This book is proof that debugging has graduated from a black art to a systematic discipline. It demystifies one of the toughest aspects of software programming, showing clearly how to discover what ...caused software failures, and fix them with minimal muss and fuss. This fully updated Second Edition includes 100+ pages of new material, including new chapters on Verifying Code, Predicting Errors, and Preventing Errors. Cutting-edge tools such as FindBUGS and AGITAR are explained, techniques from integrated environments like Jazz.net are highlighted, and all-new demos with ESC/Java and Spec#, Eclipse and Mozilla are included.It explains best practices ranging from systematically tracking error reports, to observing symptoms, reproducing errors, and correcting defects. It covers a wide range of tools and techniques from hands-on observation to fully automated diagnoses, and also explores the author's innovative techniques for isolating minimal input to reproduce an error and for tracking cause and effect through a program. It even includes instructions on how to create automated debugging tools.
The benchmark dose (BMD) concept is increasingly utilized to analyze quantitative dose–response relationships in genetic toxicology. This methodology requires the user (i.e. the toxicologist) to a ...priori define a small increase over controls that is “acceptable” to be induced by a genotoxic test substance. The increase is called benchmark response (BMR) or critical effect size (CES), depending on the software used. To render the metrics calculated from the data of animals treated with the test substance applicable for risk assessment, the BMR or CES must represent biologically relevant changes of parameters measured in in vivo genotoxicity assays such as the Micronucleus, Comet, Transgenic rodent or Pig-a assay. Current recommendations for CES in genotoxicology are arbitrary (10% increase over mean vehicle controls) or based on limited, usually 5–6, data points (i.e. the standard deviation of the concurrent vehicle control group). We have, therefore, analyzed historical vehicle control data of standard in vivo genotoxicity test systems with statistical methods. Based on this evaluation, we illustrate limitations of the currently recommended CES values and propose a pragmatic approach that may contribute to better defining endpoint-specific CES values for BMD software like PROAST.
SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small ...molecules to increase levels of functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients. It was safe and well tolerated and increased SMN protein levels up to 2-fold in patients. Nevertheless, its development was stopped as a precautionary measure because retinal toxicity was observed in cynomolgus monkeys after chronic daily oral dosing (39 weeks) at exposures in excess of those investigated in patients. Herein, we describe the discovery of 1 (risdiplam, RG7916, RO7034067) that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is undergoing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages with SMA.
When interacting with source control management system, developers often commit unrelated or loosely related code changes in a single transaction. When analyzing version histories, such tangled ...changes will make all changes to all modules appear related, possibly compromising the resulting analyses through noise and bias. In an investigation of five open-source
Java
projects, we found between 7 % and 20 % of all bug fixes to consist of multiple tangled changes. Using a multi-predictor approach to untangle changes, we show that on average at least 16.6 % of all source files are incorrectly associated with bug reports. These incorrect bug file associations seem to not significantly impact models classifying source files to have at least one bug or no bugs. But our experiments show that untangling tangled code changes can result in more accurate regression bug prediction models when compared to models trained and tested on tangled bug datasets—in our experiments, the statistically significant accuracy improvements lies between 5 % and 200 %. We recommend better change organization to limit the impact of tangled changes.
INTRODUCTION: General practitioners (GPs) play a key role in the delivery of health care in Switzerland. Assessing GPs’ workload over time is essential to meet the population’s health service demand ...and for future health care planning.
METHODS: The study involved four questionnaire-based cross-sectional studies among a representative sample of Swiss GPs on a five-yearly basis since 2005. Data on GPs’ self-estimated workload and practice administration (face-to-face consultations, house calls, nursing home visits and clinical administrative work) were analysed in hours per week (h/week) or full-time equivalents (FTE; 100% = 55 h/week).
RESULTS: The mean age of GPs (n = 2,037) in 2020 was 54.9 years, significantly higher than in 2005 (51.4 years, p <0.001, n = 1,780). The proportion of female GPs increased gradually from 16.5% in 2005 to 36.2% in 2020 (p <0.001). The GPs’ workload significantly decreased over the last 15 years from 50.2 h/week to 43.4 h/week or from 90.9% FTE in 2005 to 78.9% FTE in 2020 (p <0.001). The decreased average workload across years was less pronounced in women (–4.4% FTE) than in men (–9.0% FTE, p = 0.015). Across all survey years, women worked on average 12.7 h/week or 23.2% FTE less than men (p <0.001). The time spent with patients gradually decreased, whereas the amount of time spent on clinical administrative work remained stable since 2005 (9 h/week). In 2020, GPs were working more frequently in group practices compared to 2005 (45.0% vs. 12.4%, p <0.001).
CONCLUSION: This study demonstrates a decrease in GPs’ overall workload from 2005 to 2020, indicating that the “new” generation of GPs prefers to work part-time. This decrease is at the expense of direct face-to-face encounters with patients. Over the last 15 years, a clear trend exists towards more women in the Swiss general practice, persisting over-ageing of GPs, replacement of single-handed practices by group practices, and increasing burden of administrative tasks, a risk factor for burnout and reduced job satisfaction. To maintain an efficient healthcare system in the future, substantial efforts are crucial to provide a positive and motivating insight into general practice to pre- and postgraduate students and improve the operational working conditions of GPs.
The Centor criteria and the FeverPAIN score are recommended for guiding antibiotic prescription for tonsillitis, but they are not validated for this purpose. We aimed to identify risk factors for ...peritonsillar abscess in group A haemolytic streptococcus-negative tonsillitis and to test the performance of clinical scores and laboratory tests.
In a retrospective case-control study at two regional hospitals from January 2015 to June 2018, we identified all cases of peritonsillar abscess and used propensity score matching utilising age and gender to select two controls per case from all patients who had a rapid group A haemolytic streptococcus antigen test in the emergency department. Exclusion criteria were age <18 years, documented refusal and a positive antigen test. We abstracted patient history, physical examination and results of laboratory testing. Logistic regression analysis was used to identify risk factors.
We included 141 cases of peritonsillar abscess, matched with 282 controls. Higher Centor score, C-reactive protein and white blood cell count were significantly associated with peritonsillar abscess, but had a low performance for predicting the latter (area under the receiver operator characteristic curve ROC AUC 0.76). The FeverPAIN score was not associated with peritonsillar abscess (ROC AUC 0.51). In the multivariable analysis, difficulty swallowing (odds ratio OR 18.4, 95% confidence interval CI 6.58-51.2), dyspnoea (OR 10.2, 95% CI 1.18-89.0), tonsillar swelling (OR 4.21, 95% CI 1.39-12.7) and unilateral signs and symptoms (OR 146, 95% CI 40.9-522) were risk factors of peritonsillar abscess.
The Centor criteria, as well as C-reactive protein and white blood cell count, have a low discriminatory performance, and the FeverPAIN score is not useful in identifying patients at risk for peritonsillar abscess in group A haemolytic streptococcus-negative tonsillitis. To guide a rational antibiotic prescription, new decision tools need to be developed. These might include items such as difficulty swallowing, dyspnoea, tonsillar swelling and unilaterality.
General health check-up examinations in asymptomatic adults have not been shown to be beneficial. Instead, opportunistic prevention during regular primary care consultations is most cost-effective ...and recommended. The study aimed to elucidate the expectations about check-ups of the general Swiss population. A nationwide cross-sectional telephone survey was conducted in a representative sample of the population, stratified by sex, age, and language in November 2019. Data of 1077 respondents were analysed. Mean age was 45 years (range 18 to 89), and 51% were female. Overall, 40% of respondents expected to have check-up examinations (yearly: 41.6%), and 42% expected opportunistic prevention. Most expected check-up interventions were sex-specific such as mammography (89% of women), Pap smear test (89% of women), and blood test of prostate-specific antigen (81% of men). The least favoured ones related to counselling (tobacco: 27%; alcohol abuse: 29%). Most significant predictors of positive check-up expectations were being male (OR = 1.45, CI: 1.02-2.05 P = 0.04)), age between 45 and 59 years old (OR = 2.03, CI: 1.27-3.23, P = 0.003 vs. 18 to 29 years), having a degree from professional (OR = 1.73, 95% CIs: 1.11-2.69, P 0.015) or, middle school (OR = 1.99, 95% CIs:1.04-3.78, P = 0.037) or university (OR = 1.66, 95% CIs: 1.06-2.61, P< 0.001, vs. secondary school) and the more importance attributed to regularly checking one's health (OR = 2.12, 95% CIs: 1.70-2.36, P < 0.001) Almost half of the population expected to have mostly yearly check-up examinations in addition to regular care, which is in contradiction to recommendations. This behaviour impacts the rational use of health care resources and must be considered by physicians and given the active role of patients in the health care system.
A genotoxic carcinogen, N‐nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs in 2018, and other N‐nitrosamines, such as N‐nitrosodiethylamine (NDEA), were later ...detected in other sartan products. N‐nitrosamines are pro‐mutagens that can react with DNA following metabolism to produce DNA adducts, such as O6‐alkyl‐guanine. The adducts can result in DNA replication miscoding errors leading to GC>AT mutations and increased risk of genomic instability and carcinogenesis. Both NDMA and NDEA are known rodent carcinogens in male and female rats. The DNA repair enzyme, methylguanine DNA‐methyltransferase can restore DNA integrity via the removal of alkyl groups from guanine in an error‐free fashion and this can result in nonlinear dose responses and a point of departure or “practical threshold” for mutation at low doses of exposure. Following International recommendations (ICHM7; ICHQ3C and ICHQ3D), we calculated permissible daily exposures (PDE) for NDMA and NDEA using published rodent cancer bioassay and in vivo mutagenicity data to determine benchmark dose values and define points of departure and adjusted with appropriate uncertainty factors (UFs). PDEs for NDMA were 6.2 and 0.6 μg/person/day for cancer and mutation, respectively, and for NDEA, 2.2 and 0.04 μg/person/day. Both PDEs are higher than the acceptable daily intake values (96 ng for NDMA and 26.5 ng for NDEA) calculated by regulatory authorities using simple linear extrapolation from carcinogenicity data. These PDE calculations using a bench‐mark approach provide a more robust assessment of exposure limits compared with simple linear extrapolations and can better inform risk to patients exposed to the contaminated sartans.
The allocation and equal distribution of healthcare resources is one of the major challenges of today. Therefore, a framework to analyse the prevalence of illness in the community and the use of ...various sources of healthcare is crucial. The aim of the study was to evaluate the health-seeking behaviour of 1025 individuals in Switzerland in a 2-month period in 2018.
Population-based, cross-sectional health survey with a multistage, stratified cluster design. The LINK Institute (Luzern, Switzerland, https://www.link.ch/) interviewed a representative sample of the adult Swiss population (age ≥18 years, stratified by language region: German-, French- and Italian-speaking, 70, 25 and 5%, respectively) by telephone. There were two interview rounds to account for potential seasonal variations, in May (n = 506) and November 2018 (n = 516). The health-seeking behaviour of these individuals during the previous 2 months was analysed.
In total, data of 1025 individuals were analysed: 51% females, median age 52 years (range 1885). During the preceding 2 months, per 1000 adults, 546 had at least one symptom, 184 reported several symptoms, 243 sought medical advice, 164 first contacted their general practitioner, 81 directly contacted a specialist in a private practice, 16 were self-admitted to an accident and emergency department, 17 firstly contacted a pharmacy and 6 contacted an alternative medicine healthcare provider. In total, 21 persons were admitted to a hospital, of whom 8 underwent surgical procedures, 18 were at first transferred to a regular ward and 3 required intensive care unit services. Because of their current health problem, 387 individuals took medication and 259 bought their medication themselves. The vast majority (95%) of subjects was registered with a general practitioner.
This study represented an attempt to map the healthcare utilisation of the Swiss population. These results may be useful for further delineation of healthcare policies and medical education to meet the demand and needs of people in Switzerland. They indicate that general practitioners are the most important healthcare resource in Switzerland. Compared with specialists, they provide twice as much health advice at less costs. To optimise the health care system in Switzerland, we suggest to allocate resources where they are most needed.
The distribution of health care resources during a pandemic is challenging. The aim of the study was to describe the use of health care in a representative sample of the Swiss population during the ...SARS-CoV-2 pandemic in 2020, and to compare it to data from a survey conducted in 2018.
We conducted an observational, population-based, nationwide, repeated cross-sectional survey of the adult Swiss general population in 2018 and in March and April 2020 during the first wave of the SARS-CoV-2 pandemic. Recruitment and data acquisition was conducted by the Link Institute in Lucerne in representative samples of Swiss citizens in 2020 and in 2018. Variables of interest were estimates of health problems, health seeking behaviour, medication and health care use in the population.
In total, we included data of 1980 individuals (in 2018 N = 958 and in 2020 N = 1022). Across both rounds of data collection the median age was 46 years (range = 18-79 years) and 50% were women. Per 1000 adults, half had at least one symptom and a quarter sought medical advice across both surveys. The most frequently consulted health providers in 2020 were general practitioners (GP) (180/1000), specialist physicians (41/1000), pharmacies (38/1000), the internet (26/1000) and accident and emergency units (25/1000). Compared to 2018, we noted a significant increase in the use of health providers during the pandemic, which was independent of demographic variables for the following health care providers: use of internet (OR = 9.8), pharmacy (OR = 2.64), accident and emergency units (OR = 2.54), and a significant decrease in the number of people who consulted specialist physicians (OR = 0.46). Overall, 76/1000 contacted their GP in relation to COVID-19.
Compared to 2018, GPs remained the most important source of medical advice for the population during the first wave of the COVID-19 pandemic in Switzerland. While the self-appraisal of health problems and of the need for medical advice remained constant, individuals seemed to change their provider choice during the pandemic, with an increased utilisation of accident and emergency units and pharmacies, which represent easily accessible and low-threshold medical services.
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