Toward genome editing in X-linked RP-development of a mouse model with specific treatment relevant features.

Genome editing represents a powerful tool to treat inherited disorders. Highly specific endonucleases induce a DNA double strand break near the mutant site, which is subsequently repaired by cellular DNA repair mechanisms that involve the presence of a wild type template DNA. In vivo applications of this strategy are still rare, in part due to the absence of appropriate animal models carrying human disease mutations and knowledge of the efficient targeting of endonucleases. Here we report the generation and characterization of a new mouse model for X-linked retinitis pigmentosa (XLRP) carrying a point mutation in the mutational hotspot exon ORF15 of the RPGR gene as well as a recognition site for the homing endonuclease I-SceI. Presence of the genomic modifications was verified at the RNA and protein levels. The mutant protein was observed at low levels. Optical coherence tomography studies revealed a slowly progressive retinal degeneration with photoreceptor loss starting at 9 months of age, paralleling the onset of functional deficits as seen in the electroretinogram. Early changes to the outer retinal bands can be used as biomarker during treatment applications. We further show for the first time efficient targeting using the I-SceI enzyme at the genomic locus in a proof of concept in photoreceptors following adeno-associated virus mediated gene transfer in vivo. Taken together, our studies not only provide a human-XLRP disease model but also act as a platform to design genome editing technology for retinal degenerative diseases using the currently available endonucleases.

Hip fractures in the elderly: the impact of comorbid illnesses on hospitalisation costs.

INTRODUCTION: Hip fractures in the elderly are associated with multiple comorbidities. MATERIALS AND METHODS: We prospectively surveyed and went through all relevant medical records of 70 consecutive patients admitted to Singapore General Hospital following either a cervical or intertrochanteric femoral fracture from late February to May 2004. The total hospitalisation cost for each patient was calculated based on the costs of inpatient care up to the point of discharge. Regression modeling was performed on the 7 commonest age-related conditions (based on our data), to determine the impact of each comorbidity on total costs. RESULTS: The average age of the cohort was 77.24 years. The median length of stay was 13.6 days. In patients without comorbidities, the mean hospitalisation cost was S$9,347.5 +/- 1719.6. With the presence of comorbidities, the mean cost increased to S$11,502.3 +/- 6024.3. In univariate modeling, dementia added the largest amount to total costs [S$5,398; 95% confidence interval (CI), S$1273 to S$9523; P <0.05]. The presence of diabetes (S$758; 95% CI, S$2,051 to S$3,566), hypertension (S$644; 95% CI, S$1,986 to S$3,274) and osteoarthritis (S$915; 95% CI, S$3,721 to S$1,891) did not significantly add to total costs. When controlled for multiple comorbidities, dementia retained its significance in adding to total costs (S$6,178; 95% CI, S$1,795 to S$10,562; P = 0.006). CONCLUSION AND DISCUSSION: Hip fracture patients with comorbidities incurred higher hospitalisation costs. Cost-containment strategies in hip fracture patients should not only examine the number of comorbidities but also the type of disease.

Hip fractures in the elderly: the impact of comorbid illnesses on hospitalisation costs

<p><b>INTRODUCTION</b>Hip fractures in the elderly are associated with multiple comorbidities.</p><p><b>MATERIALS AND METHODS</b>We prospectively surveyed and went through all relevant medical records of 70 consecutive patients admitted to Singapore General Hospital following either a cervical or intertrochanteric femoral fracture from late February to May 2004. The total hospitalisation cost for each patient was calculated based on the costs of inpatient care up to the point of discharge. Regression modeling was performed on the 7 commonest age-related conditions (based on our data), to determine the impact of each comorbidity on total costs.</p><p><b>RESULTS</b>The average age of the cohort was 77.24 years. The median length of stay was 13.6 days. In patients without comorbidities, the mean hospitalisation cost was S$9,347.5 +/- 1719.6. With the presence of comorbidities, the mean cost increased to S$11,502.3 +/- 6024.3. In univariate modeling, dementia added the largest amount to total costs [S$5,398; 95% confidence interval (CI), S$1273 to S$9523; P <0.05]. The presence of diabetes (S$758; 95% CI, S$2,051 to S$3,566), hypertension (S$644; 95% CI, S$1,986 to S$3,274) and osteoarthritis (S$915; 95% CI, S$3,721 to S$1,891) did not significantly add to total costs. When controlled for multiple comorbidities, dementia retained its significance in adding to total costs (S$6,178; 95% CI, S$1,795 to S$10,562; P = 0.006).</p><p><b>CONCLUSION AND DISCUSSION</b>Hip fracture patients with comorbidities incurred higher hospitalisation costs. Cost-containment strategies in hip fracture patients should not only examine the number of comorbidities but also the type of disease.</p>