Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease that predominantly affects the right ventricle and is associated with ventricular arrhythmias that may lead to sudden cardiac death. Mutations within at least seven separate genes have been identified to cause ARVC, however a genetic culprit remains elusive in approximately 50% of cases. Although negative genetic testing may be secondary to pathogenic mutations within undiscovered genes, an alternative explanation may be the presence of large deletions or duplications involving known genes. These large copy number variants may not be detected with standard clinical genetic testing which is presently limited to direct DNA sequencing. We describe two cases of ARVC possessing large deletions involving plakophilin‐2 (PKP2) identified with microarray analysis and/or multiplex ligation‐dependent probe amplification (MLPA) that would have been classified as genotype negative with standard clinical genetic testing. A deletion of the entire coding region of PKP2 excluding exon 1 was identified in patient 1 and his son. In patient 2, MLPA analysis of PKP2 revealed deletion of the entire gene with subsequent microarray analysis demonstrating a de novo 7.9 Mb deletion of chromosome 12p12.1p11.1. These findings support screening for large copy number variants in clinically suspected ARVC cases without clear disease causing mutations following initial sequencing analysis.     

Radiotherapy for benign disease; assessing the risk of radiation-induced cancer following exposure to intermediate dose radiation

Most radiotherapy (RT) involves the use of high doses (>50 Gy) to treat malignant disease. However, low to intermediate doses (approximately 3–50 Gy) can provide effective control of a number of benign conditions, ranging from inflammatory/proliferative disorders (e.g. Dupuytren''s disease, heterotopic ossification, keloid scarring, pigmented villonodular synovitis) to benign tumours (e.g. glomus tumours or juvenile nasopharyngeal angiofibromas). Current use in UK RT departments is very variable. This review identifies those benign diseases for which RT provides good control of symptoms with, for the most part, minimal side effects. However, exposure to radiation has the potential to cause a radiation-induced cancer (RIC) many years after treatment. The evidence for the magnitude of this risk comes from many disparate sources and is constrained by the small number of long-term studies in relevant clinical cohorts. This review considers the types of evidence available, i.e. theoretical models, phantom studies, epidemiological studies, long-term follow-up of cancer patients and those treated for benign disease, although many of the latter data pertain to treatments that are no longer used. Informative studies are summarized and considered in relation to the potential for development of a RIC in a range of key tissues (skin, brain etc.). Overall, the evidence suggests that the risks of cancer following RT for benign disease for currently advised protocols are small, especially in older patients. However, the balance of risk vs benefit needs to be considered in younger adults and especially if RT is being considered in adolescents or children.     

Long‐term effectiveness of recommended boosted protease inhibitor‐based antiretroviral therapy in Europe

Objectives

The aim of the study was to evaluate the long‐term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)‐, darunavir/ritonavir (DRV/r)‐, and lopinavir/ritonavir (LPV/r)‐containing regimens.

Methods

Data were analysed for 5678 EuroSIDA‐enrolled patients starting a DRV/r‐, ATZ/r‐ or LPV/r‐containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART‐naïve subjects (8%) at ritonavir‐boosted protease inhibitor (PI/r) initiation; (2) ART‐experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV‐1 RNA copies/mL; and (3) ART‐experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan–Meier and multivariable Cox models were used to compare risks of failure by PI/r‐based regimen. The main analysis was performed with intention‐to‐treat (ITT) ignoring treatment switches.

Results

The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log‐rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART‐naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment‐experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r‐based ART.

Conclusions

Although confounding by indication and calendar year cannot be completely ruled out, in ART‐experienced subjects the long‐term effectiveness of DRV/r‐containing regimens appears to be greater than that of ATZ/r and LPV/r.

     

Geriatric Care Boot Camp: An Interprofessional Education Program for Healthcare Professionals

In response to the need for interprofessional geriatrics education, a half‐day geriatric care boot camp for healthcare professionals was held that covered core concepts in geriatric medicine: delirium and dementia, medication management, palliative care, ethics, and a general overview of older adults. Aspects of the curriculum focused on interprofessional education, and the attendees and presenters were healthcare professionals from a wide variety of fields. Primary objectives were to determine changes in knowledge of core concepts in geriatrics and level of comfort in caring for older adults. Secondary objectives assessed whether participants found the interprofessional approach beneficial and whether they used or shared this information with others in their professional activities. Participants completed pre‐ and postassessment surveys. Changes in participant understanding of each core concept were statistically significant, as was the change in comfort level of participants in caring for older adults. Furthermore, attendees found the multidisciplinary perspective of the boot camp beneficial. A 3‐month follow‐up survey assessed whether attendees applied and shared information learned in their own professional activities. Half of the respondents who reported sharing universally shared core concepts. Delirium and dementia information was most frequently shared. Information was most frequently shared with students, nurses, and patients’ families. Attendees less frequently shared, or did not share, with physicians, physician assistants, social workers, physical and occupational therapists, nutritionists, and dentists. The healthcare professionals who may benefit greatly from future education programs are those with whom the boot camp information was least frequently shared; thus, they are appropriate targets for advertisements for future programs.     

PICC-associated Bloodstream Infections: Prevalence,Patterns, and Predictors

Background

Growing use of peripherally inserted central catheters (PICCs) has led to recognition of the risk of PICC-associated bloodstream infection. We sought to identify rates, patterns, and patient, provider, and device characteristics associated with this adverse outcome.

Methods

A retrospective cohort of consecutive adults who underwent PICC placement from June 2009 to July 2012 was assembled. Using multivariable logistic and Cox-proportional hazards regression models, covariates specified a priori were analyzed for their association with PICC-associated bloodstream infection. Odds ratios (OR) and hazard ratios (HR) with corresponding 95% confidence intervals (CI) were used to express the association between each predictor and the outcome of interest.

Results

During the study period, 966 PICCs were inserted in 747 unique patients for a total of 26,887 catheter days. Indications for PICC insertion included: long-term antibiotic administration (52%, n = 503), venous access (21%, n = 201), total parenteral nutrition (16%, n = 155), and chemotherapy (11%, n = 107). On bivariate analysis, intensive care unit (ICU) status (OR 3.23; 95% CI, 1.84-5.65), mechanical ventilation (OR 4.39; 95% CI, 2.46-7.82), length of stay (hospital, OR 1.04; 95% CI, 1.02-1.06 and ICU, OR 1.03; 95% CI, 1.02-1.04), PowerPICCs (C. R. Bard, Inc., Murray Hill, NJ; OR 2.58; 95% CI, 1.41-4.73), and devices placed by interventional radiology (OR 2.57; 95% CI, 1.41-4.68) were associated with PICC-bloodstream infection. Catheter lumens were strongly associated with this event (double lumen, OR 5.21; 95% CI, 2.46-11.04, and triple lumen, OR 10.84; 95% CI, 4.38-26.82). On multivariable analysis, only hospital length of stay, ICU status, and number of PICC lumens remained significantly associated with PICC bloodstream infection. Notably, the HR for PICC lumens increased substantially, suggesting earlier time to infection among patients with multi-lumen PICCs (HR 4.08; 95% CI, 1.51-11.02 and HR 8.52; 95% CI, 2.55-28.49 for double- and triple-lumen devices, respectively).

Conclusions

PICC-associated bloodstream infection is most associated with hospital length of stay, ICU status, and number of device lumens. Policy and procedural oversights targeting these factors may be necessary to reduce the risk of this adverse outcome.