Mutation rates and adaptive variation among the clinically dominant clusters of Mycobacterium abscessus.

Mycobacterium abscessus (Mab) is a multidrug-resistant pathogen increasingly responsible for severe pulmonary infections. Analysis of whole-genome sequences (WGS) of Mab demonstrates dense genetic clustering of clinical isolates collected from disparate geographic locations. This has been interpreted as supporting patient-to-patient transmission, but epidemiological studies have contradicted this interpretation. Here, we present evidence for a slowing of the Mab molecular clock rate coincident with the emergence of phylogenetic clusters. We performed phylogenetic inference using publicly available WGS from 483 Mab patient isolates. We implement a subsampling approach in combination with coalescent analysis to estimate the molecular clock rate along the long internal branches of the tree, indicating a faster long-term molecular clock rate compared to branches within phylogenetic clusters. We used ancestry simulation to predict the effects of clock rate variation on phylogenetic clustering and found that the degree of clustering in the observed phylogeny is more easily explained by a clock rate slowdown than by transmission. We also find that phylogenetic clusters are enriched in mutations affecting DNA repair machinery and report that clustered isolates have lower spontaneous mutation rates in vitro. We propose that Mab adaptation to the host environment through variation in DNA repair genes affects the organism's mutation rate and that this manifests as phylogenetic clustering. These results challenge the model that phylogenetic clustering in Mab is explained by person-to-person transmission and inform our understanding of transmission inference in emerging, facultative pathogens.

Molecularly imprinted nanogels as synthetic recognition materials for the ultrasensitive detection of periodontal disease biomarkers.

Periodontal disease affects supporting dental structures and ranks among one of the top most expensive conditions to treat in the world. Moreover, in recent years, the disease has also been linked to cardiovascular and Alzheimer's diseases. At present, there is a serious lack of accurate diagnostic tools to identify people at severe risk of periodontal disease progression. Porphyromonas gingivalis is often considered one of the most contributing factors towards disease progression. It produces the Arg- and Lys-specific proteases Rgp and Kgp, respectively. Within this work, a short epitope sequence of these proteases is immobilised onto a magnetic nanoparticle platform. These are then used as a template to produce high-affinity, selective molecularly imprinted nanogels, using the common monomers N-tert-butylacrylamide (TBAM), N-isopropyl acrylamide (NIPAM), and N-(3-aminopropyl) methacrylamide hydrochloride (APMA). N,N-Methylene bis(acrylamide) (BIS) was used as a crosslinking monomer to form the interconnected polymeric network. The produced nanogels were immobilised onto a planar gold surface and characterised using the optical technique of surface plasmon resonance. They showed high selectivity and affinity towards their template, with affinity constants of 79.4 and 89.7 nM for the Rgp and Kgp epitope nanogels, respectively. From their calibration curves, the theoretical limit of detection was determined to be 1.27 nM for the Rgp nanogels and 2.00 nM for the Kgp nanogels. Furthermore, they also showed excellent selectivity against bacterial culture supernatants E8 (Rgp knockout), K1A (Kgp knockout), and W50-d (wild-type) strains in complex medium of brain heart infusion (BHI).

An ecological approach for skill development and performance in soccer goalkeeper training: Empirical evidence and coaching applications.

Ecological approaches in sport consider that athletes adapt to properties of the task and the surrounding environment. Thus, task and environment are key constraints of performance. Yet, the influence of task and environmental constraints on athletes' performance needs empirical examination, especially in sport-specific contexts such as soccer goalkeeping. This study aimed to examine if and how task and environmental constraints influenced goalkeepers (GKs') performances. We monitored performance coefficients of two professional female GKs across 13 training tasks that varied based on 9 constraints, referring to both interactions among athletes and properties of the surrounding landscape. Results showed that constraints explain ~ 47% of the observed variability in GKs' performances. Numerical complexity (i.e., the potential interactions between athletes) showed a major influence on performance, which indicates that number of interactions among athletes may constrain GKs' perceived opportunities for action. Field dimensions and landscape representativity (including elements such as penalty area(s), target goal(s) and constraints for shooting) showed positive relationships with performance, supporting that training designs retaining closer proximity to the game may benefit GKs' performances. Overall, results supported that athlete-environment couplings could be understood as a multifactorial model and hence, a combination of task constraints are necessary for designing effective learning environments.

A Preliminary Study of Stress, Mental Health, and Pain Related to the COVID-19 Pandemic and Odds of Persistent Prescription Opioid Use.

BACKGROUND: The COVID-19 pandemic has been associated with increased opioid prescribing. It is not known if perceived COVID-19 related stress is associated with increased odds of long-term opioid use. OBJECTIVE: To determine if greater COVID-19-related stress and worsening pain attributed to the pandemic was associated with LTOT over a 6-month observation period. DESIGN: Longitudinal cohort. PARTICIPANTS: Patients (n=477) from two midwestern health care systems, with any acute or chronic non-cancer pain, starting a new period of 30-90-day prescription opioid use, were invited to participate in the Prescription Opioids and Depression Pathways Cohort Study, a longitudinal survey study of pain, opioid use, and mental health outcomes. MAIN MEASURES: Baseline and 6-month follow-up assessments were used to measure the association between perceived COVID-19 stressors, the perception that pain was made worse by the pandemic and the odds of persistent opioid use, i.e., remaining a prescription opioid user at 6-month follow-up. Multivariate models controlled for demographics, opioid dose, and change in pain characteristics, mental health measures, and social support. KEY RESULTS: Participants were, on average, 53.9 (±11.4) years of age, 67.1% White race, and 70.9% female. The most frequently endorsed COVID-19 stressor was "worry about health of self/others" (85.7% endorsed) and the least endorsed was "worsened pain due to pandemic" (26.2%). After adjusting for all covariates, "worsened pain due to pandemic" (OR=2.88; 95%CI: 1.33-6.22), change in pain interference (OR=1.20; 95%CI: 1.04-1.38), and change in vital exhaustion (OR=0.90; 95%CI: 0.82-0.99) remained significantly associated with persistent opioid use. CONCLUSIONS: Patients who attribute worsening pain to the COVID-19 pandemic are more likely to be persistent opioid users. Further research is warranted to identify mechanisms underlying this association. Clinicians may consider discussing pain in the context of the pandemic to identify patients at high risk for persistent opioid use.

A machine learning algorithm to predict a culprit lesion after out of hospital cardiac arrest.

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.

Diagnosis, treatment, and survival from kidney cancer: real-world National Health Service England data between 2013 and 2019.

OBJECTIVES: To report the NHS Digital (NHSD) data for patients diagnosed with kidney cancer (KC) in England. We explore the incidence, route to diagnosis (RTD), treatment, and survival patterns from 2013 to 2019. MATERIALS AND METHODS: Data was extracted from the Cancer Data NHSD portal for International Classification of Diseases, 10th edition coded KC; this included Cancer Registry data, Hospital Episode Statistics, and cancer waiting times data. RESULTS: Registrations included 66 696 individuals with KC. Incidence of new KC diagnoses increased (8998 in 2013, to 10 232 in 2019), but the age-standardised rates were stable (18.7-19.4/100 000 population). Almost half of patients (30 340 [45.5%]) were aged 0-70 years and the cohort were most frequently diagnosed with Stage 1-2 KC (n = 26 297 [39.4%]). Most patients were diagnosed through non-urgent general practitioner referrals (n = 16 814 [30.4%]), followed by 2-week-wait (n = 15 472 [28.0%]) and emergency routes (n = 11 796 [21.3%]), with older patients (aged ≥70 years), Stage 4 KCs, and patients with non-specified renal cell carcinoma being significantly more likely to present through the emergency route (all P < 0.001). Invasive treatment (surgery or ablation), radiotherapy, or systemic anti-cancer therapy use varied with disease stage, patient factors, and treatment network (Cancer Alliance). Survival outcomes differed by Stage, histological subtype, and social deprivation class (P < 0.001). Age-standardised mortality rates did not change over the study duration, although immunotherapy usage is likely not captured in this study timeline. CONCLUSION: The NHSD resource provides useful insight about the incidence, diagnostic pathways, treatment, and survival of patients with KC in England and a useful benchmark for the upcoming commissioned National Kidney Cancer Audit. The RTD data may be limited by incidental diagnoses, which could confound the high proportion of 'emergency' diagnoses. Importantly, survival outcomes remained relatively unchanged.

Energetic eruptions leading to a peculiar hydrogen-rich explosion of a massive star.

Every supernova so far observed has been considered to be the terminal explosion of a star. Moreover, all supernovae with absorption lines in their spectra show those lines decreasing in velocity over time, as the ejecta expand and thin, revealing slower-moving material that was previously hidden. In addition, every supernova that exhibits the absorption lines of hydrogen has one main light-curve peak, or a plateau in luminosity, lasting approximately 100 days before declining. Here we report observations of iPTF14hls, an event that has spectra identical to a hydrogen-rich core-collapse supernova, but characteristics that differ extensively from those of known supernovae. The light curve has at least five peaks and remains bright for more than 600 days; the absorption lines show little to no decrease in velocity; and the radius of the line-forming region is more than an order of magnitude bigger than the radius of the photosphere derived from the continuum emission. These characteristics are consistent with a shell of several tens of solar masses ejected by the progenitor star at supernova-level energies a few hundred days before a terminal explosion. Another possible eruption was recorded at the same position in 1954. Multiple energetic pre-supernova eruptions are expected to occur in stars of 95 to 130 solar masses, which experience the pulsational pair instability. That model, however, does not account for the continued presence of hydrogen, or the energetics observed here. Another mechanism for the violent ejection of mass in massive stars may be required.

There is no copy and paste, but there is resonation and inhabitation: Integrating a contemporary player development framework in football from a complexity sciences perspective.

Socio-cultural constraints shape behaviour in complexifying ways. In sport, for example, interconnected constraints play an important role in shaping the way a game is played, coached, and spectated. Here, we contend that player development frameworks in sport cannot be operationalised without careful consideration of the complex ecosystem in which they reside. Concurrently, we highlight issues associated with frameworks designed in isolation from the contexts in which they are introduced for integration, guised as trying to "copy and paste" templates from country to country. As such, there is a need to understand the oft-shrouded socio-cultural dynamics that continuously influence practice in order to maximize the utility of player development frameworks in sport. Ecological dynamics offers a complexity-oriented theoretical lens that supports the evolution of context-dependent player development frameworks. Further, tenets of the Learning in Development Research Framework can show how affordances are not just material invitations but constitute a vital component of a broader socio-cultural form of life. These ideas have the potential to: (1) push against a desire to "copy and paste" what is perceived to be "successful" elsewhere, and (2), guide the integration of player development frameworks by learning to resonate with the nuanced complexities of the broader environment inhabited.

"I really had somebody in my corner." Patient experiences with a pharmacist-led opioid tapering program.

BACKGROUND: Opioid tapering has been identified as an effective strategy to prevent the dangers associated with long-term opioid therapy for patients with chronic pain. However, many patients are resistant to tapering, and conversations about tapering can be challenging for health care providers. Pharmacists can play a role in supporting both providers and patients with the process of opioid tapering. OBJECTIVE: Qualitatively describe patient experiences with a unique phone-based and pharmacy-led opioid tapering program implemented within an integrated health care system. METHODS: In-depth telephone interviews with patients who completed the program were recorded, transcribed, and analyzed. Themes were identified through a constant comparative approach. RESULTS: We completed 25 interviews; 80% of patients were women (20), with a mean age of 58 years, and 72% (18) had been using opioids for pain management for 10 or more years. Most (60%) described a positive and satisfying experience with the tapering program. Strengths of the program reported by patients included a patient-centered and compassionate taper approach, flexible taper pace, easy access to knowledgeable pharmacist advocates, and resultant improvements in quality of life (e.g., increased energy). Challenges reported included: unhelpful or difficult-to-access nonpharmacological pain management options, negative quality of life impacts (e.g., inability to exercise), and lack of choice in the taper process. At the end of tapering, most patients (72%) described their pain as reduced or manageable rather than worse and expressed willingness to use the program in the future if a need should arise. CONCLUSIONS: Patients in a pharmacist-led opioid tapering program appreciated the program's individualized approach to care and access to pharmacist' expertise. Most interviewed patients successfully reduced their opioid use and recommended that the program should continue as an offered service. To improve the program, patients suggested increased personalization of the taper process and additional support for withdrawal symptoms and nonpharmacological pain management.

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth.

The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap-/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis. Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improves Yap deficiency phenotypes, indicating functional importance of glucose-fueled nucleotide biosynthesis. Yap-regulated glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signaling in glucose metabolic homeostasis.

Development of High-Risk Geriatric Polypharmacy Electronic Clinical Quality Measures and a Pilot Test of EHR Nudges Based on These Measures.

BACKGROUND: Inappropriate polypharmacy, prevalent among older patients, is associated with substantial harms. OBJECTIVE: To develop measures of high-risk polypharmacy and pilot test novel electronic health record (EHR)-based nudges grounded in behavioral science to promote deprescribing. DESIGN: We developed and validated seven measures, then conducted a three-arm pilot from February to May 2019. PARTICIPANTS: Validation used data from 78,880 patients from a single large health system. Six physicians were pre-pilot test environment users. Sixty-nine physicians participated in the pilot. MAIN MEASURES: Rate of high-risk polypharmacy among patients aged 65 years or older. High-risk polypharmacy was defined as being prescribed ≥5 medications and satisfying ≥1 of the following high-risk criteria: drugs that increase fall risk among patients with fall history; drug-drug interactions that increase fall risk; thiazolidinedione, NSAID, or non-dihydropyridine calcium channel blocker in heart failure; and glyburide, glimepiride, or NSAID in chronic kidney disease. INTERVENTIONS: Physicians received EHR alerts when renewing or prescribing certain high-risk medications when criteria were met. One practice received a "commitment nudge" that offered a chance to commit to addressing high-risk polypharmacy at the next visit. One practice received a "justification nudge" that asked for a reason when high-risk polypharmacy was present. One practice received both. KEY RESULTS: Among 55,107 patients 65 and older prescribed 5 or more medications, 6256 (7.9%) had one or more high-risk criteria. During the pilot, the mean (SD) number of nudges per physician per week was 1.7 (0.4) for commitment, 0.8 (0.5) for justification, and 1.9 (0.5) for both interventions. Physicians requested to be reminded to address high-risk polypharmacy for 236/833 (28.3%) of the commitment nudges and acknowledged 441 of 460 (95.9%) of justification nudges, providing a text response for 187 (40.7%). CONCLUSIONS: EHR-based measures and nudges addressing high-risk polypharmacy were feasible to develop and implement, and warrant further testing.

A molecularly imprinted polymer nanoparticle-based surface plasmon resonance sensor platform for antibiotic detection in river water and milk.

Using a solid-phase molecular imprinting technique, high-affinity nanoparticles (nanoMIPs) selective for the target antibiotics, ciprofloxacin, moxifloxacin, and ofloxacin have been synthesised. These have been applied in the development of a surface plasmon resonance (SPR) sensor for the detection of the three antibiotics in both river water and milk. The particles produced demonstrated good uniformity with approximate sizes of 65.8 ± 1.8 nm, 76.3 ± 4.1 nm, and 85.7 ± 2.5 nm, and were demonstrated to have affinities of 36.2 nM, 54.7 nM, and 34.6 nM for the ciprofloxacin, moxifloxacin, and ofloxacin nanoMIPs, respectively. Cross-reactivity studies highlighted good selectivity towards the target antibiotic compared with a non-target antibiotic. Using spiked milk and river water samples, the nanoMIP-based SPR sensor offered comparable affinity with 66.8 nM, 33.4 nM, and 55.0 nM (milk) and 39.3 nM, 26.1 nM, and 42.7 nM (river water) for ciprofloxacin, moxifloxacin, and ofloxacin nanoMIPs, respectively, to that seen within a buffer standard. Estimated LODs for the three antibiotic targets in both milk and river water were low nM or below. The developed SPR sensor showed good potential for using the technology for the capture and detection of antibiotics from food and environmental samples.

Depression and Long-Term Prescription Opioid Use and Opioid Use Disorder: Implications for Pain Management in Cancer.

OPINION STATEMENT: Preventing depression in cancer patients on long-term opioid therapy should begin with depression screening before opioid initiation and repeated screening during treatment. In weighing the high morbidity of depression and opioid use disorder in patients with chronic cancer pain against a dearth of evidence-based therapies studied in this population, patients and clinicians are left to choose among imperfect but necessary treatment options. When possible, we advise engaging psychiatric and pain/palliative specialists through collaborative care models and recommending mindfulness and psychotherapy to all patients with significant depression alongside cancer pain. Medications for depression should be reserved for moderate to severe symptoms. We recommend escitalopram/citalopram or sertraline among selective serotonin reuptake inhibitors (SSRIs), or the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine, venlafaxine, or desvenlafaxine if patients have a significant component of neuropathic pain or fibromyalgia. Tricyclic antidepressants (TCAs) (consider nortriptyline or desipramine, which have better anticholinergic profiles) should be considered for patients who do not respond to or tolerate SSRI/SNRIs. Existing evidence is inadequate to definitively recommend methylphenidate or novel agents, such as ketamine or psilocybin, as adjunctive treatments for cancer-related depression and pain. Physicians who treat patients with cancer pain should utilize universal precautions to limit the risk of non-medical opioid use (non-medical opioid use). Patients should be screened for non-medical opioid use behaviors at initial consultation and at regular intervals during treatment using a non-judgmental approach that reduces stigma. Co-management with an addiction specialist may be indicated for patients at high risk of non-medical opioid use and opioid use disorder. Buprenorphine and methadone are indicated for the treatment of opioid use disorder, and while they have not been systematically studied for treatment of opioid use disorder in patients with cancer pain, they do provide analgesia for cancer pain. While an interdisciplinary team approach to manage psychological stress may be beneficial, this may not be possible for patients treated outside of comprehensive cancer centers.

Intramedullary Fixation of Double-Barrel Vascularised Fibula Grafts With Subsequent Lengthening for Reconstruction of the Distal Femur in Patients With Osteosarcoma.

BACKGROUND: The use of vascularised fibula grafts is an accepted method for reconstructing the distal femur following resection of malignant childhood tumors. Limitations relate to the mismatch of the cross-sectional area of the transplanted fibula graft and the local bone, instability of the construct and union difficulties. We present midterm results of a unique staged technique-an immediate defect reconstruction using a double-barrel vascularised fibula graft set in in A-frame configuration and a subsequent intramedullary femoral lengthening. METHODS: We retrospectively included 10 patients (mean age 10 y) with an osteosarcoma of the distal femur, who were treated according to the above-mentioned surgical technique. All patients were evaluated with regards to consolidation of the transplanted grafts, hypertrophy at the graft-host junctions, leg length discrepancies, lengthening indices, complications as well as functional outcome. RESULTS: The mean defect size after tumor resection was 14.5 cm, the mean length of the harvested fibula graft 22 cm, resulting in a mean (acute) shortening of 4.7 cm (in 8 patients). Consolidation was achieved in all cases, 4 patients required supplementary bone grafting. Hypertrophy at the graft-host junctions was observed in 78% of the evaluable junctions. In total 11 intramedullary lengthening procedures in 9 patients had been performed at the last follow up. The mean Muskuloskeletal Society Rating Scale (MSTS) score of the evaluable 9 patients was 85% (57% to 100%) with good or excellent results in 7 patients. CONCLUSIONS: A-frame vascularised fibula reconstructions showed encouraging results with respect to defect reconstruction, length as well as function and should therefore be considered a valuable option for reconstruction of the distal femur after osteosarcoma resection. The surgical implementation is demanding though, which is emphasized by the considerable high number of complications requiring surgical intervention, even though most were not serious. LEVEL OF EVIDENCE: Level IV-case series.

Characteristics of Patients with Non-Cancer Pain and Perceived Severity of COVID-19 Related Stress.

Synopsis Patients with non-cancer pain reported increased pain and pain interference during the first months of the COVID-19 pandemic. We determined if pain, prescription opioid use, and comorbidities were associated with perceived COVID-19-related stress as the pandemic peaked. Analysis of survey data revealed that depression/anxiety, pain severity, and pain interference were most strongly and consistently associated with greater stress due to COVID-19 related changes in lifestyle, worsening of emotional/mental health and worsening pain. Identifying specific stressful experiences that most impacted patients with non-cancer pain may help target public health and treatment interventions. Background: During the first months of the COVID-19 pandemic, patients with chronic pain reported increased pain severity and interference. This study measured the association between pain, prescription opioid use, and comorbidities with perceived COVID-19-related stress as the pandemic peaked in the United States. Methods: From 9/2020 to 3/2021, the first 149 subjects from a prospective cohort study of non-cancer pain, completed a survey which contained the Complementary and Integrative Research (CAIR) Pandemic Impact Questionnaire (C-PIQ). Respondents also reported whether the pandemic has contributed to their pain or opioid use. Bivariate comparisons explored patient characteristics with each CAIR domain. Results: Respondents mean age was 54.6 (±11.3) years, 69.8% were female, 64.6% were White. Respondent characteristics were not associated with reading/watching/thinking about the pandemic or with worry about health. Depression/anxiety (p=0.003), using any prescription opioid in the prior three months (p=0.009), higher morphine milligram equivalent used (p=0.005), higher pain severity (p=0.011), and higher pain interference (p=0.0004) were all positively and significantly associated with moderate to severe stress due to COVID-19 related lifestyle changes. Depression/anxiety, pain severity, and pain interference were positively associated with COVID-19-related worsening emotional/mental health. Depression/anxiety were significantly (p<0.0001) associated with reporting that the pandemic made their pain worse. Conclusion: Depression, anxiety, pain severity, and pain interference were most strongly and consistently associated with COVID-19 changes in way of life, worsening of emotional/mental health, and worsening pain. Identifying specific stressful experiences that most impacted patients with noncancer pain may inform public health and treatment interventions.

Determinants of nutrient limitation in cancer.

Proliferation requires that cells accumulate sufficient biomass to grow and divide. Cancer cells within tumors must acquire a variety of nutrients, and tumor growth slows or stops if necessary metabolites are not obtained in sufficient quantities. Importantly, the metabolic demands of cancer cells can be different from those of untransformed cells, and nutrient accessibility in tumors is different than in many normal tissues. Thus, cancer cell survival and proliferation may be limited by different metabolic factors than those that are necessary to maintain noncancerous cells. Understanding the variables that dictate which nutrients are critical to sustain tumor growth may identify vulnerabilities that could be used to treat cancer. This review examines the various cell-autonomous, local, and systemic factors that determine which nutrients are limiting for tumor growth.

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

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 .

When Physical and Social Pain Coexist: Insights Into Opioid Therapy.

The US opioid epidemic challenges us to rethink our understanding of the function of opioids and the nature of chronic pain. We have neatly separated opioid use and abuse as well as physical and social pain in ways that may not be consistent with the most recent neuroscientific and epidemiological research. Physical injury and social rejection activate similar brain centers. Many of the patients who use opioid medications long term for the treatment of chronic pain have both physical and social pain, but these medications may produce a state of persistent opioid dependence that suppresses the endogenous opioid system that is essential for human socialization and reward processing. Recognition of the social aspects of chronic pain and opioid action can improve our treatment of chronic pain and our use of opioid medications.

Green synthesis as a simple and rapid route to protein modified magnetic nanoparticles for use in the development of a fluorometric molecularly imprinted polymer-based assay for detection of myoglobin.

We have developed a low-cost molecularly imprinted polymer (MIP)-based fluorometric assay to directly quantify myoglobin in a biological sample. The assay uses a previously unreported method for the development of microwave-assisted rapid synthesis of aldehyde functionalized magnetic nanoparticles, in just 20 min. The aldehyde functionalized nanoparticles have an average size of 7.5 nm ± 1.8 and saturation magnetizations of 31.8 emu g-1 with near-closed magnetization loops, confirming their superparamagnetic properties. We have subsequently shown that protein tethering was possible to the aldehyde particles, with 0.25 ± 0.013 mg of myoglobin adsorbed to 20 mg of the nanomaterial. Myoglobin-specific fluorescently tagged MIP (F-MIP) particles were synthesized and used within the assay to capture myoglobin from a test sample. Excess F-MIP was removed from the sample using protein functionalized magnetic nanoparticles (Mb-SPION), with the remaining sample analyzed using fluorescence spectroscopy. The obtained calibration plot of myoglobin showed a linear correlation ranging from 60 pg ml-1 to 6 mg ml-1 with the limit of detection of 60 pg ml-1. This method was successfully used to detect myoglobin in spiked fetal calf serum, with a recovery rate of more than 93%.

"We Need to Taper." Interviews with Clinicians and Pharmacists About Use of a Pharmacy-Led Opioid Tapering Program.

OBJECTIVE: To 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. DESIGN: Qualitative 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. SETTING: An integrated healthcare system (HCS) in the Northwest United States. SUBJECTS: Thirty-five interviews were conducted with 20 PCPs and 15 STORM staff. METHODS: Constant 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. RESULTS: Use 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. CONCLUSIONS: PCPs 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.