Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

CDC7 kinase regulates DNA replication fork processing and its inhibition is modulated by PTBP1

CDC7 is an essential serine/threonine kinase that regulates the initiation of DNA replication by phosphorylating several sites of the MCM helicase complex. Several inhibitors of CDC7 are available that reduce cell proliferation by limiting DNA replication initiation. As these inhibitors are in development as anti-cancer therapeutics, it is crucial to identify the additional roles of CDC7 and understand cellular response to CDC7 inhibitors. Novel evidence has implicated CDC7 in the cellular response to replication stress. Replication stress can be caused by a variety of endogenous and exogenous insults that impair replication progression. It is characterised by fork slowing and arrest. One type of DNA intermediate that can form in response to replication stress is a reversed fork. This four-branched structure results from strand exchange reactions in which the nascent strands anneal and the parental strands re-anneal. Replication fork reversal maintains replication integrity and allows time for the stress or obstacle to be overcome before replication can restart. Prolonged fork stalling or incorrect processing can lead to fork collapse and genome instability, a hallmark of cancer. Using chemical inhibitors of CDC7 we have demonstrated that CDC7 activity is required for replication fork processing and a robust signalling response upon replication stress. Using biochemical approaches we find that CDC7 localises to replication forks and, along with MRE11, is retained at stalled forks in a manner dependent on CDC7 activity. We also find that MRE11 is phosphorylated in response to replication stress, and this is attenuated upon CDC7 inhibition. Importantly, we find that CDC7 promotes MRE11 dependent fork degradation in BRCA2 deficient cells. Therefore identifying CDC7 as a key modulator of replication initiation and elongation. To identify the genes that control the cellular response to CDC7 inhibition, a loss of function genome wide screen was performed in our laboratory. It has identified PTBP1 as a gene that restrains proliferation when CDC7 is inhibited. PTBP1 has roles in mRNA metabolism. It canonically functions to regulate exon usage, but also influences mRNA stability, translation and post transcriptional modifications. We use CRISPR/Cas9 technology to create a PTBP1 null cell line and a heterozygous mutant cell line. Using these cell lines we demonstrate that loss or partial depletion of PTBP1 allows cells to proliferate and have efficient DNA synthesis under conditions of limited CDC7 activity. Using RNA-seq analysis we show that loss of PTBP1 results in a drastic change in the transcriptome and a differential response to CDC7 inhibition. Interestingly, we show that PTBP1 mutated cells have attenuated checkpoint response to CDC7 inhibition and DNA alkylating agents, suggesting that PTBP1 is important for modulating the checkpoint response. These results show that expression levels of PTBP1 is a key determinant of cell sensitivity to CDC7 inhibitors.2026-09-2

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage

The CDC7 kinase is essential for the activation of DNA replication origins and has been implicated in the replication stress response. Using a highly specific chemical inhibitor and a chemical genetic approach, we now show that CDC7 activity is required to coordinate multiple MRE11-dependent processes occurring at replication forks, independently from its role in origin firing. CDC7 localizes at replication forks and, similarly to MRE11, mediates active slowing of fork progression upon mild topoisomerase inhibition. Both proteins are also retained on stalled forks, where they promote fork processing and restart. Moreover, MRE11 phosphorylation and localization at replication factories are progressively lost upon CDC7 inhibition. Finally, CDC7 activity at reversed forks is required for their pathological MRE11-dependent degradation in BRCA2-deficient cells. Thus, upon replication interference CDC7 is a key regulator of fork progression, processing and integrity. These results highlight a dual role for CDC7 in replication, modulating both initiation and elongation steps of DNA synthesis, and identify a key intervention point for anticancer therapies exploiting replication interference

Breast cancer questionnaire

Values for health state for each participant according to either standard gamble or visual analogue scale (VAS

Data from: Quantifying patient preferences for symptomatic breast clinic referral: a decision analysis study

Objectives: Decision analysis study that incorporates patient preferences and probability estimates to investigate the impact of women’s preferences for referral or an alternative strategy of watchful waiting if faced with symptoms that could be due to breast cancer. Setting: Community-based study. Participants: Asymptomatic women aged 30-60 years. Interventions: Participants were presented with 11 health scenarios that represent the possible consequences of symptomatic breast problems. Participants were asked the risk of death that they were willing to take in order to avoid the health scenario using the standard gamble (SG) utility method. This process was repeated for all 11 health scenarios. Formal decision analysis for the preferred individual decision was then estimated for each participant. Primary outcome measure: The preferred diagnostic strategy, either watchful waiting or referral to a breast clinic. Sensitivity analysis was used to examine how each varied according to changes in the probabilities of the health scenarios. Results: A total of 35 participants completed the interviews, with median age 41 years (Interquartile range 35 to 47 years). The majority of the study sample were employed (n=32, 91.4%), with a third-level (university) education (n=32, 91.4%) and with knowledge of someone with breast cancer (n=30, 85.7%). When individual preferences were accounted for, 25 (71.4%) patients preferred watchful waiting to referral for triple assessment as their preferred initial diagnostic strategy. Sensitivity analysis shows that referral for triple assessment becomes the dominant strategy at the upper probability estimate (18%) of breast cancer in the community. Conclusions: Watchful waiting is an acceptable strategy for most women who present to their GP with breast symptoms. These findings suggest that current referral guidelines should take more explicit account of women’s preferences in relation in terms of the initial diagnostic strategy for symptomatic breast problems

Quantifying patient preferences for symptomatic breast clinic referral: a decision analysis study

Objectives Decision analysis study that incorporates patient preferences and probability estimates to investigate the impact of women’s preferences for referral or an alternative strategy of watchful waiting if faced with symptoms that could be due to breast cancer. Setting Community-based study. Participants Asymptomatic women aged 30–60 years. Interventions Participants were presented with 11 health scenarios that represent the possible consequences of symptomatic breast problems. Participants were asked the risk of death that they were willing to take in order to avoid the health scenario using the standard gamble utility method. This process was repeated for all 11 health scenarios. Formal decision analysis for the preferred individual decision was then estimated for each participant. Primary outcome measure The preferred diagnostic strategy was either watchful waiting or referral to a breast clinic. Sensitivity analysis was used to examine how each varied according to changes in the probabilities of the health scenarios. Results A total of 35 participants completed the interviews, with a median age 41 years (IQR 35–47 years). The majority of the study sample was employed (n=32, 91.4%), with a third-level (university) education (n=32, 91.4%) and with knowledge of someone with breast cancer (n=30, 85.7%). When individual preferences were accounted for, 25 (71.4%) patients preferred watchful waiting to referral for triple assessment as their preferred initial diagnostic strategy. Sensitivity analysis shows that referral for triple assessment becomes the dominant strategy at the upper probability estimate (18%) of breast cancer in the community. Conclusions Watchful waiting is an acceptable strategy for most women who present to their general practitioner (GP) with breast symptoms. These findings suggest that current referral guidelines should take more explicit account of women’s preferences in relation to their GPs initial management strategy