Climate negotiators’ and scientists’ assessments of the climate negotiations

Climate negotiation outcomes are difficult to evaluate objectively because there are no clear reference scenarios. Subjective assessments from those directly involved in the negotiations are particularly important, as this may influence strategy and future negotiation participation. Here we analyze the perceived success of the climate negotiations in a sample of more than 600 experts involved in international climate policy. Respondents were pessimistic when asked for specific assessments of the current approach centered on voluntary pledges, but were more optimistic when asked for general assessments of the outcomes and usefulness of the climate negotiations. Individuals who are more involved in the negotiation process tended to be more optimistic, especially in terms of general assessments. Our results indicate that two reinforcing effects are at work: a high degree of involvement changes individuals’ perceptions and more optimistic individuals are more inclined to remain involved in the negotiations

Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer

Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy-induced ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2-GPRC5A co-regulation, thereby facilitating a signaling shift to the canonical tumor-suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum-resistant EphA2(high), GPRC5A(high) cells to the therapy-induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo-resistant cells to RSK1/2-EphA2-pS897 pathway inhibition.Peer reviewe

Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains

Polyubiquitin (pUb) chains formed between the C terminus of ubiquitin and lysine 63 (K63) or methionine 1 (M1) of another ubiquitin have been implicated in the activation of the canonical IκB kinase (IKK) complex. Here, we demonstrate that nearly all of the M1-pUb chains formed in response to interleukin-1, or the Toll-Like Receptors 1/2 agonist Pam(3)CSK(4), are covalently attached to K63-pUb chains either directly as K63-pUb/M1-pUb hybrids or indirectly by attachment to the same protein. Interleukin-1 receptor (IL-1R)-associated kinase (IRAK) 1 is modified first by K63-pUb chains to which M1-pUb linkages are added subsequently, and myeloid differentiation primary response gene 88 (MyD88) and IRAK4 are also modified by both K63-pUb and M1-pUb chains. We show that the heme-oxidized IRP2 ubiquitin ligase 1 interacting protein (HOIP) component of the linear ubiquitin assembly complex catalyzes the formation of M1-pUb chains in response to interleukin-1, that the formation of K63-pUb chains is a prerequisite for the formation of M1-pUb chains, and that HOIP interacts with K63-pUb but not M1-pUb linkages. These findings identify K63-Ub oligomers as a major substrate of HOIP in cells where the MyD88-dependent signaling network is activated. The TGF-beta–activated kinase 1 (TAK1)-binding protein (TAB) 2 and TAB3 components of the TAK1 complex and the NFκB Essential Modifier (NEMO) component of the canonical IKK complex bind to K63-pUb chains and M1-pUb chains, respectively. The formation of K63/M1-pUb hybrids may therefore provide an elegant mechanism for colocalizing both complexes to the same pUb chain, facilitating the TAK1-catalyzed activation of IKKα and IKKβ. Our study may help to resolve the debate about the relative importance of K63-pUb and M1-pUb chains in activating the canonical IKK complex

Variation in plasma calcium analysis in primary care in Sweden - a multilevel analysis

<p>Abstract</p> <p>Background</p> <p>Primary hyperparathyroidism (pHPT) is a common disease that often remains undetected and causes severe disturbance especially in postmenopausal women. Therefore, national recommendations promoting early pHPT detection by plasma calcium (P-Ca) have been issued in Sweden. In this study we aimed to investigate variation of P-Ca analysis between physicians and health care centres (HCCs) in primary care in county of Skaraborg, Sweden.</p> <p>Methods</p> <p>In this cross sectional study of patients' records during 2005 we analysed records from 154 629 patients attending 457 physicians at 24 HCCs. We used multilevel logistic regression analysis (MLRA) and adjusted for patient, physician and HCC characteristics. Differences were expressed as median odds ratio (MOR).</p> <p>Results</p> <p>There was a substantial variation in number of P-Ca analyses between both HCCs (MOR_HCC1.65 [1.44-2.07]) and physicians (MOR_physician1.95 [1.85-2.08]). The odds for a P-Ca analysis were lower for male patients (OR 0.80 [0.77-0.83]) and increased with the number of diagnoses (OR 25.8 [23.5-28.5]). Sex of the physician had no influence on P-Ca test ordering (OR 0.93 [0.78-1.09]). Physicians under education ordered most P-Ca analyses (OR 1.69 [1.35-2.24]) and locum least (OR 0.73 [0.57-0.94]). More of the variance was attributed to the physician level than the HCC level. Different mix of patients did not explain this variance between physicians. Theoretically, if a patient were able to change both GP and HCC, the odds of a P-Ca analysis would in median increase by 2.45. Including characteristics of the patients, physicians and HCCs in the MLRA model did not explain the variance.</p> <p>Conclusions</p> <p>The physician level was more important than the HCC level for the variation in P-Ca analysis, but further exploration of unidentified contextual factors is crucial for future monitoring of practice variation.</p

Coding of procedures documented by general practitioners in Swedish primary care-an explorative study using two procedure coding systems

<p>Abstract</p> <p>Background</p> <p>Procedures documented by general practitioners in primary care have not been studied in relation to procedure coding systems. We aimed to describe procedures documented by Swedish general practitioners in electronic patient records and to compare them to the Swedish Classification of Health Interventions (KVÅ) and SNOMED CT.</p> <p>Methods</p> <p>Procedures in 200 record entries were identified, coded, assessed in relation to two procedure coding systems and analysed.</p> <p>Results</p> <p>417 procedures found in the 200 electronic patient record entries were coded with 36 different Classification of Health Interventions categories and 148 different SNOMED CT concepts. 22.8% of the procedures could not be coded with any Classification of Health Interventions category and 4.3% could not be coded with any SNOMED CT concept. 206 procedure-concept/category pairs were assessed as a complete match in SNOMED CT compared to 10 in the Classification of Health Interventions.</p> <p>Conclusions</p> <p>Procedures documented by general practitioners were present in nearly all electronic patient record entries. Almost all procedures could be coded using SNOMED CT.</p> <p>Classification of Health Interventions covered the procedures to a lesser extent and with a much lower degree of concordance. SNOMED CT is a more flexible terminology system that can be used for different purposes for procedure coding in primary care.</p

Comparison of outcomes following a cytological or histological diagnosis of malignant mesothelioma

Background: Survival with the epithelioid subtype of malignant mesothelioma (MM) is longer than the biphasic or sarcomatoid subtypes. There is concern that cytology-diagnosed epithelioid MM may underdiagnose the biphasic subtype. This study examines survival differences between patients with epithelioid MM diagnosed by cytology only and other subtypes diagnosed by histology. Methods: Demographics, diagnosis method, MM subtype and survival were extracted from the Western Australia (WA) Mesothelioma Registry, which records details of all MM cases occurring in WA. Results: A total of 2024 MM cases were identified over 42 years. One thousand seven hundred forty-four (86.2%) were male, median (IQR) age was 68.6 (60.4–77.0) years. A total of 1212 (59.9%) cases were identified as epithelioid subtype of which 499 (41.2%) were diagnosed using fluid cytology only. Those with a cytology-only diagnosis were older than the histology group (median 70.2 vs 67.6 years, P<0.001), but median survival was similar (cytology 10.6 (5.5–19.2) vs histology 11.1 (4.8–19.8) months, P=0.727) and Cox regression modelling adjusting for age, sex, site and time since first exposure showed no difference in survival between the different diagnostic approaches. Conclusions: Survival of cytologically and histologically diagnosed epithelioid MM cases does not differ. A diagnostic tap should be considered adequate to diagnose epithelioid MM without need for further invasive testing

Human papillomavirus ‘reflex' testing as a screening method in cases of minor cytological abnormalities

The aim was to evaluate human papillomavirus (HPV) ‘reflex genotyping' in cases of minor cytological abnormalities detected in the gynaecological screening programme in Stockholm, Sweden. Liquid-based cytology samples showing minor cytological abnormalities were analysed using HPV genotyping (Linear Array, Roche diagnostics). Colposcopically directed cervical biopsies were obtained and the HPV test results were correlated with the histological results. In all, 63% (70/112) of the samples were high-risk (HR) HPV (HR-HPV) positive. A statistically significant correlation was found between high-grade cervical lesions and HR-HPV (P=0.019), among which HPV 16, 18, and 31 were the most important. The negative predictive value of HR-HPV detection for histologically confirmed high-grade lesions was 100%. An age limit for HPV reflex testing may be motivated in cases of low-grade squamous intraepithelial neoplasia (LSIL), because of high HR-HPV prevalence among younger women. By using HPV reflex genotyping, additional extensive workup can safely be avoided in about 50% of all cases of atypical squamous cells of undetermined significance (ASCUS) and LSIL among women ⩾30 years. This screening strategy could potentially reduce the total abnormal cytology-reporting rate in the Swedish screening programme by about 1% and provide more accurately directed follow-up, guided by cytological appearance and HPV test results

Understanding the effects of a decentralized budget on physicians' compliance with guidelines for statin prescription – a multilevel methodological approach

<p>Abstract</p> <p>Background</p> <p>Official guidelines that promote evidence-based and cost-effective prescribing are of main relevance for obvious reasons. However, to what extent these guidelines are followed and their conditioning factors at different levels of the health care system are still insufficiently known.</p> <p>In January 2004, a decentralized drug budget was implemented in the county of Scania, Sweden. Focusing on lipid-lowering drugs (i.e., statins), we evaluated the effect of this intervention across a 25-month period. We expected that increased local economic responsibility would promote prescribing of recommended statins.</p> <p>Methods</p> <p>We performed two separate multilevel regression analyses; on 110 827 individual prescriptions issued at 136 <it>publicly</it>-administered health care centres (HCCs) nested within 14 administrative areas (HCAs), and on 72 012 individual prescriptions issued by 115 <it>privately</it>-administered HCCs. Temporal trends in the prevalence of prescription of recommended statins were investigated by random slope analysis. Differences (i.e., variance) between HCCs and between HCAs were expressed by median odds ratio (MOR).</p> <p>Results</p> <p>After the implementation of the decentralized drug budget, adherence to guidelines increased continuously. At the end of the observation period, however, practice variation remained high. Prescription of recommended statins presented a high degree of clustering within both publicly (i.e., MOR_HCC= 2.18 and MOR_HCA= 1.31 respectively) and privately administered facilities (MOR_HCC= 3.47).</p> <p>Conclusion</p> <p>A decentralized drug budget seems to promote adherence to guidelines for statin prescription. However, the high practice differences at the end of the observation period may reflect inefficient therapeutic traditions, and indicates that rational statin prescription could be further improved.</p