Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial.

RATIONALE & OBJECTIVE: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. STUDY DESIGN: Phase 3, open-label, single-arm trial. SETTING & PARTICIPANTS: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 µmol/L at screening, including patients with or without systemic oxalosis. INTERVENTION: Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. OUTCOME: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. RESULTS: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. LIMITATIONS: Single-arm study without placebo control. CONCLUSIONS: Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. FUNDING: Alnylam Pharmaceuticals. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. PLAIN-LANGUAGE SUMMARY: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.

Periodontal disease and incident prediabetes and diabetes: The Hispanic Community Health Study/Study of Latinos.

AIM: To examine whether baseline periodontal disease is independently associated with incident prediabetes and incident diabetes in Hispanics/Latinos in the United States. MATERIALS AND METHODS: This study examined 7827 individuals, 18-74 years of age without diabetes, from the Hispanic Community Health Study/Study of Latinos. Participants received a full-mouth periodontal examination at baseline (2008-2011), and the disease was classified using the Centers for Disease Control and Prevention/American Academy of Periodontology case definitions. At Visit 2 (2014-2017), incident prediabetes and diabetes were assessed using multiple standard procedures including blood tests. Multivariable survey Poisson regressions estimated the rate ratio (RR) and 95% confidence intervals (CIs) of incident prediabetes and incident diabetes associated with periodontal disease severity. RESULTS: Among the individuals without prediabetes or diabetes at baseline, 38.8% (n = 1553) had developed prediabetes and 2.2% (n = 87) had developed diabetes after 6 years. Nineteen percent (n = 727) of individuals with prediabetes at baseline developed diabetes after 6 years. Adjusting for all potential confounders, no significant association was found between periodontal disease severity and either incident prediabetes (RR: 0.93; 95% CI: 0.82-1.06) or incident diabetes (RR: 0.99; 95% CI: 0.80-1.22). CONCLUSIONS: Our findings suggest that among a diverse cohort of Hispanic/Latino individuals living in the United States, there was no association between periodontal disease severity and the development of either prediabetes or diabetes during a 6-year follow-up period.

Efficacy, Safety, and Calcium Balance of an Accelerated Citrate Anticoagulated Membrane-Based Plasma Exchange Algorithm.

INTRODUCTION: To assess the safety, efficacy, and calcium flux of an accelerated algorithm for regional citrate anticoagulation in membrane-based plasma exchange. METHODS: This was an observational study in patients receiving citrate anticoagulated, membrane-based plasma exchange at the Canberra Hospital between July 2017 and May 2020. Data were collected prospectively using an electronic medical record and compared to data from our previous published algorithm. RESULTS: There were 134 plasma exchange sessions performed during the observational period. Circuit clotting occurred in 4 sessions, and 1 session was affected by symptomatic hypocalcaemia. A systemic ionized calcium <0.96 mmol/L was seen in 19.4% of sessions, which was a similar frequency to that seen in our previous algorithm. A systemic ionized Ca <0.81 mmol/L occurred in 4 sessions (all asymptomatic). This hypocalcaemia occurred towards the end of the sessions, after switching from albumin to fresh frozen plasma replacement fluid. Median treatment time was 135 min, compared to 219 min in our previously published algorithm. Mean net Ca gain/session was 7.7 ± 2.3 mmol. CONCLUSION: An accelerated algorithm for regional citrate anticoagulation achieves substantial time saving while maintaining efficacy and safety. The 4 episodes of systemic ionized calcium <0.81 mmol/L may have been due to recirculation of infused citrate but, probably more likely, are due to the additional citrate load imposed by use of fresh frozen plasma in these sessions. Future algorithms need to better account for the citrate load present in fresh frozen plasma.

Ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ): tunable halogenation and quinone formation using NaX/Oxone.

Ring-fused benzimidazolequinones are well-known anti-tumour agents, but dimeric ring-fused adducts are new. The alicyclic [1,2-a] ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ) intermediate allows late-stage functionalization of bis-p-benzimidazolequinones. DMBBQs are chlorinated and brominated at the p-dimethoxybenzene site using nontoxic sodium halide and Oxone in HFIP/water. X-ray crystallography is used to rationalize site preference in terms of the discontinuity in conjugation in the DMBBQ system. Quinone formation occurs by increasing in situ halogen generation and water. Conversely, radical trifluoromethylation occurs at the quinone of the DMBBQ.

Social capital and periodontal disease in Hispanic/Latino adults in the United States: Results from the Hispanic Community Health Study/Study of Latinos.

AIMS: To examine the association of social capital with periodontal disease severity. MATERIALS AND METHODS: We analysed data obtained from 3,994 men and women aged 18-74 years in the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study (HCHS/SOL SCAS). From 2008 to 2011, dentists assessed periodontitis status with a full-mouth periodontal examination. Periodontitis was classified using standardized case definitions. Multivariable logistic regression estimated odds of moderate-severe periodontitis associated with two measures of social capital: structural support (Social Network Index) and functional support (Interpersonal Support Evaluation List). RESULTS: For US-born participants, for each additional person in their social network, the adjusted odds of moderate-severe periodontitis was reduced 17% (OR = 0.83, 95% CI = 0.71, 0.96). However, no association was found between functional support and periodontal disease severity. CONCLUSIONS: Greater structural social support was associated with a lower prevalence of moderate-severe periodontitis in US-born Hispanics/Latinos. These findings suggest that US-born Hispanics/Latinos with less social support represent a vulnerable segment of the population at high-risk group for periodontal disease.

How to adjust drug doses in chronic kidney disease.

Drugs excreted by the kidney require dose reduction in chronic kidney disease. This adjustment depends on the severity of the disease and what proportion of the drug is eliminated by the kidneys The estimated glomerular filtration rate can generally be used to guide dose adjustment in patients with stable kidney function. However, the formula can be misleading in some patient subsets and other approaches are required At extremes of body mass, the estimated glomerular filtration rate can under- or overestimate kidney function. It may need to be adjusted for body surface area, particularly for drugs with a narrow therapeutic range or requiring a minimum concentration to be effective. Close monitoring of drug effect and toxicity is also needed and can be supported by therapeutic drug monitoring For short courses of drugs with a wide therapeutic index, dose adjustment may not be needed Alternative methods for quantifying kidney function include the Cockcroft-Gault formula (estimates creatinine clearance) or direct measures of glomerular filtration rate using exogenous isotope compounds. These are not commonly required

Better-quality diet is associated with lower odds of severe periodontitis in US Hispanics/Latinos.

AIM: We investigated the cross-sectional association between diet quality and severe periodontitis in a sample of diverse Hispanics from the Hispanic Community Health Study/Study of Latinos. MATERIALS AND METHODS: A total of 13,920 Hispanic/Latinos aged 18-74 years of different heritages underwent a full-mouth oral examination and completed two 24-hr dietary recalls during 2008-2011. Severe periodontitis was defined as having ≥30% tooth sites with clinical attachment loss ≥5 mm. Diet quality was assessed using the Alternative Healthy Eating Index (AHEI-2010). We evaluated the association of diet quality with severe periodontitis adjusting for age, sex, nativity status, income, education, last dental visit, current insurance, cigarette smoking, diabetes, and energy intake. RESULTS: Relative to those at the lowest quartile of diet quality, individuals at the highest quartile had significantly lower odds of severe periodontitis (adjusted OR = 0.57, 95% CI: 0.39-0.82), with evidence of a dose-response relationship across AHEI quartiles. Among AHEI-2010 components, higher consumption of whole grains and fruits, and lower consumption of red/processed meats were associated with lower odds of severe periodontitis. CONCLUSION: Better-quality diet was associated with lower prevalence of severe periodontitis although the causal pathways need to be clarified in future work.

Regional citrate anticoagulation in membrane based plasma exchange: Safety, efficacy and effect on calcium balance.

AIM: To assess the efficacy, safety and calcium balance of a membrane based regional citrate anticoagulation plasma exchange protocol. METHODS: This was an observational, prospective, single centre study of membrane separation plasma exchange using regional citrate anticoagulation. It was performed using a fixed dose pre-filter citrate infusion that was based on the plasma flow rate. Patients received a post filter calcium infusion that was modified during treatment based on systemic ionized calcium monitoring. Post filter ionized calcium was not assessed. Safety and efficacy were assessed by extraction of clinical events and laboratory data contemporaneously recorded in electronic health records. RESULTS: Thirty-six sessions in five patients were performed. No patients developed symptomatic hypocalcaemia, and no patient had a recorded ionized calcium below 0.81 mmol/L. Filter clotting occurred in two sessions. The mean net calcium gained was 9.6 ± 1.8 mmol per session. CONCLUSION: Regional citrate anticoagulated membrane separation plasma exchange can be performed safely and effectively without the need for post filter ionized calcium monitoring. The algorithm employed resulted in a net calcium gain.

Uric acid lowering therapies for preventing or delaying the progression of chronic kidney disease.

BACKGROUND: Non-randomised data have shown a link between hyperuricaemia and the progression or development of chronic kidney disease (CKD). If this is correct, urate lowering therapy might form an important part of chronic kidney disease care, reducing risks for cardiovascular outcomes and end-stage kidney disease. OBJECTIVES: This review aims to study the benefits and harms of uric acid lowering therapy on the progression of CKD and other cardiovascular endpoints. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 20 July 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials testing primary urate lowering therapy in patients with or without CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes or mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) if different scales were used. MAIN RESULTS: Twelve studies (1187 participants) were included in the review. Risk of bias was unclear for the majority of domains in each study.Uric acid lowering therapy may make little or no difference in death at six months (2 studies, 498 participants: RR 1.66, 95% CI 0.61 to 4.48) or two years (2 studies, 220 participants): RR 0.13, 95% CI 0.02 to 1.06) (low certainty evidence). Uric acid lowering therapy may make little of no difference (low certainty evidence) in the incidence of ESKD at one or two years. Kidney function may be improved by uric acid lowering therapy at one year with a reduction in serum creatinine (2 studies, 83 participants: MD -73.35 µmol/L, 95% CI -107.28 to -39.41) and a rise in eGFR (1 study, 113 participants: MD 5.50 mL/min/1.73 m2, 95% CI 0.59 to 10.41). However it probably makes little or no difference to eGFR at two years (2 studies, 164 participants: MD 4.00 mL/min, 95% CI -3.28 to 11.28). Uric acid lowering therapy reduced uric acid levels at all time points (3, 4, 6, 12 and 24 months) (high certainty evidence).There is insufficient evidence to support an effect on blood pressure, proteinuria or other cardiovascular markers by uric acid lowering therapy. It should be noted that the apparent benefits of treatment were not apparent at all time points, introducing the potential for bias. AUTHORS' CONCLUSIONS: There is limited data which suggests uric acid lowering therapy may prevent progression of chronic kidney disease but the conclusion is very uncertain. Benefits were not observed at all time points and study quality was generally low. Larger studies are required to study the effect of uric acid lowering therapy on CKD progression. Three ongoing studies will hopefully provide much needed high quality data.

Sleep apnea prevalence in chronic kidney disease - association with total body water and symptoms.

BACKGROUND: Sleep apnea is common and associated with poor outcome in severe chronic kidney disease, but validated screening tools are not available. Our objectives were to determine the prevalence of sleep apnea in this population, to assess the validity of screening for sleep apnea using an ApneaLink device and to investigate the relationship of sleep apnea to; symptoms, spirometry and body water. METHODS: Patients with glomerular filtration rate ≤30 mL/min/1.73 m2, whether or not they were receiving haemodialysis, were eligible for enrolment. Participants completed symptom questionnaires, performed an ApneaLink recording and had total body water measured using bioimpedance. This was followed by a multi-channel polysomnography recording which is the gold-standard diagnostic test for sleep apnea. RESULTS: Fifty-seven participants were enrolled and had baseline data collected, of whom only 2 did not have sleep apnea. An apnea hypopnea index ≥30/h was found in 66% of haemodialysis and 54% of non-dialysis participants. A central apnea index ≥5/h was present in 11 patients, with only one dialysis patient having predominantly central sleep apnea. ApneaLink underestimated sleep apnea severity, particularly in the non-dialysis group. Neither total body water corrected for body size, spirometry, subjective sleepiness nor overall symptom scores were associated with sleep apnea severity. CONCLUSIONS: This study demonstrates a very high prevalence of severe sleep apnea in patients with chronic kidney disease. Sleep apnea severity was not associated with quality of life or sleepiness scores and was unrelated to total body water corrected for body size. Routine identification of sleep apnea with polysomnography rather than screening is more appropriate in this group due to the high prevalence.

The Cancer Mortality Risk Project - Cancer Mortality Risks by Anatomic Site: Part 1 - Introductory Overview; Part II - Carcinoma of the Colon: 20-Year Mortality Follow-up Derived from 1973-2013 (NCI) SEER*Stat Survival Database.

This introductory overview describes the recommencement of the Cancer Mortality Risks project, a systematic medical-actuarial comparative analysis of selected cancer mortality risks originally initiated by the authors in the year 2002 utilizing the National Cancer Institute (NCI) SEER*Stat 4.2.3 (Surveillance, Epidemiology, and End Results) database between 1973 and 2002 and released April 3, 2002. This study is based on approximately 40 major invasive cancer anatomic sites used in previous conversions of the National Cancer Institute SEER survival data to comparative mortality in the Medical Risks monographs published in 19761 and 1990.2 Anatomic site-specific cancer mortality abstracts of SEER survival data containing 20-year comparative mortality follow-up by cohort entry-period, histologic type, age, sex, race, stage, grade and other variables was proposed for publication as a monograph, compendium or a series of concise but detailed mortality articles.

Dentists' willingness to provide expanded HIV screening in oral health care settings: results from a nationally representative survey.

OBJECTIVES: Using a nationally representative survey, we determined dentists' willingness to provide oral rapid HIV screening in the oral health care setting. METHODS: From November 2010 through November 2011, a nationally representative survey of general dentists (sampling frame obtained from American Dental Association Survey Center) examined barriers and facilitators to offering oral HIV rapid testing (n = 1802; 70.7% response). Multiple logistic regression analysis examined dentists' willingness to conduct this screening and perceived compatibility with their professional role. RESULTS: Agreement with the importance of annual testing for high-risk persons and familiarity with the Centers for Disease Control and Prevention's recommendations regarding routine HIV testing were positively associated with willingness to conduct such screening. Respondents' agreement with patients' acceptance of HIV testing and colleagues' improved perception of them were also positively associated with willingness. CONCLUSIONS: Oral HIV rapid testing is potentially well suited to the dental setting. Although our analysis identified many predictors of dentists' willingness to offer screening, there are many barriers, including dentists' perceptions of patients' acceptance, that must be addressed before such screening is likely to be widely implemented.

Weight change in chronic kidney disease: Association with mortality and kidney function.

Background: Excess body weight is a risk factor for the progression of chronic kidney disease (CKD), but weight loss in CKD has been associated with higher mortality. Consequently, blanket weight loss recommendations in this population are controversial. Little data is available on the patterns of weight-change in CKD. The authors aimed to describe weight-changes in moderate/severe CKD and explore associations with mortality and renal endpoints in patients with overweight and obesity. Methods: Non-dialysis Canberra Hospital patients with estimated glomerular filtration (eGFR) < 60 mL/min/1.73 m2 and body mass index (BMI) ≥25 kg/m2 were followed for up to 5.5 years. Weight-change ≥5% was considered clinically significant. The renal endpoint was defined as the commencement of dialysis or transplant or a ≥40% fall in eGFR. Relationships between weight-change in the first year of follow-up and mortality or the renal endpoint were assessed using Cox-regression. Results: Three hundred ten patients (median age 75, median BMI 31 kg/m2) were identified. 68% had Stage-4 CKD at baseline. Over 4.4-years median follow-up, 128 died and 140 had significant weight-change. During the first year of follow-up, 42 patients lost and 23 gained ≥5% body weight, of whom only 3 had intentionally lost weight. On multivariate regression, significant weight loss/gain at 1-year was associated with 2.74 (p < 0.0005) and 2.67 (p = 0.003) hazard of subsequent death and with 2.51 (p = 0.004) and 2.20 (p = 0.05) hazard of the renal endpoint respectively. There was no association between baseline eGFR and subsequent weight change. Conclusions: Patients with moderate/severe CKD experience significant weight-change, but this has no relationship to baseline kidney function. Significant weight-change is associated with higher subsequent mortality and loss of kidney function, but this association is likely significantly affected by confounding.

Efficient removal of antibiotics from water by highly crosslinked metal-alginate particles: Preparation, isotherms, kinetics, and microbiological assay.

Traces of antibiotics reaching aquatic environment lead to the emergence of antimicrobial resistance (AMR). The efficient removal of antibiotics (ATBs) traces from wastewater is essential to tackle the AMR. In this study, a novel solid-state crosslinking method of alginate (ALG) was developed and applied to specifically remove ATBs from water. A wide range of crosslinkers (Ca2+, Zn2+, Cu2+, Ni2+, Fe3+ and Al3+) was used and the crosslinking nature, density, and distribution were evidenced by FTIR, ICP-MS, and SEM-EDS. Compared with ionotropic gelation, the novel solid-state crosslinking method proved superior in term of ease of production, high crosslinking degree, and ATBs removal capacity. Fe-ALG and Zn-ALG showed high removal capacity of ciprofloxacin (356.5 mg/g and 928.6 mg/g) and doxycycline (90 mg/g and 690 mg/g), however, they were less effective toward amoxicillin (11.5 mg/g and 6 mg/g). Removal isotherms and kinetics followed type I and pseudo-second order suggesting a chemisorption removal mechanism. Fe-ALG was successfully regenerated with no loss in ATB removal capacity. The microbiological assay showed significant reductions of antibacterial activities after ATBs removal from water. Overall, metal-ALG systems obtained by solid-state crosslinking are promising for ATBs removal from wastewater giving the ease of production, high efficiency, regenerability, and scalability potential.

Vitamin D in dialysis: defining deficiency and rationale for supplementation.

Vitamin D status is determined by the serum concentration of one of its metabolites, 25-hydroxy-D. Defining vitamin D deficiency based on its classical roles in gut calcium absorption and bone mineralization is problematic in dialysis patients and, until recently, was ignored in the nephrology literature. The newly recognized nonclassical functions of vitamin D include effects on the immune system, cardiovascular disease, and cancer. The nonclassical effects are likely to be equally relevant in the dialysis population, but suffer from a lack of strong evidence on which to base therapeutic targets. Past medical opinion in the nondialysis population warned that higher dose vitamin D supplementation may be toxic and was unnecessary. This is because older supplementation recommendations were based on early twentieth century studies using cod-liver oil to treat rickets. The clinical resolution of rickets requires a relatively low dose of vitamin D. Current vitamin D guidelines generally target higher 25-hydroxy-D levels of 30 ng/ml, based on optimizing markers of bone health. This results in very high estimates of 50-100% for the prevalence of vitamin D deficiency in dialysis patients. This review examines the relevance of data on the classical and nonclassical effects of vitamin D in dialysis patients. An evidence-based dosing regimen for use in dialysis patients is suggested to safely and reliably achieve vitamin D sufficiency.

An interprofessional school-based initiative to increase access to oral health care in underserved Florida counties.

OBJECTIVE: To examine and describe the effect of an oral health education program on school-based nurses' acquisition of oral health knowledge. METHODS: Three-hour synchronous videoconference sessions provided training for nurses to conduct oral health risk assessments, screen for oral diseases, deliver oral health education, apply fluoride varnish, and refer children identified in need of further assessment and treatment to a dentist. Oral health knowledge acquisition was assessed by comparing pre-training and post-training examination scores. Analyses included descriptive statistics and the Wilcoxon signed-rank test. RESULTS: Seventeen nurses from Suwannee, Lafayette, and Hamilton counties participated in the oral health education training program. Analyses of the school-based nurses' test results showed a significant increase in correct answers on the post-training test (93%) compared to the pre-training test (56%). Six hundred forty-one children from six elementary public schools received oral health education, oral screenings, and fluoride varnish applications. Fifty-eight percent of the children had untreated caries, 43% had treated caries, 15% had sealant on permanent molars, and 3% required urgent care. Nurses successfully referred children identified in need of further assessment and treatment to a dentist. CONCLUSIONS: The synchronous videoconference oral health training program was effective in improving school-based nurses' oral health knowledge. The knowledge acquired by school-based nurses via oral health training programs can be leveraged to increase access to oral health care for vulnerable and unserved school-aged populations.

The yeast Arf GTPase-activating protein Age1 is regulated by phospholipase D for post-Golgi vesicular transport.

Vesicular transport shuttles cargo among intracellular compartments. Several stages of vesicular transport are mediated by the small GTPase Arf, which is controlled in a cycle of GTP binding and hydrolysis by Arf guanine-nucleotide exchange factors and Arf GTPase-activating proteins (ArfGAPs), respectively. In budding yeast the Age2 + Gcs1 ArfGAP pair facilitates post-Golgi transport. We have found the AGE1 gene, encoding another ArfGAP, can in high gene-copy number alleviate the temperature sensitivity of cells carrying mutations affecting the Age2 + Gcs1 ArfGAP pair. Moreover, increased AGE1 gene dosage compensates for the complete absence of the otherwise essential Age2 + Gcs1 ArfGAP pair. Increased dosage of SFH2, encoding a phosphatidylinositol transfer protein, also allows cell growth in the absence of the Age2 + Gcs1 pair, but good growth in this situation requires Age1. The ability of Age1 to overcome the need for Age2 + Gcs1 depends on phospholipase D activity that regulates lipid composition. We show by direct assessment of Age1 ArfGAP activity that Age1 is regulated by lipid composition and can provide ArfGAP function for post-Golgi transport.

Twelve-month tolerability and efficacy study of NP101, the sumatriptan iontophoretic transdermal system.

OBJECTIVE: To assess the long-term tolerability and efficacy of NP101, a novel transdermal sumatriptan patch being developed for the acute treatment of migraine. BACKGROUND: Nausea (with or without vomiting) and gastroparesis have been characterized as being among the most problematic challenges affecting migraine care today. Migraine-associated nausea can cause patients to delay or avoid taking oral medication with a resultant loss or reduction of therapeutic efficacy. Migraine-associated gastroparesis can impair absorption and reduce bioavailability of oral migraine medications and thereby reduce and delay therapeutic efficacy. The non-oral triptan formulations that have been used to overcome these challenges are associated with other shortcomings that can limit their use. Designed to overcome these shortcomings and treatment limitations imposed by gastrointestinal signs and symptoms, the NP101 patch avoids the need for oral administration, does not depend upon gastrointestinal absorption, and provides more consistent, predictable plasma concentrations than oral and intranasal formulations of sumatriptan and a lower maximum plasma concentration than sumatriptan injection. METHODS: Patients diagnosed with migraine who had participated in a randomized, double-blind, Phase III study of the NP101 patch were given the option to use NP101 to treat migraine episodes with moderate or severe headache pain for up to 12 months in this open-label trial. RESULTS: One hundred eighty-three patients applied 2089 study patches. The most common adverse events involved the patch application site (45% of patients). The only non-application-site adverse events reported in >2% of patients were nausea (n=6, 3.3%), upper respiratory tract infection (n=6, 3.3%), and nasopharyngitis (n=4, 2.2%). The incidence of triptan-associated adverse events was 1.6%. Across all visits for investigator assessments, the majority of patients (ranging from 74.7% at Month 1 to 92.2% at Month 9) were scored as having no erythema at patch application sites. For patient assessments, the percentage of patch placement sites scored as having no or minimal redness was 38.2% at the time of patch removal and 65.4% 24 hours after patch activation. Two hours after patch activation across all patch treatments over the 12-month study, 23.8% of initial acute migraine episodes were scored as being free from headache pain, 58.2% as having headache pain relief,78.9% as nausea free, 60.1% as phonophobia free, 53.4% as photophobia free, and 20.7% as migraine free. No evidence of waning tolerability or efficacy was observed over the 12-month study period. CONCLUSION: NP101, a transdermal sumatriptan formulation in development for the acute treatment of migraine, demonstrated tolerability and efficacy with successive uses over 12 months in this clinical trial.

Successful treatment of calciphylaxis with vitamin K in a patient on haemodialysis.

Calciphylaxis has high mortality. Vitamin K deficiency is common in haemodialysis patients and may be a trigger for calciphylaxis due to its role in activating a tissue inhibitor of calcification, matrix Gla protein. We report a second case of a female haemodialysis patient who developed calciphylaxis twice and was successfully treated with vitamin K supplementation on both occasions. She did not receive sodium thiosulphate or bisphosphonates nor was there a change made to her dialysis time or prescription. This case highlights how supplementation with vitamin K may improve the outcome of this condition.