155 research outputs found
The effect of mirabegron on patient-related outcomes in patients with overactive bladder: the results of post hoc correlation and responder analyses using pooled data from three randomized Phase III trials
Purpose To understand how improvements in the symptoms
of overactive bladder (OAB) seen with the b3-adrenoceptor
agonist mirabegron 50 mg, correlate with patient experience
as measured by validated and standard patient-reported
outcomes (PROs), and to identify whether there is overall
directional consistency in the responsiveness of PROs to
treatment effect.
Methods In a post hoc analysis of pooled data from three
randomized, double-blind, placebo-controlled, 12-week
Phase III trials of mirabegron 50 mg once daily, responder
rates for incontinence frequency (C50 % reduction in
incontinence episodes/24 h from baseline to final visit),
micturition frequency (B8 micturitions/24 h at final visit),
and PROs [minimally important differences in patient
perception of bladder condition (PPBC) and subsets of the
overactive bladder questionnaire (OAB-q) measuring total
health-related quality of life (HRQoL), and symptom
bother] were evaluated individually and in combination.
Results Mirabegron 50 mg demonstrated greater
improvement from baseline to final visit than placebo for
each of the responder analyses, whether for individual
objective and subjective outcomes or combinations thereof.
These improvements versus placebo were statistically significant
for all double and triple responder analyses and for
all single responder analyses except PPBC. PRO measurements
showed directional consistency and significant
correlations, and there were also significant correlations
between objective and subjective measures of efficacy.
Conclusions The improvements in objective measures
seen with mirabegron 50 mg translate into a meaningful
clinical benefit as evident by the directional consistency
seen in HRQoL measures of benefit
Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload
BACKGROUND: Icodextrin is a high molecular weight, starch-derived glucose polymer, which is capable of inducing sustained ultrafiltration over prolonged (12β16 hour) peritoneal dialysis (PD) dwells. The aim of this study was to evaluate the ability of icodextrin to alleviate refractory, symptomatic fluid overload and prolong technique survival in PD patients. METHODS: A prospective, open-label, pre-test/post-test study was conducted in 17 PD patients (8 females/9 males, mean age 56.8 Β± 2.9 years) who were on the verge of being transferred to haemodialysis because of symptomatic fluid retention that was refractory to fluid restriction, loop diuretic therapy, hypertonic glucose exchanges and dwell time optimisation. One icodextrin exchange (2.5 L 7.5%, 12-hour dwell) was substituted for a long-dwell glucose exchange each day. RESULTS: Icodextrin significantly increased peritoneal ultrafiltration (885 Β± 210 ml to 1454 Β± 215 ml, p < 0.05) and reduced mean arterial pressure (106 Β± 4 to 96 Β± 4 mmHg, p < 0.05), but did not affect weight, plasma albumin concentration, haemoglobin levels or dialysate:plasma creatinine ratio. Diabetic patients (n = 12) also experienced improved glycaemic control (haemoglobin Alc decreased from 8.9 Β± 0.7% to 7.9 Β± 0.7%, p < 0.05). Overall PD technique survival was prolonged by a mean of 11.6 months (95% CI 6.0β17.3 months). On multivariate Cox proportional hazards analysis, extension of technique survival by icodextrin was only significantly predicted by baseline net daily peritoneal ultrafiltration (adjusted HR 2.52, 95% CI 1.13β5.62, p < 0.05). CONCLUSIONS: Icodextrin significantly improved peritoneal ultrafiltration and extended technique survival in PD patients with symptomatic fluid overload, especially those who had substantially impaired peritoneal ultrafiltration
Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection
Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis β characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity β show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, SinΓ©ad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber
Seeking Clarity within Cloudy Effluents: Differentiating Fungal from Bacterial Peritonitis in Peritoneal Dialysis Patients
Fungal peritonitis is a serious complication of peritoneal dialysis (PD) therapy with the majority of patients ceasing PD permanently. The aims of this study were to identify risk factors and clinical associations that may discriminate between fungal from bacterial peritonitis.We retrospectively identified episodes of fungal peritonitis from 2001-2010 in PD patients at Liverpool and Westmead Hospitals (Australia). Fungal peritonitis cases were matched in a 1:2 ratio with patients with bacterial peritonitis from each institution's dialysis registry, occurring closest in time to the fungal episode. Patient demographic, clinical and outcome data were obtained from the medical records.Thirty-nine episodes of fungal peritonitis (rate of 0.02 episodes per patient-year of dialysis) were matched with 78 episodes of bacterial peritonitis. Candida species were the commonest pathogens (35/39; 90% episodes) with Candida albicans (37%), Candida parapsilosis (32%) and Candida glabrata (13%) the most frequently isolated species. Compared to bacterial peritonitis, fungal peritonitis patients had received PD for significantly longer (1133 vs. 775 catheter-days; pβ=β0.016), were more likely to have had previous episodes of bacterial peritonitis (51% vs. 10%; pβ=β0.01), and to have received prior antibacterial therapy (51% vs. 10%; pβ=β0.01). Patients with fungal peritonitis were less likely to have fever and abdominal pain on presentation, but had higher rates of PD catheter removal (79% vs. 22%; p<0.005), and permanent transfer to haemodialysis (87% vs. 24%; p<0.005). Hospital length of stay was significantly longer in patients with fungal peritonitis (26.1 days vs. 12.6 days; pβ=β0.017), but the all-cause 30-day mortality rate was similar in both groups. Fluconazole was a suitable empiric antifungal agent; with no Candida resistance detected.Prompt recognition of clinical risk factors, initiation of antifungal therapy and removal of PD catheters are key considerations in optimising outcomes
Selection of modalities, prescription, and technical issues in children on peritoneal dialysis
Peritoneal dialysis (PD) is widely employed as a dialytic therapy for uraemic children, especially in its automated form (APD), that is associated with less burden of care on patient and family than continuous ambulatory PD. Since APD offers a wide range of treatment options, based on intermittent and continuous regimens, prescription can be individualized according to patientβs age, body size, residual renal function, nutritional intake, and growth-related metabolic needs. Transport capacity of the peritoneal membrane of each individual patient should be assessed, and regularly monitored, by means of standardized peritoneal function tests validated in pediatric patients. To ensure maximum recruitment of peritoneal exchange area, fill volume should be scaled to body surface area and adapted to each patient, according to clinical tolerance and intraperitoneal pressure. PD solutions should be employed according to their biocompatibility and potential ultrafiltration capacity; new pH-neutral, glucose-free solutions can be used in an integrated way in separate dwells, or by appropriately mixing during the same dialytic session. Kinetic modelling software programs may help in the tailoring of PD prescription to individual patientsβ characteristics and needs. Owing to advances in the technology of new APD machines, greater programming flexibility, memorized delivery control, and tele-dialysis are currently possible
Dialysis-associated peritonitis in children
Peritonitis remains a frequent complication of peritoneal dialysis in children and is the most common reason for technique failure. The microbiology is characterized by a predominance of Gram-positive organisms, with fungi responsible for less than 5% of episodes. Data collected by the International Pediatric Peritonitis Registry have revealed a worldwide variation in the bacterial etiology of peritonitis, as well as in the rate of culture-negative peritonitis. Risk factors for infection include young age, the absence of prophylactic antibiotics at catheter placement, spiking of dialysis bags, and the presence of a catheter exit-site or tunnel infection. Clinical symptoms at presentation are somewhat organism specific and can be objectively assessed with a Disease Severity Score. Whereas recommendations for empiric antibiotic therapy in children have been published by the International Society of Peritoneal Dialysis, epidemiologic data and antibiotic susceptibility data suggest that it may be desirable to take the patient- and center-specific history of microorganisms and their sensitivity patterns into account when prescribing initial therapy. The vast majority of patients are treated successfully and continue peritoneal dialysis, with the poorest outcome noted in patients with peritonitis secondary to Gram-negative organisms or fungi and in those with a relapsing infection
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