IL7 in combination with radiotherapy stimulates a memory T-cell response to improve outcomes in HNSCC models.

Clinically approved head and neck squamous cell carcinoma (HNSCC) immunotherapies manipulate the immune checkpoint blockade (ICB) axis but have had limited success outside of recurrent/metastatic disease. Interleukin-7 (IL7) has been shown to be essential for effector T-cell survival, activation, and proliferation. Here, we show that IL7 in combination with radiotherapy (RT) is effective in activating CD8 + T-cells for reducing tumor growth. Our studies were conducted using both human papillomavirus related and unrelated orthotopic HNSCC murine models. Immune populations from the tumor, draining lymph nodes, and blood were compared between treatment groups and controls using flow cytometry, proteomics, immunofluorescence staining, and RNA sequencing. Treatment with RT and IL7 (RT + IL7) resulted in significant tumor growth reduction, high CD8 T-cell tumor infiltration, and increased proliferation of T-cell progenitors in the bone marrow. IL7 also expanded a memory-like subpopulation of CD8 T-cells. These results indicate that IL7 in combination with RT can serve as an effective immunotherapy strategy outside of the conventional ICB axis to drive the antitumor activity of CD8 T-cells.

The dichotomy of regulatory B cells in cancer versus allergic disease.

Regulatory B cells (Bregs) are an immunosuppressive cell phenotype that affects the immune system by limiting the inflammatory cascade. Dysregulation of Bregs can interestingly play a dichotomous role in the pathophysiology of many diseases and is especially highlighted when examining cancer pathology compared to allergic disease. This study reviews the existing literature on Bregs and compares their role in allergic disease in contrast to cancer development. Upregulation of Bregs in cancer states has been associated with poor prognostic outcomes across various cancer types, and Breg proliferation was associated with chronic interferon signaling, activation of the BCR-BTK (B cell receptor-Bruton's tyrosine kinase) pathway, and release of C-X-C motif ligand 13. In contrast, Breg dysfunction has been identified as a key mechanism in many allergic diseases, such as allergic asthma, allergic rhinitis, atopic dermatitis, and contact dermatitis. Development of Breg-targeted immunotherapies is currently at the preclinical level, but strategies differentially focus on Breg depletion in cancer versus Breg stimulation in allergy. Our review highlights the divergent functions that Bregs play in cancer compared to allergy. We conclude that natural homeostasis hinges on a fine balance between the dichotomous role of Bregs-over or underactivation can result in a pathological state.

Method for Testing Etiologic Heterogeneity Among Noncompeting Diagnoses, Applied to Impact of Perinatal Exposures on Autism and Attention Deficit Hyperactivity Disorder.

BACKGROUND: Testing etiologic heterogeneity, whether a disorder subtype is more or less impacted by a risk factor, is important for understanding causal pathways and optimizing statistical power. The study of mental health disorders especially benefits from strategic subcategorization because these disorders are heterogeneous and frequently co-occur. Existing methods to quantify etiologic heterogeneity are not appropriate for noncompeting events in an open cohort of variable-length follow-up. Thus, we developed a new method. METHODS: We estimated risks from urban residence, maternal smoking during pregnancy, and parental psychiatric history, with subtypes defined by the presence or absence of a codiagnosis: autism alone, attention deficit hyperactivity disorder (ADHD) alone, and joint diagnoses of autism + ADHD. To calculate the risk of a single diagnosis (e.g., autism alone), we subtracted the risk for autism + ADHD from the risk for autism overall. We tested the equivalency of average risk ratios over time, using a Wald-type test and bootstrapped standard errors. RESULTS: Urban residence was most strongly linked with autism + ADHD and least with ADHD only; maternal smoking was associated with ADHD only but not autism only; and parental psychiatric history exhibited similar associations with all subgroups. CONCLUSION: Our method allowed the calculation of appropriate P values to test the strength of association, informing etiologic heterogeneity wherein two of these three risk factors exhibited different impacts across diagnostic subtypes. The method used all available data, avoided neurodevelopmental outcome misclassification, exhibited robust statistical precision, and is applicable to similar heterogeneous complex conditions using common diagnostic data with variable follow-up.

Meaning-centered pain coping skills training for patients with metastatic cancer: Results of a randomized controlled pilot trial.

OBJECTIVE: For patients with advanced cancer, pain is a common and debilitating symptom that can negatively impact physical, emotional, and spiritual well-being. This trial examined the feasibility and initial effects of Meaning-Centered Pain Coping Skills Training (MCPC), a cognitive-behavioral pain management intervention with an emphasis on enhancing meaning (i.e., a personal sense of purpose, worth, and significance) and peace. METHODS: We enrolled 60 adults with stage IV solid tumor cancers and moderate-severe pain between February 2021 and February 2022. Participants were randomized 1:1 to MCPC + usual care or usual care alone. Meaning-Centered Pain Coping Skills Training consisted of four weekly 60-min individual sessions via videoconference or telephone, delivered by a trained therapist using a manualized protocol. Participants completed validated measures of pain severity, pain interference, pain self-efficacy, spiritual well-being (i.e., meaning, peace, and faith), and psychological distress at baseline and 5-week and 10-week follow-ups. RESULTS: All feasibility metrics exceeded prespecified benchmarks. Fifty-eight percent of screened patients were eligible, and 69% of eligible patients consented. Of those assigned to MCPC, 93% completed all sessions and 100% of those who completed follow-ups reported using coping skills weekly. Retention was strong at 5-week (85%) and 10-week (78%) follow-ups. Meaning-Centered Pain Coping Skills Training participants reported better scores than control participants across outcome measures, including moderate-to-large sized differences at 10-week follow-up in pain severity (Cohen's d = -0.75 [95% confidence interval: -1.36, -0.14]), pain interference (d = -0.82 [-1.45, -0.20]), and pain self-efficacy (d = 0.74 [0.13, 1.35]). CONCLUSIONS: MCPC is a highly feasible, engaging, and promising approach for improving pain management in advanced cancer. Future efficacy testing is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04431830, registered 16 June 2020.

Organoids as research models for hepatocellular carcinoma.

Organoid culture is an emerging research tool that has proved tremendously useful in a multitude of aspects, one of which is cancer research. They largely overcome the limitations of previous cancer models by their faithful recapitulation of the in vivo biology, while still remaining amenable to perturbations. Using a cocktail of biologicals that mimic the stem cell niche signaling, hepatocellular carcinoma (HCC) organoids could be generated from tissue samples of both human and murine origin. Existing reports show that HCC organoids retain key characteristics of their parental tumor tissue, including the histological architecture, genomic landscape, expression profile and intra-tumor heterogeneity. There is ongoing effort to establish living biobanks of patient-derived cancer organoids, annotated with multi-omics data and clinical data, and they can be particularly valuable in stratification of HCC subtypes, pre-clinical drug discovery and personalized medicine. In the future, efforts in the standardization of procedures and nomenclature, refinement of protocols, as well as engineering of the culture systems will enable scientists to unleash the full potential of organoid technology.

Neurocognitive Outcomes in Multiethnic Pediatric Brain Tumor Patients Treated With Proton Versus Photon Radiation.

BACKGROUND: We analyzed post-radiation (RT) neurocognitive outcomes in an ethnically diverse pediatric brain tumor population undergoing photon radiotherapy (XRT) and proton radiotherapy (PRT). PROCEDURE: Post-RT neurocognitive outcomes from 49 pediatric patients (37% Hispanic/Latino) with primary brain tumors were analyzed. Tests included cognitive outcomes, behavioral outcomes, and overall intelligence. For each outcome, proportion of patients with cognitive impairment (scores <1.5 SD) was calculated. The Fisher exact tests compared proportion of patients with impairment and t tests compared T-scores between XRT (n=32) and PRT (n=17) groups. Linear regression assessed associations between radiation modality and outcomes. RESULTS: Median follow-up was 3.2 and 1.8 years in the XRT and PRT groups, respectively. The median RT dose was 54.0 Gy. We found impairment in 16% to 42% of patients across most neurocognitive domains except executive function. There was no difference in scores between XRT and PRT groups. Regression analyses revealed no association of neurocognitive outcomes with radiation modality. Non-Hispanic patients had better Verbal Comprehension Index and General Ability Index scores than Hispanic patients ( P <0.05). CONCLUSIONS: Among pediatric patients with brain tumors receiving RT, all cognitive domains were affected except executive function. Radiation modality was not associated with neurocognitive outcomes. Hispanic patients may be more vulnerable to posttreatment cognitive effects that warrant further study.

The Mental and Physical Health of Mothers of Children with Special Health Care Needs in the United States.

OBJECTIVE: To determine the prevalence of poor mental and physical health among mothers of children with special health care needs (CSHCN) and to determine the association between maternal health and the child's number of special health care needs (SHCN) and severity of ability limitation. METHODS: We used the combined 2016-2018 National Survey of Children's Health Dataset of 102,341 children ages 0-17 including 23,280 CSHCN. We used regression models to examine the associations of a child's number of SHCN and ability limitations with maternal health. RESULTS: Twice as many mothers of CSHCN had poor mental and physical health compared to non-CSHCN (mental 10.3% vs. 4.0%, p < .001; physical 11.9% vs 5.0%, p < .001). In regression models, increased number of SHCN and severity of activity limitations were associated with significantly increased odds of poor maternal health. CONCLUSIONS FOR PRACTICE: Mothers of CSHCN have worse health compared to mothers of non-CSHCN, especially those who experience social disadvantage and those with children with complex SHCN or severe ability limitations. Interventions to improve the health of these particularly vulnerable caregivers of CSHCN are warranted.

Evaluation of U.S. state opioid prescribing restrictions using patient opioid consumption patterns from a single, urban, academic institution.

Background: Since 2017, states, insurers, and pharmacies have placed blanket limits on the duration and quantity of opioid prescriptions. In many states, overlapping duration and daily dose limits yield maximum prescription limits of 150-350 morphine milligram equivalents (MMEs). There is limited knowledge of how these restrictions compare with actual patient opioid consumption; while changes in prescription patterns and opioid misuse rates have been studied, these are, at best, weak proxies for actual pain control consumption. We sought to determine how patients undergoing surgery would be affected by opioid prescribing restrictions using actual patient opioid consumption data. Methods: We constructed a prospective database of post-discharge opioid consumption: patients undergoing surgery at one institution were called after discharge to collect opioid consumption data. Patients whose opioid consumption exceeded 150 and 350 MME were identified. Results: Two thousand nine hundred and seventy-one patients undergoing 54 common surgical procedures were included in our study. Twenty-one percent of patients consumed more than the 150 MME limit. Only 7% of patients consumed above the 350 MME limit. Typical (non-outlier) opioid consumption, defined as less than the 75th percentile of consumption for any given procedure, exceeded the 150 MME and 350 MME limits for 41 and 7% of procedures, respectively. Orthopedic, spinal/neurosurgical, and complex abdominal procedures most commonly exceeded these limits. Conclusions: While most patients undergoing surgery are unaffected by recent blanket prescribing limits, those undergoing a specific subset of procedures are likely to require more opioids than the restrictions permit; providers should be aware that these patients may require a refill to adequately control post-surgical pain. Real consumption data should be used to guide these restrictions and inform future interventions so the risk of worsened pain control (and its troublesome effects on opioid misuse) is minimized. Procedure-specific prescribing limits may be one approach to prevent misuse, while also optimizing post-operative pain control.

Evaluation of the 6-item Identify Chronic Migraine screener in a large medical group.

OBJECTIVE: To evaluate the sensitivity and specificity of the 6-item Identify Chronic Migraine screener (ID-CM[6]), designed to improve the detection of chronic migraine (CM). BACKGROUND: CM is often undertreated and underdiagnosed. Survey-based studies have found that approximately 75-80% of people meeting criteria for CM do not report having received an accurate diagnosis. METHODS: This study used claims data of patients enrolled in a large medical group who had at least one medical claim with an International Classification of Diseases 9th/10th revision diagnostic code for migraine in the 12-month prescreening period. The Identify Chronic Migraine survey was administered by e-mail, in-person, or over the telephone to all enrolled patients. A Semi-Structured Diagnostic Interview (SSDI) was administered by telephone by a trained physician. The ID-CM(6) and SSDI classifications of CM status were compared to evaluate sensitivity and specificity of the ID-CM(6) screening tool. RESULTS: The analysis of the ID-CM(6) screening tool included 109 patients, with 65/109 (59.6%) positive for CM based on the SSDI. The mean (standard deviation) age of the patient sample was 49 (15) years and 100/109 (91.7%) were female. Using the SSDI as the diagnostic gold standard, the ID-CM(6) had a sensitivity of 70.8% (46/65) and a specificity of 93.2% (41/44). CONCLUSION: The ID-CM(6) demonstrated acceptable sensitivity and good specificity in determining CM status. The results of this analysis support the real-world utility of the ID-CM(6) as a simple and useful tool to identify patients with CM.

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.

Kinetics and Optimization of the Lysine-Isopeptide Bond Forming Sortase Enzyme from Corynebacterium diphtheriae.

Site-specifically modified protein bioconjugates have important applications in biology, chemistry, and medicine. Functionalizing specific protein side chains with enzymes using mild reaction conditions is of significant interest, but remains challenging. Recently, the lysine-isopeptide bond forming activity of the sortase enzyme that builds surface pili in Corynebacterium diphtheriae (CdSrtA) has been reconstituted in vitro. A mutationally activated form of CdSrtA was shown to be a promising bioconjugating enzyme that can attach Leu-Pro-Leu-Thr-Gly peptide fluorophores to a specific lysine residue within the N-terminal domain of the SpaA protein (NSpaA), enabling the labeling of target proteins that are fused to NSpaA. Here we present a detailed analysis of the CdSrtA catalyzed protein labeling reaction. We show that the first step in catalysis is rate limiting, which is the formation of the CdSrtA-peptide thioacyl intermediate that subsequently reacts with a lysine ε-amine in NSpaA. This intermediate is surprisingly stable, limiting spurious proteolysis of the peptide substrate. We report the discovery of a new enzyme variant (CdSrtAΔ) that has significantly improved transpeptidation activity, because it completely lacks an inhibitory polypeptide appendage ("lid") that normally masks the active site. We show that the presence of the lid primarily impairs formation of the thioacyl intermediate and not the recognition of the NSpaA substrate. Quantitative measurements reveal that CdSrtAΔ generates its cross-linked product with a catalytic turnover number of 1.4 ± 0.004 h-1 and that it has apparent KM values of 0.16 ± 0.04 and 1.6 ± 0.3 mM for its NSpaA and peptide substrates, respectively. CdSrtAΔ is 7-fold more active than previously studied variants, labeling >90% of NSpaA with peptide within 6 h. The results of this study further improve the utility of CdSrtA as a protein labeling tool and provide insight into the enzyme catalyzed reaction that underpins protein labeling and pilus biogenesis.

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.

Development of a claims-based algorithm to identify potentially undiagnosed chronic migraine patients.

OBJECTIVE: To develop a claims-based algorithm to identify undiagnosed chronic migraine among patients enrolled in a healthcare system. METHODS: An observational study using claims and patient survey data was conducted in a large medical group. Eligible patients had an International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) migraine diagnosis, without a chronic migraine diagnosis, in the 12 months before screening and did not have a migraine-related onabotulinumtoxinA claim in the 12 months before enrollment. Trained clinicians administered a semi-structured diagnostic interview, which served as the gold standard to diagnose chronic migraine, to enrolled patients. Potential claims-based predictors of chronic migraine that differentiated semi-structured diagnostic interview-positive (chronic migraine) and semi-structured diagnostic interview-negative (non-chronic migraine) patients were identified in bivariate analyses for inclusion in a logistic regression model. RESULTS: The final sample included 108 patients (chronic migraine = 64; non-chronic migraine = 44). Four significant predictors for chronic migraine were identified using claims in the 12 months before enrollment: ≥15 versus <15 claims for acute treatment of migraine, including opioids (odds ratio = 5.87 [95% confidence interval: 1.34-25.63]); ≥24 versus <24 healthcare visits (odds ratio = 2.80 [confidence interval: 1.08-7.25]); female versus male sex (odds ratio = 9.17 [confidence interval: 1.26-66.50); claims for ≥2 versus 0 unique migraine preventive classes (odds ratio = 4.39 [confidence interval: 1.19-16.22]). Model sensitivity was 78.1%; specificity was 72.7%. CONCLUSIONS: The claims-based algorithm identified undiagnosed chronic migraine with sufficient sensitivity and specificity to have potential utility as a chronic migraine case-finding tool using health claims data. Research to further validate the algorithm is recommended.

Palliative care use amongst patients with bladder cancer.

OBJECTIVES: To describe the rate and determinants of palliative care use amongst Medicare beneficiaries with bladder cancer and encourage a national dialogue on improving coordinated urological, oncological, and palliative care in patients with genitourinary malignancies. PATIENTS AND METHODS: Using Surveillance, Epidemiology, and End Results-Medicare data, we identified patients diagnosed with muscle-invasive bladder cancer (MIBC) between 2008 and 2013. Our primary outcome was receipt of palliative care, defined as the presence of a claim submitted by a Hospice and Palliative Medicine subspecialist. We examined determinants of palliative care use using logistic regression analysis. RESULTS: Over the study period, 7303 patients were diagnosed with MIBC and 262 (3.6%) received palliative care. Of 2185 patients with advanced bladder cancer, defined as either T4, N+ , or M+ disease, 90 (4.1%) received palliative care. Most patients that received palliative care (>80%, >210/262) did so within 24 months of diagnosis. On multivariable analysis, patients receiving palliative care were more likely to be younger, female, have greater comorbidity, live in the central USA, and have undergone radical cystectomy as opposed to a bladder-sparing approach. The adjusted probability of receiving palliative care did not significantly change over time. CONCLUSIONS: Palliative care provides a host of benefits for patients with cancer, including improved spirituality, decrease in disease-specific symptoms, and better functional status. However, despite strong evidence for incorporating palliative care into standard oncological care, use in patients with bladder cancer is low at 4%. This study provides a conservative baseline estimate of current palliative care use and should serve as a foundation to further investigate physician-, patient-, and system-level barriers to this care.

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.

Surgical Quality Improvement: Working Toward Value or a Work in Progress?

BACKGROUND: Despite numerous national programs intended to ensure patients receive high-quality surgical care, contemporaneous quality improvement initiatives (QIIs) are limited by the challenges associated with developing universal consensus about how best to define "quality" and the identification of appropriate and actionable quality measures. MATERIALS AND METHODS: Using the Donabedian conceptual model for the evaluation of health care quality, representative examples of existing surgical QIIs at each level of health care (i.e., structure, process, and outcome) were identified, and the effectiveness of these programs was discussed. RESULTS: Surgical volume-based measures are a common structural quality indicator. It remains unclear whether volume-based QIIs, such as "Take the Volume Pledge" and the Leapfrog Group's Evidence-Based Hospital Referral initiative, would improve surgical outcomes or potentially exacerbate existing health care disparities. QIIs focused on processes of care, such as the Surgical Care Improvement Project, are frequently effective at improving measure compliance without clearly improving care quality. Risk-adjusted outcome measures remain common quality indicators. But, relevant procedure-specific outcomes are lacking, and continuing to rely on perioperative morbidity and mortality may not provide the most robust picture of surgical quality. CONCLUSIONS: Data regarding the effectiveness of existing QIIs suggest there may be important opportunities to either select measures that more accurately reflect quality surgical care or enhance the manner in which current quality indicators are measured and reported to better capture the complex dynamics of surgical services at the point of care.

Healthcare burden of pulmonary hypertension owing to lung disease and/or hypoxia.

BACKGROUND: Group 3 pulmonary hypertension (PH) encompasses PH owing to lung diseases and/or hypoxia. Treatment patterns, healthcare resource use, and economic burden to US payers of Group 3 PH patients were assessed. METHODS: This retrospective observational study extracted data from July 1, 2010 to June 30, 2013 from two Truven Health Analytics MarketScan databases. Adult Group 3 PH patients were identified based on claims for PH (ICD-9-CM 416.0/416.8), a related lung disease, and an echocardiogram or right heart catheterization (RHC). The index date was the date of the first PH claim; data were collected for 12 months pre- and post-index. A difference-in-difference approach using generalized estimating equations was done to account for baseline differences. RESULTS: Group 3 PH patients (n = 2,236) were matched 1:1 to controls on lung disease. PH patients had higher all-cause resource utilization and annual healthcare costs ($44,732 vs. $7,051) than controls. Costs were driven by inpatient admissions (35.4% of total costs), prescriptions (33.0%), and outpatient care (26.5%). Respiratory-related costs accounted for 11.4% of post-index annual costs for PH patients. PH diagnosis was not confirmed in the majority of PH patients (<7% RHC use) but nevertheless, 22% of PH patients post-index had claims for drugs approved for the treatment of pulmonary arterial hypertension (PAH). CONCLUSIONS: Group 3 PH poses a significant clinical and economic burden. Given the low use of RHC and the prevalence of PAH-indicated prescriptions that are not currently approved for Group 3 PH, this study suggests some Group 3 PH patients may not be receiving guideline-recommended treatment.

Role of human papillomavirus in cutaneous squamous cell carcinoma: a meta-analysis.

BACKGROUND: The role of human papillomavirus (HPV) in cutaneous squamous cell carcinoma (cuSCC) is not well defined, with past studies showing conflicting results. OBJECTIVE: We sought to determine if there is a significant association between HPV and cuSCC and whether cuSCC from immunosuppressed patients are more likely to carry HPV than cuSCC from immunocompetent patients. METHODS: We performed a systematic review and abstracted data from articles that included: skin samples by biopsy, HPV detection by polymerase chain reaction, and a minimum of 10 cases and 10 controls. Pooled effect size and 95% confidence intervals were calculated using random effects meta-analysis using the inverse variance method. RESULTS: cuSCC were more likely to carry HPV than normal-appearing skin (pooled effect size [ES] 3.43, 95% confidence interval 1.97-5.98, P < .0001) in all patients. An increase in HPV prevalence was found in tumors from immunosuppressed patients compared with immunocompetent patients (pooled ES 3.01, 95% confidence interval 2.00-4.52, P < .0001). LIMITATIONS: The greatest limitation is the heterogeneity of the studies included. The association of higher HPV prevalence in squamous cell carcinoma compared with normal-appearing skin does not imply causality. CONCLUSION: These results contribute to evidence that HPV is associated with cuSCC. Higher HPV burden in tumors from immunosuppressed patients compared with immunocompetent patients may have therapeutic implications.

Multidisciplinary management of advanced basal cell carcinoma: report of four cases.

BACKGROUND: Advanced basal cell carcinomas (BCC) are neoplasms with high-risk clinical characteristics that can develop as locally advanced disease or metastasis. Treatment of advanced BCC may result in significant morbidity due to the technical challenges of size and/or location or in which surgery and radiation therapy may be contraindicated. No standard of care exists for the management of advanced BCC. As such, the difficulty in managing these tumors necessitates a multidisciplinary approach to patient care. METHODS: We report four cases of advanced BCC that benefited from a multidisciplinary approach, as well as highlight treatment considerations and factors in the development of advanced BCC. RESULTS: All four complex cases of advanced BCC presented to a multidisciplinary non-melanoma skin cancer tumor board with extensive tumor involvement. Treatment of disease was effective in preventing recurrence while optimizing aesthetic outcomes. CONCLUSIONS: The multidisciplinary tumor board has a central and important role in the evaluation and management of advanced BCC.