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Introduction: Achenbach syndrome is a rare, benign condition characterized by painful discoloration of a finger. Recognition of this syndrome prevents unnecessary costly workup and risky interventions. Case Report: A healthy, 54-year-old female was transferred to our emergency department (ED) from a community ED for vascular evaluation of discoloration and numbness to her finger. After extensive workup, medical intervention, and consultation with multiple specialists, she was diagnosed with Achenbach syndrome. Conclusion: Emergency physicians may practice good healthcare stewardship and limit invasive, potentially harmful, and expensive workup by reassuring patients of the benign nature of this condition.

Abstract Background The severity of COVID-19 outbreaks is disproportionate across settings (e.g., long-term care facilities (LTCF), schools) across Canada. Few studies have examined factors associated with outbreak severity to inform prevention and response. Our study objective was to assess how outbreak severity, as measured using outbreak intensity and defined as number of outbreak-associated cases divided by outbreak duration, differed by setting and factors known to influence SARS-CoV-2 transmission. Methods We described outbreak intensity trends in 2021 using data from the Canadian COVID-19 Outbreak Surveillance System from seven provinces/territories, representing 93% of the Canadian population. A negative binomial fixed-effects model was used to assess for associations between the outcome, outbreak intensity, and characteristics of outbreaks: setting type, median age of cases, number at risk, and vaccination coverage of at least 1 dose. Also included were variables previously reported to influence SARS-CoV-2 transmission: stringency of non-pharmaceutical interventions (NPI) and the predominant SARS-CoV-2 variant detected by surveillance. Results The longest outbreaks occurred in LTCF (mean = 25.4 days) and correctional facilities (mean = 20.6 days) which also reported the largest outbreaks (mean = 29.6 cases per outbreak). Model results indicated that outbreak intensity was highest in correctional facilities. Relative to correctional facilities (referent), the second highest adjusted intensity ratio was in childcare centres (intensity ratio = 0.58 [95% CI: 0.51–0.66]), followed by LTCF (0.56 [95% CI: 0.51–0.66]). Schools had the lowest adjusted intensity ratio (0.46 [95% CI: 0.40–0.53]) despite having the highest proportion of outbreaks (37.5%). An increase in outbreak intensity was associated with increases in median age, the number at risk, and stringency of NPI. Greater vaccination coverage with at least 1 dose was associated with reduced outbreak intensity. Conclusion Descriptive and multivariable model results indicated that in Canada during 2021, outbreak intensity was greatest in closed congregate living facilities: correctional facilities and LTCF. Findings from this study support the importance of vaccination in reducing outbreak intensity when vaccines are effective against infection with circulating variants, which is especially important for closed congregate living facilities where NPIs are more challenging to implement.

Abstract For hemodialysis patients, arteriovenous fistula (AVF) patency determines whether adequate hemofiltration can be achieved, and directly influences clinical outcomes. Here, we report the development and performance of a deep learning model for automated AVF stenosis screening based on the sound of AVF blood flow using supervised learning with data validated by ultrasound. We demonstrate the importance of contextualizing the sound with location metadata as the characteristics of the blood flow sound varies significantly along the AVF. We found the best model to be a vision transformer trained on spectrogram images. Our model can screen for stenosis at a performance level comparable to that of a nephrologist performing a physical exam, but with the advantage of being automated and scalable. In a high-volume, resource-limited clinical setting, automated AVF stenosis screening can help ensure patient safety via early detection of at-risk vascular access, streamline the dialysis workflow, and serve as a patient-facing tool to allow for at-home, self-screening.

Abstract Cancer cell extravasation, a key step in the metastatic cascade, involves cancer cell arrest on the endothelium, transendothelial migration (TEM), followed by the invasion into the subendothelial extracellular matrix (ECM) of distant tissues. While cancer research has mostly focused on the biomechanical interactions between tumor cells (TCs) and ECM, particularly at the primary tumor site, very little is known about the mechanical properties of endothelial cells and the subendothelial ECM and how they contribute to the extravasation process. Here, an integrated experimental and theoretical framework is developed to investigate the mechanical crosstalk between TCs, endothelium and subendothelial ECM during in vitro cancer cell extravasation. It is found that cancer cell actin‐rich protrusions generate complex push–pull forces to initiate and drive TEM, while transmigration success also relies on the forces generated by the endothelium. Consequently, mechanical properties of the subendothelial ECM and endothelial actomyosin contractility that mediate the endothelial forces also impact the endothelium's resistance to cancer cell transmigration. These results indicate that mechanical features of distant tissues, including force interactions between the endothelium and the subendothelial ECM, are key determinants of metastatic organotropism.

Screening campaigns, especially those aimed at modulating enzyme activity, often rely on measuring substrate→product conversions. Unfortunately, the presence of endogenous substrates and/or products can limit one's ability to measure conversions. As well, coupled detection systems, often used to facilitate optical readouts, are subject to interference. Stable isotope labeled substrates can overcome background contamination and yield a direct readout of enzyme activity. Not only can isotope kinetic assays enable early screening, but they can also be used to follow hit progression in translational (pre)clinical studies. Herein, we consider a case study surrounding lipid biology to exemplify how metabolic flux analyses can connect stages of drug development, caveats are highlighted to ensure reliable data interpretations. For example, when measuring enzyme activity in early biochemical screening it may be enough to quantify the formation of a labeled product. In contrast, cell-based and in vivo studies must account for variable exposure to a labeled substrate (or precursor) which occurs via tracer dilution and/or isotopic exchange. Strategies are discussed to correct for these complications. We believe that measures of metabolic flux can help connect structure-activity relationships with pharmacodynamic mechanisms of action and determine whether mechanistically differentiated biophysical interactions lead to physiologically relevant outcomes. Adoption of this logic may allow research programs to (i) build a critical bridge between primary screening and (pre)clinical development, (ii) elucidate biology in parallel with screening and (iii) suggest a strategy aimed at in vivo biomarker development.

Abstract Regional lung cancer screening (LCS) is underway in England, involving a “lung health check” (LHC) and low-dose CT scan for those at high risk of cancer. Incidental findings from LHCs or CTs are usually referred to primary care. We describe the proportion of participants referred from the West London LCS pilot to primary care, the indications for referral, the number of general practitioner (GP) attendances and consequent changes to patient management, and provide an estimated cost-burden analysis for primary care. A small proportion (163/1542, 10.6%) of LHC attendees were referred to primary care, primarily for suspected undiagnosed chronic obstructive pulmonary disease (55/163, 33.7%) or for QRISK® (63/163, 38.7%) assessment. Ninety one of 159 (57.2%) participants consenting to follow-up attended GP appointments; costs incurred by primary care were estimated at £5.69/LHC participant. Patient management changes occurred in only 36/159 (22.6%) referred participants. LHCs result in a small increase to primary care workload provided a strict referral protocol is adhered to. Changes to patient management arising from incidental findings referrals are infrequent.

Abstract Objective: The aim of this study was to describe advertising expenditure for sugary drinks compared with alternative cold non‐alcoholic beverages (artificially sweetened beverages, plain water, plain milk) between 2016 and 2018 across Australian media channels. Methods: Monthly estimates of advertising expenditure for non‐alcoholic beverages were obtained from Nielsen Media and aggregated by product type and media. Results: Total sugary drink advertising expenditure between 2016 and 2018 ($129.5M) significantly exceeded expenditure on artificially sweetened drinks ($23.26M), plain water ($14.27M), and plain milk ($31.30M). Television and out‐of‐home advertising accounted for the largest share of sugary drink advertising (45%, 35%). Expenditure on out‐of‐home advertising was more heavily dominated by sugary drinks (75%) than advertising in all media combined (65%). Sugary drink advertising peaked in warmer months and was lowest in August. Soft drinks (26%), flavoured milks (24%) and energy drinks (21%) accounted for the majority of sugary drink advertising. Conclusions: Cold non‐alcoholic beverage advertising in Australian media is dominated by the advertising of sugary drinks. Implications for public health: Restricting unhealthy beverage advertising on television and out‐of‐home media may be most effective initially. However, comprehensive restrictions capturing a broader range of media and settings would be optimal to prevent displacement and limit advertising reach and exposure.

Both agonism and antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) lead to weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Here the authors show that this may be explained by desensitization of GIPR activity by chronic GIPR agonism in vitro and in vivo.

Background: Recent evidence suggests that the faecal immunochemical test (FIT) can rule out colorectal cancer (CRC) in symptomatic patients. To date, there is no research on usability and perception of FIT for these patients. Aim: To measure variation in attitudes and perception of FIT in patients with suspected CRC symptoms. Design & setting: A cross-sectional survey of a subset of participants of the NICE FIT study. Method: A questionnaire was co-developed with patients covering four themes on a Likert scale: FIT feasibility, faecal aversion, patient knowledge, and future intentions. Questionnaire and FIT kits were sent to patients with suspected CRC symptoms participating in the NICE FIT study. Logistic regression explored differences in patients’ test perception by ethnic group, language, age, location, deprivation, FIT use, and previous experience. Results: A total of 1151 questionnaires were analysed; 90.2% (95% confidence interval [CI] = 88.3% to 91.8%) of patients found faecal collection straightforward, 76.3% (95% CI = 73.7% to 78.6%) disagreed FIT was unhygienic, and 78.1% (95% CI = 75.6% to 80.4%) preferred FIT to colonoscopy. Preference for FIT over colonoscopy was weaker in patients aged 40–64 years than those >65 years (odds ratio [OR] 0.60; 95% CI = 0.43 to 0.84). Intention to use FIT again was stronger in patients who successfully used FIT than those unsuccessful (OR 11.08; 95% CI = 2.74 to 44.75), and white compared with non-white patients assessed (OR 3.20; 95% CI = 1.32 to 7.75). Conclusion: While most patients found FIT practical and hygienic, perception differences were found. Strategies to engage patients with more negative FIT perception should underpin symptomatic FIT pathways.

Glioblastoma’s (GBM) aggressive growth is driven by redundant activation of a myriad of signaling pathways and genomic alterations in tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), which is altered in over 50% of cases. Single agents targeting EGFR have not proven effective against GBM. In this study, we aimed to identify an effective anti-tumor regimen using pharmacogenomic testing of patient-derived GBM samples, in culture and in vivo. High-throughput pharmacological screens of ten EGFR-driven GBM samples identified the combination of erlotinib (EGFRi) and MLN0128 (a mammalian target of rapamycin inhibitor, or MTORi) as the most effective at inhibiting tumor cell viability. The anti-tumor activity of erlonitib+MLN0128 was synergistic and produced inhibition of the p-EGFR, mitogen-activated protein kinase (MAPK), and Phosphoinositide 3-kinase (PI3K) pathways in culture. Using an orthotopic murine model of GBM, we show that erlotinib+MLN0128 inhibited tumor growth in vivo and significantly prolonged the survival of tumor-bearing mice. Expression profiling of tumor tissues from treated mice revealed a unique gene signature induced by erlotinib+MLN0128, consisting of downregulation of immunosuppressive chemokines in the tumor microenvironment, including C-C motif chemokine ligand 2 (CCL2) and periostin. Lower periostin levels resulted in the inhibition of Iba1+ (tumor-promoting) macrophage infiltration of GBM xenografts. Taken together, our results demonstrate that pharmacological co-targeting of EGFR and MTOR using clinically available drugs represents an effective treatment paradigm for EGFR-driven GBMs, acting both by inhibiting tumor cell growth and modulating the immune tumor microenvironment.

Summary: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GIPR-Ab) and GLP-1 receptor (GLP-1R) agonist, by generating GIPR-Ab/GLP-1 bispecific molecules, is an approach for treating obesity and its comorbidities. In mice and monkeys, these molecules reduce body weight (BW) and improve many metabolic parameters. BW loss is greater with GIPR-Ab/GLP-1 than with GIPR-Ab or a control antibody conjugate, suggesting synergistic effects. GIPR-Ab/GLP-1 also reduces the respiratory exchange ratio in DIO mice. Simultaneous receptor binding and rapid receptor internalization by GIPR-Ab/GLP-1 amplify endosomal cAMP production in recombinant cells expressing both receptors. This may explain the efficacy of the bispecific molecules. Overall, our GIPR-Ab/GLP-1 molecules promote BW loss, and they may be used for treating obesity.

The mechanism of pathogenesis associated with APOL1 polymorphisms and risk for non-diabetic chronic kidney disease (CKD) is not fully understood. Prior studies have minimized a causal role for the circulating APOL1 protein, thus efforts to understand kidney pathogenesis have focused on APOL1 expressed in renal cells. Of the kidney cells reported to express APOL1, the proximal tubule expression patterns are inconsistent in published reports, and whether APOL1 is synthesized by the proximal tubule or possibly APOL1 protein in the blood is filtered and reabsorbed by the proximal tubule remains unclear. Using both protein and mRNA in situ methods, the kidney expression pattern of APOL1 was examined in normal human and APOL1 bacterial artificial chromosome transgenic mice with and without proteinuria. APOL1 protein and mRNA was detected in podocytes and endothelial cells, but not in tubular epithelia. In the setting of proteinuria, plasma APOL1 protein did not appear to be filtered or reabsorbed by the proximal tubule. A side-by-side examination of commercial antibodies used in prior studies suggest the original reports of APOL1 in proximal tubules likely reflects antibody non-specificity. As such, APOL1 expression in podocytes and endothelia should remain the focus for mechanistic studies in the APOL1-mediated kidney diseases.

Detection and spectroscopic measurements of gamma-ray used to rely on expensive materials such as CdZnTe crystals. Here He et al. develop a melt method to grow large size CsPbBr3 perovskite crystals and the devices achieve low cost, high energy resolving capabilities and stability.

Background: Traumatic brain injury (TBI) is a major cause of death and disability. Despite increased awareness, reliable biomarkers are urgently needed to aid in all forms of traumatic brain injury diagnosis and prognosis. Methods: Here, we aim to assess the diagnostic utility of known and novel TBI biomarkers in a pilot patient cohort of severe TBI (sTBI) patients and healthy controls. We analyzed concentrations of S100 calcium binding protein B (S100B), neuron specific enolase (NSE), human kallikrein 6 (hK6) and prostaglandin D2 synthase (PGDS) using ELISA immunoassays. Results: Plasma levels of hK6 and PGDS were significantly lower in sTBI compared with controls, while S100B and NSE were significantly higher. Furthermore, we show that ratios of NSE and S100B with hK6 and PGDS may be able to determine the presence of sTBI better than single markers alone. Conclusions: The findings presented here represent a starting point for future validation, where biomarker ratios can be tested in independent TBI cohorts.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Designing effective individualized therapies for GBM requires quality fresh tissue specimens, and a comprehensive molecular profile of this highly heterogenous neoplasm. Novel neuro-surgical approaches, such as the automated resection NICO Myriad™ system, are increasingly used by neurosurgeons to better reach the invasive front of tumors. However, no information exists on how harvesting GBM tissue using this approach may impact the translational research value of the sample. Here, we set out to characterize matched specimens from 15 patients, where one tissue sample was obtained using traditional tumor de-bulking (herein referred to as “en bloc” sample), and the other sample was obtained using the MyriadTM System (herein referred to as “Myriad” sample). We investigated the fidelity of patient derived xenografts (PDXs) for each sample type to the corresponding human tissues and evaluated the added value of sequencing both samples for each patient. Matched en bloc and Myriad samples processed in parallel, were subjected to the following assays: cell viability, self-renewal, in vivo tumorigenicity using an orthotopic model of glioma, genomic sequencing, and pharmacological testing using PI3K-MTOR pathway inhibitors. Our results demonstrate that primary GBM cultures derived from matched specimens grew at similar rates (correlation coefficient R = 0.72), generated equivalent number of neurospheres, and had equivalent tumorigenic potential in vivo (mouse survival correlation coefficient R = 0.93). DNA Sequencing using the Illumina tumor panel amplicons revealed over 70% concordance in non-synonymous mutations between matched human GBM specimens. PDX genomic profiles were also highly concordant with the corresponding patient tissues (>70%). RNA sequencing of paired GBM samples revealed unique genomic variants and differential gene expression between the en bloc and Myriad specimens, with the former molecularly resembling the “tumor core” and the latter resembling the “invasive tumor front” signature. Functionally, we show that primary-derived GBM cells—obtained after fresh specimen's dissociation—are more effectively growth-inhibited by co-targeting non-overlapping mutations enriched in each sample type, suggesting that profiling both specimens more adequately capture the molecular heterogeneity of GBM and may enhance the design accuracy and efficacy of individualized therapies.