Breathing in danger: how particulate matter pollution is putting the public at risk of lung cancer†.

We are constantly exposed to chemicals and other agents in our environment that can influence our risk of tumorigenesis, but exactly how these factors contribute to cancer development is largely unknown. Fine particulate matter measuring ≤2.5 µm (PM2.5 ) from air pollution can accumulate in alveoli, contributing to inflammation and tissue damage. Despite prior correlative studies highlighting the mortality risk, there has been a historical reluctance to lower national standards for safe PM2.5 exposure. A recent publication further highlights the attributable risk of PM2.5 exposure with lung cancer - particularly in 'never-smokers' with EGFR-driven non-small cell lung cancer. Importantly, it also elucidates a mechanistic link between PM2.5 exposure and tumorigenesis using in vivo models of EGFR non-small cell lung cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Regulation of the antigen presentation machinery in cancer and its implication for immune surveillance.

Evading immune destruction is one of the hallmarks of cancer. A key mechanism of immune evasion deployed by tumour cells is to reduce neoantigen presentation through down-regulation of the antigen presentation machinery. MHC-I and MHC-II proteins are key components of the antigen presentation machinery responsible for neoantigen presentation to CD8+ and CD4+ T lymphocytes, respectively. Their expression in tumour cells is modulated by a complex interplay of genomic, transcriptomic and post translational factors involving multiple intracellular antigen processing pathways. Ongoing research investigates mechanisms invoked by cancer cells to abrogate MHC-I expression and attenuate anti-tumour CD8+ cytotoxic T cell response. The discovery of MHC-II on tumour cells has been less characterized. However, this finding has triggered further interest in utilising tumour-specific MHC-II to harness sustained anti-tumour immunity through the activation of CD4+ T helper cells. Tumour-specific expression of MHC-I and MHC-II has been associated with improved patient survival in most clinical studies. Thus, their reactivation represents an attractive way to unleash anti-tumour immunity. This review provides a comprehensive overview of physiologically conserved or novel mechanisms utilised by tumour cells to reduce MHC-I or MHC-II expression. It outlines current approaches employed at the preclinical and clinical trial interface towards reversing these processes in order to improve response to immunotherapy and survival outcomes for patients with cancer.

Poor correlation between preclinical and patient efficacy data for tumor targeted monotherapies in glioblastoma: the results of a systematic review.

PURPOSE: Limited progress has been made in treating glioblastoma, and we hypothesise that poor concordance between preclinical and clinical efficacy in this disease is a major barrier to drug development. We undertook a systematic review to quantify this issue. METHODS: We identified phase I trials (P1Ts) of tumor targeted drugs, subsequent trial results and preceding relevant preclinical data published in adult glioblastoma patients between 2006-2019 via structured searches of EMBASE/MEDLINE/PUBMED. Detailed clinical/preclinical information was extracted. Associations between preclinical and clinical efficacy metrics were determined using appropriate non-parametric statistical tests. RESULTS: A total of 28 eligible P1Ts were identified, with median ORR of 2.9% (range 0.0-33.3%). Twenty-three (82%) had published relevant preclinical data available. Five (18%) had relevant later phase clinical trial data available. There was overall poor correlation between preclinical and clinical efficacy metrics on univariate testing. However, drugs that had undergone in vivo testing had significantly longer median overall survival (7.9 vs 5.6mo, p = 0.02). Additionally, drugs tested in ≥ 2 biologically-distinct in vivo models ('multiple models') had a significantly better median response rate than those tested using only one ('single model') or those lacking in vivo data (6.8% vs 1.2% vs. 0.0% respectively, p = 0.027). CONCLUSION: Currently used preclinical models poorly predict subsequent activity in P1Ts, and generally over-estimate the anti-tumor activity of these drugs. This underscores the need for better preclinical models to aid the development of novel anti-glioblastoma drugs. Until these become widely available and used, the use of multiple biologically-distinct in vivo models should be strongly encouraged.

Adjuvant therapies for non-muscle-invasive bladder cancer: advances during BCG shortage.

Non-muscle-invasive bladder cancer (NMIBC) represents a significant global therapeutic challenge, particularly in the era of Bacillus Calmette-Guérin (BCG) shortage. High-risk NMIBC can progress to muscle invasive or metastatic disease in 25% of patients. Optimal treatment selection, according to risk stratification, is imperative. International guidelines slightly differ in their categorisation of low, intermediate and high-risk NMIBC. Nonetheless, a single post-operative instillation of chemotherapy with Mitomycin C (MMC) or Gemcitabine improves relapse-free survival (RFS) in low-risk NMIBC. Induction and maintenance intravesical BCG remains the historical gold standard for patients with intermediate or high-risk NMIBC. However, clinicians may be forced to consider alternatives given the current BCG shortage. Both intravesical MMC and Gemcitabine have been associated with similar efficacy to BCG, albeit in smaller studies. MMC may also be manipulated using a variety of methods to potentiate its effects. BCG treatment delivery may also be modified without affecting efficacy through dose reduction and abbreviation or omission of maintenance therapy. Preliminary data also highlight that directly proceeding to radical cystectomy may not adversely affect long-term quality of life measures. Access to new systemic and intravesical therapies must be prioritised for patients with BCG recurrent or unresponsive disease. When used in conjunction with molecularly defined biomarkers, these agents herald the potential for improved survival outcomes and alleviation of the current BCG shortage.

Changes in prescribing habits for the treatment of metastatic renal clear cell carcinoma (mRCC) in Australia.

The availability of efficacious systemic therapies for metastatic clear cell renal cell carcinoma has heralded improved survival for Australians. The Pharmaceutical Benefits Schedule registry was interrogated to assess nation-wide prescribing patterns. Sunitinib remained the most commonly prescribed agent. Prescribing rates were significantly lower in Northern Territory than in other states, raising questions of disparities in access to care.

Analysing online Twitter discussions of bedwetting via a condition-specific hashtag (#Bedwetting).

AIM: Bedwetting is a common paediatric condition. #Bedwetting has been established as the official hashtag to structure Twitter discussions about the condition. We analysed online Twitter discussions for #Bedwetting. METHODS: Symplur, a Twitter analytics service was employed to aggregate Twitter activity, users and content including #Bedwetting, between October 2013 and November 2018. Activity was analysed via tweet volume and user adoption. Users were assorted using geographic location, occupation and affiliation data. Content in #Bedwetting Tweets was undertaken by retrieving information about retweets, links, frequently used words and hashtags. RESULTS: A total of 101 412 tweets and 9957 users utilising #Bedwetting were identified. Most tweets were sent with links (93%). The average ± SD number of tweets using #Bedwetting per month increased from 96 ± 87 in 2013 to 2935 ± 1644 in 2015. Tweet volume decreased to 1960 ± 257 in 2016 and subsequently increased to 2901 ± 1110 in 2017. New users increased from 4 in 2013 to 9957 users in 2018. Users tweeted from 69 countries. Advocacy organisations comprised 35% of the top 100 influencers. Common words in #Bedwetting tweets were 'potty', 'best' and 'training'. Popular associated hashtags were #Pottytraining, #Solutions and #Moms. Hyperlinks in #Bedwetting tweets included advocacy, academic and commercial websites. CONCLUSIONS: Our analysis of #Bedwetting highlights that Twitter is frequently used to discuss the condition's diagnosis and management. Various stakeholders in health care are utilising the platform to build awareness about bedwetting. We identified that Twitter is being employed to drive web traffic to other internet websites.

The Association Between Pelvic Discomfort and Erectile Dysfunction in Adult Male Bicyclists.

BACKGROUND: Bicycle riding's impact on erectile function remains a topic of great interest given cycling's popularity as a mode of transportation and exercise. AIM: We evaluated risk factors for sexual dysfunction in male cyclists with the primary intention of determining if genital/pelvic pain and numbness are associated with erectile dysfunction (ED). METHODS: We surveyed male cyclists using an online anonymous questionnaire. Cyclists were queried on their demographics, cycling experience, and sexual function using the Sexual Health Inventory for Men (SHIM). ED was diagnosed when a completed SHIM score was <22. Regression analysis was used to evaluate the risk of ED in men with genital/pelvic pain or numbness after riding. The survey was designed in the United States. OUTCOMES: Quantitative characterization of cycling habits, onset and timing of genital pain and numbness, and SHIM score. RESULTS: A total of 1635 participants completed the survey. A majority of men were over the age of 50 (58%, 934/1,607), Caucasian (88%, 1,437/1,635), had been active cyclists for over 10 years (63%, 1,025/1,635) and used road bikes (97%, 1,578/1,635). Overall, 22%, 30%, and 57% of men reported ED, genital pain, and genital numbness, respectively. While controlling for cohort demographics, body mass index, cycling intensity and equipment, and medical comorbidities, no saddle characteristics were associated with the risk of developing genital numbness. However, men reporting penile numbness were at higher risk of reporting ED (odds ratio [OR] = 1.453, P = .048). In addition, quicker onset of numbness and resolution of numbness within a day was associated with impaired erectile function. For example, numbness occurring less than 1 hour after cycling had greater odds of leading to ED than numbness after 5 hours (OR = 2.002, P = .032). Similarly, genital pain occurring less than 1 hour (OR = 2.466, P = .031) after cycling was associated with higher ED risk. STRENGTHS & LIMITATIONS: Strengths include a large sample size of high-intensity cyclists and validated questionnaire use. Limitations include reliance on anonymous self-reported survey data and minimal inquiry into the riding preferences and terrain traversed by cyclists. CONCLUSIONS: Pelvic pain and numbness are common complaints among male riders in the United States. Men with such complaints are more likely to also report ED especially if it occurs earlier in the ride. Although direction of causality and temporality are uncertain, alleviation of factors resulting in pelvic discomfort may reduce cycling's impact on sexual function. Such interventions are critical given that cycling for both active travel and aerobic exercise confers numerous health benefits. Balasubramanian A, Yu J, Breyer BN, et al. The Association Between Pelvic Discomfort and Erectile Dysfunction in Adult Male Bicyclists. J Sex Med 2020;17:919-929.

Testosterone Imposters: An Analysis of Popular Online Testosterone Boosting Supplements.

INTRODUCTION: Testosterone-boosting supplements (T-Boosters) are prominently featured on Amazon.com, with numerous dedicated pages and claims that they "naturally" increase testosterone levels. AIM: To evaluate the highest rated and frequently reviewed T-Boosters on Amazon.com to facilitate patient counseling regarding marketing myths, T-Booster formulations, and evidence for efficacy and safety. METHODS: The Amazon marketplace was queried using the key words "testosterone" + "booster," with default search settings and ranking items based on relevance. The top 5 T-Boosters identified on July 22, 2018, were reviewed based on price, ratings, reviews, manufacturer details, and ingredients. Consumer reviews were categorized using core themes in the Androgen Deficiency in the Aging Male (ADAM) questionnaire as a proxy to understand T-Booster efficacy and reanalyzed after filtration of untrustworthy comments using ReviewMeta.com, a proprietary Amazon customer review analysis software. MAIN OUTCOME MEASURES: Quantitative and qualitative evaluation of T-Boosters on Amazon.com was performed. RESULTS: The top 5 T-Boosters had an average ± SD of 2,761 ± 5,112 reviews and a rating of 4.56 ± 0.25 stars. 19 unique ingredients were identified across these T-Boosters, and literature review revealed 191 studies involving the 10 most common ingredients, of which 19% involved human subjects, 53% animal models, 15% in vitro studies, and 12% case reports or review articles. Among 37 human studies, 30% observed an increase in T levels, 3% a decrease, 46% no effect, and 22% were indeterminate. Analysis of top customer reviews from the first 2 pages of reviews for each supplement revealed differences in the ADAM score before and after ReviewMeta.com filtration. After filtration, there was a 91% decrease in users reporting increased libido, a 59% decrease in reports of increased energy, a 93% decrease in reports of improved strength/endurance, a 60% decrease in reports of improved erections, an elimination of reports of improved work performance, a 67% decrease in reports of improved sleep, and an 89% decrease in reports of improved sports ability. CLINICAL IMPLICATIONS: Our study can serve as a guide for providers to counsel patients about the efficacy of popular online T-Boosters as well as the prevalence of disingenuous reviews associated with these products on online marketplaces like Amazon.com. STRENGTHS & LIMITATIONS: Strengths include the novel approach to assess consumers' perceptions and satisfaction of T-Boosters, as well as summary information that clinicians can provide patients. Limitations include selection bias, a small number of supplements analyzed, and the proprietary nature of the Amazon review analysis software. CONCLUSION: T-Boosters are easily available online. Our investigation revealed that limited human studies have evaluated T-Boosters, resulting in no definitive findings of efficacy. In the absence of additional human studies, patients should be cautioned before considering T-Boosters, given the availability of highly effective therapies approved by the Food and Drug Administration. Balasubramanian A, Thirumavalavan N, Srivatsav A, et al. Testosterone Imposters: An Analysis of Popular Online Testosterone Boosting Supplements. J Sex Med 2019;16:203-212.

An Analysis of Popular Online Erectile Dysfunction Supplements.

INTRODUCTION: Erectile dysfunction supplements (ED-Ss) are featured on online marketplaces like Amazon.com, with dedicated pages and claims that they naturally treat ED. However, their efficacy and safety are largely unknown, limiting the ability to counsel patients regarding their use. AIM: To evaluate the highest rated and most frequently reviewed ED-Ss on Amazon.com to facilitate patient counseling regarding marketing myths, ingredient profiles, and evidence for product efficacy and safety. METHODS: The Amazon marketplace was queried using the key term "erectile dysfunction" with default search settings and ranking items based on relevance. The top 6 ED-S products identified on September 29, 2018, were reviewed based on price, ratings, reviews, manufacturer, and ingredients. Consumer reviews were categorized using subtopics within the International Index of Erectile Function (IIEF) questionnaire to better understand ED-S efficacy and then reanalyzed following filtration of untrustworthy comments using ReviewMeta.com, a proprietary Amazon review analysis software. OUTCOMES: Quantitative and qualitative evaluation of ED-S products sold on Amazon.com. RESULTS: The top 6 ED-Ss had an average of 2,121 ± 1,282 reviews and a mean rating of 3.92 ± 0.42 stars. A total of 21 ingredients were identified in these ED-Ss. Ginseng, horny goat weed, L-arginine, and tongkat ali were the most popular ingredients included in the analyzed products. Our literature review identified 413 studies involving the 21 identified ingredients, of which 59 (16%) involved human subjects. Among these 69 human studies, only 12 (17%) investigated supplement ingredients individually and reported improvement in ED. Analysis of top-ranked customer reviews from the first 2 pages of reviews for each supplement revealed differences in IIEF scores before and after ReviewMeta.com filtration. After filtration, we observed a 77% decrease in reviews reporting improved erection strength, an 83% decrease in reviews reporting improved ability to maintain erection, a 90% decrease in reviews reporting increased sexual satisfaction, an 88% decrease in reviews reporting increased enjoyment with intercourse, and an 89% decrease in reviews reporting increased erection confidence. STRENGTHS & LIMITATIONS: Study strengths include a novel approach to ascertaining consumers' perceptions and satisfaction with ED-Ss and practical summary information that clinicians can provide to patients. Limitations include selection bias, the small number of supplements analyzed, and the proprietary nature of the Amazon review analysis software. CONCLUSIONS: Our investigation revealed that human studies evaluating the efficacy of ED-S ingredients are limited and have yielded no definitive findings of the effects on ED. Patients considering ED-S use should receive appropriate counseling, given the prevalence of disingenuous reviews and the ready availability of Food and Drug Administration-approved drug therapies. Balasubramanian A, Thirumavalavan N, Srivatsav A, et al. An Analysis of Popular Online Erectile Dysfunction Supplements. J Sex Med 2019;16:843-852.

Salvage topical therapy for upper tract urothelial carcinoma.

PURPOSE: Topical therapy (TT) for upper tract urothelial carcinoma (UTUC) has been explored as a kidney sparing approach to treat carcinoma in situ (CIS) and as adjuvant for endoscopically treated Ta/T1 tumors. In bladder cancer, data support use of salvage TT for repeat induction. We investigate the outcomes of salvage TT for UTUC in patients ineligible for or refusing nephroureterectomy. METHODS: A single-center retrospective review on patients receiving salvage TT via percutaneous nephrostomy tube or cystoscopically placed ureteral catheters was performed. Primary outcome was response to therapy based on International Bladder Cancer Group criteria. RESULTS: 51 patients with 58 renal units (RUs) received TT. Of these, 17 patients with 18 RUs received the second-line TT, with a median follow-up of 36.5 months (IQR 24.5-67 months). 44% (8/18) received salvage TT for refractory disease and 56% (10/18) as reinduction. 5 RUs with CIS were unresponsive to initial TT and went on to receive salvage TT, of which 20% (1/5) responded. 13 RUs recurred or relapsed following initial TT and received salvage TT for papillary tumors, with 62% (8/13) responding. CONCLUSION: Our data provide preliminary clinical rationale for the second-line TT for refractory and recurrent, endoscopically managed papillary UTUC in patients ineligible for or refusing nephroureterectomy. However, refractory upper tract CIS appears to have poor response to salvage TT.

Transient receptor potential melastatin 8 channel inhibition potentiates the hypothermic response to transient receptor potential vanilloid 1 activation in the conscious mouse.

OBJECTIVES: Mild decrease in core temperature (therapeutic hypothermia) provides lasting neuroprotection following cardiac arrest or cerebral ischemia. However, current methods for producing therapeutic hypothermia trigger a cold-defense response that must be countered by sedatives, muscle paralytics, and mechanical ventilation. We aimed to determine methods for producing hypothermia in the conscious mouse by targeting two transient receptor potential channels involved in thermoregulation, two transient receptor potential (TRP) channels involved in thermoregulation, TRP vanilloid 1 (TRPV1) and TRP melastatin 8 (TRPM8). DESIGN: Controlled prospective animal study. SETTING: Research laboratory at academic medical center. SUBJECTS: Conscious unrestrained young and aged male mice. INTERVENTIONS: Mice were treated with the TRPV1 agonist dihydrocapsaicin, a TRPM8 inhibitor ("compound 5"), or their combination and the effects on core temperature (Tcore) were measured by implanted thermocouples and wireless transponders. MEASUREMENTS AND MAIN RESULTS: TRPV1 agonist dihydrocapsaicin produced a dose-dependent (2-4 mg/kg s.c.) drop in Tcore. A loading dose followed by continuous infusion of dihydrocapsaicin produced a rapid and prolonged (> 6 hr) drop of Tcore within the therapeutic range (32-34°C). The hypothermic effect of dihydrocapsaicin was augmented in aged mice and was not desensitized with repeated administration. TRPM8 inhibitor "compound 5" (20 mg/kg s.c.) augmented the drop in core temperature during cold exposure (8°C). When "compound 5" (30 mg/kg) was combined with dihydrocapsaicin (1.25-2.5 mg/kg), the drop in Tcore was amplified and prolonged. CONCLUSIONS: Activating warm receptors (TRPV1) produced rapid and lasting hypothermia in young and old mice. Furthermore, hypothermia induced by TRPV1 agonists was potentiated and prolonged by simultaneous inhibition of TRPM8.

Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion.

Traditional methods of therapeutic hypothermia show promise for neuroprotection against cerebral ischemia-reperfusion (I/R), however, with limitations. We examined effectiveness and specificity of pharmacological hypothermia (PH) by transient receptor potential vanilloid 1 (TRPV1) channel agonism in the treatment of focal cerebral I/R. Core temperature (T(core)) was measured after subcutaneous infusion of TRPV1 agonist dihydrocapsaicin (DHC) in conscious C57BL/6 WT and TRPV1 knockout (KO) mice. Acute measurements of heart rate (HR), mean arterial pressure (MAP), and cerebral perfusion were measured before and after DHC treatment. Focal cerebral I/R (1 h ischemia + 24 h reperfusion) was induced by distal middle cerebral artery occlusion. Hypothermia (>8 h) was initiated 90 min after start of reperfusion by DHC infusion (osmotic pump). Neurofunction (behavioral testing) and infarct volume (TTC staining) were measured at 24 h. DHC (1.25 mg/kg) produced a stable drop in T(core) (33°C) in naive and I/R mouse models but not in TRPV1 KO mice. DHC (1.25 mg/kg) had no measurable effect on HR and cerebral perfusion but produced a slight transient drop in MAP (<6 mmHg). In stroke mice, DHC infusion produced hypothermia, decreased infarct volume by 87%, and improved neurofunctional score. The hypothermic and neuroprotective effects of DHC were absent in TRPV1 KO mice or mice maintained normothermic with heat support. PH via TRPV1 agonist appears to be a well-tolerated and effective method for promoting mild hypothermia in the conscious mouse. Furthermore, TRPV1 agonism produces effective hypothermia in I/R mice and significantly improves outcome when initiated 90 min after start of reperfusion.

Deep Learning Prostate MRI Segmentation Accuracy and Robustness: A Systematic Review.

Purpose To investigate the accuracy and robustness of prostate segmentation using deep learning across various training data sizes, MRI vendors, prostate zones, and testing methods relative to fellowship-trained diagnostic radiologists. Materials and Methods In this systematic review, Embase, PubMed, Scopus, and Web of Science databases were queried for English-language articles using keywords and related terms for prostate MRI segmentation and deep learning algorithms dated to July 31, 2022. A total of 691 articles from the search query were collected and subsequently filtered to 48 on the basis of predefined inclusion and exclusion criteria. Multiple characteristics were extracted from selected studies, such as deep learning algorithm performance, MRI vendor, and training dataset features. The primary outcome was comparison of mean Dice similarity coefficient (DSC) for prostate segmentation for deep learning algorithms versus diagnostic radiologists. Results Forty-eight studies were included. Most published deep learning algorithms for whole prostate gland segmentation (39 of 42 [93%]) had a DSC at or above expert level (DSC ≥ 0.86). The mean DSC was 0.79 ± 0.06 (SD) for peripheral zone, 0.87 ± 0.05 for transition zone, and 0.90 ± 0.04 for whole prostate gland segmentation. For selected studies that used one major MRI vendor, the mean DSCs of each were as follows: General Electric (three of 48 studies), 0.92 ± 0.03; Philips (four of 48 studies), 0.92 ± 0.02; and Siemens (six of 48 studies), 0.91 ± 0.03. Conclusion Deep learning algorithms for prostate MRI segmentation demonstrated accuracy similar to that of expert radiologists despite varying parameters; therefore, future research should shift toward evaluating segmentation robustness and patient outcomes across diverse clinical settings. Keywords: MRI, Genital/Reproductive, Prostate Segmentation, Deep Learning Systematic review registration link: osf.io/nxaev © RSNA, 2024.

Trends in Opioid and Nonsteroidal Anti-Inflammatory Drug Use for Patients with Kidney Stones in United States Emergency Departments from 2015 to 2021.

Introduction: Renal colic is frequently treated with opioids; however, narcotic analgesic use can lead to dependence and abuse. We evaluated use trends of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management of kidney stones in United States emergency departments (EDs) from 2015 to 2021. Methods: Kidney stone encounters were identified using National Hospital Ambulatory Medical Care Survey data. We applied a multistage survey weighting procedure to account for selection probability, nonresponse, and population weights. Medication use trends were estimated through logistic regressions on the timing of the encounter, adjusted for selected demographic and clinical characteristics. Results: Between 2015 and 2021, there were an estimated 9,433,291 kidney stone encounters in United States EDs. Opioid use decreased significantly (annual odds ratio [OR]: 0.87, p = 0.003), and there was no significant trend in NSAID use. At discharge, male patients were more likely than females (OR: 1.93, p = 0.001) to receive opioids, and Black patients were less likely than White patients (OR: 0.34, p = 0.010) to receive opioids. Regional variation was also observed, with higher odds of discharge prescriptions in the West (OR: 3.15, p = 0.003) and Midwest (OR: 2.49, p = 0.010), compared with the Northeast. Thirty-five percent of patients received opioids that were stronger than morphine. Conclusion: These results suggest improved opioid stewardship from ED physicians in response to the national opioid epidemic. However, regional variation as well as disparities in discharge prescriptions for Black and female patients underscore opportunities for continued efforts.

Genetic sex validation for sample tracking in next-generation sequencing clinical testing.

OBJECTIVE: Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups. RESULTS: Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors (49.09%), samples from transgender participants (3.64%) and stem cell or bone marrow transplant patients (7.27%) along with undetermined sample mix-ups (40%) for which sample swaps occurred prior to arrival at genome centers, however the exact cause of the events at the sampling sites resulting in the mix-ups were not able to be determined.

Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition.

Mild decrease of core temperature (32-34°C), also known as therapeutic hypothermia, is a highly effective strategy of neuroprotection from ischemia and holds significant promise in the treatment of stroke. However, induction of hypothermia in conscious stroke patients is complicated by cold-defensive responses, such as shivering and tachycardia. Although multiple thermoregulatory responses may be altered by modulators of thermosensitive ion channels, TRPM8 (transient receptor potential melastatin 8) and TRPV1 (TRP vanilloid 1), it is unknown whether these agents affect cold-induced shivering and tachycardia. The current study aimed to determine the effects of TRPM8 inhibition and TRPV1 activation on the shivering and tachycardic responses to external cooling. Conscious mice were treated with TRPM8 inhibitor compound 5 or TRPV1 agonist dihydrocapsaicin (DHC) and exposed to cooling at 10°C. Shivering was measured by electromyography using implanted electrodes in back muscles, tachycardic response by electrocardiography, and core temperature by wireless transmitters in the abdominal cavity. The role of TRPM8 was further determined using TRPM8 KO mice. TRPM8 ablation had no effect on total electromyographic muscle activity (vehicle: 24.0 ± 1.8; compound 5: 23.8 ± 2.0; TRPM8 KO: 19.7 ± 1.9 V·s/min), tachycardia (ΔHR = 124 ± 31; 121 ± 13; 121 ± 31 beats/min) and drop in core temperature (-3.6 ± 0.1; -3.4 ± 0.4; -3.6 ± 0.5°C) during cold exposure. TRPV1 activation substantially suppressed muscle activity (vehicle: 25.6 ± 3.0 vs. DHC: 5.1 ± 2.0 V·s/min), tachycardia (ΔHR = 204 ± 25 vs. 3 ± 35 beats/min) and produced a profound drop in core temperature (-2.2 ± 0.6 vs. -8.9 ± 0.6°C). In conclusion, external cooling-induced shivering and tachycardia are suppressed by TRPV1 activation, but not by TRPM8 inhibition. This suggests that TRPV1 agonists may be combined with external physical cooling to achieve more rapid and effective hypothermia.