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The body library : a Nyquist mystery
\"In a city where words come to life and reality is infected by stories, private eye John Nyquist wakes up in a room with a dead body... The dead man's impossible whispers plunge him into a murder investigation like no other. Clues point him deeper into an unfolding story infesting its participants as reality blurs between place and genre. Only one man can hope to put it all together, enough that lives can be saved... That man is Nyquist, and he is lost.\"--Publisher's website.
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Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack
In this double-blind, randomized trial involving 13,199 patients with ischemic stroke or transient ischemic attack, ticagrelor was not superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days.
Ischemic stroke and transient ischemic attack are common, and the risk of subsequent ischemic events is particularly high during the first 90 days after the index cerebrovascular event.
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Aspirin at a dose of 50 to 325 mg daily is commonly used in this context.
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However, the benefit of aspirin in the secondary prevention of ischemic stroke is limited; even with concurrent aspirin treatment, the rate of recurrent stroke is 10 to 15% in the first 90 days, and the rate of new ischemic events when aspirin is used in the long term is only 22% lower than the . . .
Journal Article
Against nature
P.I. Duck Darley has settled into an unlikely domestic routine with a wealthy divorcée and her precocious eight-year-old son. But old nightmares return when a desperate text from Cass Kimball, the former partner Duck once took a bullet to protect, lures him back into sworn-off vices and the sinister world of professional sports. Cass cries murder after her boyfriend tumbles to his death in the Catskills while researching the tragic doping experiments that changed the lives of East German Olympic athletes during the Cold War. Following the brutal killing of a champion javelin thrower, Cass herself is arrested on charges of double homicide, leaving Duck on an impossible quest for answers while doubting everything he ever believed about his secretive sidekick. Now, caught between the secret horrors of extreme performance enhancement and shadowy criminals who stalk him relentlessly, it's sink or swim as Duck stumbles through a reckless investigation that endangers both his life and that of anyone he allows himself to hold dear.
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389 The effect of a multimodal prehabilitation programme on preoperative functional capacity and anthropometrics of gynaecological oncology patients
Introduction/BackgroundPrehabilitation, a preoperative optimization intervention, remains in its infancies within gynaecological oncology. Little is known about the direct effects of such programmes on functional capacity. It is paramount to evaluate these effects to subsequently determine the relation with postoperative outcomes. Therefore, this study aims to assess the direct effect of multimodal prehabilitation on functional status for gynaecological oncology patients.MethodologyThis was an analysis of the F4S PREHAB trial, a monocentre stepped-wedge trial, to assess the direct effect of multimodal prehabilitation on functional capacity. Participants were patients scheduled for surgical treatment for ovarian, endometrial or vulvar cancer between May 2021 and September 2023 at the Radboudumc, Nijmegen, The Netherlands. Multimodal prehabilitation included an exercise, nutritional and psychological component, a smoking cessation programme and screening for frailty and comorbidities. We compared functional capacity before and after participation in the programme. Aspects of functional capacity assessed were estimated VO2max, indirect 1-Repetition Maximum tests (1-RM), Timed Chair Stand Test (5CST), grip strength and PG-SGA scores. Multivariate analyses were used to correct for possible confounding factors such as age, BMI, ASA-score, comorbidities, haemoglobin and histology.ResultsA total of 107 participants were included in the intervention group. Median duration of the programme was twenty days (range 7–62). When assessing the effect of multimodal prehabilitation on physical fitness, significant improvements in VO2max were seen by 0.83 ml/kg/min (P=0.017), in indirect 1-RM by 16 kg (p<0.001), and grip strength by 1.2kg (p=0.008). The results from the Timed Chair Test (5-CST) significantly shortened by half a second (p=0.001). Significantly more participants had a low risk on malnutrition after multimodal prehabiliation compared to before (62% vs 70%; p=0.005), and a significant reduction by 1 point in PG-SGA score was found (p=0.002).ConclusionThis study demonstrates that multimodal prehabiliation has the ability to improve functional capacity preoperatively for gynaecological oncology patients.DisclosuresNone to disclose.
Journal Article
Hiding in plain sight
On the run from a troubled past, Kate Weller, the newest member of Price Investigations, covers her tracks, changes her name and takes a case in Charleston, South Carolina, where she can hide in plain sight. Renting a charming room with a waterfront view, Kate sets about trying to locate her adopted client's natural siblings, only to find more questions than answers when she eventually tracks down a long-lost sister. Meanwhile, her new landlord won't stop sticking his nose into her case. As far as Kate's concerned, Eric Manfredi should focus on whatever competitor is bent on ruining his family business. But when petty vandalism turns lethal, and Eric's father is arrested for murder, Kate is determined to prove his innocence. Can she find the real culprit before a killer from her own past tracks her down?
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309 Cross-ancestry exome sequencing identifies novel endometrial cancer susceptibility genes
Introduction/BackgroundEndometrial cancer (EC) is the most common gynaecological cancer in high income countries and its incidence is rising globally. Genetic susceptibility of EC have been linked with several loci of common variants, however, these only explained ~10% genetic background and the overall contribution of rare coding variants to EC is unclear.MethodologyHere, we performed exome-wide association study to evaluate the penetrance of rare coding variants on cross-ancestry datasets. The UK Biobank conprised of 1,587 EC cases and 159,324 non-cancer controls from Gaussian ancestry. Burden tests from the STAAR pipeline were applied to identify novel genes with excess pathogenic loss-of-function (pLOF) and disruptive missense (d-mis) variants in EC. We replicated these results on in house Chinese EC cohort of 239 patients compared with 10,588 Chinese controls from ChinaMAP. In vitro experients were used to assess effects of these genes.ResultsAssociations between pLOF as well as pLOF plus d-mis (pLOF_ds) variants and EC identified 50 and 26 genes at exome-wide significance (p < 2.5*10–6), respectively, including known EC susceptibility genes MSH6 and MSH2. These results were replicated in Chinese cohort, revealing X genes also contributing to EC in East Asia population. In vitro silence of these genes through small interfering RNA (siRNA) suggested that functional silence of these genes would result in decreased proliferation rates and migration capacity.ConclusionWe uncovered novel EC risk genes across European and Asia population and validated their functions. This would provide new insights on genetic background of EC and pave the way for screening of EC.DisclosuresThe authors declare no competing interests.
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Curse of the Spellmans
Izzy struggles to retain her private investigator's license after her fourth arrest, David's marriage to Petra, and Rae's teenage angst.
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B Genetically-proxied low density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations
BackgroundLow-density lipoprotein cholesterol (LDL) lowering via inhibition of PCSK9 is an important cornerstone in treatment of hypercholesterolemia. There is currently no data regarding safety of PCSK9 inhibitor therapies in pregnancy. Where clinical data is not available, the Mendelian randomization (MR) paradigm can be used to predict effects of drug target perturbation using genetic data. We aimed to leverage genetic data to explore the impact of LDL lowering, overall and via the PCSK9 drug target, on congenital malformations.MethodsUncorrelated (r2<0.1), genome-wide significant (p<5x10-8) variants for LDL and their association estimates, overall and restricted to the PCSK9 gene region +/- 10kB, were extracted from GWAS summary data of the Global Lipids Genetics Consortium (GLGC), including 188,577 individuals. Additional replication analyses were performed using UK Biobank data (n=469,897). Gene-outcome association data was extracted from GWAS results of FinnGen 7th Release (n=342,499) for congenital malformations affecting multiple systems; of eye, ear, face and neck; cardiac septum; circulatory system; digestive system; musculoskeletal system; skin; renal pelvis and ureter; vertebral, anorectal, cardiovascular, tracheo-esophageal, renal and limb anomaly (VACTERL). A two-sample drug-target MR analysis was carried out. Inverse-variance weighted MR was used for primary analysis. Bayesian tests for genetic co-localization were performed to explore the probability of shared (H4) versus distinct (H3) causal variants within the PCSK9 gene region. An expected 5% false discovery rate (FDR) was controlled for using Benjamini-Hochberg correction of p-values. ResultsGenetically-proxied LDL-lowering was associated with higher odds of malformations affecting multiple systems (OR 1.33 [1.07–1.64] p=0.010), and VACTERL (OR 1.12 [1.04–1.20] p=0.046). Genetically-proxied LDL-lowering through PCSK9 associated with higher odds of malformations affecting multiple systems (OR 3.07 [1.63–5.79] p=0.009), cardiac septum (OR 1.57 [1.13–2.18] p=0.039), skin (OR 2.16 [1.49–3.14] p=0.002), renal pelvis and ureter (OR 3.71 [1.63–8.45] p=0.019), and VACTERL (OR 1.47 [1.12–1.92] p=0.034). Replication analyses within an independent cohort derived from UK Biobank were concordant. Colocalization analyses revealed evidence suggestive of shared causal variants in the PCSK9 region for LDL with skin malformations (H4=56.2%; H3=0.5%), malformations of multiple systems (H4=18.0%; H3=0.9%); malformations of the renal pelvis and ureter (H4=11.6%; H3=1.3%), VACTERL (H4=15.0%; H3=4.2%), and malformations of the cardiac septum (H4=6.7%; H3=0.6%).Conclusions and RelevanceThese data provide genetic evidence suggesting LDL-lowering via PCSK9-inhibition is associated with higher risk of congenital malformations. This is the first substantive evidence suggesting long-lasting PCSK9-inhibition should be used with utmost caution in women planning to conceive.
Journal Article
Garrett for hire
Meet Garrett, P.I. He's a hardboiled human detective who stands out in a crowd of elves, trolls, and other otherworldly denizens in the magical city of TunFaire.
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Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study
Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries.
In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete.
Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2–6] vs 2 [0–4] vs 2 [0–4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2–5] vs 1 [0–3] vs 1 [0–2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42–65) for China versus South America, 50% (41–61) for the USA versus China, and 53% (41–66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8–16; 29 of 246) than in the USA (23%, 16–30; 30 of 130) and South America (28%, 20–37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22–10·50) and the USA (aOR 3·34, 1·50–7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70–2·96).
Global CRKP epidemics have important regional differences in patients’ baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions.
The National Institutes of Health.
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