Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants.

Unstable proteins are prone to form non-native interactions with other proteins and thereby may become toxic. To mitigate this, destabilized proteins are targeted by the protein quality control network. Here we present systematic studies of the cytosolic aspartoacylase, ASPA, where variants are linked to Canavan disease, a lethal neurological disorder. We determine the abundance of 6152 of the 6260 ( ~ 98%) possible single amino acid substitutions and nonsense ASPA variants in human cells. Most low abundance variants are degraded through the ubiquitin-proteasome pathway and become toxic upon prolonged expression. The data correlates with predicted changes in thermodynamic stability, evolutionary conservation, and separate disease-linked variants from benign variants. Mapping of degradation signals (degrons) shows that these are often buried and the C-terminal region functions as a degron. The data can be used to interpret Canavan disease variants and provide insight into the relationship between protein stability, degradation and cell fitness.

Attitudes towards risk-stratified breast cancer screening: a population-based survey among 5,001 Danish women.

BACKGROUND: The individual woman's risk of being diagnosed with breast cancer can now be estimated more precisely, and screening can be stratified accordingly. The risk assessment requires that women are willing to provide a blood test, additional personal information, to know their risk, and alter screening intervals. This study aimed to investigate Danish women's attitudes towards risk-stratified breast cancer screening. METHODS: An online, cross-sectional survey was conducted among Danish women aged 52-67 years. We used logistic regression analyses to assess how personal characteristics were associated with the women's attitudes. RESULTS: 5,001 women completed the survey (response rate 44%) of which 74% approved of risk estimation to potentially alter their screening intervals. However, only 42% would accept an extended screening interval if found to have low breast cancer risk, while 89% would accept a reduced interval if at high risk. The main determinants of these attitudes were age, education, screening participation, history of breast cancer, perceived breast cancer risk and to some extent breast cancer worry. CONCLUSION: This study indicates that women are positive towards risk-stratified breast cancer screening. However, reservations and knowledge among subgroups of women must be carefully considered and addressed before wider implementation of risk-stratified breast cancer screening in a national program.

Simple Talectomy is a Beneficial Surgical Procedure for Talipes Equinovarus and Other Severe Neuromuscular Foot Deformities.

Noninvasive techniques are gold standard to redress Severe Neuromuscular Foot Deformity (SNFD). However, simple talectomy may be considered to obtain a stable, plantigrade, pain-free foot. We present a 10-year follow-up accessing radiological correction rates, functional outcomes, complications, and patient satisfaction. This retrospective case series evaluated talectomies in 2012 to 2022. Simple talectomy was combined with Steinman pin fixation of calcaneus to tibia for approximately 6 weeks. Diagnoses primarily included arthrogryposis multiplex congenita and cerebral palsy. Indications were pain, wounds/pressure marks, severe rigidity, and residual/recurrent deformity. The primary outcome was radiological correction. Tibiotalar angle (TiTa) and tibiocalcaneal angle (TiCa) were measured on mediolateral projections. Secondary outcomes were functional scores of pain/deformity graded as good, fair or poor. Furthermore, validated patient-reported outcome measures, that is, EQ-5D-5L and the Scoliosis Research Society-30 Questionnaire (2 items) assessed health-related quality of life and patient satisfaction. Nineteen talectomies in 11 patients were analyzed. Mean follow-up was 62 months (range 9-112 months). Mean TiTa was 137° (95%CI 128;146). TiCa improved significantly: Mean difference -24° (95%CI -44;-5, p = .02). All feet became plantigrade and pain-free with no skin issues. Functional outcomes were graded as 9/19 good, 10/19 fair and 0/19 poor. Parents/primary caregivers were mainly satisfied. Perceived health was 54 (95%CI 34;75) out of 100 on a visual analogue scale, emphasizing complex medical conditions. In conclusion, simple talectomy is a suitable salvage procedure for SNFD.

Non-pharmacological treatment for pediatric pain and anxiety.

Non-pharmacological treatment for pain in children is seeing more interest as various interventions are investigated and found to be efficacious and free from adverse side effects. Some of the most used non-pharmacological treatments include distractive play, music therapy, virtual reality, hospital clowns, and hypnosis. This review summarises studies examining these modalities and finds that the available literature, although at times limited, mostly concludes that they are effective at reducing pain and/or anxiety in children. The population and setting for each modality are discussed.

The link between physician motivation and care.

Studies report an unexplained variation in physicians' care. This variation may to some extent be explained by differences in their work motivation. However, empirical evidence on the link between physician motivation and care is scarce. We estimate the associations between different types of work motivation and care. Motivation is measured using validated questions from a nation-wide survey of Danish general practices and linked to high-quality register data on their care in 2019. Using a series of regression models, we find that more financially motivated practices generate more fee-for-services per patient, whereas practices characterised by greater altruistic motivation towards the patient serve a larger share of high-need patients and issue more prescriptions for antibiotics per patient. Practices with higher altruism towards society generate lower medication costs per patient and prescribe a higher rate of narrow-spectrum penicillin, thereby reducing the risk of antimicrobial resistance in the population. Together, our results suggest that practices' motivation is associated with several dimensions of healthcare, and that both their financial motivation and altruism towards patients and society play a role. Policymakers should, therefore, consider targeting all provider motivations when introducing organisational changes and incentive schemes; for example, by paying physicians to adhere to clinical guidelines, while at the same time clearly communicating the guidelines' value from both a patient and societal perspective.

Going the extra mile? General practitioners' upcoding of fees for home visits.

General practitioners' (GPs') income often relies on self-reported activities and performances. They can therefore 'game the system' to maximize their remuneration. We investigate whether Danish GPs game their travel fees for home visits. Combining administrative and geographical data, we measure the difference between GPs' traveled and billed distances. We exploit a rise in the fees for home visits. If there is a link between the rise in fees and upcoding, we interpret this finding as indicative of gaming behavior. We find that upcoding occurs slightly more often than downcoding (16% vs. 13% of visits) for visits that can be both upcoded and downcoded. Using linear probability models with GP fixed effects, we find that the fee rise is associated with a reduction in upcoding of 0.6% of home visits (2.8% for visits where upcoding is feasible) and no change in downcoding. Importantly, we find no statistically significant differences in the reduction in upcoding across distance bands despite large differences in their fee rises. We therefore conclude that there is no causal evidence of GPs gaming their fees.

Adipose tissue fibrosis: the unwanted houseguest invited by obesity.

The prevalence of obesity is increasing exponentially across the globe. The lack of effective treatment options for long-term weight loss has magnified the enormity of this problem. Studies continue to demonstrate that adipose tissue holds a biological memory, one of the most important determinant of long-term weight maintenance. This phenomenon is consistent with the metabolically dynamic role of adipose tissue: it adapts and expands to store for excess energy and serves as an endocrine organ capable of synthesizing a number of biologically active molecules that regulate metabolic homeostasis. An important component of the plasticity of adipose tissue is the extracellular matrix, essential for structural support, mechanical stability, cell signaling and function. Chronic obesity upends a delicate balance of extracellular matrix synthesis and degradation, and the ECM accumulates in such a way that prevents the plasticity and function of the diverse cell types in adipose tissue. A series of maladaptive responses among the cells in adipose tissue leads to inflammation and fibrosis, major mechanisms that explain the link between obesity and insulin resistance, risk of type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Adipose tissue fibrosis persists after weight loss and further enhances adipose tissue dysfunction if weight is regained. Here, we highlight the current knowledge of the cellular events governing adipose tissue ECM remodeling during the development of obesity. Our goal is to delineate the relationship more clearly between adipose tissue ECM and metabolic disease, an important step toward better defining the pathophysiology of dysfunctional adipose tissue.

Mapping GPs' motivation ­ it's not all about the money: a nationwide cross-sectional survey study from Denmark.

BACKGROUND: Understanding physicians' motivation may be essential for policymakers if they are to design policies that cater to physicians' wellbeing, job retention, and quality of care. However, physicians' motivation remains an understudied area. AIM: To map GPs' work motivation. DESIGN AND SETTING: A cross-sectional analysis using registry and survey data from Denmark. METHOD: Survey data were used to measure four types of motivation: extrinsic motivation, intrinsic motivation, user orientation, and public service motivation. These were combined with register data on the characteristics of the GP, practice, and area. Using latent profile analysis, the heterogeneity in GPs' motivation was explored; the associations between GPs' motivation and the GP, practice, and area characteristics were estimated using linear regression analyses. RESULTS: There was substantial heterogeneity in GPs' motivations. Five classes of GPs were identified with different work motivations: class 1 'it is less about the money' - probability of class membership 53.2%; class 2 'it is about everything' - 26.5%; class 3 'it is about helping others' - 8.6%; class 4 'it is about the work' - 8.2%; and class 5 'it is about the money and the patient' - 3.5%. Linear regression analyses showed that motivation was associated with GP, practice, and area characteristics to a limited extent only. CONCLUSION: GPs differ in their work motivations. The finding that, for many GPs, 'it is not all about the money' indicated that their different motivations should be considered when designing new policies and organisational structures to retain the workforce and ensure a high quality of care.

Sensory Interactions between Sweetness and Fat in a Chocolate Milk Beverage.

Fat and sugar-reduced foods and beverages have become increasingly popular for a variety of reasons, mainly relating to health and wellbeing. Depending on the food or beverage, it may be difficult to reduce the fat and/or sugar content and still maintain optimal sensory properties for the specific product. One way of approaching the problem is to gain a better understanding of how a product is affected by a reduction in fat and/or sugar. This paper aims to investigate the sensory interactions between fat and sweetness perception in a chocolate-flavored milk beverage by using a descriptive analysis with a trained sensory panel. The reduction of fat significantly reduced the sweetness intensity of the chocolate milk, while the reduction of sucrose significantly decreased the cream flavor and the fruity and lactic flavor. The perception of acesulfame-K was affected by fat concentration, similarly to sucrose. These results highlight the importance of considering the effects of reducing either sugar and fat on product attributes that are not directly related to the sugar or fat.

Cerebral palsy and bisphosphonates - and what can be learned from other types of secondary osteoporosis in children: A scoping review.

AIM: We aimed to improve bone health management of children with cerebral palsy (CP) by reviewing studies investigating bisphosphonate therapy in children with CP and other types of secondary osteoporosis. METHODS: We included trials on bisphosphonate treatment reporting any direct bone measurement or fracture outcome. All studies of patients with CP were included. We also included all controlled trials of children with secondary bone fragility as well as observational studies with ≥20 participants or at least 3 years of follow-up. Studies were assessed according to PRISMA guidelines using the RoB2-tool and the Newcastle-Ottawa Scale. RESULTS: We reviewed 1104 studies and found 37 eligible. Some studies were sufficiently homogeneous to include in a meta-analysis, and we found a 1-year effect on lumbar spine bone mineral density (BMD) Z-score of +0.65 after oral and + 1.21 after intravenous bisphosphonates in children with secondary osteoporosis. Further, data on adverse events and post-treatment follow-up were reviewed. Limitations were heterogeneity and small size of the included studies. CONCLUSION: Meta-analysis consistently showed significant BMD increases with bisphosphonates in children with secondary osteoporosis. Direct evidence of the effect of bisphosphonates on reducing fractures is lacking. We found no reports of long-term adverse events yet longer studies are needed.

Intersectoral collaboration in home-based end-of-life pediatric cancer care: A qualitative multiple-case study integrating families' and professionals' experiences.

BACKGROUND: Many children and adolescents with incurable cancer and their families prefer to receive end-of-life care and to die at home. This implies a transition of care from hospital to home and presupposes the establishment of a well-functioning collaboration between the family and professionals across health care sectors. AIM: To identify and explore key elements of home-based end-of-life care collaboration for children with cancer, as experienced by their parents and grandparents and the hospital- and community-based professionals involved. DESIGN: Descriptive qualitative multiple-case study. Data were collected by semi-structured interviews and written responses to open-ended questions, and analyzed inductively across cases using qualitative content analysis. SETTING/PARTICIPANTS: Cases comprised a criterion sample of five children (aged <18 years), who died of cancer at home. Cases were represented by the children's bereaved parents (n = 8) and grandparents (n = 7), and community-based professionals (n = 16). Also, hospital-based professionals (n = 10) were interviewed about the children's end-of-life care through group interviews. RESULTS: We identified five main themes, describing key elements of the end-of-life collaboration: Establishing the collaboration, Bolstering family life, Elucidating organization and integration, Managing challenges, and Closing the collaboration. These themes all came under the overarching theme: A mutual trust-based collaboration. On this basis, we developed the "Home-Based Pediatric End-of-Life Care Model for Children with Cancer." CONCLUSIONS: By highlighting key elements in the family-centered, intersectoral and interprofessional end-of-life care collaboration, our "Home-Based Pediatric End-of-Life Care Model for Children with Cancer" offers a framework for further optimization of home-based end-of-life care services for children with cancer and their families.

Barriers to assessing vulnerability in pregnant women. A cross-sectional survey in Danish general practice.

BACKGROUND: Undetected vulnerability in pregnancy contributes to inequality in maternal and perinatal health and is associated with negative birth outcomes and adverse child outcomes. Nationwide reports indicate important barriers to assessing vulnerability among Danish general practitioners. OBJECTIVE: To explore general practitioners perceived barriers to vulnerability assessment in pregnant women and whether the barriers are associated with practice organization of antenatal care, general practitioner, and practice characteristics. METHODS: The questionnaire was sent to all Danish general practitioners (N = 3,465). Descriptive statistics described the barriers to assessing vulnerability in pregnant women. Analytical statistics with ordered logistic regression models were used to describe the association between selected barriers to vulnerability assessment and antenatal care organization, and general practitioner and practice characteristics. RESULTS: 760 general practitioners (22%) answered. Barriers to vulnerability assessment were related to lacking routines for addressing vulnerability, lacking attention to and record-keeping on vulnerability indicators, an insufficient overview of vulnerable pregnant women, and perceived insufficient remuneration for antenatal care consultations. Not prioritizing extra time when caring for vulnerable pregnant women was associated with experiencing more barriers. Always prioritizing continuity of care was associated with experiencing fewer barriers. General practitioners of either young age, male gender, or who did not prioritize extra time to care for vulnerable pregnant women experienced more barriers. CONCLUSION: Barriers to vulnerability assessment among pregnant women do exist in general practice and are associated with organizational characteristics such as lacking prioritization of extra time and continuity in antenatal care consultations. Also, general practitioner characteristics like male gender and relatively young age are associated with barriers to vulnerability assessment.

Identifying vulnerability in pregnant women is essential to prevent pregnancy-related depression or problems of mother-child attachment, and these women need extra support during pregnancy. In Denmark, all pregnant women are offered pregnancy care by their general practitioner (GP). However, identifying vulnerable pregnant women is challenging for the GPs. This questionnaire study among 760 GPs explores whether the GPs perceived barriers to identifying vulnerable pregnant women are lack of attention to and overview of vulnerable women in their clinic, insufficient record-keeping of vulnerability indicators, and insufficient communicative routines in addressing vulnerability. Additionally, lack of monetary incentives, i.e. not getting paid for spending extra time to talk about vulnerability, was perceived as a barrier. These barriers to identifying vulnerable pregnant women are related to e.g. characteristics of the GP, the practice, and the antenatal care organization in general practice. Young GPs, male GPs, and GPs who did not spend as much time caring for vulnerable pregnant women experienced the most barriers. Contrary, GPs who always prioritized continuity of care experienced fewer barriers. Continuity of care and extra time is important for improving the care of vulnerable pregnant women. Health commissioners may consider supporting the GPs in mobilizing extra time and resources to enhance their care for vulnerable pregnant women.

Effects of Transdermal Fentanyl Treatment on Acute Pain and Inflammation in Rats with Adjuvant-induced Monoarthritis.

Eliminating unnecessary pain is an important requirement of performing animal experimentation, including reducing and controlling pain of animals used in pain research. The goal of this study was to refine an adjuvant-induced monoarthritis model in rats by providing analgesia with a transdermal fentanyl solution (TFS). Male and female Sprague-Dawley rats, single- or pair-housed, were injected with 20 µL of complete Freund adjuvant (CFA) into the left ankle joint. CFA-injected rats treated with a single dose of transdermal fentanyl solution (0.33 or 1 mg/kg) were compared with an untreated CFA-injected group and sham groups that received either no treatment or TFS treatment (1 mg/kg) during 72 h. At the tested doses, TFS reduced mechanical hyperalgesia and improved the mobility, stance, rearing, and lameness scores at 6 h after CFA injection. Joint circumferences were not reduced by TFS treatment, and no significant differences were detected between the 2 doses of TFS, or between single- and pair-housed rats. Treatment with TFS did not appear to interfere with model development and characteristics. However, overall, the analgesic effect was transient, and several opioid-related side effects were observed.

Stopping Oral Polio Vaccine (OPV) After Defeating Poliomyelitis in Low- and Middle-Income Countries: Harmful Unintended Consequences? Review of the Nonspecific Effects of OPV.

Background: The live vaccines bacille Calmette-Guérin (BCG) and measles vaccine have beneficial nonspecific effects (NSEs) reducing mortality, more than can be explained by prevention of tuberculosis or measles infection. Live oral polio vaccine (OPV) will be stopped after polio eradication; we therefore reviewed the potential NSEs of OPV. Methods: OPV has been provided in 3 contexts: (1) coadministration of OPV and diphtheria-tetanus-pertussis (DTP) vaccine at 6, 10, and 14 weeks of age; (2) at birth (OPV0) with BCG; and (3) in OPV campaigns (C-OPVs) initiated to eradicate polio infection. We searched PubMed and Embase for studies of OPV with mortality as an outcome. We used meta-analysis to obtain the combined relative risk (RR) of mortality associated with different uses of OPV. Results: First, in natural experiments when DTP was missing, OPV-only compared with DTP + OPV was associated with 3-fold lower mortality in community studies (RR, 0.33 [95% confidence interval {CI}, .14-.75]) and a hospital study (RR, 0.29 [95% CI, .11-.77]). Conversely, when OPV was missing, DTP-only was associated with 3-fold higher mortality than DTP + OPV (RR, 3.23 [95% CI, 1.27-8.21]). Second, in a randomized controlled trial, BCG + OPV0 vs BCG + no OPV0 was associated with 32% (95% CI, 0-55%) lower infant mortality. Beneficial NSEs were stronger with early use of OPV0. Third, in 5 population-based studies from Guinea-Bissau and Bangladesh, the mortality rate was 24% (95% CI, 17%-31%) lower after C-OPVs than before C-OPVs. Conclusions: There have been few clinical polio cases reported in this century, and no confounding factors or bias would explain all these patterns. The only consistent interpretation is that OPV has beneficial NSEs, reducing nonpolio child mortality.

Patient costs and patient flow after implementation of S100B in Scandinavian head trauma guidelines.

INTRODUCTION: The serum biomarker S100B has been implemented in the Scandinavian Neurotrauma Committee (SNC) 2013 Head Injury Guidelines for patients classified with mild head injury (MHI). Patients with a serum S100B level less-than 0.10 µg/l sampled within six hours after trauma can be discharged without further observation or investigation. The aim of this study was to examine the influence of S100B implementation on patient costs and patient flow in an emergency department. METHODS: In this retrospective study, we included MHI patients (≥ 18 years) admitted to Rigshospitalet, Copenhagen, Denmark, between 1 February 2013 and 31 January 2014. Medical records were examined for the time of trauma, time of S100B sampling, serum S100B level, the severity of the head injury, clinical symptoms, radiological examinations, hospitalisation, discharge, surgical intervention, readmission and mortality. RESULTS: Among 2,033 patients screened for potential study candidates, 227 patients met the inclusion criteria and were enrolled in the study. Among these patients, 119 (52%) were not treated according to SNC 2013 Head Injury Guidelines, leaving 108 (48%) with full guideline adherence. Compared with MHI management without S100B, implementation of S100B produced an additional cost of €1.26 per patient. Overall, the addition of S100B did not affect the waiting time for examination with S100B sampling or CT. CONCLUSION: The use of S100B in the SNC 2013 Head Injury Guidelines did not reduce patient costs, nor did it cause substantial additional patient costs or delayed patient flow. FUNDING: none. TRIAL REGISTRATION: The Danish Data Protection Agency (journal number 2012-58-0004 and I-suite number RH-2017-164).

Prescribing antibiotics: Factors driving decision-making in general practice. A discrete choice experiment.

BACKGROUND: Antimicrobial resistance is a threat to human health. We need to strive for a rational use of antibiotics to reduce the selection of resistant bacteria. Most antibiotics are prescribed in general practice, but little is known about factors influencing general practitioners' (GPs) decision-making when prescribing antibiotics. AIM: To 1) assess the importance of factors that influence decisions by GPs to prescribe antibiotics for acute respiratory tract infections (RTIs) and 2) identify segments of GPs influenced differently when deciding to prescribe antibiotics. METHODS: A questionnaire survey including a discrete choice experiment was conducted. Danish GPs were asked to indicate whether they would prescribe antibiotics in six hypothetical choice sets with six variables: whether the GP is behind schedule, patient's temperature, patient's general condition, lung auscultation findings, C-reactive protein (CRP) level, and whether the patient expects antibiotics. Error component and latent class models were estimated and the probabilities of prescribing in different scenarios were calculated. RESULTS: The questionnaire was distributed to every Danish GP (n = 3,336); 1,152 (35%) responded. Results showed that GPs were influenced by (in prioritised order): CRP level (Relative importance (RI) 0.54), patient's general condition (RI 0.20), crackles at auscultation (RI 0.15), and fever (RI 0.10). Being behind schedule and patient expectations had no significant impact on antibiotic prescription at the aggregate level. The latent class analysis identified five classes of GPs: generalists, CRP-guided, general condition-guided, reluctant prescribers, and stethoscopy-guided. For all classes, CRP was the most important driver, while GPs were heterogeneously affected by other drivers. CONCLUSION: The most important factor affecting Danish GPs' decision to prescribe antibiotics at the aggregate level, in subgroups of GPs, and across latent classes was the CRP value. Hence, the use of CRP testing is an important factor to consider in order to promote rational antibiotic use in the battle against antimicrobial resistance.

Quality clusters in general practice: associations between cluster organization and general practitioners' self-reported benefits.

BACKGROUND: Quality clusters were introduced as a quality improvement concept in Danish general practice in 2018. This new concept anchored quality improvement in local clusters managed by general practitioners (GPs). OBJECTIVES: To describe the cluster organization and GPs' self-reported benefits of participating in them and explore the associations between cluster organization and self-reported benefits. METHODS: A national survey in Danish general practice gathering information about cluster organization (cluster size, cluster meetings, participants, and content) and GPs' self-reported benefits (overall benefit, internal changes in the clinic, and improved external collaboration). RESULTS: One hundred and eight (95%) clusters and 1,219 GPs (36%) were included. Cluster size varied from 10 to 68 GPs (34 GPs on average). Approximately 70% of GPs reported moderate to very high overall benefit from cluster participation. Most GPs experienced changes in their clinic organization (68%), drug prescriptions (78%), and patient care (77%). Collaboration was reported improved between the GPs (86%), municipality (50%), and hospital (36.2%). GPs in clusters with 3-6 planned meetings per year (odds ratio [OR] 1.9; confidence interval [CI] 1.3-2.9), mixed meeting types (OR 1.7; CI 1.2-2.4), group work (OR 1.7; CI 1.1-2.5), and use of guidelines in their meetings (OR 1.8; CI 1.3-2.4) had statistically significantly higher odds for reporting overall benefit of participating in clusters compared with GPs in clusters without these characteristics. CONCLUSIONS: Frequent and active meetings with a relevant meeting content are positively related to GPs' perceived benefits and with improved collaboration between GPs in the clusters. There seems to be a potential for developing collaboration with other healthcare providers.

Factors associated with C-reactive protein testing when prescribing antibiotics in general practice: a register-based study.

BACKGROUND: The use of C-reactive protein (CRP) tests has been shown to safely reduce antibiotic prescribing for acute respiratory tract infections (RTIs). The aim of this study was to explore patient and clinical factors associated with the use of CRP testing when prescribing antibiotics recommended for RTIs. METHODS: A nation-wide retrospective cross-sectional register-based study based on first redeemed antibiotic prescriptions issued to adults in Danish general practice between July 2015 and June 2017. Only antibiotics recommended for treatment of RTIs were included in the analysis (penicillin-V, amoxicillin, co-amoxicillin or roxithromycin/clarithromycin). Logistic regression models were used to estimate odds ratios for patient-related and clinical factors on performing a CRP test in relation to antibiotic prescribing. RESULTS: A total of 984,149 patients redeemed at least one antibiotic prescription during the two-year period. About half of these prescriptions (49.6%) had an RTI stated as the indication, and a CRP test was performed in relation to 45.2% of these scripts. Lower odds of having a CRP test performed in relation to an antibiotic prescription was found for patients aged 75 years and above (OR 0.82, 95CI 0.79-0.86), with a Charlson Comorbidity Index of more than one (OR 0.93, 95CI 0.91-0.95), unemployed or on disability pension (OR 0.84, 95CI 0.83-0.85) and immigrants (OR 0.91, 95CI 0.88-0.95) or descendants of immigrants (OR 0.90, 95CI 0.84-0.96). Living with a partner (OR 1.08, 95CI 1.07-1.10), being followed in practice for a chronic condition (OR 1.22, 95CI 1.18-1.26) and having CRP tests performed in the previous year (OR 1.78, 95CI 1.73-1.84) were associated with higher odds of CRP testing in relation to antibiotic prescribing. CONCLUSIONS: Differences were observed in the use of CRP tests among subgroups of patients indicating that both sociodemographic factors and comorbidity influence the decision to use a CRP test in relation to antibiotic prescriptions in general practice. Potentially, this means that the use of CRP tests could be optimised to increase diagnostic certainty and further promote rational prescribing of antibiotics. The rationale behind the observed differences could be further explored in future qualitative studies.

Physicians under Pressure: Evidence from Antibiotics Prescribing in England.

BACKGROUND: Many physicians are experiencing increasing demands from both their patients and society. Evidence is scarce on the consequences of the pressure on physicians' decision making. We present a theoretical framework and predict that increasing pressure may make physicians disregard societal welfare when treating patients. SETTING: We test our prediction on general practitioners' antibiotic-prescribing choices. Because prescribing broad-spectrum antibiotics does not require microbiological testing, it can be performed more quickly than prescribing for narrow-spectrum antibiotics and is therefore often preferred by the patient. In contrast, from a societal perspective, inappropriate prescribing of broad-spectrum antibiotics should be minimized as it may contribute to antimicrobial resistance in the general population. METHODS: We combine longitudinal survey data and administrative data from 2010 to 2017 to create a balanced panel of up to 1072 English general practitioners (GPs). Using a series of linear models with GP fixed effects, we estimate the importance of different sources of pressure for GPs' prescribing. RESULTS: We find that the percentage of broad-spectrum antibiotics prescribed increases by 6.4% as pressure increases on English GPs. The link between pressure and prescribing holds for different sources of pressure. CONCLUSIONS: Our findings suggest that there may be societal costs of physicians working under pressure. Policy makers need to take these costs into account when evaluating existing policies as well as when introducing new policies affecting physicians' work pressure. An important avenue for further research is also to determine the underlying mechanisms related to the different sources of pressure.JEL-code: I11, J28, J45. HIGHLIGHTS: Many physicians are working under increasing pressure.We test the importance of pressure on physicians' prescribing of antibiotics.The prescribed rate of broad-spectrum antibiotics increases with pressure.Policy makers should be aware of the societal costs of pressured physicians.[Formula: see text].

C/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer.

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network.