Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Did changes to recommended testing criteria affect the rate of vitamin D testing among Australian women

We examine whether new government criteria designed to reduce overuse of vitamin D testing changed testing rates in Australian women. Although testing initially declined, the reduction was not sustained. Women who had more doctor visits and who had been tested previously were more likely to have vitamin D testing.Vitamin D testing increased substantially in the 2000s in many countries, particularly in women. Because of concerns about potential over-testing, in 2014, the Australian criteria for subsidised testing were restricted to those at high risk of vitamin D deficiency. We aimed to describe vitamin D testing trends in Australian women (1996 to 2019) and investigate sociodemographic and health factors associated with testing under the new criteria.We used joinpoint regression to assess changes in national testing trends in Australian women (aged 15+ years) using universal health insurance system data. Additionally, we investigated the factors associated with vitamin D testing through Poisson regression with robust error variance using survey and linked insurance system data from participants born 1946-51 in the Australian Longitudinal Study on Women's Health (ALSWH).Between 1996 and 2013, vitamin D testing rates increased in all age groups. Rates declined between 2013 and 2016, but increased again between 2016 and 2019. In the ALSWH cohort, a higher likelihood of testing under the new criteria was associated with 12 or more doctor visits per year compared to two or fewer visits per year (relative risk (RR) 1.85; 95% CI 1.61-2.12), and women who had two or more vitamin D tests between 2012 and 2014 compared to no test (RR 1.55; 95% CI 1.48-1.62).The introduction of new criteria has not led to sustained declines in testing. High testing rates and repeated testing suggest that over-testing for vitamin D deficiency in Australian women is still occurring

Topological Frustration in βα-Repeat Proteins: Sequence Diversity Modulates the Conserved Folding Mechanisms of α/β/α Sandwich Proteins

The thermodynamic hypothesis of Anfinsen postulates that structures and stabilities of globular proteins are determined by their amino acid sequences. Chain topology, however, is known to influence the folding reaction, in that motifs with a preponderance of local interactions typically fold more rapidly than those with a larger fraction of nonlocal interactions. Together, the topology and sequence can modulate the energy landscape and influence the rate at which the protein folds to the native conformation. To explore the relationship of sequence and topology in the folding of -repeat proteins, which are dominated by local interactions, we performed a combined experimental and simulation analysis on two members of the flavodoxin-like, alpha/beta/alpha sandwich fold. Spo0F and the N-terminal receiver domain of NtrC (NT-NtrC) have similar topologies but low sequence identity, enabling a test of the effects of sequence on folding. Experimental results demonstrated that both response-regulator proteins fold via parallel channels through highly structured submillisecond intermediates before accessing their cis prolyl peptide bond-containing native conformations. Global analysis of the experimental results preferentially places these intermediates off the productive folding pathway. Sequence-sensitive Go-model simulations conclude that frustration in the folding in Spo0F, corresponding to the appearance of the off-pathway intermediate, reflects competition for intra-subdomain van der Waals contacts between its N- and C-terminal subdomains. The extent of transient, premature structure appears to correlate with the number of isoleucine, leucine, and valine (ILV) side chains that form a large sequence-local cluster involving the central beta-sheet and helices alpha2, alpha3, and alpha4. The failure to detect the off-pathway species in the simulations of NT-NtrC may reflect the reduced number of ILV side chains in its corresponding hydrophobic cluster. The location of the hydrophobic clusters in the structure may also be related to the differing functional properties of these response regulators. Comparison with the results of previous experimental and simulation analyses on the homologous CheY argues that prematurely folded unproductive intermediates are a common property of the -repeat motif

Income deprivation and groin wound surgical site infection: cross-sectional analysis from the groin wound infection after vascular exposure multicenter cohort study

Background: Living in deprived areas is associated with poorer outcomes after certain vascular procedures and surgical site infection in other specialties. Our primary objective was to determine whether living in more income-deprived areas was associated with groin wound surgical site infection after arterial intervention. Secondary objectives were to determine whether living in more income-deprived areas was associated with mortality and clinical consequences of surgical site infection. Methods: Postal code data for patients from the United Kingdom who were included in the Groin Wound Infection after Vascular Exposure (GIVE) multicenter cohort study was used to determine income deprivation, based on index of multiple deprivation (IMD) data. Patients were divided into three IMD groups for descriptive analysis. Income deprivation score was integrated into the final multivariable model for predicting surgical site infection. Results: Only patients from England had sufficient postal code data, analysis included 772 groin incisions (624 patients from 22 centers). Surgical site infection occurred in 9.7% incisions (10.3% of patients). Surgical site infection was equivalent between income deprivation tertiles (tertile 1 = 9.5%; tertile 2 = 10.3%; tertile 3 = 8.6%; p = 0.828) as were the clinical consequences of surgical site infection and mortality. Income deprivation was not associated with surgical site infection in multivariable regression analysis (odds ratio [OR], 0.574; 95% confidence interval [CI], 0.038–8.747; p = 0.689). Median age at time of procedure was lower for patients living in more income-deprived areas (tertile 1 = 68 years; tertile 2 = 72 years; tertile 3 = 74 years; p < 0.001). Conclusions: We found no association between living in an income-deprived area and groin wound surgical site infection, clinical consequences of surgical site infection and mortality after arterial intervention. Patients living in more income-deprived areas presented for operative intervention at a younger age, with similar rates of comorbidities to patients living in less income-deprived areas. Groin wound surgical site infection (SSI) after arterial surgery is common [1], and research into reducing SSIs in vascular surgery is recognized as a priority by both clinicians and patient/caregiver representatives [2]. Despite the substantial potential morbidity and mortality of these SSIs [3,4], the available evidence relating to contributory factors is largely historic or reliant on retrospective data [5–7]. Further research on the epidemiology of SSI in this patient group is needed to allow better risk stratification, improve pre-operative discussions of risk with patients, and to guide targeted SSI prevention strategies that often include expensive prophylactic interventions [8]. However, little is currently known about the impact of socioeconomic characteristics on groin wound SSIs in this population. Socioeconomic deprivation is linked to health [9], and lifestyle-influenced cardiovascular diseases are more prevalent in more deprived areas [10]. Higher rates of unhealthy lifestyles (smoking, poor diet, and lack of physical exercise) in deprived areas are postulated to cause higher rates of cardiovascular risk increasing comorbidities, such as obesity and hyperlipidemia [10–12]. Several cardiovascular risk factors (e.g., smoking, body mass index, and diabetes mellitus), and peripheral arterial disease itself, are well recognized risk factors for SSI [13–16]. The association between socioeconomic deprivation and SSIs has previously been demonstrated in orthopedic surgery, cardiac surgery, and general surgery [17–19]. It is currently unknown whether living in an income-deprived area is associated with groin wound SSIs after arterial intervention. It was recently demonstrated in a large registry study in the United Kingdom, that outcomes following endovascular intervention for occlusive peripheral arterial disease were worse for patients living in deprived areas [20]. To the best of our knowledge, this aspect of outcomes after arterial intervention through a groin incision has not been investigated. Furthermore, studies demonstrating higher prevalence of cardiovascular disease risk factors in more deprived areas are now mostly historic and have not specifically investigated those presenting for arterial intervention through a groin incision for demographic differences in relation to deprivation [9–12]. Updated, prospective evidence is required to determine whether health inequalities persist for such patients today. Our primary objective was to determine whether residing in a more income-deprived area was associated with a higher risk of groin wound SSI after arterial intervention, by analyzing a subset of patients enrolled in the Groin wound Infection after Vascular Exposure (GIVE) multicenter cohort study [1,21]. Secondary objectives were to determine whether living in more income-deprived areas was associated with 30-day mortality and the clinical sequelae of SSI, and whether patients living in more income-deprived areas differed in terms of demographics and comorbidities compared with patients from less income-deprived areas

Shiga toxin pathogenesis : kidney complications and renal failure

The kidneys are the major organs affected in diarrhea-associated hemolytic uremic syndrome (D(+)HUS). The pathophysiology of renal disease in D(+)HUS is largely the result of the interaction between bacterial virulence factors such as Shiga toxin and lipopolysaccharide and host cells in the kidney and in the blood circulation. This chapter describes in detail the current knowledge of how these bacterial toxins may lead to kidney disease and renal failure. The toxin receptors expressed by specific blood and resident renal cell types are also discussed as are the actions of the toxins on these cells