Sr/Ca ratios indicate frugivory versus folivory in primates: a case study using handheld XRF in Kibale National Park, Uganda.

Researchers often use trace element concentrations, including strontium-calcium ratios (Sr/Ca), to reconstruct paleodiets. While most commonly used as a proxy for meat consumption, a more appropriate application may be to differentiate frugivory from folivory. Sr/Ca ratios in animal tissue reflect the Sr/Ca ratios of the highest calcium components of that animal's diet. Because plants have much higher concentrations of calcium than meat, meat consumption signals are often overwhelmed by the variation in Sr/Ca ratios coming from different plant parts. This study uses faunal and plant data from Kibale National Park, a protected forest in southwestern Uganda home to numerous primate species (for example, common chimpanzees and baboons), to assess the reliability of Sr/Ca ratios to differentiate between primate dietary groups. We find that leaves consistently have higher strontium and calcium concentrations than fruits and that this is mirrored in higher Sr/Ca ratios in folivorous primates compared to frugivorous primates. Plant species differ widely in both their overall Sr/Ca ratios and the differences between their fruit and leaf Sr/Ca ratios, but this variation does not overwhelm the dietary signal separating frugivores and folivores. Furthermore, this research demonstrates that non-destructive and portable X-ray florescence (XRF) methods are an effective means of gathering Sr/Ca data from plant and faunal material, increasing the opportunities to apply such methods to fossil material in the future.

Pain perception during baroreceptor unloading by lower body negative pressure.

BACKGROUND: People with high blood pressure have reduced sensitivity to pain, known as blood pressure hypoalgesia. One proposed mechanism for this is altered baroreceptor sensitivity. In healthy volunteers, stimulating the carotid baroreceptors causes reduced sensitivity to acute pain; however, this effect may be confounded by a rise in blood pressure due to baroreflex stimulation. The present study tests whether baroreceptor unloading contributes to the physiological mechanism of blood pressure-related hypoalgesia. METHODS: In the present study, pain perception to thermal stimulation of the forearm was studied in 20 healthy volunteers during baroreceptor unloading by lower body negative pressure (LBNP) at -5 and -20 mmHg. Blood pressure and heart rate were measured continuously throughout. To address issues relating to stimulation order, the sequence of LBNP stimulation was counterbalanced across participants. RESULTS: Increased heart rate was observed at a LBNP of -20 mmHg, but not -5 mmHg, but neither stimulus had an effect on blood pressure. There was no change in warm or cold sensory detection thresholds, heat or cold pain thresholds nor perceived pain from a 30s long thermal heat stimulus during LBNP. CONCLUSION: Therefore, baroreceptor unloading with maintained systemic blood pressure did not alter pain perception. The current study does not support the hypothesis that an altered baroreflex may underlie the physiological mechanism of blood pressure-related hypoalgesia. SIGNIFICANCE: This work provides evidence that, when measured in normotensive healthy young adults, the baroreflex response to simulated hypovolaemia did not lead to reduced pain sensitivity (known as blood pressure hypoalgesia).

Cell-type-specific responses to the microbiota across all tissues of the larval zebrafish.

Animal development proceeds in the presence of intimate microbial associations, but the extent to which different host cells across the body respond to resident microbes remains to be fully explored. Using the vertebrate model organism, the larval zebrafish, we assessed transcriptional responses to the microbiota across the entire body at single-cell resolution. We find that cell types across the body, not limited to tissues at host-microbe interfaces, respond to the microbiota. Responses are cell-type-specific, but across many tissues the microbiota enhances cell proliferation, increases metabolism, and stimulates a diversity of cellular activities, revealing roles for the microbiota in promoting developmental plasticity. This work provides a resource for exploring transcriptional responses to the microbiota across all cell types of the vertebrate body and generating new hypotheses about the interactions between vertebrate hosts and their microbiota.

Apoptosis-modulatory miR-361-3p as a novel treatment target in endocrine-responsive and endocrine-resistant breast cancer.

Breast cancer (BC) is the most diagnosed cancer in women worldwide. In estrogen receptor (ER)-positive disease, anti-estrogens and aromatase inhibitors (AI) improve patient survival; however, many patients develop resistance. Dysregulation of apoptosis is a common resistance mechanism; thus, agents that can reinstate the activity of apoptotic pathways represent promising therapeutics for advanced drug-resistant disease. Emerging targets in this scenario include microRNAs (miRs). To identify miRs modulating apoptosis in drug-responsive and -resistant BC, a high-throughput miR inhibitor screen was performed, followed by high-content screening microscopy for apoptotic markers. Validation demonstrated that miR-361-3p inhibitor significantly increases early apoptosis and reduces proliferation of drug-responsive (MCF7), plus AI-/antiestrogen-resistant derivatives (LTED, TamR, FulvR), and ER- cells (MDA-MB-231). Importantly, proliferation-inhibitory effects were observed in vivo in a xenograft model, indicating the potential clinical application of miR-361-3p inhibition. RNA-seq of tumour xenografts identified FANCA as a direct miR-361-3p target, and validation suggested miR-361-3p inhibitor effects might be mediated in part through FANCA modulation. Moreover, miR-361-3p inhibition resulted in p53-mediated G1 cell cycle arrest through activation of p21 and reduced BC invasion. Analysis of publicly available datasets showed miR-361-3p expression is significantly higher in primary breast tumours vspaired normal tissue and is associated with decreased overall survival. In addition, miR-361-3p inhibitor treatment of BC patient explants decreased levels of miR-361-3p and proliferation marker, Ki67. Finally, miR-361-3p inhibitor showed synergistic effects on BC growth when combined with PARP inhibitor, Olaparib. Together, these studies identify miR-361-3p inhibitor as a potential new treatment for drug-responsive and -resistant advanced BC.

CT pulmonary angiography: optimising acute thoracic imaging by fixed-timing contrast medium delivery with a modified breathing instruction.

AIM: To compare the thoracic vascular opacification achieved using the standard bolus-tracking protocol (BTP) with a fixed-timing protocol (FTP) with a modified breathing instruction during computed tomography pulmonary angiography (CTPA) examinations. MATERIALS AND METHODS: A single-centre review of CTPA examinations performed between July 2018 and January 2019 using the BTP or FTP and weight-based contrast dosing of 20 mg iodine/kg body weight/s for 20 seconds at 100 kV tube potential. Radiodensity (in Hounsfield units) was analysed in the right ventricle, main pulmonary artery (MPA), left atrium, left ventricle, and ascending and descending thoracic aorta (DTA). A p-value of <0.05 was considered significant. RESULTS: Of 782 examinations, 88 BTP and 90 FTP examinations were included. Mean attenuation of the MPA was similar in the FTP (396 ± 106 HU) and BTP (362 ± 119 HU; p=0.06); however, good-quality (≥250 HU) MPA opacification was achieved in more FTP examinations (87/90, 96.7%) compared to the BTP (73/88, 82.9%; p=0.002). Mean attenuation of the DTA was better in the FTP (325 ± 72 HU) than the BTP (228 ± 75 HU; p <0.0001), with good-quality opacification (≥250 HU) in 76/90 (84.4%) FTP examinations compared with 36/88 (40.9%) BTP examinations (p <0.001). CONCLUSION: The FTP achieves better opacification of the MPA and DTA compared to the BTP.

Range and Frequency of Congenital Malformations Among Children With Cleft Lip and/or Palate.

To assess the range and frequency of additional congenital malformations identified among children born alive with CL/P.Analysis of patient-level data from a national registry of cleft births linked to national administrative data of hospital admissions.National Health Service, England.Children born between 2000 and 2012 receiving cleft care in English NHS hospitals.The proportion of children with ICD-10 codes for additional congenital malformations, according to cleft type.The study included 9403 children. Of these 2114 (22.5%) had CL±A, 4509 (48.0%) had CP, 1896 (20.2%) had UCLP, and 884 (9.4%) had BCLP. A total of 3653 (38.8%) children had additional congenital malformations documented in their hospital admission records. The prevalence of additional congenital malformations was greatest among children with CP (53.0%), followed by those with BCLP (33.5%), UCLP (26.3%), and then CL±A (22.2%) (P < .001). Among those with UCLP, children with right-sided clefts were more likely to have additional malformations than those with left-sided clefts (31.6% vs 23.0%, P < .001). Malformations of the skeletal system and circulatory system were most common, affecting 10.5% and 10.2% of the included children, respectively. A total of 16.8% of children had additional congenital malformations affecting 2 or more structural systems.Congenital malformations are common among children born alive with a cleft, affecting over half of some cleft subgroups. Given the frequency of certain structural malformations, clinicians should consider standardized screening for these children. Establishing good links with pediatric and genetic services is recommended.

Early Career Training in Addiction Medicine: A Qualitative Study with Health Professions Trainees Following a Specialized Training Program in a Canadian Setting.

Background: There has been a notable deficiency in the implementation of addiction science in clinical practice and many healthcare providers feel unprepared to treat patients with substance use disorders (SUD) following training. However, the perceptions of addiction medicine training by learners in health professions have not been fully investigated. This qualitative study explored perceptions of prior training in SUD care among early-career trainees enrolled in Addiction Medicine fellowships and electives in Vancouver, Canada. Methods: From April 2015 - August 2018, we interviewed 45 early-career physicians, social workers, nurses, and 17 medical students participating in training in addiction medicine. We coded transcripts inductively using qualitative data analysis software (NVivo 11.4.3). Results: Findings revealed six key themes related to early-career training in addiction medicine: (1) Insufficient time spent on addiction education, (2) A need for more structured addictions training, (3) Insufficient hands-on clinical training and skill development, (4) Lack of patient-centeredness and empathy in the training environment, (5) Insufficient implementation of evidence-based medicine, and (6) Prevailing stigmas toward addiction medicine. Conclusion: Early clinical training in addiction medicine appears insufficient and largely focused on symptoms, rather than etiology or evidence. Early career learners in health professions perceived benefit to expanding access to quality education and reported positive learning outcomes after completing structured training programs.

Exercise Improves Redox Homeostasis and Mitochondrial Function in White Adipose Tissue.

Exercise has beneficial effects on energy balance and also improves metabolic health independently of weight loss. Adipose tissue function is a critical denominator of a healthy metabolism but the adaptation of adipocytes in response to exercise is insufficiently well understood. We have previously shown that one aerobic exercise session was associated with increased expression of antioxidant and cytoprotective genes in white adipose tissue (WAT). In the present study, we evaluate the chronic effects of physical exercise on WAT redox homeostasis and mitochondrial function. Adult male Wistar rats were separated into two groups: a control group that did not exercise and a group that performed running exercise sessions on a treadmill for 30 min, 5 days per week for 9 weeks. Reactive oxygen species (ROS) generation, antioxidant enzyme activities, mitochondrial function, markers of oxidative stress and inflammation, and proteins related to DNA damage response were analyzed. In WAT from the exercise group, we found higher mitochondrial respiration in states I, II, and III of Complex I and Complex II, followed by an increase in ATP production, and the ROS/ATP ratio when compared to tissues from control rats. Regarding redox homeostasis, NADPH oxidase activity, protein carbonylation, and lipid peroxidation levels were lower in WAT from the exercise group when compared to control tissues. Moreover, antioxidant enzymatic activity, reduced glutathione/oxidized glutathione ratio, and total nuclear factor erythroid-2, like-2 (NFE2L2/NRF2) protein levels were higher in the exercise group compared to control. Finally, we found that exercise reduced the phosphorylation levels of H2AX histone (γH2AX), a central protein that contributes to genome stability through the signaling of DNA damage. In conclusion, our results show that chronic exercise modulates redox homeostasis in WAT, improving antioxidant capacity, and mitochondrial function. This hormetic remodeling of adipocyte redox balance points to improved adipocyte health and seems to be directly associated with the beneficial effects of exercise.

Computed tomography-derived fractional flow reserve (FFRCT) has no additional clinical impact over the anatomical Coronary Artery Disease - Reporting and Data System (CAD-RADS) in real-world elective healthcare of coronary artery disease.

AIM: To evaluate the impact of computed tomography-derived fractional flow reserve (FFRCT) compared to the anatomical Coronary Artery Disease - Reporting and Data System (CAD-RADS) in the elective assessment of coronary artery disease in real-world cardiology practise. MATERIALS AND METHODS: A retrospective review was undertaken of 1,239 coronary CT examinations from August 2018 to December 2019 with a minimum follow-up period of 1 year. Coronary disease was classified according to the CAD-RADS system. A non-occlusive ≥30% maximum diameter stenosis was considered eligible for FFRCT. Lesion-specific FFRCT and FFR were considered positive if ≤ 0.80. The patients were followed up using the hospital radiology information system and the electronic patient record. A positive outcome was defined by a subsequent invasive angiogram (ICA) showing disease requiring revascularisation or FFR ≤0.80 or a positive stress test or medical therapy for angina in CAD-RADS 4. RESULTS: Of the 1,145 analysable studies (mean follow up 618 ± 153 days) the incidence of a positive result was 7% with a 5.4% elective revascularisation rate. Two hundred and forty-five patients (CAD-RADS 2-4) had FFRCT. FFRCT reduced the accuracy of the CAD-RADS grade from 91% to 78.4% (p<0.001). In CAD-RADS 2, the accuracy is reduced from 99% to 90.7% (p=0.005), and in CAD-RADS 3 from 93.9% to 67.7% (p<0.001). In CAD-RADS 4, FFRCT increases accuracy from 69.4% to 75.5% (p=0.025), but 89.8% of FFRCT are positive and specificity is low (26.7%). CONCLUSION: In the present "real-world" practise, FFRCT does not improve standard radiological assessment of coronary disease graded by the CAD-RADS alone.

A quality-improvement project to enhance systemic arterial contrast opacification in CT for trans-catheter aortic valve implantation.

AIM: To assess improvement in arterial opacification by optimising the contrast medium dosing protocol for computed tomography (CT) prior to trans-catheter aortic valve implantation (TAVI). MATERIALS AND METHODS: A wide variation in arterial opacification was observed in the initial CT TAVI protocol (standard protocol). The practice was optimised by considering the time required for the examination and optimising contrast medium flux. This became the optimised protocol with a 30-second contrast medium bolus of iodine flux 15-19 mg iodine/kg body weight/second (mg/kg/s). Attenuation (mean HU) in (a) the ascending aorta (gated systolic acquisition) and (b) the ascending, descending thoracic (at carina), infra-renal abdominal aorta, and right common iliac artery (non-gated acquisition) was measured. Thirty-one sequential optimised examinations were compared to 31 prior standard protocol examinations. RESULTS: There was no difference between the standard and optimised groups regarding age, sex, weight, body mass index (BMI), or voltage. The mean bolus durations were 24.9±4.4 seconds for the standard and 30±0.3 seconds for the optimised protocols (p<0.001). Although there was no difference in the attenuation in the gated ascending aorta (p>0.99), there was improvement at all other anatomical points in the non-gated examinations of the optimised protocol (p<0.002). CONCLUSION: Optimising contrast medium flux and matching bolus duration to the CT technology dramatically improves the vascular access component of TAVI planning and provides a reliable method to achieve objectively enhanced arterial opacification. This work highlights how to obtain good arterial contrast medium opacification in haemodynamically fragile patients without excessive contrast medium volumes.

The effect of left ventricular longitudinal strain on left atrial function and ventricular filling in hypertension.

AIM: To assess the relationship of global longitudinal strain during left atrial (LA) and left ventricular (LV) filling and emptying. MATERIALS AND METHODS: Using magnetic resonance imaging in 47 hypertensive patients, biplane global LV longitudinal strain was evaluated and related to LA and LV filling and emptying (by volumetric analysis), and to pulmonary vein and trans-mitral flow (by phase-contrast imaging). The results were compared to normal subjects. RESULTS: In hypertensive patients, reduced global longitudinal LV strain was associated with reduced LA reservoir (47 ± 10 versus 53 ± 9%, p<0.05), reduced LA conduit function (21 ± 9 versus 32 ± 11%, p<0.004), reduced LA early peak emptying rate (150 ± 77 versus 230 ± 88 ml/s, p=0.007), and slower early LV filling (373 ± 141 versus 478 ± 141 ml/s, p=0.03). LA peak filling rate showed a positive correlation to LV peak emptying rate (R=0.331, p=0.02). CONCLUSION: In hypertensive heart disease, impaired LV longitudinal systolic function causes reduced LA filling and emptying, and this leads directly to impaired LV filling and diastolic dysfunction.

Piper tectoniifolium Kunth: A New Natural Source of the Bioactive Neolignan (-)-Grandisin.

The Piper species are a recognized botanical source of a broad structural diversity of lignans and its derivatives. For the first time, Piper tectoniifolium Kunth is presented as a promising natural source of the bioactive (-)-grandisin. Phytochemical analyses of extracts from its leaves, branches and inflorescences showed the presence of the target compound in large amounts, with leaf extracts found to contain up to 52.78% in its composition. A new HPLC-DAD-UV method was developed and validated to be selective for the identification of (-)-grandisin being sensitive, linear, precise, exact, robust and with a recovery above 90%. The absolute configuration of the molecule was determined by X-ray diffraction. Despite the identification of several enantiomers in plant extracts, the major isolated substance was characterized to be the (-)-grandisin enantiomer. In vascular reactivity tests, it was shown that the grandisin purified from botanical extracts presented an endothelium-dependent vasorelaxant effect with an IC50 of 9.8 ± 1.22 µM and around 80% relaxation at 30 µM. These results suggest that P. tectoniifolium has the potential to serve as a renewable source of grandisin on a large scale and the potential to serve as template for development of new drugs for vascular diseases with emphasis on disorders related to endothelial disfunction.

Enteric nervous system modulation of luminal pH modifies the microbial environment to promote intestinal health.

The enteric nervous system (ENS) controls many aspects of intestinal homeostasis, including parameters that shape the habitat of microbial residents. Previously we showed that zebrafish lacking an ENS, due to deficiency of the sox10 gene, develop intestinal inflammation and bacterial dysbiosis, with an expansion of proinflammatory Vibrio strains. To understand the primary defects resulting in dysbiosis in sox10 mutants, we investigated how the ENS shapes the intestinal environment in the absence of microbiota and associated inflammatory responses. We found that intestinal transit, intestinal permeability, and luminal pH regulation are all aberrant in sox10 mutants, independent of microbially induced inflammation. Treatment with the proton pump inhibitor, omeprazole, corrected the more acidic luminal pH of sox10 mutants to wild type levels. Omeprazole treatment also prevented overabundance of Vibrio and ameliorated inflammation in sox10 mutant intestines. Treatment with the carbonic anhydrase inhibitor, acetazolamide, caused wild type luminal pH to become more acidic, and increased both Vibrio abundance and intestinal inflammation. We conclude that a primary function of the ENS is to regulate luminal pH, which plays a critical role in shaping the resident microbial community and regulating intestinal inflammation.

Electrocardiography-gated CT for acute aortic syndrome: quantifying the potential impact of subspecialty national recommendations on emergency general radiology reporting.

AIM: To evaluate the detection of acute aortic syndrome (AAS) and the prevalence of alternative diagnoses that may explain the presentation or require follow-up. MATERIALS AND METHODS: This was a retrospective, blinded re-evaluation of consecutive electrocardiography (ECG)-gated computed tomography (CT) aortic studies by a cardiovascular radiologist performed between September 2019 and May 2020 in a tertiary-referral cardiothoracic centre. RESULTS: There were 118 identified examinations, six examinations were excluded leaving 112 (mean age = 61 ± 17; 56% male). Three cases of AAS were present (prevalence 2.7%); only one was reported on initial review. There were no false-positive diagnoses of AAS. The heart was mentioned in 79 (70.5%) reports and 73 (65.2%) of reviews revealed a total of 114 new observations; 111 (97.4%) of these were cardiovascular with 44/112 (39.3%) patients potentially having a significant previously unsuspected cardiovascular diagnosis. CONCLUSION: The implementation of national clinical guidance to increase testing and improve image quality led to a series of challenges. The real value of ECG-gated CT may lie in detecting other diseases that mimic AAS. With the additional workload, increased subspecialty expertise is required but there needs to be a willingness to learn with an adequate support infrastructure.

Social inclusion, intersectionality, and profiles of vulnerable groups of young people seeking mental health support.

BACKGROUND: headspace centres provide enhanced primary mental healthcare for young people. A priority is to provide services for all young people irrespective of a range of social disadvantages or social exclusion. The aims of this study were to: (i) delineate extent of social inclusion across domains of housing, studying/employment, functioning, alcohol, and other drug use; and (ii) map profiles of young people deemed vulnerable to experiencing additional barriers to accessing services based on their social inclusion domains (e.g., those living in unstable housing, not in employment/education, and/or experiencing intersecting or multiple forms of disadvantage or difficulties), including detailing their clinical characteristics. METHODS: Young people were recruited from five headspace centres. Data relevant to social inclusion were examined. Multivariate logistic regression models were used to determine overlap between vulnerable groups, functional, social, clinical, and behavioural factors. RESULTS: 1107 young people participated, aged 12-25 years (M = 18.1 years, SD = 3.3), most living in stable housing (96.5%) and engaged in studying/employment (84.8%). Specific vulnerabilities were evident in young people with NEET status (15.2%); in unstable accommodation (3.5%); of culturally diverse backgrounds (CALD) (12.2%); living in regional areas (36.1%); and identifying as lesbian, gay, bisexual, transgender, intersex, queer/questioning, and asexual plus (LGBTIQA+; 28.2%). Higher levels of distress, substance use, functional impairment, and lower social support were reported by those who were NEET and/or in unstable housing. LGBTIQA+ status was associated with high distress, depressive symptoms, and suicidal ideation. CONCLUSIONS: Most participants reported good social support, stable housing, and engagement in work or education. Those deemed vulnerable were likely to experience social exclusion across multiple domains and reported more mental health problems. The co-occurrence of mental ill-health and social exclusion highlights the importance of integrated mental healthcare.

Surgical management of superficial digital flexor tendon luxation in dogs: 48 cases (2005-2020).

OBJECTIVES: To report the outcome, frequency of complications and potential prognostic factors associated with surgical repair of superficial digital flexor tendon (SDFT) luxation in dogs. MATERIALS AND METHODS: Medical records from 10 referral hospitals were reviewed retrospectively for cases of SDFT luxation in dogs that underwent surgical stabilisation. Signalment, clinical presentation, diagnostic imaging, surgical method, type and length of post-operative limb immobilisation, nature of and length of exercise restriction, presence of post-operative complications and outcomes were recorded. Data were summarised descriptively and prognostic risk factors assessed for association with surgical outcome using risk ratios. RESULTS: Forty-eight cases were included. A successful surgical outcome was recorded in 35 of 48 (73%) cases. Re-luxation of the SDFT occurred in seven of 48 (15%). Six out of 48 (13%) had a persistent lameness despite a stable non-luxating SDFT. A high frequency of post-operative complications occurred (71%), with the majority resolved medically. The risk of surgical failure was 60% higher (risk ratio 1.6, 95% confidence interval 1.1 to 2.4) where absorbable suture material was used compared to non-absorbable suture material. Surgical failure was more common in cases managed with non-rigid immobilisation post-operatively (57% failure) compared to cases managed with rigid immobilisation (19% failure), although this result was not statistically significant. Limb immobilisation of 6 weeks or longer did not significantly affect surgical outcome, compared to shorter periods of exercise restriction or limb immobilisation. CLINICAL SIGNIFICANCE: A good outcome can be expected following surgical stabilisation of SDFT luxation. The use of non-absorbable suture was associated with a more successful surgical outcome.

The psychometric characteristics of the Kessler Psychological Distress Scale (K6) in help-seeking youth: What do you miss when using it as an outcome measure?

This is the first study to describe psychometric properties of the Kessler Psychological Distress Scale (K6) in a large cohort of help-seeking young people presenting to primary mental health care services. The aim was to determine whether the K6 was appropriate for monitoring outcomes in such settings. 1067 young people were recruited from Australian headspace services. We examined dimensionality of the K6, measurement invariance, and how the K6 correlated with the the Patient Health Questionnaire-9 (PHQ-9)and the Generalised Anxiety Disorder-7 Scale (GAD-7). Standardised Response Mean (SRM) and Cohen's d effect size (ES) were used to examine 3-month stability of the K6. The best-fitting model was a two-factor model: (i) nervous and restlessness; and (ii) hopeless, worthless, depressed and effort. Measurement non-invariance was observed for sex and age groups. K6 strongly correlated with the PHQ-9 and GAD-7. The K6 was less sensitive to change compared to these other two measures. There was some support for the K6 being a screener for young people presenting to primary care; however, there issues arise with its use as an outcome measure. These issues include measurement non-invariance, concern about the dimensionality and focus of items, and its sensitivity to change.

Individualized prescribing portraits to reduce inappropriate initiation of opioid analgesics to opioid naïve patients in primary care: Protocol for a randomized controlled trial.

Background Opioid analgesics are frequently initiated for chronic and acute pain despite weak evidence of benefit, although prescribing rates of some analgesics decreased in the context of the epidemic. In some populations, up to a quarter of opioid naïve persons prescribed opioids for non-cancer pain develop prescription opioid use disorder (OUD). Audit and feedback interventions rely on constructive use of routinely collected data to align professional behaviours and clinical practice with best evidence. These interventions have been shown to help reduce inappropriate initiation. However, effectiveness and acceptability of individualized "portraits" of physicians' prescribing patterns, to reduce inappropriate initiation of opioid analgesics to opioid naïve persons, have not been evaluated. Methods REDONNA is a mixed-methods randomized study testing the effectiveness of individualized prescribing Portraits to reduce inappropriate initiation of opioid analgesics. This intervention to improve safety of opioid prescribing in primary care in British Columbia (BC), Canada involves mailing individual prescribing portraits to an 'early group' of 2604 family physicians, followed in 6 months by a mailing to 2553 family physicians in the 'delayed group'. Primary outcome is number of new opioid prescriptions initiated in opioid naïve people, measured using administrative data from a centralized medication monitoring database covering all prescription opioids dispensed from BC community pharmacies. Secondary endpoints will compare prescribing impact between the two groups. A qualitative sub-study will examine feasibility among a purposive sample of physicians and patients. Discussion This trial provides important evidence on the intervention's potential to steer policy and practice on inappropriate opioid analgesics initiation. Trial registration: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).