Linkage,recombination and mutation rate analyses of 16 X-chromosomal STR loci in Sri Lankan Sinhalese pedigrees

International Journal of Legal Medicine - This study investigated genetic linkage, recombination fractions and mutation rates of 16 X chromosomal short tandem repeat (X-STR) markers using a...     

Blur adaptation: clinical and refractive considerations

The human visual system is amenable to a number of adaptive processes; one such process, or collection of processes, is the adaptation to blur. Blur adaptation can be observed as an improvement in vision under degraded conditions, and these changes occur relatively rapidly following exposure to blur. The potential important future directions of this research area and the clinical implications of blur adaptation are discussed.     

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.Subject terms: Acute myeloid leukaemia, Targeted therapies     

What Is the Relationship Between Depressive Symptoms and Pain During Functional Tasks in Persons Undergoing TKA? A 6-year Perioperative Cohort Study

Background

Preoperative depressive symptoms have been shown in some but not all studies to be associated with poor self-reported pain and function outcomes. In addition, depressive symptoms after surgery have been shown to improve relative to preoperative levels.

Questions/purposes

We hypothesized that (1) preoperative depressive symptoms would predict postoperative pain; (2) depressive symptoms would decrease after surgery; and (3) preoperative depressive symptoms would increase as the scheduled surgery date approached.

Methods

Data from the Osteoarthritis Initiative, a National Institutes of Health-funded prospective multiyear cohort study, were used in this retrospective analysis. Persons from four communities were eligible if they had radiographic knee osteoarthritis or were at risk for developing knee osteoarthritis based on occupational, medical history, or body weight risk factors. A total of 4796 persons participated and rates of followup were 80% or greater over the course of the study. Participants completed a validated depressive symptom scale and the Knee Injury and Osteoarthritis Outcome Scale pain scale each year for 3 years before and 3 years after TKA. Latent growth curve modeling was used to model intercepts and slopes of pre- and postoperative depression and pain. Preoperative trajectories and intercepts were then used to predict postoperative pain and depressive symptoms adjusting for confounding variables.

Results

After adjustment for potential confounding, we found no evidence that preoperative depressive symptoms predicted postoperative pain with function (estimate, 0.1; 95% confidence interval, −0.31 to 0.50; p = 0.64) or that depressive symptoms were reduced after surgery (z = 0.06, p = 0.80). We also found no evidence to indicate that preoperative depressive symptoms increased as the date of surgery approached (linear slope = 0.28, SE = 0.19, p = 0.15).

Conclusions

Preoperative and postoperative depressive symptoms in patients before and after TKA did not appreciably change over a 6-year perioperative period. Patient depressive symptoms were not reduced after surgery and did not appear to be related to less pain postoperatively. Our findings of no association between preoperative depressive symptom severity and postoperative pain and no reduction in postoperative depressive symptoms run counter to other available evidence, potentially attributable, in part, to a data collection process that occurred outside of orthopaedic surgeons’ offices. Future research is needed to more fully explore the potential role of social desirability, the concept that patients respond in a way that they think the researcher or clinician wants them to respond in lieu of responding in a way that truly reflects the patient’s status. Social desirability may influence a TKA patient’s pain and function outcome assessment.

Level of Evidence

Level I, prognostic study.     

Retrograde Inversion Stripping as a Complication of the Clarivein? Mechanochemical Venous Ablation Procedure

The endovenous revolution has accelerated the development of new techniques and devices for the treatment of varicose veins. The ClariVein^® mechanochemical ablation device offers tumescentless treatment with a rotating ablation tip that can theoretically become stuck in tissue. We present the first report of retrograde stripping of the small saphenous vein without anaesthesia following attempted use of the ClariVein^® device, without adverse sequelae.     

Difference in outcomes after antibody‐mediated rejection between abo‐incompatible and positive cross‐match transplantations

Graft survival seems to be worse in positive cross‐match (HLAi) than in ABO‐incompatible (ABOi) transplantation. However, it is not entirely clear why these differences exist. Sixty‐nine ABOi, 27 HLAi and 10 combined ABOi+HLAi patients were included in this retrospective study, to determine whether the frequency, severity and the outcome of active antibody‐mediated rejection (AMR) were different. Five‐year death‐censored graft survival was better in ABOi than in HLAi and ABOi+HLAi patients (99%, 69% and 64%, respectively, P = 0.0002). Features of AMR were found in 38%, 95% and 100% of ABOi, HLAi and ABOi+HLAi patients that had a biopsy, respectively (P = 0.0001 and P = 0.001). After active AMR, a declining eGFR and graft loss were observed more frequently in HLAi and HLAi+ABOi than in ABOi patients. The poorer prognosis after AMR in HLAi and ABOi+HLAi transplantations was not explained by a higher severity of histological lesions or by a less aggressive treatment. In conclusion, ABOi transplantation offers better results than HLAi transplantation, partly because AMR occurs less frequently but also because outcome after AMR is distinctly better. HLAi and combined ABOi+HLAi transplantations appear to have the same outcome, suggesting there is no synergistic effect between anti‐A/B and anti‐HLA antibodies.