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Aims: We studied the pharmacokinetics and exposure–response relationships of the brentuximab vedotin (BV) antibody–drug conjugate (ADC) and unconjugated monomethyl auristatin E in haematologic malignancies. Methods: This population pharmacokinetic analysis included data from five adult and three paediatric studies. Exposures in virtual adult and paediatric populations following BV 1.8 mg/kg (maximum 180 mg) intravenously every 3 weeks were simulated. Clinical endpoints included overall response rate, grade ≥2 peripheral neuropathy (PN) and grade ≥3 neutropenia. Results: BV ADC exhibited linear pharmacokinetics, well‐described by a three‐compartment model, with body weight being the only significant covariate for exposure. Monomethyl auristatin E exhibited time‐varying formation rate. Simulated steady‐state BV ADC exposures in patients aged 12 to <18 years were similar to those of adult patients, but 23%–38% lower in patients aged 2 to <12 years. Despite lower exposure, clinical activity was observed with BV 1.8 mg/kg every 3 weeks in those aged 2 to <12 years (overall response rate: 2 to <12 years, 60%; 12 to <18 years, 43%). In adult, but not paediatric patients, increased BV ADC exposures were associated with grade ≥2 PN and grade ≥3 neutropenia occurrence. Conclusions: BV pharmacokinetics in adult and paediatric patients were consistent. BV ADC exposures were lower in patients aged 2 to <12 years vs. ≥12 years, but no apparent clinically relevant differences in efficacy, grade ≥2 PN or grade ≥3 neutropenia were observed. These data support body weight‐based dosing of BV in patients irrespective of age; thus, dose adjustment in those 2 to <12 years does not appear warranted. [ABSTRACT FROM AUTHOR]

Importance: Trimethoprim‐sulfamethoxazole (TMP‐SMX) may increase digoxin concentration, a medication with a narrow therapeutic index. Small changes in digoxin concentration could predispose individuals to the risk of toxicity. Objective: To characterize the risk of digoxin toxicity in older adults taking digoxin following co‐prescription of TMP‐SMX compared with co‐prescription of amoxicillin. Design, Settings, and Participants: Retrospective population‐based cohort study in Ontario, Canada (2002–2020) using linked health care data. Participants comprised 47,961 older adults taking digoxin (58% women; median age 80 years [interquartile range 74–86]) who were newly treated with TMP‐SMX (n = 10,273) compared with those newly treated with amoxicillin (n = 37,688). Exposure: Co‐prescription of TMP‐SMX versus amoxicillin in older adults concurrently taking digoxin. Main Outcome and Measure: The primary outcome was a hospital encounter (i.e., hospital admission or emergency department visit) with digoxin toxicity within 30 days of the antibiotic prescription. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. The number needed to harm (NNH) was calculated as 1/RD. Results: A hospital encounter with digoxin toxicity occurred in 49/10,273 (0.48%) patients treated with TMP‐SMX versus 32/37,688 (0.08%) in those treated with amoxicillin (weighted RR, 5.71 [95% confidence interval (CI), 3.19 to 10.24]; weighted RD, 0.39% [95% CI, 0.25% to 0.53%]; NNH 256 [95% CI, 233 to 400]). Conclusion and Relevance: In older adults taking digoxin, the 30‐day risk of a hospital encounter with digoxin toxicity was nearly 6 times higher in those co‐prescribed TMP‐SMX versus amoxicillin, although the absolute risk difference was low (0.4%). Physicians should prescribe an alternative antibiotic when clinically appropriate. If TMP‐SMX must be co‐prescribed with digoxin (if the benefit is believed to outweigh the risk), digoxin should be dose‐reduced on an individual basis. [ABSTRACT FROM AUTHOR]

Clinician‐reported outcome measures (ClinROMs) are essential for assessment of vitiligo in clinical trials and daily practice. Several instruments have been developed and tested to measure, for example, vitiligo extent, repigmentation and activity. The goal of this review was to identify all introductory publications of ClinROMs for vitiligo that include at least some aspects of validation and to describe the instruments' characteristics, intention for use and practical strengths and limitations. A search strategy was conducted in PubMed, Embase and Cochrane Library (CENTRAL) from inception to July 2022. Based on the literature search (n = 2860), 10 articles were identified, describing 14 different ClinROMs. Six ClinRoms measured disease extent and/or repigmentation, seven evaluated disease activity and one was a composite score. The Vitiligo Area Scoring Index (VASI), and Vitiligo Extent Score (VES and VESplus) measure overall disease extent and/or repigmentation. The VASI relies on hand units (1% body surface area), whereas the VES and VESplus use a picture‐based scoring technique. The Vitiligo Extent Score for a Target Area (VESTA) measures repigmentation percentage for target lesions. One global assessment score for extent has been validated. Vitiligo disease activity scores included a static measure of clinical activity signs (Vitiligo Signs of Activity Score [VSAS]) and two measures assessing dynamic evolution (Vitiligo Disease Activity Score [VDAS] and Vitiligo Disease Improvement Score [VDIS]). The Vitiligo European Task Force assessment tool (VETFa) is a composite score. Depending on the practical strengths and limitations as well as the research question and setting (clinical trials vs. daily practice), the choice of an appropriate ClinROM may differ. Fourteen ClinROMs in vitiligo were identified to measure vitiligo extent, repigmentation, and activity. Further research evaluating the validity, reliability, and responsiveness of each instrument and worldwide consensus on which instrument to use for a specific outcome (domain) is greatly needed. [ABSTRACT FROM AUTHOR]

This translates to an unadjusted risk difference of 23.2 (95% CI 14.4, 32.0) per 10,000 patients and a propensity score-weighted risk difference of 5.9 (95% CI -3.7, 15.5) per 10,000 patients. Biologic therapy is not associated with increased COVID-19 severity in patients with hidradenitis suppurativa: initial findings from the global hidradenitis suppurativa COVID-19 registry. Crude risk of COVID-19-related hospitalization, representing the real-world risk for patients with comorbidities, was higher in HS patients than controls. [Extracted from the article]

Background and Aims: Quetiapine is an atypical antipsychotic predominantly metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. We studied the risk of adverse events following coprescription of clarithromycin (a strong CYP3A4 inhibitor) versus azithromycin (not a CYP3A4 inhibitor) in quetiapine users. Materials and Methods: This was a population‐based retrospective cohort study from 2004 to 2020 in Ontario, Canada in adult quetiapine users newly co‐prescribed clarithromycin (n = 16,909) or azithromycin (n = 25,267). The primary outcome was the composite of hospital encounters with encephalopathy (defined as a diagnosis of delirium, disorientation, transient alteration of awareness, transient ischemic attack, or unspecified dementia), a fall, or a fracture within 30 days of new coprescription. Secondary outcomes were individual components of the composite outcome, hospital encounter with computed tomography (CT) head scan, and all‐cause mortality. Results: Coprescription of clarithromycin versus azithromycin with quetiapine was associated with a higher risk of the primary composite outcome (365 of 16,909 clarithromycin users [2.2%] vs. 309 of 16,929 azithromycin users [1.8%]; absolute risk increase, 0.34% [95% confidence interval, CI, 0.04–0.63]; relative risk [RR], 1.19 [95% CI, 1.02–1.38]). This was primarily driven by an increase in fragility fractures (78 of 16,909 clarithromycin users [0.5%] vs. 45 of 16,923 azithromycin users [0.3%]; absolute risk increase, 0.20% [95% CI, 0.07–0.32]; RR, 1.74 [95% CI, 1.21–2.52]). Hospital encounters with a CT head scan were higher in clarithromycin users (220 of 16,909 [1.3%] vs. 175 of 16,923 azithromycin users [1.0%]; absolute risk increase, 0.27% [95% CI, 0.04–0.50]; RR, 1.26 [95% CI, 1.04–1.54]), but there was no difference in hospital encounters with encephalopathy, falls, or all‐cause mortality between macrolide groups. Conclusion: Among adults taking quetiapine, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically greater 30‐day risk of a hospital encounter for encephalopathy, falls, or fracture, which was predominantly related to a higher rate of fragility fractures. [ABSTRACT FROM AUTHOR]

Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population‐based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m2). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one‐third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over‐the‐counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population‐based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m2. Future studies should investigate strategies to mitigate hypocalcemia. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

This information challenges recent studies describing MMS as an infrequently used modality for porocarcinoma.[4] Curiously, Western and rural cases were more likely to use MMS for AC. The purpose of this study was to describe demographics, investigate prognoses, and analyze Mohs micrographic surgery (MMS) and wide local excision (WLE) use rates for AC. Information on surgical management and survival for adnexal carcinomas (AC) lacks strong evidence-based guidance. [Extracted from the article]

Objective: Increasing deceased organ donation registration may increase the number of available organs for transplant to help save lives. This study aimed to identify which behaviour change techniques (BCTs; or 'active ingredients') are reported within randomized trials of interventions promoting deceased organ donation registration and of those, which are associated with a larger intervention effect.Methods: We conducted a secondary analysis of 45 trials included in a Cochrane systematic review of deceased organ donation registration interventions. Two researchers used the BCT Taxonomy v1 to independently code intervention content in all trial groups. Outcome data were pooled and we used meta-regression to explore associations between individual and combinations of recurring BCTs and effect on registration intention and/or registration behaviour.Results: A total of 27 different BCTs (mean = 3.7, range = 1-9) were identified in intervention groups across the 45 trials. The five most common BCTs were: 'Information about health consequences' (71%); 'Instruction on how to perform the behaviour' (47%); 'Salience of consequences' (40%); 'Adding objects to the environment' (28%); and 'Credible source' (27%). Comparator groups in 20/45 trials also included identifiable BCTs (n = 12, mean = 3.1, range = 1-7). Meta-regression revealed that a combination of the three most common BCTs was associated with a larger intervention effect size for registration behaviour (k = 8, β = .19, p = .02).Conclusions: Trials of deceased organ donation registration interventions focus predominantly on providing information, instruction, and a means to register. While potentially effective, a much wider set of possible BCTs could be leveraged to address known barriers to registration. [ABSTRACT FROM AUTHOR]

The association between pre‐transplant dialysis duration and post‐transplant outcomes may vary by the population and endpoints studied. We conducted a population‐based cohort study using linked healthcare databases from Ontario, Canada including kidney transplant recipients (n = 4461) from 2004 to 2014. Our primary outcome was total graft failure (i.e., death, return to dialysis, or pre‐emptive re‐transplant). Secondary outcomes included death‐censored graft failure, death with graft function, mortality, hospitalization for cardiovascular events, hospitalization for infection, and hospital readmission. We presented results by pre‐transplant dialysis duration (pre‐emptive transplant, and.01–1.43, 1.44–2.64, 2.65–4.25, 4.26–6.45, and 6.46–36.5 years, for quintiles 1–5). After adjusting for clinical characteristics, pre‐emptive transplantation was associated with a lower rate of total graft failure (adjusted hazard ratio [aHR].68, 95% CI:.46,.99), while quintile 4 was associated with a higher rate (aHR 1.31, 95% CI: 1.01, 1.71), when compared to quintile 1. There was no significant relationship between dialysis duration and death‐censored graft failure, cardiovascular events, or hospital readmission. For death with graft function and mortality, quintiles 3–5 had a significantly higher aHR compared to quintile 1, while for infection, quintiles 2–5 had a higher aHR. Longer time on dialysis was associated with an increased rate of several adverse post‐transplant outcomes. [ABSTRACT FROM AUTHOR]

We examined a novel database linking national donor registry identifiers to records from a US pharmaceutical claims warehouse (2007‐2015) to describe opioid and NSAID prescription patterns among LKDs during the first year postdonation, divided into three periods: 0‐14 days, 15‐182 days, and 183‐365 days. Associations of opioid and NSAID prescription fills with baseline factors were examined by logistic regression (adjusted odds ratio, LCLaORUCL). Among 23,565 donors, opioid prescriptions were highest during days 0‐14 (36.6%), but 12.6% of donors filled opioids during days 183‐365. NSAID prescriptions rose from 0.5% during days 0‐14 to 3.3% during days 183‐365. Women filled opioids more commonly than men, and black donors filled both opioids and NSAIDs more commonly than white donors. After covariate adjustment, significant correlates of opioid prescription fills during days 183‐365 included obesity (aOR,1.241.381.53), less than college education (aOR,1.191.311.43), smoking (aOR,1.331.451.58), and nephrectomy complications (aOR,1.111.291.49). NSAID prescription fills in year 1 were not associated with differences in estimated glomerular filtration rate, incidence of proteinuria or new‐onset hypertension at the first and second year postdonation. Prescription fills for opioids and NSAIDs for LKDs varied with demographic and clinic traits. Future work should examine longer‐term outcome implications to help inform safe analgesic regimen choices after donation. [ABSTRACT FROM AUTHOR]

Speckle noise is an undesirable phenomenon that exhibits granular pattern which reduces the diagnostic capability of clinical ultrasound (US) images. In this study, a new speckle denoising method based on modelling of detail band shearlet coefficients of log‐transformed US images is presented. In each detail shearlet subband, coefficients corresponding to signal and speckle noise are modelled as normal inverse Gaussian and Gaussian priors, respectively. These coefficients, based on image local statistics are segmented into different regions of heterogeneity viz. homogeneous, heterogeneous and strongly heterogeneous regions, respectively, so as to control over smoothing of denoised images. Then, using the prior distributions maximum a posteriori (MAP) estimation is performed over all regions of detail bands except those regions that represent strongly heterogeneous coefficients. For better performance, an adaptive weight function is also used in the MAP expression which reduces the loss of feature information. Experimentation is done on noise‐free synthetic kidney and foetus US images and a set of 60 real US images. The results are presented for objective and subjective quality assessment of the proposed method and five other methods for speckle denoising. The potential of the proposed method in comparison to other methods can easily be ascertained from the obtained denoising results. [ABSTRACT FROM AUTHOR]

We examine family physicians' responses to financial incentives for medical services in Ontario, Canada. We use administrative data covering 2003-2008, a period during which family physicians could choose between the traditional fee for service (FFS) and blended FFS known as the Family Health Group (FHG) model. Under FHG, FFS physicians are incentivized to provide comprehensive care and after-hours services. A two-stage estimation strategy teases out the impact of switching from FFS to FHG on service production. We account for the selection into FHG using a propensity score matching model, and then we use panel-data regression models to account for observed and unobserved heterogeneity. Our results reveal that switching from FFS to FHG increases comprehensive care, after-hours, and nonincentivized services by 3%, 15%, and 4% per annum. We also find that blended FFS physicians provide more services by working additional total days as well as the number of days during holidays and weekends. Our results are robust to a variety of specifications and alternative matching methods. We conclude that switching from FFS to blended FFS improves patients' access to after-hours care, but the incentive to nudge service production at the intensive margin is somewhat limited. [ABSTRACT FROM AUTHOR]

Adding pertuzumab to trastuzumab (both monoclonal antibodies targeting human epidermal growth factor receptor 2 [HER2]) has proven survival benefits when combined with chemotherapy for patients with HER2‐positive breast cancer. The combination of pertuzumab and trastuzumab together in 1 vial for subcutaneous (SC) administration is being developed as a ready‐to‐use formulation to reduce the treatment burden on patients while improving healthcare efficiency. An open‐label, 2‐part, phase Ib dose‐finding study (NCT02738970) was undertaken in healthy male volunteers (part 1) and female patients with HER2‐postive early breast cancer who had completed standard (neo)adjuvant treatment (part 2). This study aimed to identify an SC pertuzumab dose given with recombinant human hyaluronidase that results in comparable exposure to that of the intravenous (IV) pertuzumab dose, based on pertuzumab serum trough concentration and area under the serum concentration–time curve. Pharmacokinetics (PK), safety, and tolerability of a single dose of SC pertuzumab given alone or in a fixed‐dose combination (comixed or coformulated) with trastuzumab were also assessed. A maintenance dose of 600 mg for SC pertuzumab resulted in an equivalent exposure to that of IV pertuzumab, and no new safety signals were identified for SC pertuzumab or trastuzumab. A loading dose of 1200 mg for SC pertuzumab was selected based on approximate dose proportionality. The PK and safety results support further development of a fixed‐dose coformulation combination of pertuzumab and trastuzumab for SC administration, which will be investigated in an upcoming phase III trial in patients with HER2‐positive early breast cancer. [ABSTRACT FROM AUTHOR]

The 2nd Annual Symposium on Hidradenitis Suppurativa Advances (SHSA) took place on 03‐05 November 2017 in Detroit, Michigan, USA. This symposium was a joint meeting of the Hidradenitis Suppurativa Foundation (HSF Inc.) founded in the USA, and the Canadian Hidradenitis Suppurativa Foundation (CHSF). This was the second annual meeting of the SHSA with experts from different disciplines arriving from North America, Europe and Australia, in a joint aim to discuss most recent innovations, practical challenges and potential solutions to issues related in the management and care of Hidradenitis Suppurativa patients. The last session involved clinicians, patients and their families in an effort to educate them more about the disease. [ABSTRACT FROM AUTHOR]

Aim: To describe the direct and indirect costs incurred by Australian living kidney donors. Methods: A total of 55 living kidney donors from three centres in Perth, Australia and one centre in Melbourne, Australia (2010–2014) was studied. Forty‐nine donors provided information on expenses incurred during the donor evaluation period and up to 3 months after donation. A micro‐costing approach was used to measure and value the units of resources consumed. Expenses were grouped as direct costs (ground and air travel, accommodation, and prescription medications) and indirect costs (lost wages and lost productivity). Costs were standardized to the year 2016 in Australian dollars. Results: The most common direct costs were for ground travel (100%), parking (76%), and post‐donation pain medications or antibiotics (73%). The highest direct costs were for air travel (median $1986 [three donors]) and ground travel (median $459 [49 donors]). Donors also reported lost wages (median $9891 [37 donors]). The inability to perform household activities or care for dependants were reported by 32 (65%) and 23 (47%) donors. Total direct costs averaged $1682 per donor (median $806 among 49 donors). Total indirect costs averaged $7249 per donor (median $7273 among 49 donors). Total direct and indirect costs averaged $8932 per donor (median $7963 among 49 donors). Conclusion: Many Australian living kidney donors incur substantial costs during the donation process. Our findings inform the continued development of policies and programmes designed to minimize costs incurred by living kidney donors. Summary at a Glance: This study made use of a micro‐costing approach to measure the direct costs as a result of living kidney donation. Indirect costs were also reported. Such findings will give insights to policy development to minimize costs incurred by living kidney donors. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: A recent regulatory warning and case reports have described the development of muscle complications with the use of 5‐α reductase inhibitors (5ARIs). We wished to determine if there was a link between rhabdomyolysis and 5ARI usage. Methods: We used a matched cohort design and linked administrative data from the province of Ontario, Canada, to investigate the risk of rhabdomyolysis in men using either finasteride or dutasteride. A total of 99 covariates were measured. We identified 93 197 men ≥66 years of age who initiated a new prescription for a 5ARI, and they were matched using a propensity score to an equal number of men not prescribed a 5ARI. Results: New initiation of 5ARIs was not associated with a significantly increased risk of rhabdomyolysis (hazard ratio [HR] 1.21, 95% confidence interval [CI], 1.00‐1.48, P = .06). When we examined the risk of rhabdomyolysis in the year prior to the initiation of a 5ARI, we found that men who would go on to use a 5ARI in the future had an elevated risk of rhabdomyolysis even prior to starting the medication (HR 1.31, 95% CI, 1.05‐1.64, P = .01). Our secondary outcome of myositis and myopathy was significantly higher among 5ARI users (HR 1.63, 95% CI, 1.48‐1.80, P < .01), and this risk was not present prior to 5ARI usage. Conclusion: 5‐α reductase inhibitors do not appear to be associated with the development of rhabdomyolysis; however, they may be associated with an increased risk of myopathy and myositis. [ABSTRACT FROM AUTHOR]

Acute hemorrhagic leukoencephalitis is the most fulminant form of the inflammatory demyelinating diseases of the central nervous system. The ideal management of this condition is debatable, but aggressive immunosuppressive regimens are mostly recommended. A 19-year-old man presented with sudden onset altered sensorium, seizures, and focal neurological deficit after 2 weeks of fever and malaise. His magnetic resonance imaging showed an asymmetric predominantly posteriorly located T2 hyperintense white matter lesion with hemorrhage evident on gradient recalled echo sequences along with profound edema and mass effect. Decompressive craniectomy, pulse methylprednisolone, intravenous immunoglobulin, plasma exchange, cyclophosphamide and rituximab were tried over the next 24-48 h, which failed to arrest the aggressicve course of the illness. The clinical diagnosis and management of acute hemorrhagic leukoencephalitis can be challenging. Early recognition and aggressive treatment offers the only hope of meaningful survival in these patients. [ABSTRACT FROM AUTHOR]

Objective To examine the 30-day risk of hospitalization with hyponatremia associated with carbamazepine, valproic acid (V), phenytoin (P), or topiramate (T) use compared to nonuse in the outpatient setting among older adults. Methods We conducted two population-based, retrospective cohort studies in Ontario, Canada, between 2003 and 2015 using administrative health care databases of older adults. The first study compared carbamazepine users to a propensity-score matched group of antiepileptic drug nonusers, whereas the second compared V-P-T users to a propensity-score matched group of antiepileptic nonusers. The primary outcome was hospitalization with hyponatremia within 30 days of an antiepileptic prescription. Results The baseline characteristics between matched groups were similar in both cohorts. Carbamazepine use versus nonuse was associated with a higher 30-day risk of hospitalization with hyponatremia (82/21,191 [0.39%] versus 30/63,573 [0.05%]; relative risk [RR] 8.20, 95% confidence interval [CI] 5.40-12.46). Similarly, V-P-T use versus nonuse was associated with a higher 30-day risk of hospitalization with hyponatremia (34/20,155 [0.17%] versus 26/40,310 [0.06%]; RR 2.62, 95% CI 1.57-4.36). Significance Older adults prescribed carbamazepine and V-P-T have a higher risk of being hospitalized with hyponatremia compared to other adults with similar indicators of baseline health who were not prescribed antiepileptic drugs. Physicians should be mindful of this risk; when a patient presents to a hospital with symptomatic hyponatremia these drugs should be considered as potential causes. [ABSTRACT FROM AUTHOR]

Aim: Placental redistribution has been shown to improve haematological outcomes in the immediate neonatal period and early infancy. This study compared the effects of delayed cord clamping (DCC) and umbilical cord milking (UCM) on haematological and growth parameters at 12 months of age.Methods: This was a follow-up study of a randomised control trial, conducted in a tertiary care paediatric centre from August 2013 to August 2014. We studied 200 apparently healthy Indian infants randomised at birth to receive DCC for 60-90 seconds or UCM. The outcome measures were iron status and physical growth parameters at 12 months.Results: Of the 200 babies, 161 completed the follow-up and baseline characteristics were comparable in both groups. The mean haemoglobin in the DCC group (102.2 (17.2) g/L and serum ferritin 16.44 (2.77) μg/L) showed no significant differences to the UCM group (98.6 (17.1) g/L and 18.2 (2.8) μg/L) at one year. In addition, there were no significant differences in weight, height and mid-upper arm circumference in the two groups.Conclusion: Term-born Indian infants who had DCC at 60-90 seconds or UCM showed no significant differences in ferritin and haemoglobin levels and growth parameters at 12 months of age. [ABSTRACT FROM AUTHOR]

The article discusses a study conducted to assess the risk of hospitalization with acute kidney injury in a population of older adults and compare patients prescribed sodium picosulfate to a similar group of patients prescribed with polyethlyene glycol (PEG). While no difference in risk of acute kidney injury comparing sodium picosulfate to PEG was observed, a higher risk of hypotension and acute dialysis among patients prescribed PEG was found.

Insulin/ IGF-1-like signalling ( IIS) and dietary restriction ( DR) are the two major modulatory pathways controlling longevity across species. Here, we show that both pathways license a common chromatin modifier, ZFP-1/ AF10. The downstream transcription factors of the IIS and select DR pathways, DAF-16/ FOXO or PHA-4/ FOXA, respectively, both transcriptionally regulate the expression of zfp-1. ZFP-1, in turn, negatively regulates the expression of DAF-16/ FOXO and PHA-4/ FOXA target genes, apparently forming feed-forward loops that control the amplitude as well as the duration of gene expression. We show that ZFP-1 mediates this regulation by negatively influencing the recruitment of DAF-16/ FOXO and PHA-4/ FOXA to their target promoters. Consequently, zfp-1 is required for the enhanced longevity observed during DR and on knockdown of IIS. Our data reveal how two distinct sensor pathways control an overlapping set of genes, using different downstream transcription factors, integrating potentially diverse and temporally distinct nutritional situations. [ABSTRACT FROM AUTHOR]

Prescription narcotic use among living kidney donors is not well described. Using a unique database that integrates national registry identifiers for living kidney donors (1987-2007) in the United States with billing claims from a private health insurer (2000-2007), we identified pharmacy fills for prescription narcotic medications in periods 1-4 and >4 yr post-donation and estimated relative likelihoods of post-donation narcotic use by Cox regression. We also compared narcotic fill rates and medication possession ratios (MPRs, defined as (days of medication supplied)/(days observed)), between donors and age- and sex-matched non-donors. Overall, rates of narcotic medication fills were 32.3 and 32.4 per 100 person-years in periods 1-4 and >4 yr post-donation. After age and race adjustment, women were approximately twice as likely as men to fill a narcotic prescription in years 1-4 (adjusted hazard ratio, aHR, 2.28; 95% confidence interval, CI, 1.86-2.79) and >4 yr (aHR 1.70; 95% CI 1.50-1.93). MPRs in donors were low (<2.5% days exposed), and lower than among age- and sex-matched non-donors. Prescription narcotic medication use is more common among women than men in the intermediate term after live kidney donation. Overall, total narcotic exposure is low, and lower than among non-donors from the general population. [ABSTRACT FROM AUTHOR]

Aims The Beta-blocker to LOwer CArdiovascular Dialysis Events ( BLOCADE) Feasibility Study aims to determine the feasibility of a large-scale randomized controlled trial with clinical endpoints comparing the beta-blocking agent carvedilol with placebo in patients receiving dialysis. Methods The BLOCADE Feasibility Study is a randomized, double-blind, placebo-controlled, parallel group feasibility study comparing the beta-blocking agent carvedilol with placebo. Patients receiving dialysis for ≥3 months and who are aged ≥50 years, or who are ≥18 years and have diabetes or cardiovascular disease, were eligible. The primary outcome was the proportion of participants who complete a 6-week run-in phase in which all participants received carvedilol titrated from 3.125 mg twice daily to 6.25 mg twice daily. Other measures included how many patients are screened, the proportion recruited, the overall recruitment rate, the proportion of participants who remain on study drug for 12 months and the incidence of intra-dialytic hypotension while on randomized treatment. Results The BLOCADE Feasibility Study commenced recruiting in May 2011 and involves 11 sites in Australia and New Zealand. Conclusions The BLOCADE Feasibility Study will inform the design of a larger clinical endpoint study to determine whether beta-blocking agents provide benefit to patients receiving dialysis, and define whether such a study is feasible. [ABSTRACT FROM AUTHOR]

Individuals with moderate-to-severe reduced renal function have greater risk of gastrointestinal bleeding than those with normal renal function. We conducted a retrospective matched cohort study to assess whether living kidney donors share a similar risk. We reviewed pre-donation charts for living kidney donations from 1992 to 2009 in Ontario, Canada, and linked this information to healthcare databases. We selected healthy non-donors from the general population and matched ten non-donors to every donor. Of the 2009 donors and 20 090 matched non-donors, none had evidence of gastrointestinal bleeding prior to cohort entry. The cohort was followed for a median of 8.4 yr (maximum 19.7 yr; loss to follow-up <7%). There was no significant difference in the rate of hospitalization with gastrointestinal bleeding in donors compared to non-donors (18.5 vs. 14.9 events per 10 000 person-years; rate ratio 1.24; 95% confidence interval [CI] 0.85-1.81). Similar results were obtained when we assessed the time to first hospitalization with gastrointestinal bleeding (hazard ratio 1.25, 95% CI 0.87-1.79). In conclusion, we found living kidney donation was not associated with a higher risk of hospitalization with gastrointestinal bleeding. These results are reassuring for the safety of the practice. [ABSTRACT FROM AUTHOR]

In many countries, adolescents can choose to register a deceased organ donation wish when they apply for a driver's license. They often receive education about deceased organ donation in order to make an informed choice. The objective of this review was to describe the effectiveness of school-based educational programs on deceased organ donation among adolescents. We reviewed any study of adolescent students receiving a school-based educational program on deceased organ donation. The outcomes were knowledge, attitudes, intent to register a preference toward deceased organ donation, and whether such education fostered family discussions about organ donation. Fifteen studies were summarized from nine countries, of which six were randomized controlled trials. Most educational programs consisted of one or two classroom sessions. The methods employed in five studies received a high-quality rating. Educational programs increased knowledge in 10 studies, and attitudes in five studies, with variable effects on intent to affirmative registration. Seven studies reported success in promoting family discussions. Adolescent classroom education is a promising strategy to improve knowledge about deceased organ donation and appears to increase public support for donation. Subjecting these programs to additional evaluation will clarify their impact on affirmative donor registration and realized donations. [ABSTRACT FROM AUTHOR]

BACKGROUND: In this phase 1/2 study, the authors tested the hypothesis that single-fraction stereotactic body radiotherapy (SBRT) for previously unirradiated spinal metastases is a safe, feasible, and efficacious treatment approach. METHODS: All patients were evaluated by a multidisciplinary team. Spinal magnetic resonance imaging studies were obtained before treatment and at regular intervals to define both target volume and response to treatment. SBRT was delivered to a peripheral dose of 16 to 24 grays in a single fraction while limiting the dose to the spinal cord. Higher doses were used for renal cell histology. The National Cancer Institute Common Toxicity Criteria 2.0 and McCormick neurologic function score were used as toxicity assessment tools. RESULTS: In total, 61 patients who had 63 tumors of the noncervical spine were enrolled and received SBRT between 2005 and 2010 on a prospective, phase 1/2 trial at The University of Texas M. D. Anderson Cancer Center. The mean follow-up was 20 months. The actuarial 18-month imaging local control rate for all patients was 88%, the actuarial 18-month overall survival rate for all patients was 64%, and the median survival for all patients was 30 months. No significant differences in outcomes were noted with respect to tumor histology or SBRT dose. Two patients experienced radiation adverse events (grade 3 or higher). The actuarial rate of 18-month freedom from neurologic deterioration from any cause was 82%. CONCLUSIONS: Data from this phase 1/2 trial supported an expanded indication for SBRT as first-line treatment of spinal metastases in selected patients. The authors concluded that additional studies that can prospectively identify predictive factors for spinal cord toxicity after SBRT are warranted to minimize the incidence of this serious yet rare complication. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Inhibition of cholesteryl ester transfer protein (CETP) is a potential new mechanism for the treatment of dyslipidaemia. Anacetrapib is a novel CETP inhibitor in development. Warfarin is a commonly prescribed anticoagulant that has a narrow therapeutic index. A drug interaction study for warfarin with a novel CETP inhibitor is expected to be helpful in defining dosing regimens. WHAT THIS STUDY ADDS • This is the first study to show that there is no clinically meaningful pharmacokinetic interaction between anacetrapib and warfarin. The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib. AIM Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted. METHODS In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg CoumadinTM) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 × 100 mg) beginning on day −14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied. RESULTS Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC(0-∞) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(−) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin Cmax were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(−) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC(0-168 h) was 0.93 (0.89, 0.96). CONCLUSION The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib. [ABSTRACT FROM AUTHOR]

Acute primary cutaneous leishmaniasis typically presents microscopically with a lymphohistiocytic infiltrate containing admixed plasma cells, parasitized macrophages and abundant organisms. Tuberculoid granulomatous changes may occur in the later phases of primary infection. A 23-year-old male presented 1 month after visiting Peru with classic clinical findings of acute primary cutaneous leishmaniasis, while histopathology showed a tuberculoid granulomatous process that lacked any organisms in hematoxylin-eosin and fungal stains. Polymerase chain reaction (PCR) analysis and tissue cultures confirmed the diagnosis of cutaneous leishmaniasis with Leishmania (Viannia) panamensis infection. A pauci-organism tuberculoid granulomatous process may uncommonly be the presenting histopathology in the acute infectious phase of cutaneous leishmaniasis. Clinicians and dermatopathologists should be aware of this atypical presentation, which may cause diagnostic confusion and delay proper treatment. PCR testing should be employed in cases with high clinical suspicion when histopathology is not definitive. Miller DD, Gilchrest BA, Garg A, Goldberg LJ, Bhawan J. Acute New World cutaneous leishmaniasis presenting as tuberculoid granulomatous dermatitis. [ABSTRACT FROM AUTHOR]

ABSTRACT Anacetrapib is currently being developed for the oral treatment of dyslipidemia. A clinical study was conducted in healthy subjects to assess the potential for an interaction with orally administered digoxin. Anacetrapib was generally well tolerated when co-administered with digoxin in the healthy subjects in this study. The geometric mean ratios (GMR) for (digoxin + anacetrapib/digoxin alone) and 90% confidence intervals (CIs) for digoxin AUC0-last and AUC0-∞ were 1.05 (0.96, 1.15) and 1.07 (0.98, 1.17), respectively, both being contained in the accepted interval of bioequivalence (0.80, 1.25), the primary hypothesis of the study. The GMR (digoxin + anacetrapib /digoxin alone) and 90% CIs for digoxin Cmax were 1.23 (1.14, 1.32). Median Tmax and mean apparent terminal t½ of digoxin were comparable between the two treatments. The single-dose pharmacokinetics of orally administered digoxin were not meaningfully affected by multiple-dose administration of anacetrapib, indicating that anacetrapib does not meaningfully inhibit P-glycoprotein. Thus, no dosage adjustment for digoxin is necessary when co-administered with anacetrapib. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Insomnia is a common condition that affects one's ability to sleep comfortably and consequently to work effectively. Its etiology is multifactorial and involves plethora of risk factors. Consequences can vary from mild sleepiness to more sever psychiatric disturbances and ischemic stroke. Despite several diagnostic criteria it is poorly diagnosed and less often treated. Benzodiazepines formed the mainline therapy for many years till the advent of newer nonbenzodiazepine group of drugs including zolpidem. Zolpidem is an imidazo-pyridine compound that enhances the GABAA receptor function by interaction with Omega-1 receptor subtype. Its pharmacokinetic profile allows the patients to use it later in the night when having trouble falling asleep without any residual cognitive impairment the next morning. It has rapid onset of action, improves total sleep duration, and reduces night-time awakenings. Its adverse effect profile is satisfactory as it appears to have low addiction potential. This review will focus on the current role of zolpidem in the management of insomnia. [ABSTRACT FROM AUTHOR]

BACKGROUND: [ABSTRACT FROM AUTHOR]

The article discusses research conducted to investigate the effect the CYP3A inhibitor diltiazem had on the pharmacokinetics of the cholesteryl ester transfer protein inhibitor anacetrapib. Researchers evaluated healthy male and female subjects between the ages of 18 to 55. They found that exposure to anacetrapib was increased by diltiazem and that anacetrapib is a moderately sensitive CYP3A substrate.

The small ubiquitin-like modifier (SUMO) can undergo self-modification to form polymeric chains that have been implicated in cellular processes such as meiosis, genome maintenance and stress response. Investigations into the biological role of polymeric chains have been hampered by the absence of a protocol for the purification of proteins linked to SUMO chains. In this paper, we describe a rapid affinity purification procedure for the isolation of endogenous polySUMO-modified species that generates highly purified material suitable for individual protein studies and proteomic analysis. We use this approach to identify more than 300 putative polySUMO conjugates from cultured eukaryotic cells. [ABSTRACT FROM AUTHOR]

The International Quotidian Dialysis Registry (IQDR) is a global initiative designed to study practices and outcomes associated with the use of hemodialysis (HD) regimens of increased frequency and/or duration. The IQDR grew out of the initiative that lead to the randomized prospective studies of nocturnal HD and short hours daily dialysis vs. conventional thrice weekly HD that are conducted by the Frequent Hemodialysis Network sponsored by the National Institutes of Health. These 2 separate studies are drawing to a close and the first results are expected to be reported later this year. These studies use surrogate outcomes for their primary endpoints as they are not powered to look at outcomes of mortality and hospitalization. The IQDR attempts to aggregate long-term follow-up data from centers utilizing alternative HD regimens worldwide and will have adequate statistical power to examine those important outcomes. To date, the IQDR has enrolled patients from Canada, the United States, Australia, New Zealand, and France and has linked with commercial databases and national registries. This sixth annual report of the IQDR describes: (1) An update on the governance structure; (2) The recommendations made at the first general meetings of the IQDR Scientific Committee and Advisory Board; (3) The status of those recommendations; (4) A summary of current data sources and participating registries; (5) The status of recruitment to date; (6) The creation of a specific Canadian IQDR data set and; (7) The current research agenda. [ABSTRACT FROM AUTHOR]

According to the Barker hypothesis, intrauterine growth restriction and premature delivery adversely affect cardiovascular health in adult life. The association of childhood hypertension as a cardiovascular risk factor and birth weight has been understudied. In a prospective cohort study, the authors evaluated the effect of birth weight, gestational age, maternal prepregnancy body mass index (BMI), and child BMI z score at the time of enrollment on the systolic and diastolic blood pressure (BP) z score in 3024 (1373 women) consecutive outpatient clinic patients aged 2.05 to 18.58 years. The latest National Health and Nutrition Examination Survey (NHANES III) was used to calculate the age-dependent z scores. The median z scores of BMI (+0.48, range −6.96-6.64), systolic BP (+0.41, range −4.50-6.73), and diastolic BP (+0.34, range −3.15-+6.73) were all significantly greater than the NHANES III reference population. Systolic BP z score did not correlate with birth weight or gestational age, but did correlate with maternal prepregnancy BMI ( r=.090, P<.0001) and BMI z score ( r=.209, P<.0001). Diastolic BP z score positively correlated with birth weight (0.037, P=.044), gestational age ( r=.052, P=.005), BMI z score( r=.106, P<.0001), and maternal prepregnancy BMI ( r=.062, P=.0007). In contrast to what would be expected from the Barker hypothesis, the authors found no negative correlation between BP z score and birth weight or gestational age. This study suggests that a high BMI, a big mom, and a high birth weight are more important risk factors for hypertension during childhood than low birth weight or gestational age. J Clin Hypertens (Greenwich). 2011;13:35-41. ©2010 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Doshi M, Garg AX, Gibney E, Parikh C. Race and renal function early after live kidney donation: an analysis of the United States Organ Procurement and Transplantation Network database. Clin Transplant 2010 DOI: 10.1111/j.1399-0012.2010.01209.x. © 2010 John Wiley & Sons A/S. Among Americans, the risk for kidney disease is higher in individuals of African descent (AA) when compared with Caucasians. We considered whether there are similar racial differences in kidney function soon after donor nephrectomy. Of the 31 928 live kidney donors that donated between the years 2000 and 2005, 16 996 (53%) had post-donation serum creatinine recorded at a mean follow-up of 156 d (range 1-1410 d). A total of 14 525 (85%) were Caucasians and 2471 (15%) were AA. When compared with Caucasians, AA donors were more likely to be younger, heavier, and male, had a higher baseline serum creatinine and a shorter duration of follow-up. After accounting for these differences, the serum creatinine after donation and fractional rise in serum creatinine after donation were similar between the two groups (AA vs. Caucasian donors, 1.3 ± 0.3 vs. 1.2 ± 0.3 mg/dL; 53% vs. 45%) and the post-donation estimated glomerular filtration rate was also similar (57.2 ± 0.6 vs. 56.0 ± 0.2 mL/min per 1.73 m2). We observed no major clinical difference in glomerular filtration rate and ability to compensate for loss of renal mass soon after live kidney donation between Caucasian and AA donors. [ABSTRACT FROM AUTHOR]

J Clin Hypertens(Greenwich). 2010;12:613–620. © 2010 Wiley Periodicals, Inc. The authors evaluated the risk for pregnancy-related hypertension among previously healthy women who conceived within 5 years of exposure to drinking water contaminated with Escherichia coli O157.H7 in Walkerton, Canada (2000). Chronic hypertension was defined as systolic/diastolic blood pressure ≥140/90 mm Hg before 20 weeks gestation; gestational hypertension was defined as new onset systolic/diastolic blood pressure ≥140/90 mm Hg ≥20 weeks gestation. The incidence of hypertension was compared between women who were asymptomatic during the outbreak to those who experienced acute gastroenteritis. Blood pressure data were available for 135 of 148 eligible pregnancies. The adjusted relative risks for chronic and gestational hypertension were 1.5 (95% confidence interval [CI]: 0.3–7.7) and 1.0 (95% CI: 0.4–2.5), respectively. Mean arterial pressure before 20 weeks gestation was 2.7 mm Hg higher in women who had acute gastroenteritis (95% CI: 0.05–5.4). A trend toward higher chronic hypertension and mean arterial pressure in early pregnancy was observed among women who experienced gastroenteritis after exposure to bacterially-contaminated drinking water. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for the treatment of dyslipidaemia. Whereas several studies have described the effects of the CETP inhibitors, torcetrapib (Pfizer) and dalcetrapib (Roche), on lipids and lipoproteins, few studies have characterized the effect of rising single doses on the pharmacokinetics and pharmacodynamics (CETP activity) of an individual CETP inhibitor or have described the effects of intrinsic and extrinsic factors on the pharmacokinetics and pharmacodynamics of these agents. WHAT THIS STUDY ADDS • We have characterized the exposure/response relationship for the inhibition of CETP activity over a wide exposure range. We have shown that single doses of anacetrapib produced marked and dose-dependent inhibition of serum CETP activity with peak effects of ∼90% inhibition at tmax and persistent inhibition at 24 h post-dose. We have also shown that whereas food increased exposures to anacetrapib significantly and variably, age, gender and obese status did not meaningfully influence the pharmacokinetics and pharmacodynamics of anacetrapib. AIMS Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. METHODS Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. RESULTS Anacetrapib was rapidly absorbed, with peak concentrations occurring at ∼4 h post-dose and an apparent terminal half-life ranging from ∼9 to 62 h in the fasted state and from ∼42 to ∼83 h in the fed state. Plasma AUC and Cmax appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of ∼90% inhibition at tmax and ∼58% inhibition at 24 h post-dose. An Emax model best described the plasma anacetrapib concentration vs CETP activity relationship with an E C50 of ∼22 nm. Food increased exposure to anacetrapib; up to ∼two–three-fold with a low-fat meal and by up to ∼six–eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. CONCLUSIONS Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for the treatment of dyslipidaemia, for which hydroxy-3-methylglutaryl coenzyme A reductase inhibitors remain a cornerstone of therapy. • Clinical studies published to date with other investigational CETP inhibitors, torcetrapib (Pfizer) and dalcetrapib (Roche), have been evaluated in the presence of statins, but it remains unclear whether there is a clinically meaningful interaction between a CETP inhibitor and a statin, and whether the low-density lipoprotein-cholesterol (LDL-C)-lowering effects are additive with the combination. WHAT THIS STUDY ADDS • This is the first study to show that there is no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin. • When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C- and apolipoprotein (Apo) B-lowering efficacy, due to CETP inhibition, the magnitude of which appears greater than any combination of CETP inhibitor and statin evaluated to date. • The study also provides useful insights into the LDL-C- and Apo B-lowering effects when a CETP inhibitor is given in combination with a statin. AIMS Anacetrapib is an orally active, potent inhibitor of cholesteryl ester transfer protein (CETP), which is in development for the treatment of dyslipidaemia. Because of the likely use of anacetrapib with hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, we aimed to evaluate the potential for a pharmacokinetic interaction with simvastatin. METHODS A randomized, two-period, two-treatment, balanced, open-label, crossover study in 12 healthy subjects was performed. Subjects received simvastatin 40 mg alone or anacetrapib 150 mg co-administered with simvastatin 40 mg, once daily. Both treatments were administered following a low-fat breakfast for 14 days, separated by a wash-out period of at least 14 days. Safety and tolerability, simvastatin and simvastatin acid concentrations, and lipoproteins, were assessed. RESULTS Both treatments were well tolerated. The pharmacokinetics of simvastatin and simvastatin acid were similar with and without anacetrapib administration {AUC0–24 h geometric mean ratio [90% confidence interval (CI)] for simvastatin acid and simvastatin were 1.36 [1.17, 1.57] and 1.30 [1.14, 1.47], respectively} based on the prespecified comparability bounds of (0.50, 2.00). Treatment with simvastatin alone led to a mean (95% CI) % reduction from baseline in low-density lipoprotein-cholesterol (LDL-C) of −36% (−27, −46) compared with a reduction of −54% (−44, −63) for anacetrapib co-administered with simvastatin. CONCLUSIONS There appears to be no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin. When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C-lowering efficacy, due to CETP inhibition. Co-administration of anacetrapib and simvastatin was well tolerated. [ABSTRACT FROM AUTHOR]

In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probeinhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC[sub0-∞] and C[submax] were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole - specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/ anacetrapib alone for AUC[sub0-∞] and C[submax] were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A. [ABSTRACT FROM AUTHOR]

Panniculitis in association with autoimmune colitis (AC) is mostly confined to reports of erythema nodosum (EN) and Crohn’s disease. We expand the repertoire of panniculitides associated with autoimmune bowel disease through a unique case report of nodular vasculitis (NV) that developed in parallel fashion to flares of ulcerative colitis (UC). A 51-year-old woman with a clinical history of surgically treated UC developed lesions on the lower legs that were initially diagnosed and treated as EN. Two years later, during a clinical exacerbation of UC, she developed similar lesions that on biopsy examination showed features consistent with NV. While treatment with antibiotics resulted in amelioration of both bowel symptoms and leg lesions, cessation of the same resulted in recurrence of both. This report implies an association between NV and UC. [ABSTRACT FROM AUTHOR]

The autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome is characterized by the presence of chronic mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism. Almost all patients have skin or nail findings early in the course of the disease. Therefore, the dermatologist is in the unique position of being able to identify patients with this syndrome early in its course and to facilitate careful monitoring of potentially lethal complications. [ABSTRACT FROM AUTHOR]

In view of the need to study both intermediate and definitive outcomes associated with daily and extended-hours hemodialysis (HD), our group has undertaken the design and implementation of an international registry to collect data describing the treatments and outcomes of patients treated with these regimens. The International Quotidian Dialysis Registry began recruiting patients in June 2004. There are currently 229 patients enrolled in the registry, up from 199 last year. The projected growth is 2000 patients by 2008. This paper constitutes the third annual report of progress of patient and center recruitment, and includes descriptive data drawn from the 3 primary patient groups currently tracked by the registry: home nocturnal, home short-daily, and in-center short-daily HD. As the cohort grows, patients will be compared with control subjects drawn from their respective national registries, and comparative analyses will follow. [ABSTRACT FROM AUTHOR]

India has good reasons to be concerned about climate change as it could adversely affect the achievement of vital national development goals related to socio-economic development, human welfare, health, energy availability and use, and infrastructure. The paper attempts to develop a framework for integrated impact assessment and adaptation responses, using a recently built railroad coastal infrastructure asset in India as an example. The framework links climate change variables — temperature, rainfall, sea level rise, extreme events, and other secondary variables — and sustainable development variables — technology, institutions, economic, and other policies. The study indicates that sustainable development variables generally reduce the adverse impacts on the system due to climate change alone, except when they are inadequately applied. The paper concludes that development is a vital variable for integrated impact assessment. Well crafted developmental policies could result in a less-GHG intensive future, enhanced adaptive capacities of communities and systems, and lower impacts due to climate change. [ABSTRACT FROM AUTHOR]

Interest in short daily and nocturnal hemodialysis (HD) regimens continues to grow worldwide. Despite growing optimism that these therapies will afford better patient outcomes over conventional HD, the current literature has not been viewed as sufficiently compelling to affect widespread implementation in most jurisdictions. Before these therapies can gain wider acceptance, larger and more rigorous studies will likely be needed. In June 2004, the Quotidian Dialysis Registry, based at the Lawson Health Research Institute at the University of Western Ontario, Canada, began recruiting patients across North America. By using an Internet-based data entry platform, patients from various centers worldwide will eventually be recruited, and studied prospectively. This paper constitutes the second annual update on patient and center recruitment, patient and treatment characteristics, and future directions for the registry. [ABSTRACT FROM AUTHOR]