The adaptor protein 2 (AP2) complex modulates habituation and behavioral selection across multiple pathways and time windows.

Animals constantly integrate sensory information with prior experience to select behavioral responses appropriate to the current situation. Genetic factors supporting this behavioral flexibility are often disrupted in neuropsychiatric conditions, such as the autism-linked ap2s1 gene which supports acoustically evoked habituation learning. ap2s1 encodes an AP2 endocytosis adaptor complex subunit, although its behavioral mechanisms and importance have been unclear. Here, we show that multiple AP2 subunits regulate acoustically evoked behavior selection and habituation learning in zebrafish. Furthermore, ap2s1 biases escape behavior choice in sensory modality-specific manners, and broadly regulates action selection across sensory contexts. We demonstrate that the AP2 complex functions acutely in the nervous system to modulate acoustically evoked habituation, suggesting several spatially and/or temporally distinct mechanisms through which AP2 regulates escape behavior selection and performance. Altogether, we show the AP2 complex coordinates action selection across diverse contexts, providing a vertebrate model for ap2s1's role in human conditions including autism spectrum disorder.

Data-Driven Design of Polymer-Based Biomaterials: High-throughput Simulation, Experimentation, and Machine Learning.

Polymers, with the capacity to tunably alter properties and response based on manipulation of their chemical characteristics, are attractive components in biomaterials. Nevertheless, their potential as functional materials is also inhibited by their complexity, which complicates rational or brute-force design and realization. In recent years, machine learning has emerged as a useful tool for facilitating materials design via efficient modeling of structure-property relationships in the chemical domain of interest. In this Spotlight, we discuss the emergence of data-driven design of polymers that can be deployed in biomaterials with particular emphasis on complex copolymer systems. We outline recent developments, as well as our own contributions and takeaways, related to high-throughput data generation for polymer systems, methods for surrogate modeling by machine learning, and paradigms for property optimization and design. Throughout this discussion, we highlight key aspects of successful strategies and other considerations that will be relevant to the future design of polymer-based biomaterials with target properties.

Diagnostic Delay and Disease Burden in Primary Aldosteronism: An International Patient Survey.

BACKGROUND: Primary aldosteronism (PA) is a common but underdiagnosed cause of hypertension. Many patients experience preventable end-organ injury due to delayed or missed diagnosis but data on the experience of patients are limited. METHODS: We evaluated the lived experience of PA and determines factors associated with diagnostic delay through an international anonymous online cross-sectional survey, codesigned by researchers and PA consumers. We distributed the survey through academic medical centers, Amazon Mechanical Turk, Twitter, PA patient advocacy groups, and hypertension support groups on Facebook between March 21 and June 5, 2022. RESULTS: Of 684 eligible respondents, 66.5% were women. Diagnostic delay (defined as ≥5 years between the diagnosis of hypertension and PA) was reported in 35.6%. Delay was more likely in women than in men (odds ratio, 1.55 [95% CI, 1.10-2.20]) and respondents with ≥3 comorbidities versus none (odds ratio, 1.77 [95% CI, 1.05-3.02]), ≥10 symptoms versus none (odds ratio, 2.73 [95% CI, 1.74-4.44]), and on ≥4 antihypertensive medications versus none (odds ratio, 18.23 [95% CI, 6.24-77.72]). Three-quarters of patients (74.4%) experienced reduced symptom burden following targeted PA treatment. Quality of life improved in 62.3% of patients, and greater improvement was associated with being a woman (odds ratio, 1.42, [95% CI, 1.02-1.97]), receiving adrenalectomy (odds ratio, 2.36 [95% CI, 1.67-3.35]), and taking fewer antihypertensive medications following diagnosis (odds ratio, 5.28 [95% CI, 3.55-7.90]). CONCLUSIONS: One-third of patients with PA experienced prolonged diagnostic delays. Targeted treatment led to reduced symptom burden and improved quality of life. Gender differences in diagnostic delay and symptom burden are prominent. These findings suggest that routine screening for PA at the onset of hypertension may reduce diagnostic delay and facilitate timely diagnosis.

Achilles tendon disorders: An overview of diagnosis and conservative treatment.

ABSTRACT: Achilles tendon-related pain affects up to 6% of the US population during their lifetime and is commonly encountered by primary care providers. An accurate diagnosis and early conservative management can improve patient quality of life and reduce unnecessary surgical consultations, saving healthcare dollars. Achilles tendon pathologies can be categorized into acute (pain lasting less than 6 weeks), chronic (pain lasting more than 6 weeks), and acute on chronic (worsening of pain with preexisting chronic Achilles tendon pathology). This article describes the diagnosis, conservative management, indications for imaging, and indications for surgical referral for acute and chronic Achilles tendon rupture, Achilles tendinitis, gastrocnemius strain, plantaris rupture, insertional Achilles tendinopathy, Haglund deformity, and noninsertional Achilles tendinopathy.

Automated analysis of vessel morphometry in retinal images from a Danish high street optician setting.

PURPOSE: To evaluate the test performance of the QUARTZ (QUantitative Analysis of Retinal vessel Topology and siZe) software in detecting retinal features from retinal images captured by health care professionals in a Danish high street optician chain, compared with test performance from other large population studies (i.e., UK Biobank) where retinal images were captured by non-experts. METHOD: The dataset FOREVERP (Finding Ophthalmic Risk and Evaluating the Value of Eye exams and their predictive Reliability, Pilot) contains retinal images obtained from a Danish high street optician chain. The QUARTZ algorithm utilizes both image processing and machine learning methods to determine retinal image quality, vessel segmentation, vessel width, vessel classification (arterioles or venules), and optic disc localization. Outcomes were evaluated by metrics including sensitivity, specificity, and accuracy and compared to human expert ground truths. RESULTS: QUARTZ's performance was evaluated on a subset of 3,682 images from the FOREVERP database. 80.55% of the FOREVERP images were labelled as being of adequate quality compared to 71.53% of UK Biobank images, with a vessel segmentation sensitivity of 74.64% and specificity of 98.41% (FOREVERP) compared with a sensitivity of 69.12% and specificity of 98.88% (UK Biobank). The mean (± standard deviation) vessel width of the ground truth was 16.21 (4.73) pixels compared to that predicted by QUARTZ of 17.01 (4.49) pixels, resulting in a difference of -0.8 (1.96) pixels. The differences were stable across a range of vessels. The detection rate for optic disc localisation was similar for the two datasets. CONCLUSION: QUARTZ showed high performance when evaluated on the FOREVERP dataset, and demonstrated robustness across datasets, providing validity to direct comparisons and pooling of retinal feature measures across data sources.

Sequence Patterning, Morphology, and Dispersity in Single-Chain Nanoparticles: Insights from Simulation and Machine Learning.

Single-chain nanoparticles (SCNPs) are intriguing materials inspired by proteins that consist of a single precursor polymer chain that has collapsed into a stable structure. In many prospective applications, such as catalysis, the utility of a single-chain nanoparticle will intricately depend on the formation of a mostly specific structure or morphology. However, it is not generally well understood how to reliably control the morphology of single-chain nanoparticles. To address this knowledge gap, we simulate the formation of 7680 distinct single-chain nanoparticles from precursor chains that span a wide range of, in principle, tunable patterning characteristics of cross-linking moieties. Using a combination of molecular simulation and machine learning analyses, we show how the overall fraction of functionalization and blockiness of cross-linking moieties biases the formation of certain local and global morphological characteristics. Importantly, we illustrate and quantify the dispersity of morphologies that arise due to the stochastic nature of collapse from a well-defined sequence as well as from the ensemble of sequences that correspond to a given specification of precursor parameters. Moreover, we also examine the efficacy of precise sequence control in achieving morphological outcomes in different regimes of precursor parameters. Overall, this work critically assesses how precursor chains might be feasibly tailored to achieve given SCNP morphologies and provides a platform to pursue future sequence-based design.

Coronary embolism due to probable clinical bioprosthetic aortic valve thrombosis: a case report.

BACKGROUND: Coronary embolism is a relatively rare but important non-atherosclerotic cause of acute coronary syndrome, mainly caused by atrial fibrillation and mechanical heart valve thrombosis due to subtherapeutic anticoagulation. There have been increasing reports of bioprosthetic valve thrombosis (BPVT), but thromboembolic events are rare and mainly affect the cerebrovascular system. Coronary embolism is an extremely rare complication of BPVT. CASE PRESENTATION: A 64-year-old male presented with non-ST-Elevation myocardial infarction (NSTEMI) to an Australian regional health service. Three years ago, he had undergone Bentall procedure with bioprosthetic aortic valve replacement for severe aortic regurgitation and significant aortic root dilatation. Diagnostic coronary angiography revealed embolic occlusion of first diagonal branch in the absence of underlying atherosclerosis. Prior to NSTEMI presentation, the patient was clinically asymptomatic apart from the progressive increase in transaortic mean pressure gradient on transthoracic echocardiography which was first detected seven months after surgical aortic valve replacement. Transoesophageal echocardiography showed restrictions of the aortic leaflet opening but no evidence of mass or vegetation. After eight weeks of warfarin therapy, the raised aortic valve gradient returned to normal. Lifelong warfarin was prescribed, and patient remained clinically well at 39-month follow-up. CONCLUSION: We experienced a case of coronary embolism in a patient with probable BPVT. Reversible bioprosthetic valve hemodynamic deterioration after anticoagulation strongly supports the diagnosis in the absence of histopathology. Early moderate-to-severe hemodynamic valve deterioration warrants further investigations, including cardiac computed tomography and sequential echocardiography, to investigate for probable BPVT and consideration of timely anticoagulation initiation to prevent thromboembolic events.

LC-MS/MS method for quantification of raspberry ketone in rat plasma: application to preclinical pharmacokinetic studies.

Background: Raspberry ketone (RK), derived from red raspberry fruit (Rubus idaeus, family Rosaceae), is a reported potent antiobesity agent. This study aims to investigate method development, validation, and in vitro and in vivo pharmacokinetics in rats. Materials & methods: LC-MS/MS was used to conduct method development, validation, stability, and oral PK samples of RK in plasma analyses. Results: RK was highly soluble in Tris buffer and stable in gastrointestinal fluids as well as plasma. Rat liver microsomal stability of RK in phase I and II studies was 84.96 ± 2.39 and 69.98 ± 8.69%, respectively, after 60 min. Intestinal permeability was 4.39 ± 1.37 × 10-5 cm/s. Maximal concentration was 1591.02 ± 64.76 ng/ml, which was achieved after 1 h (time to maximal concentration), and absolute oral bioavailability was 86.28%. Conclusion: Pharmacokinetic data serve as a keystone for preclinical and clinical adjuvant therapy.

Using LC­MS/MS, a method was developed and validated for RK, and investigated the preclinical pharmacokinetics and bioavailability in Sprague Dawley rats.

GWAS on retinal vasculometry phenotypes.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa.

The calcium-sensing receptor (CaSR) regulates zebrafish sensorimotor decision making via a genetically defined cluster of hindbrain neurons.

Decision making is a fundamental nervous system function that ranges widely in complexity and speed of execution. We previously established larval zebrafish as a model for sensorimotor decision making and identified the G-protein-coupled calcium-sensing receptor (CaSR) to be critical for this process. Here, we report that CaSR functions in neurons to dynamically regulate the bias between two behavioral outcomes: escapes and reorientations. By employing a computational guided transgenic strategy, we identify a genetically defined neuronal cluster in the hindbrain as a key candidate site for CaSR function. Finally, we demonstrate that transgenic CaSR expression targeting this cluster consisting of a few hundred neurons shifts behavioral bias in wild-type animals and restores decision making deficits in CaSR mutants. Combined, our data provide a rare example of a G-protein-coupled receptor that biases vertebrate sensorimotor decision making via a defined neuronal cluster.

Modified Sick Neonatal Score and Delta: Modified Sick Neonatal Scores As Prognostic Indicators in Neonatal Intensive Care Units.

Background Modified Sick Neonatal Score (MSNS) is a modification of the Sick Neonatal Score (SNS) by adding perinatal factors such as birth weight and gestational age to the scoring. A significantly higher sensitivity and specificity were obtained by adding the above parameters to SNS. The parameters in MSNS were simple and easy to score, but the scoring was done only once, and the utility of the score to assess the response to treatment was not analysed. In this study, we aimed to determine the role of MSNS as a prognostic indicator in the neonatal intensive care unit (NICU) and to study the correlation of the change in the MSNS (Delta-MSNS) 24 hours after admission with the outcomes and as a measure of response to treatment. Methodology A cross-sectional study was conducted for six months on all neonates admitted to the NICU during the study period. All babies were scored using MSNS containing eight basic clinical parameters, namely, respiratory rate, heart rate, axillary temperature, peripheral capillary refill time, random blood sugar, oxygen saturation, gestational age, and birth weight. Scoring by MSNS was done on the following two occasions: first score at admission, and second score 24 hours later. A change in the score during the first 24 hours of NICU stay (Delta-MSNS) was analysed for babies with an initial score of less than or equal to 12. All babies were followed up for analysis of outcomes, and outcomes were documented as discharge from the hospital or death. Length of hospital stay was documented for the babies that were discharged. Statistical analysis was done using the software RStudio v1.1.456. Kruskal-Wallis rank sum test was used to compare individual parameters of the score as well as the mean score between the expired and discharged groups. Spearman rank-order correlation coefficient was used to correlate the scores with length of hospital stay. Results A total of 248 neonates were considered for inclusion in the study. The mean score at admission was 7.94 (SD = 1.89) in the expired group and 14.46 (SD = 1.84) in the discharged group. The p-value for each of these was <0.001. Using MSNS as a test variable, a receiver operating characteristic (ROC) curve was generated, and as measured by the area under the curve was 0.98. A cut-off score of 10 was obtained that had a sensitivity of 88.24%, specificity of 95.2%, positive predictive value of 57.69%, and negative predictive value of 99%. A significant negative correlation was observed with a Spearman correlation coefficient of -0.67 when the initial MSNS was correlated with length of hospital stay in patients who were discharged. A significant negative correlation with a coefficient of -0.39 and p-value of 0.017 was determined when delta MSNS score was correlated with the discharged babies who had an initial score of less than 12. Conclusions MSNS is an easy-to-use bedside scoring system that requires minimal training and no invasive procedures. It has shown a high sensitivity in predicting mortality and length of hospital stay. Additionally, calculation of delta score was equally useful. It is a simplified score that enables providers to objectively assess the severity of illness with nominal training both in NICU as well as in low-resource settings.

Retinal microvascular associations with cardiometabolic risk factors differ by diabetes status: results from the UK Biobank.

AIMS/HYPOTHESIS: The aim of the study was to examine the association of retinal vessel morphometry with BP, body composition and biochemistry, and to determine whether these associations differ by diabetes status. METHODS: The UK Biobank ocular assessment included 68,550 participants aged 40-70 years who underwent non-mydriatic retinal photography, BP and body composition measurements, and haematological analysis. A fully automated image analysis program provided measurements of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiometabolic risk factors by diabetes status were examined using multilevel linear regression, to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing for within-person clustering). RESULTS: A total of 50,233 participants (a reduction from 68,550) were included in these analyses. Overall, those with diabetes had significantly more tortuous venules and wider arteriolar diameters compared with those without. Associations between venular tortuosity and cardiometabolic risk factors differed according to diabetes status (p interaction <0.01) for total fat mass index, HbA1c, C-reactive protein, white cell count and granulocyte count. For example, a unit rise in white cell count was associated with a 0.18% increase (95% CI 0.05, 0.32%) in venular tortuosity for those without diabetes and a 1.48% increase (95% CI 0.90, 2.07%) among those with diabetes. For arteriolar diameter, significant interactions were evident for systolic BP, diastolic BP, mean arterial pressure (MAP) and LDL-cholesterol. For example, a 10 mmHg rise in systolic BP was associated with a -0.92 µm difference (95% CI -0.96 to -0.88 µm) in arteriolar diameter for those without diabetes, and a -0.58 µm difference (95% CI -0.76 to -0.41 µm) among those with diabetes. No interactions were observed for arteriolar tortuosity or venular diameters. CONCLUSIONS/INTERPRETATION: We provide clear evidence of the modifying effect of diabetes on cardiometabolic risk factor associations with retinal microvascular architecture. These observations suggest the occurrence of preclinical disease processes, and may be a sign of impaired autoregulation due to hyperglycaemia, which has been suggested to play a pivotal role in the development of diabetes-related microvascular complications. DATA AVAILABILITY: The data supporting the results reported here are available through the UK Biobank ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

Machine Learning on a Robotic Platform for the Design of Polymer-Protein Hybrids.

Polymer-protein hybrids are intriguing materials that can bolster protein stability in non-native environments, thereby enhancing their utility in diverse medicinal, commercial, and industrial applications. One stabilization strategy involves designing synthetic random copolymers with compositions attuned to the protein surface, but rational design is complicated by the vast chemical and composition space. Here, a strategy is reported to design protein-stabilizing copolymers based on active machine learning, facilitated by automated material synthesis and characterization platforms. The versatility and robustness of the approach is demonstrated by the successful identification of copolymers that preserve, or even enhance, the activity of three chemically distinct enzymes following exposure to thermal denaturing conditions. Although systematic screening results in mixed success, active learning appropriately identifies unique and effective copolymer chemistries for the stabilization of each enzyme. Overall, this work broadens the capabilities to design fit-for-purpose synthetic copolymers that promote or otherwise manipulate protein activity, with extensions toward the design of robust polymer-protein hybrid materials.

Machine-Assisted Discovery of Chondroitinase ABC Complexes toward Sustained Neural Regeneration.

Among the many molecules that contribute to glial scarring, chondroitin sulfate proteoglycans (CSPGs) are known to be potent inhibitors of neuronal regeneration. Chondroitinase ABC (ChABC), a bacterial lyase, degrades the glycosaminoglycan (GAG) side chains of CSPGs and promotes tissue regeneration. However, ChABC is thermally unstable and loses all activity within a few hours at 37 °C under dilute conditions. To overcome this limitation, the discovery of a diverse set of tailor-made random copolymers that complex and stabilize ChABC at physiological temperature is reported. The copolymer designs, which are based on chain length and composition of the copolymers, are identified using an active machine learning paradigm, which involves iterative copolymer synthesis, testing for ChABC thermostability upon copolymer complexation, Gaussian process regression modeling, and Bayesian optimization. Copolymers are synthesized by automated PET-RAFT and thermostability of ChABC is assessed by retained enzyme activity (REA) after 24 h at 37 °C. Significant improvements in REA in three iterations of active learning are demonstrated while identifying exceptionally high-performing copolymers. Most remarkably, one designed copolymer promotes residual ChABC activity near 30%, even after one week and notably outperforms other common stabilization methods for ChABC. Together, these results highlight a promising pathway toward sustained tissue regeneration.

Evaluation of the Pharmacokinetics of the Pancreastatin Inhibitor PSTi8 Peptide in Rats: Integration of In Vitro and In Vivo Findings.

PSTi8 is a pancreastatin inhibitory peptide that is effective in the treatment of diabetic models. This study investigates the pharmacokinetic (PK) properties of PSTi8 in Sprague Dawley rats, for the first time. In vitro and in vivo PK studies were performed to evaluate the solubility, stability in plasma and liver microsomes, plasma protein binding, blood-plasma partitioning, bioavailability, dose proportionality, and gender difference in PK. Samples were analyzed using the validated LC-MS/MS method. The solubility of PSTi8 was found to be 9.30 and 25.75 mg/mL in simulated gastric and intestinal fluids, respectively. The protein binding of PSTi8 was estimated as >69% in rat plasma. PSTi8 showed high stability in rat plasma and liver microsomes and the blood-plasma partitioning was >2. The bioavailability of PSTi8 after intraperitoneal and subcutaneous administration was found to be 95.00 ± 12.15 and 78.47 ± 17.72%, respectively, in rats. PSTi8 showed non-linear PK in dose proportionality studies, and has no gender difference in the PK behavior in rats. The high bioavailability of PSTi8 can be due to high water solubility and plasma protein binding, low clearance and volume of distribution. Our in vitro and in vivo findings support the development of PSTi8 as an antidiabetic agent.

The effect of gender dyads on the quality of narrative assessments of general surgery trainees.

BACKGROUND: Prior studies have shown that gender can influence how learners are assessed and the feedback they receive. We investigated the quality of faculty narrative comments in general surgery trainee evaluation using trainee-assessor gender dyads. METHODS: Narrative assessments of surgical trainees at the University of British Columbia were collected and rated using the McMaster Narrative Comment Rating Scale (MNCRS). Variables from the MNCRS were inputted into a generalized linear mixed model to explore the impact of gender dyads on the quality of narrative feedback. RESULTS: 2,469 assessments were collected. Women assessors tended to give higher-quality comments (p's < 0.05) than men assessors. Comments from men assessors to women trainees were significantly more positive than comments from men assessors to men trainees (p = 0.02). Men assessors also tended to give women trainees more reinforcing than corrective comments than to men trainees (p < 0.01). CONCLUSIONS: There are significant differences in the quality of faculty feedback to trainees by gender dyads. A range of solutions to improve and reduce differences in feedback quality are discussed.

A retrospective analysis of rates of allergic reaction to Patent V blue dye used in sentinel lymph node biopsies for melanoma.

Sentinel lymph node biopsies are a well-established component of the assessment and treatment pathway for patients with cutaneous melanoma in the UK. Commonly utilised techniques involve the use of blue dye which has an established risk of inducing allergic reactions in patients. Such reactions can be life-threatening, and this risk is important to highlight to patients. We conducted a retrospective review of all patients who had undergone this procedure at our melanoma centre in Cambridge, UK. From a group of 715 patients who received blue dye as part of the procedure, six patients suffered an allergic reaction (0.84%) with one of these treated as anaphylaxis. Our incidence of anaphylaxis is almost ten times greater than that reported in the NAP6 report led by the National Institute of Academic Anaesthesia and significantly higher than reported by others. We propose several reasons why our results differ from previous estimates. This study has focused only on patients undergoing a sentinel node procedure for melanoma, others have focused on such procedures performed on patients with breast cancer and some have combined the two. The administration technique, volume and anatomical distribution of disease all differ significantly from melanoma, possibly influencing rates and severity of allergic reactions.

Genetic Stratification of Age-Dependent Parkinson's Disease Risk by Polygenic Hazard Score.

BACKGROUND: Parkinson's disease (PD) is a highly age-related disorder, where common genetic risk variants affect both disease risk and age at onset. A statistical approach that integrates these effects across all common variants may be clinically useful for individual risk stratification. A polygenic hazard score methodology, leveraging a time-to-event framework, has recently been successfully applied in other age-related disorders. OBJECTIVES: We aimed to develop and validate a polygenic hazard score model in sporadic PD. METHODS: Using a Cox regression framework, we modeled the polygenic hazard score in a training data set of 11,693 PD patients and 9841 controls. The score was then validated in an independent test data set of 5112 PD patients and 5372 controls and a small single-study sample of 360 patients and 160 controls. RESULTS: A polygenic hazard score predicts the onset of PD with a hazard ratio of 3.78 (95% confidence interval 3.49-4.10) when comparing the highest to the lowest risk decile. Combined with epidemiological data on incidence rate, we apply the score to estimate genetically stratified instantaneous PD risk across age groups. CONCLUSIONS: We demonstrate the feasibility of a polygenic hazard approach in PD, integrating the genetic effects on disease risk and age at onset in a single model. In combination with other predictive biomarkers, the approach may hold promise for risk stratification in future clinical trials of disease-modifying therapies, which aim at postponing the onset of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical and financial burden of spinal infections in people who inject drugs.

BACKGROUND: People who inject drugs (PWID) are known to be at increased risk of infectious diseases including bacterial and blood-borne viral infections. However, there is limited literature surrounding the burden of spinal infections as a complication of injecting drug use (IDU). AIMS: To quantify the clinical and financial burden of IDU-related spinal infections. METHODS: Retrospective chart review of adult PWID with spinal infections requiring hospital admission to a tertiary health service in Melbourne, Australia between 2011 and 2019. RESULTS: Fifty-seven PWID with 63 episodes of spinal infections were identified with a median hospital stay of 47 days (interquartile range (IQR) 16; range 4-243 days). One-third of episodes required neurosurgical intervention and 11 (17%) episodes required intensive care unit admission (range 2-17 days). Staphylococcus aureus was the most common causative pathogen, present in three-quarters of all episodes (n = 47). The median duration of antibiotic regime was 59 days (IQR 42) and longer courses were associated with known bacteraemia (P = 0.048), polymicrobial infections (P = 0.001) and active IDU (P = 0.066). Predictors of surgery include neurological symptoms at presentation (relative risk (RR) 2.6; P = 0.010), inactive IDU status (RR 3.0; P = 0.002), a diagnosis of epidural abscess (RR 4.1; P = 0.001) and spinal abscess (RR ∞; P < 0.001). Completion of planned antimicrobial therapy was reported in 51 (82%) episodes. Average expenditure per episode was  A$61 577. CONCLUSIONS: Spinal infections in PWID are an underreported serious medical complication of IDU. Although mortality is low, there is significant morbidity with prolonged admissions, large antimicrobial requirements and surgical interventions generating a substantial cost to the health system.

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

BACKGROUND: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. MATERIALS AND METHODS: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. RESULTS: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. CONCLUSION: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.