Risk of adverse events in patients prescribed long‐term opioids: a cohort study in the UK Clinical Practice Research Datalink

Background Long‐term opioid prescribing for musculoskeletal pain is controversial due to uncertainty regarding effectiveness and safety. This study examined the risks of a range of adverse events in a large cohort of patients prescribed long‐term opioids using the UK Clinical Practice Research Datalink. Methods Patients with musculoskeletal conditions starting a new long‐term opioid episode (defined as ≥3 opioid prescriptions within 90 days) between 2002 and 2012 were included. Primary outcomes: major trauma and intentional overdose (any). Secondary outcomes: addiction (any), falls, accidental poisoning, attempted suicide/self‐harm, gastrointestinal pathology and bleeding, and iron deficiency anaemia. “Control” outcomes (unrelated to opioid use): incident eczema and psoriasis. Results A total of 98,140 new long‐term opioids users (median age 61, 41% male) were followed for (median) 3.4 years. Major trauma risk increased from 285 per 10,000 person‐years without long‐term opioids to 369/10,000 for a long‐term opioid episode (<20 mg MED), 382/10,000 (20–50 mg MED), and 424/10,000 (≥50 mg MED). Adjusted hazard ratios were 1.09 (95% CI; 1.04, 1.14 for <20 mg MED vs. not being in an episode of long‐term prescribing), 1.24 (95% CI; 1.16, 1.32: 20–50 mg MED) and 1.34 (95% CI; 1.20, 1.50: ≥50 mg MED). Significant dose‐dependent increases in the risk of overdose (any type), addiction, falls, accidental poisoning, gastrointestinal pathology, and iron deficiency anaemia were also found. Conclusions Patients prescribed long‐term opioids are vulnerable to dose‐dependent serious adverse events. Opioid prescribing should be reviewed before long‐term use becomes established, and periodically thereafter to ensure that patients are not being exposed to increased risk of harm, which is not balanced by therapeutic benefit. Significance Long‐term opioid use is associated with serious adverse events such as major trauma, addiction and overdose. The risk increases with higher opioid doses. Opioid prescribing should be reviewed before long‐term use becomes established, and periodically thereafter to assess ongoing effectiveness

Electron-phonon renormalization of the absorption edge of the cuprous halides

Compared to most tetrahedral semiconductors, the temperature dependence of the absorption edges of the cuprous halides (CuCl, CuBr, CuI) is very small. CuCl and CuBr show a small increase of the gap $E_0$ with increasing temperature, with a change in the slope of $E_0$ vs. $T$ at around 150 K: above this temperature, the variation of $E_0$ with $T$ becomes even smaller. This unusual behavior has been clarified for CuCl by measurements of the low temperature gap vs. the isotopic masses of both constituents, yielding an anomalous negative shift with increasing copper mass. Here we report the isotope effects of Cu and Br on the gap of CuBr, and that of Cu on the gap of CuI. The measured isotope effects allow us to understand the corresponding temperature dependences, which we also report, to our knowledge for the first time, in the case of CuI. These results enable us to develop a more quantitative understanding of the phenomena mentioned for the three halides, and to interpret other anomalies reported for the temperature dependence of the absorption gap in copper and silver chalcogenides; similarities to the behavior observed for the copper chalcopyrites are also pointed out.Comment: 14 pages, 5 figures, submitted to Phys. Rev.

Industrial relations in European hypermarkets: Home and host country influences

YesIn this article we examine the industrial relations practices of three large European food retailers when they transfer the hypermarket format to other countries. We ask, first, how industrial relations in hypermarkets differ from those in other food retailing outlets. Second, we examine how far the approach characteristic of each company’s country-of-origin (Germany, France and the UK) shapes the practices adopted elsewhere. Third, we ask how they respond to the specific industrial relations systems of each host country (Turkey, Poland, Ireland and Spain)

Australian women's use of complementary and alternative medicines to enhance fertility: exploring the experiences of women and practitioners

<p>Abstract</p> <p>Background</p> <p>Studies exploring the use of complementary and alternative medicine (CAM) to enhance fertility are limited. While Australian trends indicate that women are using CAM during pregnancy, little is known about women's use of CAM for fertility enhancement. With the rising age of women at first birth, couples are increasingly seeking assisted reproductive technologies (ART) to achieve parenthood. It is likely that CAM use for fertility enhancement will also increase, however this is not known. This paper reports on an exploratory study of women's use of CAM for fertility enhancement.</p> <p>Methods</p> <p>Three focus groups were conducted in Melbourne, Australia in 2007; two with women who used CAM to enhance their fertility and one with CAM practitioners. Participants were recruited from five metropolitan Melbourne CAM practices that specialise in women's health. Women were asked to discuss their views and experiences of both CAM and ART, and practitioners were asked about their perceptions of why women consult them for fertility enhancement. Groups were digitally recorded (audio) and transcribed verbatim. The data were analysed thematically.</p> <p>Results</p> <p>Focus groups included eight CAM practitioners and seven women. Practitioners reported increasing numbers of women consulting them for fertility enhancement whilst also using ART. Women combined CAM with ART to maintain wellbeing and assist with fertility enhancement. Global themes emerging from the women's focus groups were: women being willing to 'try anything' to achieve a pregnancy; women's negative experiences of ART and a reluctance to inform their medical specialist of their CAM use; and conversely, women's experiences with CAM being affirming and empowering.</p> <p>Conclusions</p> <p>The women in our study used CAM to optimise their chances of achieving a pregnancy. Emerging themes suggest the positive relationships achieved with CAM practitioners are not always attained with orthodox medical providers. Women's views and experiences need to be considered in the provision of fertility services, and strategies developed to enhance communication between women, medical practitioners and CAM practitioners. Further research is needed to investigate the extent of CAM use for fertility enhancement in Australia, and to explore the efficacy and safety of CAM use to enhance fertility, in isolation or with ART.</p

Patients visiting the complementary medicine clinic for pain: a cross sectional study

<p>Abstract</p> <p>Background</p> <p>Pain is one of the most common reasons for seeking medical care. The purpose of this study was to characterize patients visiting the complementary medicine clinic for a pain complaint.</p> <p>Methods</p> <p>This is a cross-sectional study. The study took place at Clalit Health Services (CHS) complementary clinic in Beer-Sheva, Israel. Patients visiting the complementary clinic, aged 18 years old and older, Hebrew speakers, with a main complaint of pain were included. Patients were recruited consecutively on random days of the month during a period of six months. Main outcome measures were: pain levels, location of pain, and interference with daily activities. Once informed consent was signed patients were interviewed using a structured questionnaire by a qualified nurse. The questionnaire included socio-demographic data, and the Brief Pain Inventory (BPI).</p> <p>Results</p> <p>Three-hundred and ninety-five patients were seen at the complementary medicine clinic during the study period, 201 (50.8%) of them met the inclusion criteria. Of them, 163 (81.1%) agreed to participate in the study and were interviewed. Pain complaints included: 69 patients (46.6%) with back pain, 65 (43.9%) knee pain, and 28 (32.4%) other limbs pain. Eighty-two patients (50.3%) treated their pain with complementary medicine as a supplement for their conventional treatment, and 55 (33.7%) felt disappointed from the conventional medicine experience. Eighty-three patients (50.9%) claimed that complementary medicine can result in better physical strength, or better mental state 51 (31.3%). Thirty-seven patients (22.7%) were hoping that complementary medicine will prevent invasive procedures.</p> <p>Conclusion</p> <p>Given the high proportion of patients with unsatisfactory pain relief using complementary and alternative medicine (CAM), general practitioners should gain knowledge about CAM and CAM providers should gain training in pain topics to improve communication and counsel patients. More clinical research to evaluate safety and efficiency of CAM for pain is needed to provide evidence based counseling.</p

eXtraembryonic ENdoderm (XEN) Stem Cells Produce Factors that Activate Heart Formation

Initial specification of cardiomyocytes in the mouse results from interactions between the extraembryonic anterior visceral endoderm (AVE) and the nascent mesoderm. However the mechanism by which AVE activates cardiogenesis is not well understood, and the identity of specific cardiogenic factors in the endoderm remains elusive. Most mammalian studies of the cardiogenic potential of the endoderm have relied on the use of cell lines that are similar to the heart-inducing AVE. These include the embryonal-carcinoma-derived cell lines, END2 and PYS2. The recent development of protocols to isolate eXtraembryonic ENdoderm (XEN) stem cells, representing the extraembryonic endoderm lineage, from blastocyst stage mouse embryos offers new tools for the genetic dissection of cardiogenesis.Here, we demonstrate that XEN cell-conditioned media (CM) enhances cardiogenesis during Embryoid Body (EB) differentiation of mouse embryonic stem (ES) cells in a manner comparable to PYS2-CM and END2-CM. Addition of CM from each of these three cell lines enhanced the percentage of EBs that formed beating areas, but ultimately, only XEN-CM and PYS2-CM increased the total number of cardiomyocytes that formed. Furthermore, our observations revealed that both contact-independent and contact-dependent factors are required to mediate the full cardiogenic potential of the endoderm. Finally, we used gene array comparison to identify factors in these cell lines that could mediate their cardiogenic potential.These studies represent the first step in the use of XEN cells as a molecular genetic tool to study cardiomyocyte differentiation. Not only are XEN cells functionally similar to the heart-inducing AVE, but also can be used for the genetic dissection of the cardiogenic potential of AVE, since they can be isolated from both wild type and mutant blastocysts. These studies further demonstrate the importance of both contact-dependent and contact-independent factors in cardiogenesis and identify potential heart-inducing proteins in the endoderm

Management of primary chronic headache in the general population: the Akershus study of chronic headache

Primary chronic headaches cause more disability and necessitate high utilisation of health care. Our knowledge is based on selected populations, while information from the general population is largely lacking. An age and gender-stratified cross-sectional epidemiological survey included 30,000 persons aged 30–44 years. Respondents with self-reported chronic headache were interviewed by physicians. The International Classification of Headache Disorders was used. Of all primary chronic headache sufferers, 80% had consulted their general practitioner (GP), of these 19% had also consulted a neurologist and 4% had been hospitalised. Co-occurrence of migraine increased the probability of contact with a physician. A high Severity of Dependence Scale score increased the probability for contact with a physician. Complementary and alternative medicine (CAM) was used by 62%, most often physiotherapy, acupuncture and chiropractic. Contact with a physician increased the probability of use of CAM. Acute headache medications were taken by 87%, while only 3% used prophylactic medication. GPs manage the majority of those with primary chronic headache, 1/5 never consults a physician for their headache, while approximately 1/5 is referred to a neurologist or hospitalised. Acute headache medication was frequently overused, while prophylactic medication was rarely used. Thus, avoidance of acute headache medication overuse and increased use of prophylactic medication may improve the management of primary chronic headaches in the future

Health service utilization patterns of primary care patients with osteoarthritis

Contains fulltext : 53455.pdf ( ) (Open Access)BACKGROUND: To assess factors associated with visits to GPs, orthopaedists, and non-physician practitioners of complementary medicine (alternative practitioners) by primary care patients with osteoarthritis (OA). METHODS: Cross-sectional survey among 1250 consecutively addressed patients from 75 primary care practices in Germany. All patients suffered from OA of the knee or hip according to ACR criteria. They received questionnaires collecting sociodemographic data, data about health service utilisation, prescriptions, comorbidities. They also included established instruments as the Arthritis Impact Measurement Scale (AIMS2-SF) to assess disease-specific quality of life and the Patient Health Questionnaire (PHQ-9) to assess depression. Hierarchical stepwise multiple linear regression models were used to reveal significant factors influencing health service utilization. RESULTS: 1021 of 1250 (81.6%) questionnaires were returned. Nonrespondents did not differ from participants. Factors associated with health service use (HSU) varied between providers of care. Not being in a partnership, achieving a high score on the PHQ-9, increased pain severity reflected in the "symptom" scale of the AIMS2-SF, and an increased number of drug prescriptions predicted a high frequency of GP visits. The PHQ-9 score was also a predictor for visits to orthopaedists, as were previous GP contacts, a high score in the "symptom" scale as well as a high score in the "lower limb scale" of the AIMS2-SF. Regarding visits to alternative practitioners, a high score in the AIMS -"social" scale was a positive predictor as older people were less likely to visit them. CONCLUSION: Our results emphasize the need for awareness of psychological factors contributing to the use of health care providers. Addressing the revealed factors associated with HSU appropriately may lead to decreased health care utilization. But further research is needed to assess how this can be done successfully

MLH1 mediates PARP-dependent cell death in response to the methylating agent N-methyl-N-nitrosourea

Background:Methylating agents such as N-methyl-N-nitrosourea (MNU) can cause cell cycle arrest and death either via caspase-dependent apoptosis or via a poly(ADP-ribose) polymerase (PARP)-dependent form of apoptosis. We wished to investigate the possible role of MLH1 in signalling cell death through PARP.Methods:Fibroblasts are particularly dependent on a PARP-mediated cell death response to methylating agents. We used hTERT-immortalised normal human fibroblasts (WT) to generate isogenic MLH1-depleted cells, confirmed by quantitative PCR and western blotting. Drug resistance was measured by clonogenic and cell viability assays and effects on the cell cycle by cell sorting. Damage signalling was additionally investigated using immunostaining.Results:MLH1-depleted cells were more resistant to MNU, as expected. Despite having an intact G2/M checkpoint, the WT cells did not initially undergo cell cycle arrest but instead triggered cell death directly by PARP overactivation and nuclear translocation of apoptosis-inducing factor (AIF). The MLH1-depleted cells showed defects in this pathway, with decreased staining for phosphorylated H2AX, altered PARP activity and reduced AIF translocation. Inhibitors of PARP, but not of caspases, blocked AIF translocation and greatly decreased short-term cell death in both WT and MLH1-depleted cells. This MLH1-dependent response to MNU was not blocked by inhibitors of ATM/ATR or p53.Conclusion:These novel data indicate an important role for MLH1 in signalling PARP-dependent cell death in response to the methylating agent MNU

Identification of Inappropriately Reprogrammed Genes by Large-Scale Transcriptome Analysis of Individual Cloned Mouse Blastocysts

Although cloned embryos generated by somatic/embryonic stem cell nuclear transfer (SECNT) certainly give rise to viable individuals, they can often undergo embryonic arrest at any stage of embryogenesis, leading to diverse morphological abnormalities. In an effort to gain further insights into reprogramming and the properties of SECNT embryos, we performed a large-scale gene expression profiling of 87 single blastocysts using GeneChip microarrays. Sertoli cells, cumulus cells, and embryonic stem cells were used as donor cells. The gene expression profiles of 87 blastocysts were subjected to microarray analysis. Using principal component analysis and hierarchical clustering, the gene expression profiles were clearly classified into 3 clusters corresponding to the type of donor cell. The results revealed that each type of SECNT embryo had a unique gene expression profile that was strictly dependent upon the type of donor cells, although there was considerable variation among the individual profiles within each group. This suggests that the reprogramming process is distinct for embryos cloned from different types of donor cells. Furthermore, on the basis of the results of comparison analysis, we identified 35 genes that were inappropriately reprogrammed in most of the SECNT embryos; our findings demonstrated that some of these genes, such as Asz1, Xlr3a and App, were appropriately reprogrammed only in the embryos with a transcriptional profile that was the closest to that of the controls. Our findings provide a framework to further understand the reprogramming in SECNT embryos