Renal Association Clinical Practice Guideline on Haemodialysis.

This guideline is written primarily for doctors and nurses working in dialysis units and related areas of medicine in the UK, and is an update of a previous version written in 2009. It aims to provide guidance on how to look after patients and how to run dialysis units, and provides standards which units should in general aim to achieve. We would not advise patients to interpret the guideline as a rulebook, but perhaps to answer the question: "what does good quality haemodialysis look like?"The guideline is split into sections: each begins with a few statements which are graded by strength (1 is a firm recommendation, 2 is more like a sensible suggestion), and the type of research available to back up the statement, ranging from A (good quality trials so we are pretty sure this is right) to D (more like the opinion of experts than known for sure). After the statements there is a short summary explaining why we think this, often including a discussion of some of the most helpful research. There is then a list of the most important medical articles so that you can read further if you want to - most of this is freely available online, at least in summary form.A few notes on the individual sections: 1. This section is about how much dialysis a patient should have. The effectiveness of dialysis varies between patients because of differences in body size and age etc., so different people need different amounts, and this section gives guidance on what defines "enough" dialysis and how to make sure each person is getting that. Quite a bit of this section is very technical, for example, the term "eKt/V" is often used: this is a calculation based on blood tests before and after dialysis, which measures the effectiveness of a single dialysis session in a particular patient. 2. This section deals with "non-standard" dialysis, which basically means anything other than 3 times per week. For example, a few people need 4 or more sessions per week to keep healthy, and some people are fine with only 2 sessions per week - this is usually people who are older, or those who have only just started dialysis. Special considerations for children and pregnant patients are also covered here. 3. This section deals with membranes (the type of "filter" used in the dialysis machine) and "HDF" (haemodiafiltration) which is a more complex kind of dialysis which some doctors think is better. Studies are still being done, but at the moment we think it's as good as but not better than regular dialysis. 4. This section deals with fluid removal during dialysis sessions: how to remove enough fluid without causing cramps and low blood pressure. Amongst other recommendations we advise close collaboration with patients over this. 5. This section deals with dialysate, which is the fluid used to "pull" toxins out of the blood (it is sometimes called the "bath"). The level of things like potassium in the dialysate is important, otherwise too much or too little may be removed. There is a section on dialysate buffer (bicarbonate) and also a section on phosphate, which occasionally needs to be added into the dialysate. 6. This section is about anticoagulation (blood thinning) which is needed to stop the circuit from clotting, but sometimes causes side effects. 7. This section is about certain safety aspects of dialysis, not seeking to replace well-established local protocols, but focussing on just a few where we thought some national-level guidance would be useful. 8. This section draws together a few aspects of dialysis which don't easily fit elsewhere, and which impact on how dialysis feels to patients, rather than the medical outcome, though of course these are linked. This is where home haemodialysis and exercise are covered. There is an appendix at the end which covers a few aspects in more detail, especially the mathematical ideas. Several aspects of dialysis are not included in this guideline since they are covered elsewhere, often because they are aspects which affect non-dialysis patients too. This includes: anaemia, calcium and bone health, high blood pressure, nutrition, infection control, vascular access, transplant planning, and when dialysis should be started.

The effect of sparging rate on transmembrane pressure and critical flux in an AnMBR.

Anaerobic membrane bioreactors (AnMBRs) have been shown to be successful units for the treatment of low strength wastewaters, however, the issue of membrane fouling is still a major problem in terms of economic viability. Biogas sparging has been shown to reduce fouling substantially, and hence this study monitored the effect of biogas sparging rate on an AnMBR. The critical flux under a sparging rate of 6 l per minute (LPM) was found to be 11.8 l m(-2) h(-1) (LMH), however, membrane hysteresis was found to have an effect on the critical flux, and where the AnMBR had previously been operated with a 2 LPM sparging rate, the critical flux fell to 7.2 LMH. The existence of a "critical sparging rate" was also investigated under the condition that 'there exists a sparging rate beyond which any further decrease in sparging rate will cause a dramatic rise in TMP'. For an AnMBR operating at a flux of 7.2 LMH the critical sparging rate was found to be 4 LPM.

Population balance modeling of aggregation and breakage in turbulent Taylor-Couette flow.

An experimental and computational study of aggregation and breakage processes for fully destabilized polystyrene latex particles under turbulent-flow conditions in a Taylor-Couette apparatus is presented. To monitor the aggregation and breakage processes, an in situ optical imaging technique was used. Consequently, a computational study using a population balance model was carried out to test the various parameters in the aggregation and breakage models. Very good agreement was found between the time evolution of the cluster size distribution (CSD) calculated with the model and that obtained from experiment. In order to correctly model the left-hand side of the CSD (small clusters), it was necessary to use a highly unsymmetric fragment-distribution function for breakage. As another test of the model, measurements with different solid volume fractions were performed. Within the range of the solid volume fractions considered here, the steady-state CSD was not significantly affected. In order to correctly capture the right-hand side of the CSD (large aggregates) at the higher solid volume fraction, a modified aggregation rate prefactor was used in the population balance model.

Pharmacometric Modeling of Naloxegol Efficacy and Safety: Impact on Dose and Label.

Naloxegol is a peripherally acting µ-opioid receptor antagonist that was developed for the treatment of opioid-induced constipation. Modeling and simulation of naloxegol efficacy and tolerability informed selection of doses for phase III studies and provided comprehensive dosage recommendations for the naloxegol US package insert.

Enhancement of platelet recovery after myelosuppressive chemotherapy by recombinant human megakaryocyte growth and development factor in patients with advanced cancer.

PURPOSE: To explore the influence of dose and schedule on the ability of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) to abrogate thrombocytopenia after multiple cycles of chemotherapy and to mobilize peripheral-blood progenitor cells (PBPC). PATIENTS AND METHODS: In this open-label study, 68 patients with advanced cancer were randomized to receive PEG-rHuMGDF subcutaneously at different doses and durations before administration of carboplatin 600 mg/m(2), cyclophosphamide 1,200 mg/m(2), and filgrastim 5 microgram/kg/d. PEG-rHuMGDF was not given after the first cycle of chemotherapy but was given after the second and subsequent cycles. Chemotherapy was given every 28 days for up to six cycles. RESULTS: In patients who received the same dose of chemotherapy for at least two cycles, the platelet nadir was significantly higher (47.5 x 10(9)/L v 35.5 x 10(9)/L; P =.003) and duration of grade 3 or 4 thrombocytopenia significantly shorter (0 v 3 days; P =.004) when PEG-rHuMGDF was administered after chemotherapy. There was no evidence of an effect of PEG-rHuMGDF when it was given before chemotherapy. Platelet recovery after the first cycle of chemotherapy was no different for different PEG-rHuMGDF regimens, and there was no difference between patients treated with PEG-rHuMGDF and historical controls treated with identical chemotherapy. There was a modest dose-related increase in progenitor cell levels after administration of PEG-rHuMGDF alone. Peak levels of PBPC occurred later in cycle 2 than in cycle 1 but were not different in magnitude. CONCLUSION: PEG-rHuMGDF abrogated severe thrombocytopenia after dose-intensive chemotherapy. However, it had only a modest effect on progenitor cell levels and did not enhance progenitor cell mobilization after chemotherapy and filgrastim.

CFD simulation of aggregation and breakage processes in laminar Taylor-Couette flow.

An experimental and computational investigation of the effects of local fluid shear rate on the aggregation and breakage of approximately 10 microm latex spheres suspended in an aqueous solution undergoing laminar Taylor-Couette flow was carried out according to the following program. First, computational fluid dynamics (CFD) simulations were performed and the flow field predictions were validated with data from particle image velocimetry experiments. Subsequently, the quadrature method of moments (QMOM) was implemented into the CFD code to obtain predictions for mean particle size that account for the effects of local shear rate on the aggregation and breakage. These predictions were then compared with experimental data for latex sphere aggregates (using an in situ optical imaging method) and with predictions using spatial average shear rates. The mean particle size evolution predicted by CFD and QMOM using appropriate kinetic expressions that incorporate information concerning the particle morphology (fractal dimension) and the local fluid viscous effects on aggregation collision efficiency match well with the experimental data.

Assessment of neutrophil function in the elderly using antibody coated polyacrylamide gel (immunobeads) and nitroblue tetrazolium (NBT) reduction as a combined test.

Neutrophil function was assessed in 35 elderly individuals (age greater than 75) and 20 normal young individuals (age 20-45) by combining ingestion of antibody coated polyacrylamide gel and nitroblue tetrazolium reduction in a single test. This test evaluates phagocytosis and metabolic integrity simultaneously and appears to be a sensitive and reliable test of neutrophil function. No significant difference was found (by using this test) between neutrophils from healthy elderly people and the neutrophils from young controls, or between the sexes in either age group.

The osteopetrotic rabbit: general and skeletal features of a new outbred stock.

Stock of the lethal osteopetrotic mutation in the rabbit has been outbred to robust New Zealand White stock. Features of this new stock include skeletal sclerosis and failure of tooth eruption characteristic of osteopetrosis, together with hypocalcemia, hypophosphatemia, and osteoclasts of reduced numbers and abnormal cytology. No abnormalities of carbonic anhydrase II were detectable by electrophoresis. The commercial availability of mutants of this new stock makes them a potentially important source of information about both osteopetrosis and osteoclast biology.

Cost-effectiveness of infective endocarditis prophylaxis for mitral valve prolapse with or without a mitral regurgitant murmur.

To assess the cost-effectiveness of prevention of infective endocarditis (IE) and to calculate cost-effectiveness of currently recommended regimens in patients with mitral valve prolapse (MVP), data on risk of death, complications, and health-care use, and cumulative incremental health-care costs due to the occurrence of IE were combined with data on the prevalence and manifestations of MVP, estimated years of life lost, and efficacy of antibiotic prophylaxis. Effectiveness and costs of standard endocarditis prophylaxis regimens were calculated per IE case prevented and years of life saved. Under the most likely scenario, oral amoxicillin prophylaxis for all MVP patients would prevent 32 cases of IE per million dental procedures at approximate costs of $119,000 per prevented case and $21,000 per year of life saved. Limiting prophylaxis to patients with mitral murmurs would prevent 80 cases of IE per million procedures at costs of about $19,000 per prevented case and $3,000 per year of life saved. Erythromycin prophylaxis was slightly less expensive than amoxicillin per benefit because of lower cost and lack of drug anaphylaxis, whereas intravenous ampicillin was 7 to 30 times more costly. Sensitivity analyses suggested that erythromycin prophylaxis might be cost-saving under some scenarios, whereas intravenous ampicillin use might cause net loss of life. Thus, prevention with oral antibiotics of the cumulative morbidity and incremental health care costs due to IE in MVP patients is reasonably cost-effective for MVP patients with mitral murmurs.

Sjögren's syndrome: current therapies remain inadequate for a common disease.

Sjögren's syndrome (SS) is a systematic autoimmune disease characterised by dysfunction of the lacrimal and salivary glands. This dryness leads to the symptoms of dry eyes and keratoconjunctivitis sicca, which is painful and may predispose patients to ocular infections. Also, SS patients develop dry mouth, which is uncomfortable and associated with progressive dental disease. SS is divided into secondary SS (where the dryness symptoms are associated with another well defined autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or scleroderma) and primary SS (where the patients do not fulfil criteria for another well defined associated autoimmune disease). Primary SS has extra glandular organ involvement including lung (interstitial pneumonitis), renal (interstitial nephritis), peripheral and central nervous system manifestations, vasculitis of skin and other organs and increased frequency of lymphoma. This review will concentrate on primary SS. Therapies are divided into agents for topical replacement of deficient secretions (artificial tears, artificial salivas), stimulation of muscarinic M3 receptors (pilocarpine, cevimeline) to increase aqueous secretions, reduction of topical inflammation (topical cyclosporin or corticosteroids for the eye and fluorides or antibacterial varnishes for the mouth) and modification of the immune response in a manner similar to treatment of systemic lupus (antimalarial drugs, methotrexate, cyclophosphamide and perhaps newer agents such as leflunomide or TNF inhibitors).

Primary Sjogren syndrome: clinical and immunopathologic features.

Primary Sjogren syndrome is an autoimmune condition in which dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) result from lymphocytic infiltration of lacrimal and salivary glands. Clinical and laboratory features of 60 primary Sjogren syndrome patients seen at our clinic during the past three years are presented. These patients illustrate the wide spectrum of extraglandular features that may occur as a result of lymphoid infiltration of lung, kidney, skin, stomach, liver, and muscle. They further emphasize the difficulty in classifying a patient as primary or secondary Sjogren syndrome (ie, sicca symptoms associated with systemic lupus erythematosus, rheumatoid arthritis, or scleroderma), particularly early in the disease course. As an initial step in understanding the pathogenesis, the lymphocytes that infiltrate the salivary glands and lymph nodes were characterized by using monoclonal antibodies that recognize distinct lymphocyte subsets and by using in vitro functional assays. These studies have demonstrated that affected tissues have infiltrates of T cells with helper/inducer activity and with a high frequency of "activation antigens." The immunohistologic techniques are useful in differentiating "benign" and "pseudolymphoma" lesions (both due predominantly to T cells) from non-Hodgkin lymphoma (usually due to B-cell infiltrates). Although there is no "cure" for primary Sjogren syndrome patient's symptoms may be significantly improved by measures aimed at prevention of ocular and dental complications and by the recognition of extraglandular features that may be amenable to specific treatment.

Fiber-laser-based frequency comb with a tunable repetition rate.

A phase-locked, self-referenced frequency comb generated by a mode-locked fiber soliton laser with a tunable repetition rate is presented. The spacing of the frequency comb is set by the laser's repetition rate, which can be scanned from 49.3 MHz to 50.1 MHz while one tooth of the comb is held phase-locked to a stable RF source. This variable repetitionrate frequency comb should be useful for wavelength and length metrology, synchronization of different fiber laser-based frequency combs, and the generation of precise swept wavelength sources.

Multi-purpose silastic dual-lumen central venous catheters for both collection and transplantation of hematopoietic progenitor cells.

Autologous peripheral blood progenitor cell (PBPC) transplantation frequently requires sequential placement and use of two separate central venous catheters: (1) a short-term, large-bore, stiff device inserted for leukapheresis, and after removal of that device, (2) a long-term, multi-lumen, flexible, Silastic catheter for administration of high-dose chemotherapy, re-infusion of hematopoietic cells, and intensive supportive care. We reviewed our recent experience with two dual-lumen, large-bore, Silastic multi-purpose ('hybrid') catheters, each of which can be used as a single device for both leukapheresis and long-term supportive care throughout the transplant process. Quinton-Raaf PermCath and Bard-Hickman hemodialysis/apheresis dual-lumen catheters were used as the sole venous access device in 112 consecutive patients who underwent autologous PBPC collection and transplantation. The catheter exit site was monitored three times a week, and lumen patency was assessed using clinical and radiologic techniques. Catheters were removed prematurely for persistent thrombus, positive blood cultures despite appropriate antibiotics, or mechanical dysfunction. There were no intra-operative or immediate post-operative complications relating to insertion. Thirty-two patients experienced catheter occlusion necessitating urokinase instillation. Persistent occlusive problems were noted in 16 patients, and in 10 patients the catheter had to be removed. Two exit site infections and 17 bacteremias occurred. Catheters had to be removed for persistent infection in two subjects and for mechanical problems in five others. Cost analysis comparing the hybrid catheters alone vs conventional devices revealed a charge of $4230 in patients with hybrid catheters vs. $7530 in those requiring a temporary non-Silastic dialysis catheter in addition to a flexible, long-term Silastic catheter. Hybrid, Silastic, dual-lumen, large-bore central venous catheters are safe, cost-effective and convenient multi-purpose venous access devices that may be used in the setting of autologous PBPC collection and transplantation. The rate of thrombotic, infectious and mechanical complications appears comparable to other central venous access devices.

Treatment of the patient with Sjögren's syndrome.

SS is a systemic autoimmune disease characterized by lymphocytic infiltrations of lacrimal and salivary glands. Extraglandular organs including skin, nerve, lung, and kidney may be involved. At the present time, there remains a great deal of confusion regarding the precise definition of SS. As a result, both patients and clinicians frequently have a difficult time in making a specific diagnosis and instituting a specific plan of therapy. Regardless of the diagnostic label, all patients with significant eye and mouth dryness should receive conservative therapy of tear replacement and intensive oral hygiene. Based on the presence or absence of clinical or laboratory features of systemic autoimmunity, additional therapies may prove beneficial in controlling the symptoms and progression of SS.

Criteria for diagnosis of Sjögren's syndrome.

The criteria for diagnosis of SS remain controversial, and several sets of diagnostic criteria have been proposed. On one hand, we have used a stringent set of criteria (termed the San Diego criteria) that requires evidence for an autoimmune process associated with destruction of salivary and lacrimal gland tissues. At the other extreme, several groups (including the Copenhagen and EEC Study group) have based their diagnostic criteria on clinical findings of dry eyes and mouth with no absolute requirement for gland biopsy or presence of autoantibodies. The EEC study group believe that the San Diego criteria identify only the tip of the iceberg--namely, those patients with full-blown disease--and ignore those patients with milder forms of SS. Until the underlying pathogenesis of SS is known, we suggest the continued use of the San Diego criteria for classification of SS, because it identifies a group of patients with serologic and histologic evidence for a systemic autoimmune process in association with their sicca symptoms. In patients lacking such evidence for an autoimmune process, we suggest the classification "sicca syndrome" or "dry mouth syndrome." This will allow the clinicians and clinical trials to focus on a more homogeneous group of SS patients who may share a common pathogenesis, treatment response, and prognosis. Also, patients lacking evidence of an autoimmune role in pathogenesis can be reassured, and other causes for their sicca symptoms can be investigated. Further, in the United States the particular diagnosis codes may have implications in obtaining insurance and other medical benefits. Thus, classification criteria involve not only future epidemiologic studies but also economic considerations for the individuals who are given a particular diagnostic code.

Potential role of Epstein-Barr virus in Sjögren's syndrome.

Sjögren's syndrome is an autoimmune disease characterized by lymphocytic infiltration and destruction of salivary and lacrimal glands. This condition may occur as a primary condition or may be associated with other autoimmune disorders such as rheumatoid arthritis or systemic lupus. Because the environmental factors that initiate SS are unknown, we have investigated the potential role of EBV, CMV, and other viruses. We observed that epithelial cells in salivary gland biopsies of patients with SS contained antigens reactive with monoclonal antibodies against EBV-associated antigens. These antigens were not found in other tissues of patients with SS and were not detectable in salivary gland biopsies from normal persons and patients with other autoimmune diseases lacking SS. The molecular weight of the antigens present in the SS salivary gland extracts was similar to that expressed in cells containing reactivated EBV. Also, the content of EBV DNA in the saliva of patients with SS was significantly greater than in age-, sex-matched controls or persons with other autoimmune disorders. These studies provide one of the first examples where a specific viral agent may be implicated in perpetuating a chronic autoimmune disease. These results also may provide insight into other autoimmune diseases where the target organ is less accessible to biopsy.

Laboratory evaluation of patients with Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by lymphocytic infiltration of the lacrymal and salivary glands, leading to severe dryness of eyes (keratoconjunctivitis sicca) and mouth (xerostomia). SS may exist as a primary disorder (1 degree-SS) or in association with other autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus or progressive systemic sclerosis (scleroderma). Diagnosis of 1 degree-SS is confirmed by minor salivary gland biopsy and the presence of circulating autoantibodies. Minor salivary gland biopsies exhibit focal lymphocytic infiltrates that are present in the majority of lobules. Incorrect methods of biopsy and failure to determine the average focus score are common causes for false-positive and false-negative biopsies. SS patients frequently have a positive antinuclear antibody test due to presence of SS-A (Ro) and SS-B (La) autoantibodies. Molecular analysis has revealed multiple "SS-A" proteins (60 kd, 54 kd, 52 kd) that react with sera from SS patients, as well as a 48 kd SS-B protein. Rheumatoid factor (anti-IgG Fc antibody) in 1 degree-SS patients exhibits restriction in its light chain-associated idiotype, in contrast to RA patients where no restriction of idiotype was detected. Other autoantibodies found in a subpopulation of SS patients include anti-ADP ribose polymerase, anti-cardiolipin, anti-mitochondrial, anti-mitotic spindle apparatus, anti-parietal cell, and anti-thyroid associated antibodies. Due to the high frequency of dryness syndromes in patients due to other causes (ranging from drug side effects to normal aging processes), the use of strict criteria for diagnosis of SS will lead to improved cost-efficient medical care avoiding needless anxiety in the patient.

Development and validation of a measure of attitudes toward malocclusion.

The Orthodontic Attitude Survey was designed to assess children's and their parents' attitudes toward malocclusion and orthodontic treatment. Five consistent clusters of attitudes had discriminant validity, and were significantly related to plans for orthodontic treatment and to objective and subjective indicators of the child's occlusal status and appearance.

Variables discriminating individuals who seek orthodontic treatment.

Overall, these results support the view that dental-facial esthetics and self-perceptions of occlusal appearance, as well as attitudes toward malocclusion and orthodontic treatment, are important factors in the individual's decision to obtain orthodontic treatment. The data indicate that psychosocial variables not directly related to occlusal problems and treatment, do not add significantly to the description of differences between those who seek treatment and those who do not. While these analyses did not include a number of variables--such as socioeconomic factors or attitudes of significant others--which may also be important in predicting individual response to malocclusion, they do suggest strongly that psychosocial factors directly related to need for treatment are probably most productively assessed in terms of self-perceptions of occlusal appearance and attitudes regarding dental malrelations and their treatment.

Sjögren's syndrome. Controversies and progress.

Diagnostic criteria for Sjögren's syndrome (SS) are required by both physicians and patients to (1) provide a rational basis for their symptoms, assess their prognosis, and guide therapy; (2) identify a group of patients who are most likely to share a common etiopathogenesis, in order to identify those genetic and environmental factors that are crucial in pathogenesis; (3) fill out the myriad medical insurance forms that require a diagnosis code; and (4) serve as a "shorthand" code that alerts specialists in different fields (oral medicine, ophthalmology, and a variety of specialists in internal medicine) to search for particular clinical problems found in the SS patient. The key question in this article is whether the term "Sjögren's syndrome" should apply to a rather restricted group of individuals (those with an autoimmune basis for exocrinopathy) or to a rather large group of individuals who share a similar symptom complex of dry eyes and mouth. Primary SS, as defined by San Diego criteria, is a systemic autoimmune disease that is characterized by keratoconjunctivitis sicca and xerostomia resulting from lymphocytic infiltrates of the lacrimal and salivary glands. The criteria for the diagnosis of SS continues to be controversial, leading to confusion in the clinical and research literature. It is important to distinguish SS (an idiopathic autoimmune process) from other processes including hepatitis C infection, retroviral infection, lymphoma, autonomic neuropathy, depression, primary fibromyalgia, and drug side effects that can result in sicca symptoms. Recent studies on pathogenesis of SS in human and animal models have examined the clonality of the T-cell infiltrates, the production of cytokines by lymphocytes and glandular epithelial cells, neuroendocrine and hormonal factors that affect glandular secretion, and the fine structure of antigens recognized by T cells and B cells. Studies in SS have allowed comparison of lymphocytes in blood and in the glandular tissue lesions; important differences in the gland microenvironment play an important role in the initiation and perpetuation of the autoimmune process. For example, apoptotic death depends on the balance of Fas, Fas ligand, nuclear factors (such as bcl-2, bax, and myc), cytokines, neuropeptides, and cell membrane interactions with extracellular matrix. Although increased rates of apoptosis may be present in the blood T cells of SS patients, some glandular T cells are resistant to apoptosis. Recent advances have led to improved understanding of signal transduction in response to cytokines and hormones that play a role in the local and systemic manifestations of SS.