Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment of acute myeloid leukaemia (AML). Resistance to ivosidenib due to a second site ...mutation of IDH1 R132C, leading to IDH1 R132C/S280F, has emerged. We describe biochemical, crystallographic, and cellular studies on the IDH1 R132C/S280F and R132H/S280F variants that inform on the mechanism of second-site resistance, which involves both modulation of inhibitor binding at the IDH1 dimer-interface and alteration of kinetic properties, which enable more efficient 2-HG production relative to IDH1 R132C and IDH1 R132H. Importantly, the biochemical and cellular results demonstrate that it should be possible to overcome S280F mediated resistance in AML patients by using alternative inhibitors, including some presently in phase 2 clinical trials.
New approach to interstage care for palliated high-risk patients with congenital heart disease Dobrolet, Nancy C., MD; Nieves, Jo Ann, MSN, CPN, ARNP, PNP-BC; Welch, Elizabeth M., MD ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
10/2011, Letnik:
142, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Objective Home surveillance monitoring might identify patients at risk for interstage death after stage 1 palliation for hypoplastic left heart syndrome. We sought to identify the effect that a ...high-risk program might have on interstage mortality and identification of residual/recurrent lesions after neonatal palliative operations. Methods Between January 2006 to January 2010, newborns after stage 1 palliation for hypoplastic left heart syndrome or shunt placement were invited to participate in our high-risk program. Patients enrolled in our high-risk program comprise the study group. Patients who had similar operations between January 2002 and December 2005 comprise the control group. Comparisons are made between the 2 groups with respect to interstage mortality and the frequency and timing of interstage admissions requiring medical, catheter, or surgical treatment. Results Seventy-two patients met the criteria for our high-risk program. Fifty-nine (82%) of 72 patients were enrolled. Among 19 patients with hypoplastic left heart syndrome in our high-risk program, outpatient interstage mortality was zero. Outpatient interstage mortality for the 36 control subjects with hypoplastic left heart syndrome was 6%. Among 40 patients with shunts in the study group, there was 1 outpatient interstage death compared with 4 (6%) deaths in 68 subjects in the control group. Significant residual/recurrent lesions were identified with similar frequency between the 2 groups. However, after shunt operations, these lesions were detected and treated at significantly younger mean ages for patients followed in the high-risk program ( P < .005). Conclusions Initiation of a high-risk program might decrease interstage mortality after high-risk neonatal palliative operations. Such an approach might contribute to earlier detection of significant residual/recurrent lesions amenable to therapy.
What does the future hold for academic primary care? Despite building world-leading research infrastructure, and responding to the COVID-19 pandemic,2 career pathways remain unclear, clinical ...credibility is questioned, and recruitment is challenging - potentially threatening the discipline's future. As the latest cohort in the Oxford International Primary Care Research Leadership Programme, we present the 'ten things we wish we had known' for anyone considering a career in academic primary care. There has long been tension between teal doctors' and teal academics', with academic GPs making up only a tiny fraction of all GPs.10 Remember that, apart from your role in clinical practice, you can make a difference through contributions to education, research, health policy, and service development. Sustained advocacy for the discipline is required in partnership with clinicians and patients.
Randomised controlled trials are generally regarded as the 'gold standard' experimental design to determine the effectiveness of an intervention. Unfortunately, many trials either fail to recruit ...sufficient numbers of participants, or recruitment takes longer than anticipated. The current embedded trial evaluates the effectiveness of optimised patient information sheets on recruitment of participants in a falls prevention trial.
A three-arm, embedded randomised methodology trial was conducted within the National Institute for Health Research-funded REducing Falls with ORthoses and a Multifaceted podiatry intervention (REFORM) cohort randomised controlled trial. Routine National Health Service podiatry patients over the age of 65 were randomised to receive either the control patient information sheet (PIS) for the host trial or one of two optimised versions, a bespoke user-tested PIS or a template-developed PIS. The primary outcome was the proportion of patients in each group who went on to be randomised to the host trial.
Six thousand and nine hundred patients were randomised 1:1:1 into the embedded trial. A total of 193 (2.8%) went on to be randomised into the main REFORM trial (control n = 62, template-developed n = 68; bespoke user-tested n = 63). Information sheet allocation did not improve recruitment to the trial (odds ratios for the three pairwise comparisons: template vs control 1.10 (95% CI 0.77-1.56, p = 0.60); user-tested vs control 1.01 (95% CI 0.71-1.45, p = 0.94); and user-tested vs template 0.92 (95% CI 0.65-1.31, p = 0.65)).
This embedded methodology trial has demonstrated limited evidence as to the benefit of using optimised information materials on recruitment and retention rates in the REFORM study.
International Standard Randomised Controlled Trials Number registry, ISRCTN68240461 . Registered on 01 July 2011.
Treatment of OA by stratifying for commonly used and novel therapies will likely improve the range of effective therapy options and their rational deployment in this undertreated, chronic disease. In ...order to develop appropriate datasets for conducting post hoc analyses to inform approaches to stratification for OA, our aim was to develop recommendations on the minimum data that should be recorded at baseline in all future OA interventional and observational studies.
An Arthritis Research UK study group comprised of 32 experts used a Delphi-style approach supported by a literature review of systematic reviews to come to a consensus on core data collection for OA studies.
Thirty-five systematic reviews were used as the basis for the consensus group discussion. For studies with a primary structural endpoint, core domains for collection were defined as BMI, age, gender, racial origin, comorbidities, baseline OA pain, pain in other joints and occupation. In addition to the items generalizable to all anatomical sites, joint-specific domains included radiographic measures, surgical history and anatomical factors, including alignment. To demonstrate clinical relevance for symptom studies, the collection of mental health score, self-efficacy and depression scales were advised in addition to the above.
Currently it is not possible to stratify patients with OA into therapeutic groups. A list of core and optional data to be collected in all OA interventional and observational studies was developed, providing a basis for future analyses to identify predictors of progression or response to treatment.
Following consultation, the report was published on the FSA's website on March 18 at www.food.gov.uk/multimedia/pdfs/botulisminsheepgoats.pdf The FSA will review the advice if new evidence emerges ...that the botulinum toxin types that affect people (such as A, B and E) cause outbreaks in ruminants.
Sacroiliac (SI) joint pain is an often overlooked cause of low back pain. SI joint arthrodesis has been reported to relieve pain and improve quality of life in patients suffering from degeneration or ...disruption of the SI joint who have failed non-surgical care. We report herein early results of a multicenter prospective single-arm cohort of patients with SI joint degeneration or disruption who underwent minimally invasive fusion using the iFuse Implant System®.
The safety cohort includes 94 subjects at 23 sites with chronic SI joint pain who met study eligibility criteria and underwent minimally invasive SI joint fusion with the iFuse Implant System® between August 2012 and September 2013. Subjects underwent structured assessments preoperatively, immediately postoperatively, and at 1, 3, and 6 months postoperatively, including SI joint and back pain visual analog scale (VAS), Oswestry Disability Index (ODI), Short Form-36 (SF-36), and EuroQoL-5D (EQ-5D). Patient satisfaction with surgery was assessed at 6 months. The effectiveness cohort includes the 32 subjects who have had 6-month follow-up to date.
Mean subject age was 51 years (n=94, safety cohort) and 66% of patients were women. Subjects were highly debilitated at baseline (mean VAS pain score 78, mean ODI score 54). Three implants were used in 80% of patients; two patients underwent staged bilateral implants. Twenty-three adverse events occurred within 1 month of surgery and 29 additional events occurred between 30 days and latest follow-up. Six adverse events were severe but none were device-related. Complete 6-month postoperative follow-up was available in 26 subjects. In the effectiveness cohort, mean (± standard deviation) SI joint pain improved from a baseline score of 76 (±16.2) to a 6-month score of 29.3 (±23.3, an improvement of 49 points, P<0.0001), mean ODI improved from 55.3 (±10.7) to 38.9 (±18.5, an improvement of 15.8 points, P<0.0001) and SF-36 PCS improved from 30.7 (±4.3) to 37.0 (±10.7, an improvement of 6.7 points, P=0.003). Ninety percent of subjects who were ambulatory at baseline regained full ambulation by month 6; median time to full ambulation was 30 days. Satisfaction with the procedure was high at 85%.
Minimally invasive SI joint fusion using the iFuse Implant System® is safe. Mid-term follow-up indicates a high rate of improvement in pain and function with high rates of patient satisfaction.
Patients undergoing congenital heart surgery may occasionally require additional surgical procedures in the form of tracheostomy and gastrostomy. These procedures are often performed in an attempt to ...diminish hospital morbidity and length of stay. We reviewed the Web-based medical records of all patients undergoing congenital heart surgery at Miami Children’s Hospital from February 2002 through August 2007. Patients who were deemed preterm and had undergone closure of a patent ductus arteriosis were eliminated. The records of all other patients were queried for the terms gastrostomy, g-tube, Nissan, fundal plication, tracheostomy, or tracheotomy. Patients’ medical records in which these terms appeared in any portion were completely reviewed. There were 1660 congenital heart operations performed in the study period. There were 592 operations performed on patients whose age ranged from 1 month to 1 year and 441 neonatal operations. Mortality was 2%. Median postoperative stay was 8 days (range, 1–191 days), 12 days for neonates (range, 3–142 days), and 19 days for neonates undergoing RACHS-1 category 6 operations (range, 4–142 days). Tracheostomies were performed in four patients (0.2%). Gastrostomies were performed on eight patients (0.4%), representing 0.8% of patients <1 year of age, 1.4% of neonates, and 2.4% of patients undergoing RACHS-1 category 6 operations. The rate of patients undergoing either tracheostomy or gastrostomy after congenital heart surgery at our institution was quite low. Avoidance of either of these two procedures was achieved without increased morbidity or length of stay. The rate at which these procedures need to be performed may reflect the magnitude of the patients’ lifetime trauma related to their underlying condition and acute and total surgical experiences.
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