients, 327 observations) were best described by a two-compartment model, and CLCR was a covariate for CLR. Mean CLR was 17 L/h (CV 22%) and mean CLNR/F was 1.6 L/h (69%).The median recovery of metformin in urine was 49% (range 19-75%) over a dosage interval. When CLR increased due to improved renal function, AUC0-τ decreased proportionally, while CLNR/F did not change with kidney function. Target doses (mg/day) of metformin can be reached using CLCR/3 × 100 to obtain median AUC0-12 of 18-26 mg/L/h for metformin IR and AUC0-24 of 38-51 mg/L/h for metformin XR, with Cmax < 5 mg/L. CONCLUSIONS: The proposed dosing algorithm can be used to dose metformin in patients with various degrees of kidney function to maintain consistent drug exposure. However, there is still marked IIV and therapeutic drug monitoring of metformin plasma concentrations is recommended.

Trends in metformin utilisation and dose appropriateness in Australia.

PURPOSE: The study aimed to (1) determine the trends in the utilisation of metformin in Australia, (2) determine the appropriateness of metformin dosing in an Australian teaching hospital and (3) gather the opinions of prescribers on the relationship between metformin dose and renal function. METHODS: National prescription data between 1990 and 2012 were accessed. A retrospective audit (2008-2012) of metformin doses and patient renal function (20 % random sample of all in-patients prescribed metformin) was conducted at St Vincent's Hospital (SVH), Sydney. Prescribers of metformin were interviewed (semi-structured; consultants at SVH) or surveyed (Australian endocrinologists) to gather their understanding of metformin dosing in relation to renal function. RESULTS: Metformin utilisation increased fivefold nationally between 1995 and 2012. Metformin tended to be under-dosed in SVH patients with normal renal function (83.5 %) and over-dosed in patients with impaired renal function (estimated glomerular filtration rate (eGFR) <30 mL/min, 50 %). Consultants indicated that metformin doses needed to be reduced in renal impairment. Most endocrinologists (61 %) were comfortable prescribing metformin down to eGFRs around 30 mL/min. CONCLUSION: The use of metformin increased greatly over the period of the study. Metformin is prescribed frequently for patients with eGFR values below the minimal level approved in the product label (60 mL/min). While prescribers expressed their understanding of the need to reduce metformin doses in patients with renal impairment, we found that metformin doses were higher than appropriate in patients with impaired renal function. Metformin may be used safely when renal function is poor provided dosage is appropriately reduced.

Understanding and improving the use of allopurinol in a teaching hospital.

BACKGROUND: An emphasis on renal function in deciding maintenance doses of allopurinol to prevent allopurinol hypersensitivity has resulted in ineffective prevention of attacks of gout. New therapeutic guidelines for gout have shifted the focus back to titrating maintenance doses to reach a serum uric acid (SUA) concentration target of ≤ 0.36 mmol/L. AIMS: To examine trends in the prescribing of allopurinol in a teaching hospital and their concordance with the new guidelines for gout management, and to explore prescribers' approaches and attitudes to the use of allopurinol. METHODS: An audit was conducted of all inpatients prescribed allopurinol at a teaching hospital between January 2008 and December 2012. Allopurinol dose, SUA, serum creatinine concentrations and estimated glomerular filtration rates were extracted from the hospital databases. Doctors from medical units who regularly prescribed allopurinol were interviewed. RESULTS: The allopurinol dose prescribed in gout patients most commonly was a continuation of the pre-admission dosage. Dosage change during admission was rarely observed. Dosages reflected a consideration of renal function. SUA concentrations were measured in only 21% (n = 269) of gout patients. Prescriber interviews (n = 12) reflected adequate knowledge regarding allopurinol use, but most maintained that the primary care setting was more suitable for the management of dose titration in gout. CONCLUSIONS: SUA concentrations were not routinely measured in the majority of admitted gout patients taking allopurinol. Without SUA measurements and allopurinol dose titration, patients with SUA > 0.36 mmol/L are at increased risk for acute attacks of gout in hospital.

Changes in diet, cardiovascular risk factors and modelled cardiovascular risk following diagnosis of diabetes: 1-year results from the ADDITION-Cambridge trial cohort.

AIMS: To describe change in self-reported diet and plasma vitamin C, and to examine associations between change in diet and cardiovascular disease risk factors and modelled 10-year cardiovascular disease risk in the year following diagnosis of Type 2 diabetes. METHODS: Eight hundred and sixty-seven individuals with screen-detected diabetes underwent assessment of self-reported diet, plasma vitamin C, cardiovascular disease risk factors and modelled cardiovascular disease risk at baseline and 1 year (n = 736) in the ADDITION-Cambridge trial. Multivariable linear regression was used to quantify the association between change in diet and cardiovascular disease risk at 1 year, adjusting for change in physical activity and cardio-protective medication. RESULTS: Participants reported significant reductions in energy, fat and sodium intake, and increases in fruit, vegetable and fibre intake over 1 year. The reduction in energy was equivalent to an average-sized chocolate bar; the increase in fruit was equal to one plum per day. There was a small increase in plasma vitamin C levels. Increases in fruit intake and plasma vitamin C were associated with small reductions in anthropometric and metabolic risk factors. Increased vegetable intake was associated with an increase in BMI and waist circumference. Reductions in fat, energy and sodium intake were associated with reduction in HbA1c , waist circumference and total cholesterol/modelled cardiovascular disease risk, respectively. CONCLUSIONS: Improvements in dietary behaviour in this screen-detected population were associated with small reductions in cardiovascular disease risk, independently of change in cardio-protective medication and physical activity. Dietary change may have a role to play in the reduction of cardiovascular disease risk following diagnosis of diabetes.

Changes in physical activity and modelled cardiovascular risk following diagnosis of diabetes: 1-year results from the ADDITION-Cambridge trial cohort.

AIMS: To describe change in physical activity over 1 year and associations with change in cardiovascular disease risk factors in a population with screen-detected Type 2 diabetes. METHODS: Eight hundred and sixty-seven individuals with screen-detected diabetes underwent measurement of self-reported physical activity, cardiovascular disease risk factors and modelled cardiovascular disease risk at baseline and 1 year (n = 736) in the ADDITION-Cambridge trial. Multiple linear regression was used to quantify the association between change in different physical activity domains and cardiovascular disease risk factors at 1 year. RESULTS: There was no change in self-reported physical activity over 12 months. Even relatively large changes in physical activity were associated with relatively small changes in cardiovascular disease risk factors after allowing for changes in self-reported medication and diet. For every 30 metabolic equivalent-h increase in recreational activity (equivalent to 10 h/brisk walking/week), there was an average reduction of 0.1% in HbA(1c) in men (95% CI -0.15 to -0.01, P = 0.021) and an average reduction of 2 mmHg in systolic blood pressure in women (95% CI -4.0 to -0.05, P = 0.045). CONCLUSIONS: Few associations were observed between change in different physical activity domains and cardiovascular disease risk factors in this trial cohort. Cardiovascular disease risk reduction appeared to be driven largely by factors other than changes in self-reported physical activity in the first year following diagnosis.

Comparing dose prediction software used to manage gentamicin dosing.

BACKGROUND: Current Australian guidelines recommend initiating directed therapy of gentamicin if administration exceeds 48 h. Directed doses of gentamicin require the monitoring of plasma concentrations of gentamicin to determine the 24-h area under the time course of plasma gentamicin concentrations (AUC) and a dosage prediction program, for example TCIWorks or Aladdin. However, doses calculated by such programs have not been compared with an established program. AIM: To compare the directed dosage of gentamicin calculated by TCIWorks, Aladdin and an Excel-based program, with an established program, Abbottbase. METHODS: Peak and trough plasma concentrations after the first and second administered doses of gentamicin were available from three patient groups (n = 20-23) with varying creatinine clearances (<40, 40-80, >80 mL/min). The directed dose needed to produce 24-h AUC values of 80 mg.h/L was calculated using each program. RESULTS: There was a strong correlation between the directed doses predicted by each of the three programs compared with Abbottbase, following the first administered dose (r(2) > 0.97, P < 0.0001). The mean ratio (90% confidence intervals) of these directed doses of the gentamicin were: TCIWorks/Abbottbase 106% (105-107%), Aladdin/Abbottbase 102% (101-103%) and Excel/Abbottbase 108% (106-109%). The correlations and dose ratios were also similar when comparisons were made following the second administered dose. For each of the three renal function groups, all programs yielded similar directed doses. CONCLUSIONS: The four programs used in the calculation of directed doses of gentamicin yielded similar results. Any would be suitable for use in clinical practice.

Metformin therapy in patients with chronic kidney disease.

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open-label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15-40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250-2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3-5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.

Initiating allopurinol therapy: do we need to know the patient's human leucocyte antigen status?

AIMS: Allopurinol hypersensitivity (AH) can rarely be manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) that have high mortality rates. Less serious, but still significant, skin and systemic hypersensitivity reactions form part of the AH spectrum. One hundred per cent of Han Chinese with SJS/TEN due to allopurinol have been found to be at least heterozygous for HLA-B*5801, the carriage rate for this allele in the Han Chinese population being about 15%. The association has been found to be weaker in Caucasians whose HLA-B*5801 carriage rate is less than 6%. We examined the relationship between the different skin hypersensitivity reactions to allopurinol and the HLA-B locus in Australian patients. METHODS: We examined 23 patients referred with AH. RESULTS: Five of six Australian SJS/TEN patients were heterozygous for HLA-B*5801 and four were of South-East Asian origin. Five AH patients without SJS/TEN were all Caucasian and only one of these was positive for HLA-B*5801. Twelve patients with allopurinol-induced maculopapular exanthema were negative for HLA-B*5801, including one South-East Asian. CONCLUSIONS: Cases of AH manifesting as SJS/TENS in Australians are more likely to be in those of Asian heritage. The place of routine testing for HLA-B*5801 prior to commencing allopurinol therapy requires further investigation. However, Han Chinese origin patients commencing allopurinol might be informed of the test and may elect to have it performed as there are alternative hypouricaemic medicines, such as probenecid thereby reducing the risk of a catastrophic reaction to allopurinol.

Eliciting views of Australian pharmaceutical industry employees on collaboration and the concept of Quality Use of Medicines.

BACKGROUND: Pharmaceutical industry involvement in biomedicine has produced major benefits but has also caused concern. At present, there is no consensus as to how medical and government organizations should relate to the pharmaceutical industry and this is partly due to the absence of systematic study of the various alternatives. In Australia industry cooperation has been elicited through the 'Quality Use of Medicines' (QUM) framework within the 'National Medicines Policy'. Little is known about the way employees of pharmaceutical companies respond to the QUM policy and strategies. AIMS: To examine the engagement of the Australian pharmaceutical industry with QUM with a view to assisting medical, government and consumer organizations who may wish to collaborate with industry. METHODS: We carried out a qualitative study using in-depth, semistructured interviews with industry employees, primarily from medical and regulatory affairs departments. RESULTS: Employees of pharmaceutical companies claim that collaboration is important, and that they are altruistic and committed to QUM. At the same time, there is little evidence from this study to support the notion that QUM has brought about structural changes to industry or is positioned as the central goal or framework in designing a company's operational strategies. Moreover, there is a significant degree of ambivalence towards governments and medical organizations. CONCLUSIONS: Employees within the pharmaceutical industry claim a commitment to collaboration and QUM. While these claims cannot be taken entirely at face value, there is potential for meaningful collaboration with industry.

Who attends a UK diabetes screening programme? Findings from the ADDITION-Cambridge study.

AIMS: One of the factors influencing the cost-effectiveness of population screening for Type 2 diabetes may be uptake. We examined attendance and practice- and individual-level factors influencing uptake at each stage of a diabetes screening programme in general practice. METHODS: A stepwise screening programme was undertaken among 135, 825 people aged 40-69 years without known diabetes in 49 general practices in East England. The programme included a score based on routinely available data (age, sex, body mass index and prescribed medication) to identify those at high risk, who were offered random capillary blood glucose (RBG) and glycosylated haemoglobin tests. Those screening positive were offered fasting capillary blood glucose (FBG) and confirmatory oral glucose tolerance tests (OGTT). RESULTS: There were 33 539 high-risk individuals invited for a RBG screening test; 24 654 (74%) attended. Ninety-four per cent attended the follow-up FBG test and 82% the diagnostic OGTT. Seventy per cent of individuals completed the screening programme. Practices with higher general practitioner staff complements and those located in more deprived areas had lower uptake for RBG and FBG tests. Male sex and a higher body mass index were associated with lower attendance for RBG testing. Older age, prescription of antihypertensive medication and a higher risk score were associated with higher attendance for FBG and RBG tests. CONCLUSIONS: High attendance rates can be achieved by targeted stepwise screening of individuals assessed as high risk by data routinely available in general practice. Different strategies may be required to increase initial attendance, ensure completion of the screening programme, and reduce the risk that screening increases health inequalities.

Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide.

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with conventional drugs without clear evidence of safety or the risk of herb-drug interactions. The aim of this study was to assess potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between St John's wort and gliclazide in healthy subjects with different cytochrome P450 2C9 (CYP2C9) genotypes. EXPERIMENTAL APPROACH: A crossover controlled study was conducted in 21 healthy subjects. Each received gliclazide (80 mg) either alone or during 15 days treatment with St John's wort. The area under the plasma concentration-time curve (AUC(0-infinity)), apparent clearance (CL/F) and elimination half-life (t 1/2) of gliclazide and incremental changes in glucose and insulin AUC(0-4) were compared. CYP2C9*2 and CYP2C9*3 alleles were identified using PCR followed by restriction enzyme digestion analysis. KEY RESULTS: St John's wort significantly altered gliclazide pharmacokinetics in all except for four healthy subjects. The mean ratio and 90% confidence interval (CI) of gliclazide AUC(0-infinity) and CL/F were 0.67 (0.55-0.81) and 1.50 (1.24-1.81), respectively, after St John's wort treatment. St John's wort decreased gliclazide t (1/2), with mean ratio and 90% CI of 0.85 (0.74-0.93). There were no significant changes in glucose or insulin AUC(0-4) after St John's wort treatment and no significant differences according to CYP2C9 genotype. CONCLUSIONS AND IMPLICATIONS: Treatment with St John's wort significantly increases the apparent clearance of gliclazide which is independent of CYP2C9 genotype. People with diabetes receiving this combination should be closely monitored to evaluate possible signs of reduced efficacy.

Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects.

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb-drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. EXPERIMENTAL APPROACH: An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25 mg warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between warfarin and herbal medicines. KEY RESULTS: Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin, which is worthy of further investigation. CONCLUSIONS AND IMPLICATIONS: Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly. Co-administration of warfarin and cranberry requires careful monitoring.

How much might cardiovascular disease risk be reduced by intensive therapy in people with screen-detected diabetes?

AIMS: To assess the cardiovascular disease (CVD) risk of people with screen-detected Type 2 diabetes and to estimate the risk reduction achievable through early intensive pharmacological intervention. METHODS: In ADDITION-Cambridge, diabetic patients were identified among people aged 40-69 years through a stepwise screening procedure including a risk score, random and fasting capillary blood glucose, HbA(1c) and oral glucose tolerance test. In those without prior macrovascular disease, 10-year CVD risk was computed using UK Prospective Diabetes Study (UKPDS) and Framingham engines. The absolute risk reduction achievable and its plausible range were predicted using relative risk reductions for individual therapies from published trials and sensitivity analysis. RESULTS: Of the 867 individuals with undiagnosed diabetes, 19% had pre-existing CVD, 97% were overweight or obese, 86% had hypertension, 75% had dyslipidaemia, 20% had microalbuminuria and 18% were smokers. Of those with hypertension, 35% were not prescribed drugs and 42% were suboptimally treated. Of participants with dyslipidaemia, 68% were not prescribed medications and 22% were poorly controlled. Median 10-year CVD risk was 34.0%[interquartile range (IQR) 26.2-44.6] in men and 21.5% (IQR 15.7-28.7) in women using the UKPDS engine; 38.6% (IQR 27.8-53.0) in men and 24.6% (IQR 17.2-32.9) in women using Framingham equations. In the most conservative scenario (no additive effect of therapies), the absolute risk reduction achievable through multifactorial therapy ranged from 4.9 to 9.5% (UKPDS) and from 5.4 to 10.5% (Framingham). The corresponding ranges of numbers needed to treat were 11-20 and 10-19. CONCLUSIONS: People with screen-detected diabetes have an adverse cardiovascular risk profile, which is potentially modifiable through application of existing treatment recommendations.

Biochemical and genetic defects in the DNA-dependent protein kinase in murine scid lymphocytes.

The scid gene product has been identified as the 460-kDa catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs p460), a member of the phosphatidylinositol 3-kinase family. DNA-PK activity is undetectable in scid cells, but the molecular basis for this defect has not been identified. Here we report that expression of p460 in scid lymphocyte precursors is detectable but is reduced at least 10-fold relative to that in wild-type lymphocytes. In addition, we show that the scid mutation disturbs p460 nuclear association, presumably affecting its role in DNA repair pathways. To examine the molecular basis for our observations, we used a degenerate PCR strategy to clone the C-terminal p460 kinase domain from wild-type and scid thymocytes. Northern (RNA) analysis with these probes revealed normal steady-state p460 mRNA levels in scid cells, suggesting that the reduced abundance of p460 protein is due to a posttranscriptional defect. Sequence comparisons identified a single-base-pair alteration in the scid C-terminal p460 kinase domain, resulting in a premature stop codon. This mutation is predicted to truncate p460 by approximately 8 kDa, but it preserves the conserved motifs required for kinase activity in members of the phosphoinositidyl 3-kinase family. Despite a computed molecular weight alteration of less than 2%, we were able to visualize this difference by Western blot (immunoblot) analysis of wild-type and scid p460. These data demonstrate that the scid DNA-PKes mutation is not a null allele and suggest a molecular rationale for the well-described leakiness of the scid phenotype.

Has the use of disease-modifying anti-rheumatic drugs changed as a consequence of controlled access to high-cost biological agents through the Pharmaceutical Benefits Scheme?

BACKGROUND: A prerequisite for access to biological agents for the treatment of rheumatoid arthritis under Australia's Pharmaceutical Benefits Scheme (PBS) is evidence of an adequate trial of conventional disease-modifying anti-rheumatic drugs (DMARDs). The aim of this study was to examine whether there were changes in prescribing DMARDs since the introduction of the PBS criteria for access to biologicals in August 2003. METHODS: A retrospective study was undertaken of the national use of DMARDs in the period before and after the introduction of biologicals under the PBS. Dispensing data were analysed for changes in patterns of DMARD prescription rates (2000-2005). RESULTS: There were 2 887 746 prescriptions for DMARDs between August 2000 and June 2005. PBS prescriptions accounted for 95% of these. Government expenditure for the DMARDs was $A156m. Trends in the use of DMARDs remained relatively steady over the study period without a significant change around the time the PBS criteria for biologicals were introduced. Use of hydroxychloroquine and leflunomide increased steadily, use of methotrexate and sulfasalazine was stable and use of gold preparations and penicillamine was considerably lower during this 5-year period. CONCLUSION: Introduction of PBS criteria for access to biologicals did not alter the trends in use of DMARDs based on national dispensing data. This study emphasized the value that would accrue from availability of more comprehensive, de-identified, individual patient data that would enable more detailed examination of the use of medicines. These data are available, but cannot be easily accessed. It is time to make the data available for approved, ethical research in the interests of better outcomes from medicines supplied under PBS.

The features of mucosa-associated microbiota in primary sclerosing cholangitis.

BACKGROUND: Little is known about the role of the microbiome in primary sclerosing cholangitis. AIM: To explore the mucosa-associated microbiota in primary sclerosing cholangitis (PSC) patients across different locations in the gut, and to compare it with inflammatory bowel disease (IBD)-only patients and healthy controls. METHODS: Biopsies from the terminal ileum, right colon, and left colon were collected from patients and healthy controls undergoing colonoscopy. Microbiota profiling using bacterial 16S rRNA sequencing was performed on all biopsies. RESULTS: Forty-four patients were recruited: 20 with PSC (19 with PSC-IBD and one with PSC-only), 15 with IBD-only and nine healthy controls. The overall microbiome profile was similar throughout different locations in the gut. No differences in the global microbiome profile were found. However, we observed significant PSC-associated enrichment in Barnesiellaceae at the family level, and in Blautia and an unidentified Barnesiellaceae at the genus level. At the operational taxa unit level, most shifts in PSC were observed in Clostridiales and Bacteroidales orders, with approximately 86% of shifts occurring within the former order. CONCLUSIONS: The overall microbiota profile was similar across multiple locations in the gut from the same individual regardless of disease status. In this study, the mucosa associated-microbiota of patients with primary sclerosing cholangitis was characterised by enrichment of Blautia and Barnesiellaceae and by major shifts in operational taxa units within Clostridiales order.

The incidence, mortality and timing of Pneumocystis jiroveci pneumonia after hematopoietic cell transplantation: a CIBMTR analysis.

Pneumocystis jiroveci pneumonia (PJP) is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Little is known about PJP infections after HSCT because of the rarity of disease given routine prophylaxis. We report the results of a Center for International Blood and Marrow Transplant Research study evaluating the incidence, timing, prophylaxis agents, risk factors and mortality of PJP after autologous (auto) and allogeneic (allo) HSCT. Between 1995 and 2005, 0.63% allo recipients and 0.28% auto recipients of first HSCT developed PJP. Cases occurred as early as 30 days to beyond a year after allo HSCT. A nested case cohort analysis with supplemental data (n=68 allo cases, n=111 allo controls) revealed that risk factors for PJP infection included lymphopenia and mismatch after HSCT. After allo or auto HSCT, overall survival was significantly poorer among cases vs controls (P=0.0004). After controlling for significant variables, the proportional hazards model revealed that PJP cases were 6.87 times more likely to die vs matched controls (P<0.0001). We conclude PJP infection is rare after HSCT but is associated with high mortality. Factors associated with GVHD and with poor immune reconstitution are among the risk factors for PJP and suggest that protracted prophylaxis for PJP in high-risk HSCT recipients may improve outcomes.

Enantiomers in arthritic disorders.

Drugs which have a center of asymmetry are often administered as an equal mixture of the two possible enantiomeric forms i.e. a racemate. However, there are frequently large pharmacodynamic and pharmacokinetic differences between enantiomers. Consequently, it is possible that while one enantiomer mediates the antiinflammatory or antirheumatic action, the other enantiomer, although adding little to the efficacy of the drug, may contribute to its adverse effects. Asymmetric drugs may also serve as sensitive pharmacological probes of the mechanisms underlying the action of drugs and the inflammatory processes which they modulate. These concepts are the focus for this review.