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- Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria. [JOURNAL ARTICLE]
- Cochrane Database Syst Rev 2014 Oct 30.:CD010340.
Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, not malignant, disease of the hematopoietic stem cells, associated with significant morbidity and mortality. It is a rare disease with an estimated incidence of 1.3 new cases per one million individuals per year. The treatment of PNH has been largely empirical and symptomatic, with blood transfusions, anticoagulation, and supplementation with folic acid or iron. Eculizumab, a biological agent that inhibits complement cascade, was developed for preventing hemolytic anemia and severe thrombotic episodes.To assess the clinical benefits and harms of eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria (PNH).We conducted a comprehensive search strategy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2014, Issue 5), Ovid MEDLINE (from 1946 to 15 May 2014), EMBASE (from 1980 to 25 June 2014), and LILACS (from 1982 to 25 June 2014). We did not apply any language restrictions.We included randomized controlled trials (RCTs) irrespective of their publication status or language. No limits were applied with respect to period of follow-up. We excluded quasi-RCTs. We included trials comparing eculizumab with placebo or best available therapy. We included any patient with a confirmed diagnosis of PNH. Primary outcome was overall survival.We independently performed a duplicate selection of eligible trials, risk of bias assessment, and data extraction. We estimated risk ratios (RRs) and 95% confidence interval (CIs) for dichotomous outcomes, and mean differences (MDs) and 95% CIs for continuous outcomes. We used a random-effects model for analysis.We identified one multicenter (34 sites) phase III RCT involving 87 participants. The trial compared eculizumab versus placebo, and was conducted in the US, Canada, Europe, and Australia with 26 weeks of follow-up. This small trial had high risk of bias in many domains (attrition and selective reporting). It was sponsored by a pharmaceutical company. No patients died during the study. By using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (scores can range from 0 to 100, with higher scores on the global health status and functioning scales indicating improvement), the trial showed improvement in health-related quality of life in patients treated with eculizumab (mean difference (MD) 19.4, 95% CI 8.25 to 30.55; P = 0.0007; low quality of evidence). By using the Functional Assessment of Chronic Illness Therapy Fatigue instrument (scores can range from 0 to 52, with higher scores indicating improvement in fatigue), the trial showed a reduction in fatigue (MD 10.4, 95% CI 9.97 to 10.83; P = 0.00001; moderate quality of evidence) in the eculizumab group compared with placebo. Eculizumab compared with placebo showed a greater proportion of patients with transfusion independence: 51% (22/43) versus 0% (0/44); risk ratio (RR) 46.02, 95% CI 2.88 to 735.53; P = 0.007; moderate quality of evidence; and withdrawal for any reason: 4.7% (2/43) versus 22.72% (10/44); RR 0.20, 95% CI 0.05 to 0.88; P = 0.03; moderate quality of evidence. Due to the low rate of events observed, the included trial did not show any difference between eculizumab and placebo in terms of serious adverse events: 9.3% (4/43) versus 20.4% (9/44); RR 0.15, 95% CI 0.15 to 1.37; P = 0.16; low quality of evidence. We did not observe any difference between intervention and placebo for the most frequent adverse events. One participant receiving placebo showed an episode of thrombosis. The trial did not assess overall survival, transformation to myelodysplastic syndrome and acute myelogenous leukemia, or development or recurrence of aplastic anemia on treatment.This review has detected an absence of evidence for eculizumab compared with placebo for treating paroxysmal nocturnal hemoglobinuria (PNH), in terms of overall survival, nonfatal thrombotic events, transformation to myelodysplastic syndrome and acute myelogenous leukemia, and development and recurrence of aplastic anemia on treatment. Current evidence indicates that compared with placebo, eculizumab increases health-related quality of life and increases transfusion independence. During the execution of the included trial, no patients died. Furthermore, the intervention seems to reduce fatigue and withdrawals for any reason. The safety profile of eculizumab is unclear. These conclusions are based on one small trial with risk of attrition and selective reporting bias.Therefore, prescription of eculizumab for treating patients with PNH can neither be supported nor rejected, unless new evidence from a large high quality trial alters this conclusion. Therefore, we urge the reader to interpret the trial results with much caution. Future trials on this issue should be conducted according to the SPIRIT statement and reported according to the CONSORT statement by independent investigators, and using the Foundation of Patient-Centered Outcomes Research recommendations.
- Quantifying the Contribution of Hosts with Different Parasite Concentrations to the Transmission of Visceral Leishmaniasis in Ethiopia. [JOURNAL ARTICLE]
- PLoS Negl Trop Dis 2014 Oct; 8(10):e3288.
An important factor influencing the transmission dynamics of vector-borne diseases is the contribution of hosts with different parasitemia (no. of parasites per ml of blood) to the infected vector population. Today, estimation of this contribution is often impractical since it relies exclusively on limited-scale xenodiagnostic or artificial feeding experiments (i.e., measuring the proportion of vectors that become infected after feeding on infected blood/host).We developed a novel mechanistic model that facilitates the quantification of the contribution of hosts with different parasitemias to the infection of the vectors from data on the distribution of these parasitemias within the host population. We applied the model to an ample data set of Leishmania donovani carriers, the causative agent of visceral leishmaniasis in Ethiopia.Calculations facilitated by the model quantified the host parasitemias that are mostly responsible for the infection of vector, the sand fly Phlebotomus orientalis. Our findings indicate that a 3.2% of the most infected people were responsible for the infection of between 53% and 79% (mean - 62%) of the infected sand fly vector population.Our modeling framework can easily be extended to facilitate the calculation of the contribution of other host groups (such as different host species, hosts with different ages) to the infected vector population. Identifying the hosts that contribute most towards infection of the vectors is crucial for understanding the transmission dynamics, and planning targeted intervention policy of visceral leishmaniasis as well as other vector borne infectious diseases (e.g., West Nile Fever).
- Treatment of the Patulous Eustachian Tube With Soft-Tissue Bulking Agent Injections. [JOURNAL ARTICLE]
- Otol Neurotol 2014 Oct 29.
A patulous Eustachian tube ([ET] tuba aperta) may cause symptoms as autophony, breath synchronous tinnitus, pressure sensation, and conductive hearing loss and thus lead to an enormous cutback in quality of life. In combination with "sniffing," it can trigger the development of cholesteatoma. Because of the ambiguous symptoms, the diagnosis can be challenging. A patulous ET can only be diagnosed through a well-structured examination, including patient history, physical examination with thorough observation of the movements of the tympanic membrane, and tympanometry with reflex-decay.Transnasal endoscopic injection of injectable soft-tissue bulking agent into the torus tubarius was performed in 20 patients as a new treatment option for patulous ET. All patients were followed up 6 weeks and 6 and 12 months after treatment. For each intervention, 0.8 to 2 mL of injectable soft-tissue bulking agent was used.In nine patients, more than one procedure was necessary. On follow-up, 10 out of 15 patients were satisfied with the result. Only three out of 15 patients reported no improvement of their symptoms. The procedure was minimally invasive, fast, and easy to perform.There is no gold standard for the therapy of patulous ET. The injection of soft-tissue bulking agent in the torus tubarius is a new minimally invasive therapeutic approach, but much more clinical experience is needed. LEVEL OF EVIDENCE: IV.
- Monolithic scaffolds for highly selective ion sensing/removal of Co(ii), Cu(ii), and Cd(ii) ions in water. [JOURNAL ARTICLE]
- Analyst 2014 Oct 30.
High exposure to metals, such as cobalt (Co), copper (Cu) and cadmium (Cd), potentially has adverse effects, and can cause severe health problems, leading to a number of specific diseases. This study primarily aims to monitor, detect, separate, and remove the trace concentrations of Co(ii), Cu(ii), and Cd(ii) ions in water, without a preconcentration process, using aluminosilica optical sensor (ASOS) monoliths. These monolithic scaffolds with advantageous physical features (i.e., large surface area-to-volume ratios of the scaffolds, active acid sites and uniform mesocage cubic pores) can strongly induce H-bonding and dispersive interactions with organic chelating agent, resulting in the formation of stable ASOS. In this engineering process, ASOS offers a simple and one-step sensing/capture procedure for the quantification and visual detection of the target elements from water, without requiring sophisticated instrumentation. The key result in this study is the ion selectivity exhibited by the designed ASOS toward the targets, Co(ii), Cu(ii), and Cd(ii) ions, in environmental and waste disposal samples, as well as its reproducibility over a number of analysis/regeneration cycles. These findings can be useful in the fabrication of ASOS can be tailored to suit various applications.
- Effects of approach and injection volume on diffusion of mepivacaine hydrochloride during local analgesia of the deep branch of the lateral plantar nerve in horses. [JOURNAL ARTICLE]
- J Am Vet Med Assoc 2014 Nov 15; 245(10):1153-1159.
Objective-To compare the effects of 2 approaches and 2 injection volumes on diffusion of mepivacaine hydrochloride for local analgesia of the deep branch of the lateral plantar nerve (DBLPN) in horses. Design-Experimental study. Animals-16 adult horses. Procedures-Either 2 mL (low volume) or 8 mL (high volume) of mepivacaine hydrochloride-iohexol (50:50 mixture) was injected by means of 1 of 2 techniques to produce analgesia of the DBLPN. For technique 1, the needle was inserted 15 mm distal to the head of the fourth metatarsal bone and directed perpendicular to the limb. For technique 2, the needle was inserted 20 mm distal to the head of the fourth metatarsal bone and was directed in a proximodorsal direction. Lateromedial radiographs were obtained before and 5, 15, 30, and 60 minutes after injection. Radiographs were evaluated to determine the proximal and distal extent of diffusion of the contrast solution and presumably anesthetic agent and whether contrast agent appeared to be present in the tarsal sheath or tarsometatarsal joint. Results-A high degree of variability in contrast solution diffusion was noted among injections. High-volume injections diffused significantly further proximally and distally than did low-volume injections. Contrast agent was documented within the tarsal sheath in 5 of 32 (16%) injections and within the tarsometatarsal joint in 2 of 32 (6%) injections. No significant difference was found for risk of inadvertent tarsal sheath or tarsometatarsal joint injection between the 2 techniques or the 2 volumes of anesthetic used. Mepivacaine diffused significantly further distally with technique 1 than with technique 2 but diffused significantly further proximally with technique 2 than with technique 1. For both techniques, diffusion in the distal but not the proximal direction significantly increased over time. Conclusions and Clinical Relevance-Results indicated that the proximal and distal diffusion of the mepivacaine-iohexol solution was quite variable following either DBLPN nerve block technique.
- Formulation of the Microbicide INP0341 for In Vivo Protection against a Vaginal Challenge by Chlamydia trachomatis. [JOURNAL ARTICLE]
- PLoS One 2014; 9(10):e110918.
The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.
- Estimating Location without External Cues. [JOURNAL ARTICLE]
- PLoS Comput Biol 2014 Oct; 10(10):e1003927.
The ability to determine one's location is fundamental to spatial navigation. Here, it is shown that localization is theoretically possible without the use of external cues, and without knowledge of initial position or orientation. With only error-prone self-motion estimates as input, a fully disoriented agent can, in principle, determine its location in familiar spaces with 1-fold rotational symmetry. Surprisingly, localization does not require the sensing of any external cue, including the boundary. The combination of self-motion estimates and an internal map of the arena provide enough information for localization. This stands in conflict with the supposition that 2D arenas are analogous to open fields. Using a rodent error model, it is shown that the localization performance which can be achieved is enough to initiate and maintain stable firing patterns like those of grid cells, starting from full disorientation. Successful localization was achieved when the rotational asymmetry was due to the external boundary, an interior barrier or a void space within an arena. Optimal localization performance was found to depend on arena shape, arena size, local and global rotational asymmetry, and the structure of the path taken during localization. Since allothetic cues including visual and boundary contact cues were not present, localization necessarily relied on the fusion of idiothetic self-motion cues and memory of the boundary. Implications for spatial navigation mechanisms are discussed, including possible relationships with place field overdispersion and hippocampal reverse replay. Based on these results, experiments are suggested to identify if and where information fusion occurs in the mammalian spatial memory system.
- Characteristics and Short-Term Outcomes of Patients with Type 2 Diabetes Mellitus Treated with Canagliflozin in a Real-World Setting. [JOURNAL ARTICLE]
- Curr Med Res Opin 2014 Oct 30.:1-21.
Abstract Objective: Canagliflozin is a sodium glucose co-transporter 2 that has been shown to improve glycemic control in type 2 diabetes mellitus (T2DM). This study aimed to describe the characteristics, treatment utilization, and outcomes of patients treated with canagliflozin in the real-world within the first six months it was commercially available. Methods: This retrospective cohort study used a large US health plan data for commercial and Medicare Advantage enrollees. Patients aged 18 and over with T2DM who filled a canagliflozin prescription during 4/1/2013-9/30/2013 were eligible for inclusion. Patients were required to be enrolled for 6 months before (baseline period) and 3 months after (follow-up period) the first canagliflozin claim. Results: Overall, 3,234 patients met study criteria (mean age was 55.7 years; 43.4% were female). Among patients with available lab data at baseline and follow-up, mean HbA1c decreased from 8.54% at baseline to 7.76% at follow-up (p<0.001); the proportion of patients with HbA1c≥9.0% decreased by more than half (from 32.0% at baseline to 15.5% at follow-up, p<0.001). Almost all (94.8%) patients received at least 1 baseline antihyperglycemic agent; among them, 33.6% received 2 and 41.5% received 3 or more agents. Compared to baseline, usage of antihyperglycemic agents during follow-up was lower for metformin, sulfonylureas, insulin, DPP-4 inhibitors, GLP-1 receptor agonists and thiazolidinediones. Conclusions: Patients treated with canagliflozin when first available in the U.S. typically had poorly controlled HbA1c levels at baseline and had received multiple prior antihyperglycemic agents. Following the first canagliflozin claim, they had an improvement in HbA1c levels and used fewer antihyperglycemic agents. These study results should help clinicians and payers better understand the initial profile of patients receiving canagliflozin and short-term outcomes in the real world. Given the short follow-up time frame and HbA1c data was not available in all patients; future research on longer term outcomes is warranted.
- A case of Beauveria bassiana keratitis confirmed by internal transcribed spacer and LSU rDNA D1-D2 sequencing. [Journal Article]
- New Microbes New Infect 2014 May; 2(3):84-7.
We describe a case of fungal keratitis due to Beauveria bassiana in a farmer with Fuchs' dystrophy, treated with amphotericin B. Surgery with penetrating keratoplasty was necessary to resolve the lesions. Susceptibility testing and molecular sequencing permitted the identification and treatment of this rare aetiological agent of invasive fungal disease.
- Fusobacterium necrophorum, an emerging pathogen of otogenic and paranasal infections? [Journal Article]
- New Microbes New Infect 2014 May; 2(3):52-7.
Fusobacterium necrophorum is a rare causative agent of otitis and sinusitis. Most commonly known is the classic Lemièrre's syndrome of postanginal sepsis with suppurative thrombophlebitis of the jugular vein. We report five patients diagnosed recently with a complicated infection with F. necrophorum originating from otitis or sinusitis. Two patients recovered completely, one patient died due to complications of the infection, one patient retained a slight hemiparesis and one patient had permanent hearing loss. Diagnosis and management are discussed. A possible factor in the emergence of F. necrophorum is proposed.