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Effective communication skills are essential for optimally managing chronic pain and opioids. This exploratory, sequential mixed methods study tested the effect of a novel framework designed to improve pain-related communication and outcomes.Study 1 developed a novel 5-step framework for helping primary care clinicians discuss chronic pain and opioids with patients. Study 2 pilot tested an intervention for teaching this framework using standardized patient instructors-actors trained to portray patients and provide immediate clinician feedback-deployed during regular clinic hours. Primary care physicians were randomized to receive either the intervention or pain management recommendations from the Centers for Disease Control and Prevention. Primary outcomes were pain-related interference at 2 months and clinician use of targeted communication skills (coded from transcripts of audio-recorded visits); secondary outcomes were pain intensity at 2 months, clinician self-efficacy for communicating about chronic pain, patient experience, and clinician-reported visit difficulty.We enrolled 47 primary care physicians from 2 academic teaching clinics and recorded visits with 48 patients taking opioids for chronic pain who had an appointment scheduled with an enrolled physician. The intervention was not associated with significant changes in primary or secondary outcomes other than clinician self-efficacy, which was significantly greater in the intervention group.This study developed a novel framework and intervention for teaching clinician pain-related communications skills. Although the intervention showed promise, more intensive or multicomponent interventions may be needed to have a significant impact on clinicians' pain-related communication and pain outcomes.

Background: we aimed to develop a machine learning algorithm to predict the presence of a culprit lesion in patients with out-of-hospital cardiac arrest (OHCA). Methods: we used the King's Out-of-Hospital Cardiac Arrest Registry, a retrospective cohort of 398 patients admitted to King's College Hospital between May 2012 and December 2017. The primary outcome was the presence of a culprit coronary artery lesion, for which a gradient boosting model was optimized to predict. The algorithm was then validated in two independent European cohorts comprising 568 patients. Results: a culprit lesion was observed in 209/309 (67.4%) patients receiving early coronary angiography in the development, and 199/293 (67.9%) in the Ljubljana and 102/132 (61.1%) in the Bristol validation cohorts, respectively. The algorithm, which is presented as a web application, incorporates nine variables including age, a localizing feature on electrocardiogram (ECG) (≥2 mm of ST change in contiguous leads), regional wall motion abnormality, history of vascular disease and initial shockable rhythm. This model had an area under the curve (AUC) of 0.89 in the development and 0.83/0.81 in the validation cohorts with good calibration and outperforms the current gold standard-ECG alone (AUC: 0.69/0.67/0/67). Conclusions: a novel simple machine learning-derived algorithm can be applied to patients with OHCA, to predict a culprit coronary artery disease lesion with high accuracy.

Long-term opioid therapy (LTOT) is associated with increased risk for depression. It is not known if the frequency of opioid use during LTOT is associated with new onset depression. We used Optum's de-identified Integrated Claims-Clinical dataset (2010-2018) to create a cohort of 5,146 patients, 18 - 80 years of age with an encounter or claims in the year before new LTOT. New LTOT was defined by > 90 day opioid use after remaining 6-months opioid free. Opioid use frequency during the first 90 days of LTOT was categorized into occasional use (< 50% days covered), intermittent use (50% to < 80% days covered), frequent use (80% to < 90% days covered) and daily use (≥ 90% days covered). Propensity scores and inverse probability of exposure weighting controlled for confounding in models estimating risk for new onset depression. Patients were on average, 54.5 (SD±13.6) years of age, 55.7% were female, 72.5% were white and 9.5% were African-American. After controlling for confounding, daily users (HR=1.40; 95%CI:1.14-1.73) and frequent users (HR=1.34; 95%CI:1.05-1.71) were significantly more likely to develop new onset depression compared to occasional users. This association remained after accounting for the contribution of post-index pain diagnoses and opioid use disorder. In LTOT, risk for new depression episodes is up to 40% greater in near daily users compared to occasional users. Patients could reduce depression risk by avoiding opioid use on as many low pain days as possible. Repeated screening for depression during LTOT is warranted.

The Right to Pain Relief and Other Deep Roots of the Opioid Epidemic aims to reach beneath popular narratives that blame profit-seeking pharmaceutical companies and healthcare practitioners for opioid overprescribing and the resulting epidemic of opioid addiction, overdose, and death. This book argues that the opioid epidemic arises from serious misunderstandings of both opioids and pain. Based on opioid use for acute pain, clinicians believed that opioids were specific “painkillers” that relieved pain but left the person alone. Recent research has shown that opioids have diverse functions within the human brain to modulate many forms of stress and support emotional function and socialization. We have also misunderstood the role of pain in human life. Over the past millennium, Western society has shifted from considering pain a religious problem, then a social problem, and now a medical problem. Innovations in the care of patients at the end of life led us to consider pain control to be an important medical responsibility independent of disease control, and to consider opioids to be safe and effective. Even though we understand chronic pain as a biopsychosocial condition, we have built mechanical causal models of chronic pain that support a moral model of pain as a form of passive and innocent suffering for which it is appropriate to claim a right to pain relief. To end our current opioid epidemic and prevent future epidemics, we need to reintegrate pain with the rest of human suffering as a necessary part of a full human life.

Upper tract urothelial carcinoma (UTUC), although rarer than urothelial carcinoma of the bladder, is more aggressive with 60% of patients presenting with invasive disease. Bilateral synchronous UTUC is scarcer still, with much literature quoting a 2% lifetime risk of recurrence in the contralateral upper tract. This case aims to discuss and reinforce the key evidence supporting current guidance and management algorithm in managing a patient with UTUC and examines the role of renal autotransplantation in the patient with bilateral UTUC; a principal that could also apply to invasive UTUC in a solitary kidney.

Schizophrenia is associated with an elevated risk for impulsive aggression for which there are few psychosocial treatment options. Neurocognitive and social cognitive deficits have been associated with aggression with social cognitive deficits seemingly a more proximal contributor. The current study examined the effects of combining cognitive and social cognition treatment on impulsive aggression among inpatients with chronic schizophrenia and schizoaffective disorder and a history of aggression compared to cognitive remediation treatment alone.The two-center study randomized 130 participants to receive 36 sessions of either a combination of cognitive remediation and social cognition treatment or cognitive remediation plus a computer-based control. Participants had at least one aggressive incident within the past year or a Life History of Aggression (LHA) score of 5 or more. Participants completed measures of neurocognition, social cognition, symptom severity, and aggression at baseline and endpoint.Study participants were mostly male (84.5 %), had a mean age 34.9 years, and 11.5 years of education. Both Cognitive Remediation Training (CRT) plus Social Cognition Training (SCT) and CRT plus control groups were associated with significant reductions in aggression measures with no group differences except on a block of the Taylor Aggression Paradigm (TAP), a behavioral task of aggression which favored the CRT plus SCT group. Both groups showed significant improvements in neurocognition and social cognition measures with CRT plus SCT being associated with greater improvements.CRT proved to be an effective non-pharmacological treatment in reducing impulsive aggression in schizophrenia inpatient participants with a history of aggressive episodes. The addition of social cognitive training did not enhance this anti-aggression treatment effect but did augment the CRT effect on cognitive functions, on emotion recognition and on mentalizing capacity of our participants.

OBJECTIVES The claim of a right to pain relief was made in recent decades by pain professionals, courts, and patient advocacy groups and likely contributed to increased opioid prescribing, overdose deaths, and addictions, but the origins and nature of this right have not been investigated. MATERIALS AND METHODS Relevant clinical, ethical, and legal literature concerning patient rights to pain care was reviewed. RESULTS The record describes the effort to improve end-of-life and cancer pain care in the 1980s and 1990s, which simultaneously legitimated pain relief as an independent goal of medical care and opioids as a safe and effective means to achieve this relief. In 1997, the US Supreme Court denied the right to assisted suicide but affirmed a right to palliative care to prevent dying in overwhelming pain. Other guidelines and regulations extended this right to pain relief from end-of-life care to chronic pain care, along with the titrate-to-effect principle, which specified that the correct opioid dose was the dose that relieved pain. DISCUSSION The most important consequence of combining the right to pain relief with the titrate-to-effect principle was the idea that a high pain score must not be ignored. This extension of the right to pain relief neglected important differences between end-of-life care and chronic pain care including: time frame, clinical setting and context, target of titration, and nature of iatrogenic harms. To help end our current opioid epidemic and prevent a future epidemic, we need to demedicalize pain and reintegrate it with the rest of human suffering as an experience connected to other personal behaviors and meanings.

In preparation for photometric classification of transients from the Legacy Survey of Space and Time (LSST) we run tests with different training data sets. Using estimates of the depth to which the 4-metre Multi-Object Spectroscopic Telescope (4MOST) Time Domain Extragalactic Survey (TiDES) can classify transients, we simulate a magnitude-limited sample reaching $r_{\textrm{AB}} \approx$ 22.5 mag. We run our simulations with the software snmachine, a photometric classification pipeline using machine learning. The machine-learning algorithms struggle to classify supernovae when the training sample is magnitude-limited, in contrast to representative training samples. Classification performance noticeably improves when we combine the magnitude-limited training sample with a simulated realistic sample of faint, high-redshift supernovae observed from larger spectroscopic facilities; the algorithms' range of average area under ROC curve (AUC) scores over 10 runs increases from 0.547-0.628 to 0.946-0.969 and purity of the classified sample reaches 95 per cent in all runs for 2 of the 4 algorithms. By creating new, artificial light curves using the augmentation software avocado, we achieve a purity in our classified sample of 95 per cent in all 10 runs performed for all machine-learning algorithms considered. We also reach a highest average AUC score of 0.986 with the artificial neural network algorithm. Having `true' faint supernovae to complement our magnitude-limited sample is a crucial requirement in optimisation of a 4MOST spectroscopic sample. However, our results are a proof of concept that augmentation is also necessary to achieve the best classification results., MNRAS accepted version Aug 2021

4MOST is a new high-multiplex, wide-field spectroscopic survey facility under construction for ESO's 4m-VISTA telescope at Paranal, Chile. Its key specifications are: a large field of view of 4.4 square degrees, a high multiplex fibre positioner based on the tilting spine principle that positions 2436 science fibres in the focal surface of which 1624 fibres go to two low-resolution optical spectrographs (R = lambda/Delta lambda similar to 6500) and 812 fibres transfer light to the high-resolution optical spectrograph (R similar to 20,000). Currently, almost all subsystems are completed and full testing in Europe will be finished in spring 2023, after which 4MOST will be shipped to Chile. An overview is given of instrument construction and capabilities, the planned science of the consortium and the recently selected community programmes, and the unique operational scheme of 4MOST.

The management trend of low-risk kidney cancer over the last decade has been from treatment with radical nephrectomy, to use of nephron sparing procedures of partial nephrectomy and ablation, as well as the option of active surveillance (AS). This narrative review aims to summarise the available guidelines related to AS and review the published descriptions of regional practices on the management of low-risk kidney cancer worldwide. A search of PubMed, Google Scholar and Cochrane Library databases for studies published 2010 to June 2020 identified 15 studies, performed between 2000 and 2019, which investigated 13 different cohorts of low-risk kidney cancer patients on AS. Although international guidelines show a level of agreement in their recommendation on how AS is conducted, in terms of patient selection, surveillance strategy and triggers for intervention, cohort studies show distinct differences in worldwide practice of AS. Prospective studies showed general agreement in their predefined selection criteria for entry into AS. Retrospective studies showed that patients who were older, with greater comorbidities, worse performance status and smaller tumours were more likely to be managed with AS. The rate of percutaneous renal mass biopsy varied between studies from 2% to 56%. The surveillance protocol was different across all studies in terms of recommended modality and frequency of imaging. Of the 6 studies which had set indications for intervention, these were broadly in agreement. Despite clear criteria for intervention, patient or surgeon preference was still the reason in 11–71% of cases of delayed intervention across 5 studies. This review shows that AS is being applied in a variety of centres worldwide and that key areas of patient selection criteria and surveillance strategy have large similarities. However, the rate of renal mass biopsy and of delayed intervention varies significantly between studies, suggesting the process of diagnosing malignant SRM and decision making whilst on AS are varying in practice. Further research is needed on the diagnosis and characterisation of incidentally found small renal masses (SRM), using imaging and histology, and the natural history of these SRM in order to develop evidence-based active surveillance protocols.

Despite a common assumption that reductions in chronic pain intensity must precede improvements in other pain-relevant domains, there has been limited empirical inquiry into the temporal ordering of improvements in chronic pain treatment. Cross-lagged models using retrospective clinical data examined relationships between average pain intensity and symptoms of psychological distress, difficulties with sleep initiation and maintenance, and disability in 666 treatment-seeking patients with chronic pain who demonstrated improvement in pain intensity (≥1-point reduction on 0-10 numeric rating scale) over a 1-year span. Results indicated that decreased difficulties with sleep initiation, depressive and anxious symptoms, and disability predicted later improvement in pain intensity, whereas greater pain intensity predicted only later difficulties in sleep initiation and maintenance. A combined lagged model highlighted fewer baseline symptoms of post-traumatic stress disorder and lower levels of baseline disability as significant predictors of later improvements in pain. Overall, our results indicate that reductions in pain intensity may not be the first factors to change in effective chronic pain management. The current findings should be replicated using prospective studies utilizing structured approaches to maximize data capture, as well as uniform interventional approaches to permit greater inferences regarding causal and temporal aspects of the model. Perspective This study demonstrates that pain intensity scores are not robust predictors of psychosocial outcomes longitudinally. Instead, other factors such as sleep initiation, psychological distress and disability appear to be important targets for intervention that may promote effective pain reduction.

ObjectiveTo identify factors that influence or interfere with referrals by primary care providers (PCPs) to a pharmacist-led telephone-based program to assist patients undergoing opioid tapering. The Support Team Onsite Resource for Management of Pain (STORM) program provides individualized patient care and supports PCPs in managing opioid tapers.DesignQualitative interviews were conducted with referring PCPs and STORM staff. Interview guides addressed concepts from the RE-AIM framework, focusing on issues affecting referral to the STORM program.SettingAn integrated healthcare system (HCS) in the Northwest United States.SubjectsThirty-five interviews were conducted with 20 PCPs and 15 STORM staff.MethodsConstant comparative analysis was used to identify key themes from interviews. A codebook was developed based on interview data and a qualitative software program was used for coding, iterative review, and content analysis. Representative quotes illustrate identified themes.ResultsUse of the STORM opioid tapering program was influenced by PCP, patient, and HCS considerations. Factors motivating use of STORM included lack of PCP time to support chronic pain patients requiring opioid tapering and the perception that STORM is a valued partner in patient care. Impediments to referral included PCP confidence in managing opioid tapering, patient resistance to tapering, forgetting about program availability, and PCP resistance to evolving guidelines regarding opioid tapering goals.ConclusionsPCPs recognized that STORM supported patient safety and reduced clinician burden. Utilization of the program could be improved through ongoing PCP education about the service and consistent co-location of STORM pharmacists within primary care clinics.

The multitude of treatments available for tens of millions of US adults with moderate/severe chronic pain have limited efficacy. Long-term opioid therapy (LTOT) is a widely available option for controlling pain among patients with chronic pain refractory to other treatments. The recent recognition of LTOT inefficacy and complications has led to more frequent opioid tapering, which in turn has revealed its own set of complications. The occurrence of the same set of symptoms—worsening pain, declining function, and clinical instability—in contrasting contexts of LTOT ineffectiveness and opioid tapering has led to increasing recognition of the utility of complex persistent opioid dependence (CPOD), a clinically distinct but biologically similar state compared with opioid use disorder as an explanatory diagnosis/heuristic. Recent guidelines for LTOT tapering have incorporated buprenorphine treatment based on CPOD concepts as a recommended treatment for problems due to opioid tapering with limited supportive evidence. The increasing utilization of buprenorphine for both LTOT ineffectiveness and opioid tapering problems raises the urgent need for a review of the clinical definition, mechanisms, and treatment of CPOD and pertinent policies. In this manuscript, we discuss various issues related to CPOD that requires further clarification through research and policy development.

Long-term opioid therapy has the potential for serious adverse outcomes and is often used in a vulnerable population. Because adverse effects or failure to maintain benefits is common with long-term use, opioid taper or discontinuation may be indicated in certain patients. Concerns about the adverse individual and population effects of opioids have led to numerous strategies aimed at reductions in prescribing. Although opioid reduction efforts have had generally beneficial effects, there have been unintended consequences. Abrupt reduction or discontinuation has been associated with harms that include serious withdrawal symptoms, psychological distress, self-medicating with illicit substances, uncontrolled pain, and suicide. Key questions remain about when and how to safely reduce or discontinue opioids in different patient populations. Thus, health care professionals who reduce or discontinue long-term opioid therapy require a clear understanding of the associated benefits and risks as well as guidance on the best practices for safe and effective opioid reduction. An interdisciplinary panel of pain clinicians and one patient advocate formulated recommendations on tapering methods and ongoing pain management in primary care with emphasis on patient-centered, integrated, comprehensive treatment models employing a biopsychosocial perspective.

Purpose: The purpose of this article is to present the first reported case of a renal tumour classified as tuberous sclerosis complex-associated renal cell carcinoma in the UK and discuss its clinical implications. Case report: A female, aged 65 years, with tuberous sclerosis complex was found on surveillance imaging to have interval growth of multiple right renal tumours up to 19 mm. Right partial nephrectomy was performed. Histology showed multiple tiny angiomyolipomas and a 20 mm tumour classified as tuberous sclerosis complex-associated renal cell carcinoma. These tumour cells showed abundant clear cytoplasm with a branched elongated arrangement encircled in dense smooth muscle stroma. Literature review: Renal cell carcinoma in patients with tuberous sclerosis complex is rare, occurring in approximately 4% of cases. Tuberous sclerosis complex-associated renal cell carcinoma is a relatively new histological entity, having previously been described as clear cell or chromophobe-like, with only one published case series from the USA. These tumours have three histological entities which are distinct from all other renal cell carcinoma classifications. Based on case series, tuberous sclerosis complex-associated renal cell carcinoma tends to occur more often in females, present at a younger age, have multiple tumours, and tend to show an indolent course, although metastases have been reported. Learning points: Patients with tuberous sclerosis complex can develop renal cell carcinoma, though the risk is thought to be no higher than for sporadic renal cell carcinoma. Given the limited literature, more evidence is required to help predict the future behaviour of these tumours. Level of evidence: 5

BackgroundThere are significant medical risks of long-term opioid therapy (LTOT) for chronic pain. Consequently, there is a need to identify effective interventions for the reduction of high-dose full-agonist opioid medication use.MethodsThe current study details a retrospective review of 240 patients with chronic pain and LTOT presenting for treatment at a specialty opioid refill clinic. Patients first were initiated on an outpatient taper or, if taper was not tolerated, transitioned to buprenorphine. This study analyzes potential predictors of successful tapering, successful buprenorphine transition, or failure to complete either intervention and the effects of this clinical approach on pain intensity scores.ResultsOne hundred seven patients (44.6%) successfully tapered their opioid medications under the Centers for Disease Control and Prevention guideline target dose (90 mg morphine-equianalgesic dosage), 45 patients (18.8%) were successfully transitioned to buprenorphine, and 88 patients (36.6%) dropped out of treatment: 11 patients during taper, eight during buprenorphine transition, and 69 before initiating either treatment. Conclusions. Higher initial doses of opioids predicted a higher likelihood of requiring buprenorphine transition, and a co-occurring benzodiazepine or z-drug prescription predicted a greater likelihood of dropout from both interventions. Patterns of change in pain intensity according to treatment were mixed: among successfully tapered patients, 52.8% reported greater pain and 23.6% reported reduced pain, whereas 41.8% reported increased pain intensity and 48.8% reported decreased pain after buprenorphine transition. Further research is needed on predictors of treatment retention and dropout, as well as factors that may mitigate elevated pain scores after reduction of opioid dosing.

GMagAO-X is the near first light ExAO coronagraphic instrument for the 25.4m GMT. It is designed for a slot on the folded port of the GMT. To meet the strict ExAO fitting and servo error requirement (2KHz correction speeds. To minimize wavefront/segment piston error GMagAO-X has an interferometric beam combiner on a vibration isolated table, as part of this "21,000 actuator parallel DM". Piston errors are sensed by a Holographic Dispersed Fringe Sensor (HDFS). In addition to a coronagraph, it has a post-coronagraphic Lyot Low Order WFS (LLOWFS) to sense non-common path (NCP) errors. The LLOWFS drives a non-common path DM (NCP DM) to correct those NCP errors. GMagAO-X obtains high-contrast science and wavefront sensing in the visible and/or the NIR. Here we present our successful externally reviewed (Sept. 2021) CoDR optical-mechanical design that satisfies GMagAO-X's top-level science requirements and is compliant with the GMT instrument requirements and only requires COTS parts., 15 pages, 20 figures, Proc SPIE 12185 "Adaptive Optics Systems", "Telescopes and Instrumentation", July 2022, Montreal, Canada

Funder: AstraZeneca (GB), Background: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). Methods: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0���1, cM0���1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ��� 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ���30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. Discussion: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. Trial registration: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018���003056-21.