Most programs today are written not by professional software developers, but by people with expertise in other domains working towards goals for which they need computational support. For example, a ...teacher might write a grading spreadsheet to save time grading, or an interaction designer might use an interface builder to test some user interface design ideas. Although these end-user programmers may not have the same goals as professional developers, they do face many of the same software engineering challenges, including understanding their requirements, as well as making decisions about design, reuse, integration, testing, and debugging. This article summarizes and classifies research on these activities, defining the area of End-User Software Engineering (EUSE) and related terminology. The article then discusses empirical research about end-user software engineering activities and the technologies designed to support them. The article also addresses several crosscutting issues in the design of EUSE tools, including the roles of risk, reward, and domain complexity, and self-efficacy in the design of EUSE tools and the potential of educating users about software engineering principles.
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IZUM, KILJ, NUK, PILJ, SAZU, UL, UM, UPUK
This study (EGF10004) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ...ErbB2-overexpressing advanced-stage refractory solid tumors.
Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks.
Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer-two of whom were classified as having inflammatory breast cancer-had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for > or = 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose.
Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.
The most common treatment for placenta accreta spectrum (PAS) disorders is planned primary cesarean hysterectomy. However, other management strategies may improve outcomes and/or allow fertility ...preservation. The objective of this study was to describe the course and outcomes of patients with PAS managed by leaving the placenta in situ.
This is a series of 11 patients with PAS managed by leaving the placenta in situ at a single academic center in the United States from 2015 to 2022. The approach described involves delivery of the fetus via cesarean, no attempt at placental removal, closure of the hysterotomy, prophylactic intravenous antibiotics for up to 1 week, and close outpatient follow-up until the uterus is empty.
The uterus was successfully preserved in six (55%), minimally invasive hysterectomy was performed in four (36%), and abdominal hysterectomy was performed in 1 (9%). During cesarean delivery, the median estimated blood loss was 650mL (range: 200-1,000mL). The majority of patients had no vaginal discharge for several weeks after delivery, followed by brown or bloody discharge, and intermittent mild-to-moderate cramping. The median time to resolution of PAS was 18 weeks in patients with successful uterine preservation (range: 5-25 weeks). Indications for hysterectomy included hemorrhage (
=1), coagulopathy (
=1), endomyometritis (
=2), and pain (
=1), and these occurred at a median of 5 weeks postpartum (range: 1-25 weeks). Four patients had subsequent pregnancies of whom three were live births at or near term and one was a spontaneous abortion at 19 weeks.
Leaving the placenta in situ may be an appropriate management strategy for some carefully selected and counseled patients with PAS.
· Overall, 55% had uterine preservation (6/11).. · Minimally invasive approach in 80% of hysterectomies (4/5).. · Of patients, 67% with uterine preservation had subsequent pregnancies (4/6)..
Escherichia coli is a leading cause of bloodstream infections. Developing interventions to reduce E coli infections requires an understanding of the frequency of nosocomial transmission, but the ...available evidence is scarce. We aimed to detect and characterise transmission of E coli and associated plasmids in a hospital setting.
In this prospective observational cohort study, patients were admitted to two adult haematology wards at the Cambridge University Hospitals NHS Foundation Trust in England. Patients aged 16 years and older who were treated for haematological malignancies were included. Stool samples were collected from study participants on admission, once per week, and at discharge. We sequenced multiple E coli isolates (both extended spectrum β-lactamase ESBL-producing and non-ESBL-producing) from each stool sample. A genetic threshold to infer E coli transmission was defined by maximum within-host single nucleotide polymorphism (SNP) diversity and the probability of drawing observed pairs of between-patient isolates at different SNP thresholds. Putative transmission clusters were identified when sequences were less than the genetic threshold. Epidemiological links for each transmission event were investigated. We sequenced all E coli positive blood samples from the two adult haematology wards.
We recruited 174 (51%) of 338 adult patients admitted to the wards between May 13 and Nov 13, 2015. We obtained and cultured 376 stool samples from 149 patients, of which 152 samples from 97 (65%) patients grew E coli. Whole-genome sequencing was done on 970 isolates. We identified extensive diversity in the bacterial population (90 sequence types) and mixed E coli sequence type carriage. 24 (26%) patients carried two sequence types, 12 (13%) carried three, and six (6%) patients carried four or more sequence types. Using a 17 SNP cutoff we identified ten clusters in 20 patients. The largest cluster contained seven patients, whereas four patients were included in multiple clusters. Strong epidemiological links were found between patients in seven clusters. 17 (11%) of 149 patients had stool samples positive for ESBL-producing E coli, the most common of which was associated with blaCTX-M-15 (12 71% of 17). Long-read sequencing revealed that blaCTX-M-15 was often integrated into the chromosome, with little evidence for plasmid transmission. Seven patients developed E coli bloodstream infection, four with identical strains to those in their stool; two of these had documented nosocomial acquisition.
We provide evidence of bacterial transmission and endogenous infection during routine care by integrating genomic and epidemiological data and by determining a genetic cutoff informed by within-host diversity in the studied population. Our findings challenge single colony-based investigations, and the widely accepted notion of plasmid spread.
UK Department of Health, Wellcome Trust, UK National Institute for Health Research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
During meiosis, DNA double‐strand breaks undergo interhomolog repair to yield crossovers between homologous chromosomes. To investigate how interhomolog sequence polymorphism affects crossovers, we ...sequenced multiple recombinant populations of the model plant Arabidopsis thaliana. Crossovers were elevated in the diverse pericentromeric regions, showing a local preference for polymorphic regions. We provide evidence that crossover association with elevated diversity is mediated via the Class I crossover formation pathway, although very high levels of diversity suppress crossovers. Interhomolog polymorphism causes mismatches in recombining molecules, which can be detected by MutS homolog (MSH) mismatch repair protein heterodimers. Therefore, we mapped crossovers in a msh2 mutant, defective in mismatch recognition, using multiple hybrid backgrounds. Although total crossover numbers were unchanged in msh2 mutants, recombination was remodelled from the diverse pericentromeres towards the less‐polymorphic sub‐telomeric regions. Juxtaposition of megabase heterozygous and homozygous regions causes crossover remodelling towards the heterozygous regions in wild type Arabidopsis, but not in msh2 mutants. Immunostaining showed that MSH2 protein accumulates on meiotic chromosomes during prophase I, consistent with MSH2 regulating meiotic recombination. Our results reveal a pro‐crossover role for MSH2 in regions of higher sequence diversity in A. thaliana.
Synopsis
Meiotic DNA double‐strand breaks undergo interhomolog repair to yield crossovers between homologous chromosomes. Sequencing of polymorphisms in wild‐type and mutant plants reveals an unexpected pro‐crossover role of the mismatch repair protein MSH2 in regions of higher relative sequence diversity.
Meiotic crossovers are positively associated with interhomolog polymorphism both at chromosome level and fine scales in Arabidopsis.
Class I crossovers mediate association of recombination with diversity – although very high polymorphism levels suppress crossovers.
Total crossover numbers are unchanged in msh2 mutants, but recombination is remodelled from the diverse pericentromeres towards the less polymorphic sub‐telomeres.
Juxtaposition of megabase‐scale heterozygous and homozygous regions causes crossover remodeling towards the heterozygous regions, which is MSH2‐dependent.
Sequencing of polymorphisms between homologous chromosomes in wild‐type and mutant plants reveals an unexpected pro‐crossover role of the mismatch repair protein MSH2 in regions of higher relative sequence diversity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This was a pilot study to assess the biologic effects of lapatinib on various tumor growth/survival pathways in patients with advanced ErbB1 and/or ErbB2-overexpressing solid malignancies.
Heavily ...pretreated patients with metastatic cancers overexpressing ErbB2 and/or expressing ErbB1 were randomly assigned to one of five dose cohorts of lapatinib (GW572016) administered orally once daily continuously. The biologic effects of lapatinib on tumor growth and survival pathways were assessed in tumor biopsies obtained before and after 21 days of therapy. Clinical response was determined at 8 weeks.
Sequential tumor biopsies from 33 patients were examined. Partial responses occurred in four patients with breast cancer, and disease stabilization occurred in 11 others with various malignancies. Responders exhibited variable levels of inhibition of p-ErbB1, p-ErbB2, p-Erk1/2, p-Akt, cyclin D1, and transforming growth factor alpha. Even some nonresponders demonstrated varying degrees of biomarker inhibition. Increased tumor cell apoptosis (TUNEL) occurred in patients with evidence of tumor regression but not in nonresponders (progressive disease). Clinical response was associated with a pretreatment TUNEL score > 0 and increased pretreatment expression of ErbB2, p-ErbB2, Erk1/2, p-Erk1/2, insulin-like growth factor receptor-1, p70 S6 kinase, and transforming growth factor alpha compared with nonresponders.
Lapatinib exhibited preliminary evidence of biologic and clinical activity in ErbB1 and/or ErbB2-overexpressing tumors. However, the limited sample size of this study and the variability of the biologic endpoints suggest that further work is needed to prioritize biomarkers for disease-directed studies, and underscores the need for improved trial design strategies in early clinical studies of targeted agents.
Fetal electrocardiogram (ECG) ST changes are associated with fetal cardiac hypoxia. Our objective was to evaluate ST changes by maternal diabetic status and stage of labor.
This was a secondary ...analysis of a multicentered randomized-controlled trial in which laboring patients with singleton gestations underwent fetal ECG scalp electrode placement and were randomly assigned to masked or unmasked ST-segment readings. Our primary outcome was the frequency of fetal ECG tracings with ST changes by the stage of labor. ECG tracings were categorized into mutually exclusive groups (ST depression, ST elevation without ST depression, or no ST changes). We compared participants with DM, gestational diabetes mellitus (GDM), and no DM.
Of the 5,436 eligible individuals in the first stage of labor (95 with pregestational DM and 370 with GDM), 4,427 progressed to the second stage. ST depression occurred more frequently in the first stage of labor in participants with pregestational DM (15%, adjusted odds ratio aOR 2.20, 95% confidence interval CI 1.14-4.24) and with GDM (9.5%, aOR 1.51, 95% CI 1.02-2.25) as compared with participants without DM (5.7%). The frequency of ST elevation was similar in participants with pregestational DM (33%, aOR 0.79, 95% CI 0.48-1.30) and GDM (33.2%, aOR 0.91, 95% CI 0.71-1.17) as compared with those without DM (34.2%). In the second stage, ST depression did not occur in participants with pregestational DM (0%) and occurred more frequently in participants with GDM (3.5%, aOR 2.01, 95% CI 1.02-3.98) as compared with those without DM (2.0%). ST elevation occurred more frequently in participants with pregestational DM (30%, aOR 1.81, 95% CI 1.02-3.22) but not with GDM (19.0%, aOR 1.06, 95% CI 0.77-1.47) as compared with those without DM (17.8%).
ST changes in fetal ECG occur more frequently in fetuses of diabetic mothers during labor.
gov number, NCT01131260.
ST changes in fetal ECG, a marker of fetal cardiac hypoxia, occur more frequently in fetuses of diabetic parturients.
· Fetal hypertrophic cardiomyopathy (HCM) and cardiac dysfunction occur frequently among fetuses of diabetic patients.. · Fetal ECG changes such as ST elevation and depression reflect cardiac hypoxia.. · Fetuses of diabetic patients demonstrate a higher prevalence of fetal ECG tracings with ST changes..
The aim of this study was to evaluate the association of mild gestational diabetes mellitus (GDM) and obesity with metabolic and cardiovascular markers 5 to 10 years after pregnancy.
This was a ...secondary analysis of 5- to 10-year follow-up study of a mild GDM treatment trial and concurrent observational cohort of participants ineligible for the trial with abnormal 1-hour glucose challenge test only. Participants with 2-hour glucose tolerance test at follow-up were included. The primary exposures were mild GDM and obesity. The outcomes were insulinogenic index (IGI), 1/homeostatic model assessment of insulin resistance (HOMA-IR), and cardiovascular markers vascular endothelial growth factor, (VEGF), vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 40 ligand (CD40L), growth differentiation factor 15 (GDF-15), and suppression of tumorgenesis 2 (ST-2). Multivariable linear regression estimated the association of GDM and obesity with biomarkers.
Of 951 participants in the parent study, 642 (68%) were included. Lower 1/HOMA-IR were observed in treated and untreated GDM groups, compared with non-GDM (mean differences, -0.24 and -0.15; 95% confidence intervals CIs, -0.36 to -0.12 and -0.28 to -0.03, respectively). Lower VCAM-1 (angiogenesis) was observed in treated GDM group (mean difference, -0.11; 95% CI, -0.19 to -0.03). GDM was not associated with IGI or other biomarkers. Obesity was associated with lower 1/HOMA-IR (mean difference, -0.42; 95% CI, -0.52 to -0.32), but not other biomarkers.
Prior GDM and obesity are associated with more insulin resistance but not insulin secretion or consistent cardiovascular dysfunction 5 to 10 years after delivery.
· Mild GDM increases the risk of insulin resistance 5 to 10 years postpartum but not pancreatic dysfunction.. · Obesity increases the risk of insulin resistance 5 to 10 years postpartum but not pancreatic dysfunction.. · Neither mild GDM nor obesity increased the risk of cardiovascular dysfunction 5 to 10 years postpartum..
Individuals hospitalized with preterm prelabor rupture of membranes are often advised to limit their activity or adhere to bed rest. Some evidence suggests that greater activity is associated with ...longer latency and improved outcomes, but no high-quality evidence from a randomized controlled trial exists.
This study aimed to evaluate whether encouragement to ambulate at least 2000 steps daily affects latency among individuals with preterm prelabor rupture of membranes compared with usual care.
This was a multisite unblinded, 2-arm randomized trial of individuals at 23 0/7 to 35 0/7 weeks of gestation undergoing inpatient expectant management of preterm prelabor rupture of membranes with planned delivery at least 7 days away. Each participant wore a Fitbit Inspire that tracked steps. The intervention arm was encouraged (verbal and Fitbit-based reminders) to reach a goal of 2000 steps per day. The usual-care arm was allowed ad libitum activity with no step goal or reminders. The primary outcome was latency (days) from randomization to delivery. Secondary analyses included composite neonatal and maternal clinical outcomes and maternal mental health survey results. Statistical analyses were conducted with an intent-to-treat approach under a Bayesian framework using neutral priors (a priori assumed 50:50 likelihood of longer latency in either arm). A total of 100 participants were required to have 80% power to demonstrate a 4-day difference in latency with 75% certainty (Bayesian probability).
Among 163 eligible individuals, 100 (61%) were randomized, and after loss to follow-up, 95 were analyzed. Gestational age at randomization was 29 3/7 weeks (interquartile range, 26 2/7 to 31 5/7) in the intervention arm and 27 4/7 weeks (interquartile range, 25 4/7 to 29 6/7) in the usual-care arm. Median step counts were 1690 per day in the intervention arm (interquartile range, 1031-2641) and 1338 per day in the usual-care arm (interquartile range, 784-1913). Median days of latency were 9 days in the intervention arm (interquartile range, 4-17) and 6 days in the usual-care arm (interquartile range, 2-14). The primary analysis indicated a 65% posterior probability that the intervention increased latency relative to usual care (posterior relative risk, 1.09; 95% credible interval, 0.70-1.71). The relative risk was 0.55 (95% credible interval, 0.32-0.82) for the composite neonatal adverse outcome, with 99% posterior probability of intervention benefit, and was 0.94 (95% credible interval, 0.72-1.20) for the composite maternal adverse outcome, with 70% posterior probability of intervention benefit. There was a 94% posterior probability of the intervention arm having a greater decrease in maternal stress score from baseline to before delivery compared with the usual-care arm (mean arm difference, 3.24 points 95% credible interval, -7.23 to 0.79). Adjustment for gestational age at randomization had minimal impact on secondary outcome results.
Individuals with preterm prelabor rupture of membranes randomized to encouragement to ambulate had a longer latency to delivery and improved neonatal and mental health outcomes, with similar maternal clinical outcomes compared with usual care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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