Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparison of salvage chemotherapy regimens and prognostic significance of minimal residual disease in relapsed/refractory acute myeloid leukemia

Abstract We compared the outcomes of salvage chemotherapy in 146 patients with relapsed (57.5%) or refractory (42.5%) AML who received CLAG-M (51%), MEC (39%) or CLAG (10%). Minimal residual disease (MRD) was assessed by flow cytometry. Bivariate, Kaplan–Meier, and Cox regression analyses were conducted. Complete remission (CR) rate of 46% (CLAG-M 54% versus MEC/CLAG 40%, p = .045) was observed with MRD-negative CR of 33% (CLAG-M 39% versus MEC/CLAG 22%, p = .042). Median overall survival (OS) was 9.7 months; the longest OS occurred with CLAG-M (13.3, 95%CI 2.4–24.3) versus MEC (6.9, 95%CI 2.9–10.9) or CLAG (6.2, 95%CI 2.4–12.6) (p = .025). When adjusted for age, gender, relapsed/refractory AML, poor risk AML, MRD, chemotherapy and transplant, CLAG-M (HR 0.63, 95% CI 0.40–0.98, p = .042), MRD-negativity (HR 0.15, 95% CI 0.07–0.30, p < .001) and transplant (HR 0.22, 95% CI 0.13–0.39, p < .001) were associated with higher OS. Our findings confirm that CLAG-M is a reasonable salvage regimen for RR-AML followed by transplant.
Estimating Downstream Budget Impacts in Implementation Research

Health care decision makers often request information showing how a new treatment or intervention will affect their budget (i.e., a budget impact analysis; BIA). In this article, we present key topics for considering how to measure downstream health care costs, a key component of the BIA, when implementing an evidence-based program designed to reduce a quality gap. Tracking health care utilization can be done with administrative or self-reported data, but estimating costs for these utilization data raises 2 issues that are often overlooked in implementation science. The first issue has to do with applicability: are the cost estimates applicable to the health care system that is implementing the quality improvement program? We often use national cost estimates or average payments, without considering whether these cost estimates are appropriate. Second, we need to determine the decision maker’s time horizon to identify the costs that vary in that time horizon. If the BIA takes a short-term time horizon, then we should focus on costs that vary in the short run and exclude costs that are fixed over this time. BIA is an increasingly popular tool for health care decision makers interested in understanding the financial effect of implementing an evidence-based program. Without careful consideration of some key conceptual issues, we run the risk of misleading decision makers when presenting results from implementation studies.
Epidemiology, Presentation, and Diagnosis of Celiac Disease.

The incidence of celiac disease is increasing, partly due to improved recognition of, and testing for, the disease. The rise in incidence is also due to a real increase of this immune-based disorder, independent of disease detection. The reasons for this true rise in recent decades are unknown but may be related to environmental factors that may promote loss of tolerance to dietary gluten. Strategies to reduce the development of celiac disease have not been proven successful in randomized trials, but the quantity of early-life gluten exposure has been a major focus of prevention efforts. The criteria for diagnosis of celiac disease are changing, but in adults diagnosis still depends on the presence of duodenal villous atrophy while the patient is on a gluten-containing diet, along with findings form serology analysis. Though guidelines in the United States continue to mandate a biopsy at all ages, some children receive a diagnosis of celiac disease without a biopsy. If proven accurate and scalable, assays that detect gluten-HLA tetramer complexes might be used in diagnosis to be made in the context of a gluten-free diet, without intestinal biopsy.
Studies on Indian Culicoides (Ceratopogonidae: Diptera)

The 12 species described as new bring the Indian Culicoides fauna to a total of 31 species and one variety. The authors describe fully all species known to them in nature, and comment on the salient characters of those they know only from the literature. Their key to males includes 21 species; that to females, 27 species and one variety. Dorsal pattern, wings, spermathecae, and male genitalia of numerous species are illustrated.
Clinical utility of a type 4 portable device for in-home screening of sleep disordered breathing.

BACKGROUND Portable monitoring devices have been developed for in-home screening and to aid in the diagnosis of sleep disordered breathing (SDB) while increasing accessibility and reducing costs. Although there are many different devices available in the market, most have not undergone rigorous validation. Therefore, although such devices are promising, more research on their clinical utility is necessary. The purpose of this study was to assess the clinical utility of a type 4 home sleep apnea test (HSAT) as an in-home screening for SDB. METHODS We investigated consecutive subjects who underwent in-laboratory overnight polysomnography following in-home screening using HSAT. We evaluated the correlation between apnea-hypopnea index (AHI) by in-laboratory overnight polysomnography and by HSAT and evaluated the sensitivity and specificity for AHI ≥5 and AHI ≥30 by the receiver operating characteristic (ROC) analysis. RESULTS Finally, data of 387 participants (86.8% men, mean age 55.3±13.3 years and body mass index 25.1±4.1 kg/m2) were assessed. In all patients, AHI by HSAT correlated significantly with AHI by polysomnography (r=0.670, P<0.001). The area under curves of ROC for AHI ≥5 and AHI ≥30 were 0.854±0.029 and 0.841±0.022, respectively. The best cut-off of AHI by HSAT for detecting AHI by polysomnography ≥5 was 10.3 events/h (sensitivity, 82.8%; and specificity, 76.0%), and AHI by HSAT for detecting AHI by polysomnography ≥30 was 24.5 events/h (sensitivity, 75.8%; and specificity, 80.4%). CONCLUSIONS This type 4 HSAT may have potential as a screening tool for SDB and thus have sufficient clinical utility.
Socioeconomic Risk for Adolescent Cognitive Control and Emerging Risk-Taking Behaviors.

This study examined whether cognitive control mediated the association between socioeconomic status (SES; composite of income-to-needs ratio and parent education) and changes in risk-taking behaviors. The sample included 167 dyads of adolescents (53% male; Mage = 14.07 years at Time 1) and their parents, assessed annually across 4 years. Parents reported socioeconomic variables at Time 1. Adolescents reported risk-taking behaviors at Times 1 and 4, and completed a functional magnetic resonance imaging cognitive control task at Times 2 and 3. Lower SES was associated with lower behavioral (but not neural) cognitive control, which was associated with increases in risk-taking behaviors. The findings suggest that elevated socioeconomic risk may compromise cognitive control which can cascade into maladaptive behaviors in adolescence.
Multiple Sclerosis Disease‐Modifying Therapies in the COVID‐19 Era

Introduction Disease-modifying therapies (DMTs) for multiple sclerosis (MS) influence the immune system in many ways. It is necessary to understand how these medications might impact susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and/or whether they are associated with more severe coronavirus disease 2019 (COVID-19) for clinical decision-making and patient counseling. In this webinar, the American Neurological Association (ANA) interviewed three academic MS subspecialists: Dr Elena Grebenciucova at Northwestern University, Dr Brandon Moss at Cleveland Clinic, and Dr Scott Newsome at Johns Hopkins. The panel discussed emerging data from national and international registries of MS patients with COVID-19, and key patient and DMT characteristics to consider when making clinical decisions during the pandemic, including expected impacts on immune responses to an eventual SARS-CoV-2 vaccine.
Validation of the clinical applicability of knowledge‐based planning models in single‐isocenter volumetric‐modulated arc therapy for multiple brain metastases

Abstract Purpose To validate the clinical applicability of knowledge‐based (KB) planning in single‐isocenter volumetric‐modulated arc therapy (VMAT) for multiple brain metastases using the k‐fold cross‐validation (CV) method. Methods This study comprised 60 consecutive patients with multiple brain metastases treated with single‐isocenter VMAT (28 Gy in five fractions). The patients were divided randomly into five groups (Groups 1–5). The data of Groups 1–4 were used as the training and validation dataset and those of Group 5 were used as the testing dataset. Four KB models were created from three of the training and validation datasets and then applied to the remaining Groups as the fourfold CV phase. As the testing phase, the final KB model was applied to Group 5 and the dose distributions were calculated with a single optimization process. The dose‐volume indices (DVIs), modified Ian Paddick Conformity Index (mIPCI), modulation complexity scores for VMAT plans (MCSv), and the total number of monitor units (MUs) of the final KB plan were compared to those of the clinical plan (CL) using a paired Wilcoxon signed‐rank test. Results In the fourfold CV phase, no significant differences were observed in the DVIs among the four KB plans (KBPs). In the testing phase, the final KB plan was statistically equivalent to the CL, except for planning target volumes (PTVs) D2% and D50%. The differences between the CL and KBP in terms of the PTV D99.5%, normal brain, and Dmax to all organs at risk (OARs) were not significant. The KBP achieved a lower total number of MUs and higher MCSv than the CL with no significant difference. Conclusions We demonstrated that a KB model in a single‐isocenter VMAT for multiple brain metastases was equivalent in dose distribution, MCSv, and total number of MUs to a CL with a single optimization.
Personalized drug testing in a patient with non-small-cell lung cancer using cultured cancer cells from pleural effusion

Objective Patients with non-small-cell lung cancer (NSCLC) and primary or acquired resistance do not respond to targeted drugs. We explored whether cancer cells can be cultured from liquid biopsies from patients with primary resistance to tyrosine kinase inhibitors (TKIs). We aimed to predict patients’ responses to drugs according to in vitro drug testing results. Methods Cancer cell cultures were established from the pleural effusion of a patient with TKI-resistant NSCLC using a conditional reprogramming technique. Phenotypic drug sensitivity tests were performed using the Cell Counting Kit-8 assay. We tested individual drugs and compared the synergistic and inhibitory effects of drug combinations. Results The results of our in vitro sensitivity test using the combination of cisplatin and pemetrexed were correlated with the patient’s response. Conclusion This represents the first successful report of predictive testing for combination therapy in patients with epidermal growth factor receptor-mutant NSCLC and primary TKI resistance. This strategy should be applicable to both chemotherapies and targeted therapies, and it will significantly improve the clinical treatment and management of patients with NSCLC and primary or acquired resistance to targeted therapies, as well as patients lacking targetable mutations.
Experiences and needs of direct support staff working with people with intellectual disabilities during the COVID‐19 pandemic: A thematic analysis

Abstract Background The present study aimed to explore the experiences and needs of direct support staff during the initial stage of the COVID‐19 lockdown in the Netherlands. Method Overall, eleven direct support staff were recruited from five intellectual disability services to participate in this descriptive qualitative study. They recorded 34 audio messages during the considered period. Thematic analysis was used to analyse these audio recordings. Results Four themes emerged: (1) Emotional impact, which pertained to various emotions they experienced in their work; (2) Cognitive impact, which referred to challenges and changes they had undergone in their work; (3) Practical impact, which centred on the practical impact of the pandemic on their work; and (4) Professional impact, which concerned their experiences with other professionals. Conclusions This study provides valuable insights into the experiences and needs of direct support staff during the COVID‐19 pandemic, which, in turn, can help inform practice in preparation for a second wave of COVID‐19 or another future pandemic.
Association of Heart Rate Trajectory Patterns with the Risk of Adverse Outcomes for Acute Heart Failure in a Heart Failure Cohort in Taiwan.

Background Heart rate trajectory with multiple heart rate measurements is considered to be a more sensitive predictor of outcomes than single heart rate measurements. The association of heart rate trajectory patterns with acute heart failure outcomes has not been well studied. We examined the association of heart rate trajectory patterns with post-discharge outcomes. Methods This prospective cohort study was based on an acute heart failure registry in Taiwan. A total of 1509 patients were enrolled in the Taiwan Society of Cardiology - Heart Failure with Reduced Ejection Fraction Registry from May 2013 to October 2015. The outcomes were post-discharge all-cause mortality and heart failure re-admission. Results Two heart trajectory patterns were identified in group-based trajectory analysis. One started with a higher heart rate and had an increasing trend over 6 months then a subsequent decline (high-increasing-decreasing group; n = 352; 23.9%). The other started with a lower heart rate and had a relatively stable pattern (low-stable group; n = 1121; 76.1%). Compared with those in the low-stable group, patients in the high-increasing-decreasing group had a higher risk of events (all-cause mortality: hazard ratio 3.10 and 95% confidence interval 1.24-7.77; heart failure re-admission: hazard ratio 1.13 and 95% confidence interval 0.55-2.32). Conclusions Patients with a high-increasing-decreasing heart rate trajectory pattern had a higher risk of all-cause mortality than those with a low-stable pattern.
Structure of the Plasmodium falciparum PfSERA5 pseudo‐zymogen

PfSERA5, a significantly abundant protein present within the parasitophorous vacuole (PV) and essential for normal growth during the blood‐stage life cycle of the malaria parasite Plasmodium falciparum, displays structural similarity to many other cysteine proteases. However, PfSERA5 does not exhibit any detectable protease activity and therefore the role of the PfSERA5 papain‐like domain (PfSERA5E), thought to remain bound to its cognate prodomain, remains unknown. In this study, we present a revised structure of the central PfSERA5E domain at a resolution of 1.2 Å, and the first structure of the “zymogen” of this papain‐like domain including its cognate prodomain (PfSERA5PE) to 2.2 Å resolution. PfSERA5PE is somewhat structurally similar to that of other known proenzymes, retaining the conserved overall folding and orientation of the prodomain through, and occluding, the archetypal papain‐like catalytic triad “active‐site” cleft, in the same reverse direction as conventional prodomains. Our findings are congruent with previously identified structures of PfSERA5E and of similar “zymogens” and provide a foundation for further investigation into the function of PfSERA5.
Formyl peptide receptor type 2 agonists to kick‐start resolution pharmacology

One way to develop innovative approaches for the treatment of chronic diseases is to exploit the biology of the resolution of inflammation. With this terminology, we identify the integrated and complex network of mediators and pathways that ensure a timely and spatially regulated inflammatory response. Pro‐resolving mediators act on specific receptors. This provides an opportunity for developing a new arm of pharmacology we have termed “resolution pharmacology. ” Here we present the reasoning behind the need to develop new medicines based on resolution and use a prototype GPCR as an example. Understanding how the formyl peptide receptor type 2 (FPR2) operates in a cell‐specific manner can guide the development of agonists as new therapeutics that could be of benefit as a therapy or co‐therapy for several diseases that affect our society. FPR2 agonists would be among the first drugs to establish “resolution pharmacology” as the pharmacological approach for the third decade of the millennium.
Beat-to-Beat Blood Pressure Variability in the First Trimester Is Associated With the Development of Preeclampsia in a Prospective Cohort

Supplemental Digital Content is available in the text. Women with preeclampsia, a hypertensive disorder of pregnancy, exhibit greater beat-to-beat blood pressure variability (BPV) in the third trimester after clinical onset of the disorder. However, it remains unknown whether elevated BPV precedes the development of preeclampsia. A prospective study cohort of 139 women (age 30.2±4.0 years) were enrolled in early pregnancy (<14 weeks gestation). BPV was quantified by time domain analyses of 10-minute continuous beat-to-beat blood pressure recordings via finger photoplethysmography in the first, second, and third trimesters. Aortic stiffness (carotid-femoral pulse wave velocity) and spontaneous cardiovagal baroreflex sensitivity were also measured each trimester. Eighteen women (13%) developed preeclampsia. Systolic BPV was higher in all trimesters among women who developed versus did not develop preeclampsia (first: 4.8±1.3 versus 3.7±1.2, P=0.001; second: 5.1±1.8 versus 3.8±1.1, P=0.02; third: 5.2±0.8 versus 4.0±1.1 mm Hg, P=0.002). Elevated first trimester systolic BPV was associated with preeclampsia (odds ratio, 1.94 [95% CI, 1.27–2.99]), even after adjusting for risk factors (age, body mass index, systolic blood pressure, history of preeclampsia, and diabetes mellitus) and was a significant predictor of preeclampsia (area under the receiver operator characteristic curve=0.75±0.07; P=0.002). Carotid-femoral pulse wave velocity was elevated in the first trimester among women who developed preeclampsia (5.9±0.8 versus 5.2±0.8 m/s; P=0.002) and was associated with BPV after adjustment for mean blood pressure (r=0.26; P=0.005). First trimester baroreflex sensitivity did not differ between groups (P=0.23) and was not related to BPV (P=0.36). Elevated systolic BPV is independently associated with the development of preeclampsia as early as the first trimester, possibly mediated in part by higher aortic stiffness.
Chemical Sterilization of the Screw-Worm

Treatment of the screw-worm ( Cochliomyia hominivorax (Coquerel)) with apholate (2,2,4,4,6,6-hexa(1-aziridinyl)-2,4,6-triphospha-1,3,5,triazine) resulted in complete sexual sterility in many instances. Sterilization was accoumplished in either the larval, prepupal, or adult stage, but pupal treatment resulted in only partial sterility. Sterilization was achieved by treatment of media containing the larvae, by dusting prepupae or adults, by dipping prepupae, by topical applications to adults, or by feeding the adults the apholate. Treatment with the compound also caused a reduction in the number of eggs produced. In nearly all tests, females were more affected than males. Slight differences in the age of the insect within each stage treated affected the control of reproduction. Some mortality was experienced when larvae or prepupae were treated, but no noticeable mortality occurred with adults treated at sterilizing dosages. Morphological examination showed a reduction in the size of the ovaries and testes and a distortion and reduction in number of the eggs in the ovaries. Treatment of larvae caused a marked change in the shape and form of the resulting pupae and adults.
Convergent and distinctive functions of transcription factors VdYap1, VdAtf1, and VdSkn7 in the regulation of nitrosative stress resistance, microsclerotia formation, and virulence in Verticillium dahliae

Abstract Reactive oxygen/nitrogen species (ROS/RNS) play a fundamental role in plant–fungal interactions. How pathogenic fungi manipulate plant‐derived ROS/RNS is of importance to the outcomes of these interactions. In this study, we explored the individual and combined contributions of three transcription factors, VdAtf1, VdYap1, and VdSkn7, in the response to ROS/RNS, microsclerotia formation, and virulence in the plant wilt pathogen Verticillium dahliae. We showed that VdYap1 is essential for ROS response. Additionally, mutants lacking any combination of the three genes shared significant hypersensitivity to nitro‐oxidative stress like sodium nitroprusside dehydrate and double deletions lacking VdYap1 and VdAtf1 resulted in further increased sensitivity to ROS. Double deletion of VdAtf1 and VdSkn7 reduced melanin production and virulence while simultaneous lack of VdSkn7 and VdYap1 disrupted nitrogen metabolism and ROS resistance. Finally, comparison of transcriptional profiles of the respective single or double mutants in response to nitro‐oxidative stress revealed that the three transcription factors are involved in denitrification of nitrated alkanes and lipids to protect against nitro‐oxidative stress. Taken together, our results demonstrate convergent and distinctive functions of VdYap1, VdAtf1, and VdSkn7 in V. dahliae, and provide new data on their roles in response to ROS/RNS in fungi.
Local Rossby Wave Packet Amplitude, Phase Speed, and Group Velocity: Seasonal Variability and Their Role in Temperature Extremes

Transient Rossby wave packets (RWPs) are a prominent feature of the synoptic to planetary upper-tropospheric flow at the midlatitudes. Their demonstrated role in various aspects of weather and climate prompts the investigation of characteristic properties like their amplitude, phase speed, and group velocity. Traditional frameworks for the diagnosis of the two latter have so far remained nonlocal in space or time, thus preventing a detailed view on the spatiotemporal evolution of RWPs. The present work proposes a method for the diagnosis of horizontal Rossby wave phase speed and group velocity locally in space and time. The approach is based on the analytic signal of upper-tropospheric meridional wind velocity and RWP amplitude, respectively. The new diagnostics are first applied to illustrative examples from a barotropic model simulation and the real atmosphere. The main seasonal and interregional variability features of RWP amplitude, phase speed, and group velocity are then explored using ERA5 reanalysis data for the time period 1979–2018. Apparent differences and similarities in these respects between the Northern and Southern Hemispheres are also discussed. Finally, the role of RWP amplitude and phase speed during central European short-lived and persistent temperature extremes is investigated based on changes of their distribution compared to the climatology of the region. The proposed diagnostics offer insight into the spatiotemporal variability of RWP properties and allow the evaluation of their implications at low computational demands.