Skewed X-inactivation is common in the general female population

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants

The efficacy of continuous-flow cryo and cyclic compression therapy after hip fracture surgery on postoperative pain: Design of a prospective, open-label, parallel, multicenter, randomized controlled, clinical trial

Background: The number of hip fractures and resulting post-surgical outcome are a major public health concern and the incidence is expected to increase significantly. The acute recovery phase after hip fracture surgery in elder patients is often complicated by severe pain, high morphine consumption, perioperative blood loss with subsequent transfusion and delirium. Postoperative continuous-flow cryocompression therapy is suggested to minimize these complications and to attenuate the inflammatory reaction that the traumatic fracture and subsequent surgical trauma encompass. Based on a pilot study in patients undergoing total hip arthroplasty for osteoarthritis, it is anticipated that patients treated with continuous-flow cryocompression therapy will have less pain, less morphine consumption and lower decrease of postoperative hemoglobin levels. These factors are associated with a shorter hospital stay and better long-term (functional) outcome. Methods/design: One hundred and sixty patients with an intra or extracapsular hip fracture scheduled for internal fixation (intramedullary hip nail, dynamic hip screw or cannulated screws) or prosthesis surgery (total hip or hemiarthroplasty) will be included in this prospective, open-label, parallel, multicenter, randomized controlled, clinical superiority trial. Patients will be allocated to two treatment arms: group 'A' will be treated with continuous-flow cryocompression therapy and compared to group 'B' that will receive standard care. Routine use of drains and/or compressive bandages is allowed in both groups. The primary objective of this study is to compare acute pain the first 72 h postoperative, measured with numeric rating scale for pain. Secondary objectives are: (non-) morphine analgesic use; adjusted postoperative hemoglobin level; transfusion incidence; incidence, duration and severity of delirium and use of psychotropic medication; length of stay; location and duration of rehabilitation; functional outcome; short-term patient-reported health outcome; general and cryotherapy related complications and feasibility. Discussion: This is the first randomized controlled trial that will assess the analgesic efficiacy of continuous-flow cryocompression therapy in the acute recovery phase after hip fracture surgery. Trial registration: www.trialregister.nl, NTR4152 (23rd of August 2013)

Postoperative continuous-flow cryocompression therapy in the acute recovery phase of hip fracture surgery-A randomized controlled clinical trial

BACKGROUND: The acute recovery phase after hip fracture surgery is often complicated by severe pain, postoperative blood loss with subsequent transfusion, and delirium. Prevalent comorbidity in hip fracture patients limit the use of opioid-based analgesic therapies, yielding a high risk for inferior pain treatment. Postoperative cryotherapy is suggested to provide an analgesic effect, and to reduce postoperative blood loss. In this prospective, open-label, parallel, multicentre, randomized controlled, clinical trial, we aimed to determine the efficacy of continuous-flow cryocompression therapy (CFCT) in the acute recovery phase after hip fracture surgery. METHODS: Patients with an intra or extracapsular hip fracture scheduled for surgery were included. Subjects were allocated to receive postoperative CFCT or usual care. The primary endpoint was numeric rating scale (NRS) pain the first 72 postoperative hours. Secondly, analgesic use; postoperative haemoglobin change and transfusion incidence; functional outcome; length of stay; delirium incidence; location of rehabilitation; patient-reported health outcome; complications and feasibility were assessed. RESULTS: Sixty-one subjects in the control group, and 64 subjects in the CFCT group were analysed. Within the CFCT group, post treatment NRS pain declined 0.31 (p=0.07) at 24h, 0.28 (p=0.07) at 48h, and 0.47 (p=0.002) at 72h relative to pre treatment NRS pain. Sensitivity analysis at 72h showed that NRS pain was 0.92 lower in the CFCT group when compared to the control group (1.50 vs. 2.42; p=0.03). Postoperative analgesic use was comparable between groups. Between postoperative day one and three haemoglobin declined 0.29mmol/l in the CFCT group and 0.51mmol/l in controls (p=0.06), and transfusion incidence was comparable. The timed up and go test and length of stay were also comparable between both groups. Complications, amongst delirium and cryotherapy-related adverse events were not statistically significantly different. Discharge locations did not differ between groups. At outpatient follow-up subjects did not differ in patient-reported health outcome scores. Subjects rated CFCT satisfaction with an average of 7.1 out of 10 points. CONCLUSIONS: No evidence was recorded to suggest that CFCT has an added value in the acute recovery phase after hip fracture surgery. If patients complete the CFCT treatment schedule, a mild analgesic effect is observed at 72h