Mental disorder prevalence in chronic pain patients using opioid versus non-opioid analgesics: A registry-linkage study

Background Chronic pain and mental disorders are leading causes of disability worldwide. Individuals with chronic pain are more likely to experience mental disorders compared to individuals without chronic pain, but large-scale estimates are lacking. We aimed to calculate overall prevalence of mental health diagnoses from primary and secondary care among individuals treated for chronic pain in 2019 and to compare prevalence among chronic pain patients receiving opioid versus non-opioid analgesics, according to age and gender. Methods It is a population-based cohort study. Linked data from nationwide health registers on dispensed drugs and diagnoses from primary (ICPC-2) and secondary (ICD-10) health care. Chronic pain patients were identified as all patients over 18 years of age filling at least one prescription of an analgesic reimbursed for non-malignant chronic pain in both 2018 and 2019 (N = 139,434, 69.3% women). Results Prevalence of any mental health diagnosis was 35.6% (95% confidence interval: 35.4%–35.9%) when sleep diagnoses were included and 29.0% (28.8%–29.3%) when excluded. The most prevalent diagnostic categories were sleep disorders (14% [13.8%–14.2%]), depressive and related disorders (10.1% [9.9%–10.2%]) and phobia and other anxiety disorders (5.7% [5.5%–5.8%]). Prevalence of most diagnostic categories was higher in the group using opioids compared to non-opioids. The group with the highest overall prevalence was young women (18–44 years) using opioids (50.1% [47.2%–53.0%]). Conclusions Mental health diagnoses are common in chronic pain patients receiving analgesics, particularly among young individuals and opioid users. The combination of opioid use and high psychiatric comorbidity suggests that prescribers should attend to mental health in addition to somatic pain. Significance This large-scale study with nation-wide registry data supports previous findings of high psychiatric burden in chronic pain patients. Opioid users had significantly higher prevalence of mental health diagnoses, regardless of age and gender compared to users of non-opioid analgesics. Opioid users with chronic pain therefore stand out as a particularly vulnerable group and should be followed up closely by their physician to ensure they receive sufficient care for both their mental and somatic symptoms.Mental disorder prevalence in chronic pain patients using opioid versus non-opioid analgesics: A registry-linkage studyacceptedVersionpublishedVersio

A Reduction in Ribonucleotide Reductase Activity Slows Down the Chromosome Replication Fork but Does Not Change Its Localization

BACKGROUND:It has been proposed that the enzymes of nucleotide biosynthesis may be compartmentalized or concentrated in a structure affecting the organization of newly replicated DNA. Here we have investigated the effect of changes in ribonucleotide reductase (RNR) activity on chromosome replication and organization of replication forks in Escherichia coli. METHODOLOGY/PRINCIPAL FINDINGS:Reduced concentrations of deoxyribonucleotides (dNTPs) obtained by reducing the activity of wild type RNR by treatment with hydroxyurea or by mutation, resulted in a lengthening of the replication period. The replication fork speed was found to be gradually reduced proportionately to moderate reductions in nucleotide availability. Cells with highly extended C periods showed a "delay" in cell division i.e. had a higher cell mass. Visualization of SeqA structures by immunofluorescence indicated no change in organization of the new DNA upon moderate limitation of RNR activity. Severe nucleotide limitation led to replication fork stalling and reversal. Well defined SeqA structures were not found in situations of extensive replication fork repair. In cells with stalled forks obtained by UV irradiation, considerable DNA compaction was observed, possibly indicating a reorganization of the DNA into a "repair structure" during the initial phase of the SOS response. CONCLUSION/SIGNIFICANCE:The results indicate that the replication fork is slowed down in a controlled manner during moderate nucleotide depletion and that a change in the activity of RNR does not lead to a change in the organization of newly replicated DNA. Control of cell division but not control of initiation was affected by the changes in replication elongation

An Easy-To-Use Simulation Program Demonstrates Variations in Bacterial Cell Cycle Parameters Depending on Medium and Temperature

Many studies are performed on chromosome replication and segregation in Escherichia coli and other bacteria capable of complex replication with C phases spanning several generations. For such investigations an understanding of the replication patterns, including copy numbers of origins and replication forks, is crucial for correct interpretation of the results

The Stringent Response and Cell Cycle Arrest in Escherichia coli

The bacterial stringent response, triggered by nutritional deprivation, causes an accumulation of the signaling nucleotides pppGpp and ppGpp. We characterize the replication arrest that occurs during the stringent response in Escherichia coli. Wild type cells undergo a RelA-dependent arrest after treatment with serine hydroxamate to contain an integer number of chromosomes and a replication origin-to-terminus ratio of 1. The growth rate prior to starvation determines the number of chromosomes upon arrest. Nucleoids of these cells are decondensed; in the absence of the ability to synthesize ppGpp, nucleoids become highly condensed, similar to that seen after treatment with the translational inhibitor chloramphenicol. After induction of the stringent response, while regions corresponding to the origins of replication segregate, the termini remain colocalized in wild-type cells. In contrast, cells arrested by rifampicin and cephalexin do not show colocalized termini, suggesting that the stringent response arrests chromosome segregation at a specific point. Release from starvation causes rapid nucleoid reorganization, chromosome segregation, and resumption of replication. Arrest of replication and inhibition of colony formation by ppGpp accumulation is relieved in seqA and dam mutants, although other aspects of the stringent response appear to be intact. We propose that DNA methylation and SeqA binding to non-origin loci is necessary to enforce a full stringent arrest, affecting both initiation of replication and chromosome segregation. This is the first indication that bacterial chromosome segregation, whose mechanism is not understood, is a step that may be regulated in response to environmental conditions

Prescription opioids among older adults: ten years of data across five countries

ABSTRACT: BACKGROUND: Opioid use has increased globally in the recent decade. Although pain remains a significant problem among older adults, susceptibility to opioid-related harms highlights the importance of careful opioid therapy monitoring on individual and societal levels. We aimed to describe the trends of prescription opioid utilisation among residents aged ≥65 in all Nordic countries during 2009–2018. METHODS: We conducted cross-sectional measurements of opioid utilisation in 2009–2018 from nationwide registers of dispensed drugs in Denmark, Finland, Iceland, Norway, and Sweden. The measures included annual opioid prevalence, defined daily doses (DDDs) per 1000 inhabitants per day (DIDs), and morphine milligram equivalents (MMEs) per user per day. RESULTS: From 2009 to 2018, an average of 808,584 of adults aged ≥65 used opioids yearly in all five countries; an average annual prevalence of 17.0%. During this time period, the prevalence decreased in Denmark, Norway, and Sweden due to declining codeine and/or tramadol use. Iceland had the highest opioid prevalence in 2009 (30.2%), increasing to 31.7% in 2018. In the same period, DIDs decreased in all five countries, and ranged from 28.3 in Finland to 58.5 in Denmark in 2009, and from 23.0 in Finland to 54.6 in Iceland in 2018. MMEs/user/day ranged from 4.4 in Iceland to 19.6 in Denmark in 2009, and from 4.6 in Iceland to 18.8 in Denmark in 2018. In Finland, Norway, and Sweden, MMEs/user/day increased from 2009 to 2018, mainly due to increasing oxycodone utilisation. CONCLUSIONS: The stable or decreasing opioid utilisation prevalence among a majority of older adults across the Nordic countries coincides with an increase in treatment intensity in 2009–2018. We found large cross-national differences despite similarities across the countries’ cultures and healthcare systems. For the aged population, national efforts should be placed on improving pain management and monitoring future trends of especially oxycodone utilisation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-022-03125-0

RecA-Dependent Replication in the nrdA101(Ts) Mutant of Escherichia coli under Restrictive Conditions▿

Cells carrying the thermosensitive nrdA101 allele are able to replicate entire chromosomes at 42°C when new DNA initiation events are inhibited. We investigated the role of the recombination enzymes on the progression of the DNA replication forks in the nrdA101 mutant at 42°C in the presence of rifampin. Using pulsed-field gel electrophoresis (PFGE), we demonstrated that the replication forks stalled and reversed during the replication progression under this restrictive condition. DNA labeling and flow cytometry experiments supported this finding as the deleterious effects found in the RecB-deficient background were suppressed specifically by the absence of RuvABC; however, this did not occur in a RecG-deficient background. Furthermore, we show that the RecA protein is absolutely required for DNA replication in the nrdA101 mutant at restrictive temperature when the replication forks are reversed. The detrimental effect of the recA deletion is not related to the chromosomal degradation caused by the absence of RecA. The inhibition of DNA replication observed in the nrdA101 recA mutant at 42°C in the presence of rifampin was reverted by the presence of the wild-type RecA protein expressed ectopically but only partially suppressed by the RecA protein with an S25P mutation [RecA(S25P)], deficient in the rescue of the stalled replication forks. We propose that RecA is required to maintain the integrity of the reversed forks in the nrdA101 mutant under certain restrictive conditions, supporting the relationship between DNA replication and recombination enzymes through the stabilization and repair of the stalled replication forks