Effects of SRI-32743, a Novel Quinazoline Structure-Based Compound, on HIV-1 Tat and Cocaine Interaction with Norepinephrine Transporter.

Prolonged exposure to HIV-1 transactivator of transcription (Tat) protein dysregulates monoamine transmission, a physiological change implicated as a key factor in promoting neurocognitive disorders among people living with HIV. We have demonstrated that in vivo expression of Tat in Tat transgenic mice decreases dopamine uptake through both dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex. Further, our novel allosteric inhibitor of monoamine transporters, SRI-32743, has been shown to attenuate Tat-inhibited dopamine transport through DAT and alleviates Tat-potentiated cognitive impairments. The current study reports the pharmacological profiles of SRI-32743 in basal and Tat-induced inhibition of human NET (hNET) function. SRI-32743 exhibited less affinity for hNET binding than desipramine, a classical NET inhibitor, but displayed similar potency for inhibiting hDAT and hNET activity. SRI-32743 concentration-dependently increased hNET affinity for [3H]DA uptake but preserved the Vmax of dopamine transport. SRI-32743 slowed the cocaine-mediated dissociation of [3H]Nisoxetine binding and reduced both [3H]DA and [3H]MPP+ efflux but did not affect d-amphetamine-mediated [3H]DA release through hNET. Finally, we determined that SRI-32743 attenuated a recombinant Tat1-86-induced decrease in [3H]DA uptake via hNET. Our findings demonstrated that SRI-32743 allosterically disrupts the recombinant Tat1-86-hNET interaction, suggesting a potential treatment for HIV-infected individuals with concurrent cocaine abuse.

Characteristics of Matched vs Nonmatched Dermatology Applicants.

Dermatology residency continues to be one of the most competitive specialties, with a match rate of 84.7% in 2019. We surveyed 475 dermatology applicants who applied to the Mayo Clinic in Scottsdale, Arizona, during the 2018-2019 application cycle and 629 dermatology applicants who applied to the Mayo Clinic in Scottsdale; Rochester, Minnesota; and Jacksonville, Florida, during the 2019-2020 application cycle. The initial survey obtained application and demographic information. The follow-up survey obtained match data. The initial 2019 and 2020 surveys were completed by 149 and 142 dermatology applicants, respectively, and 112 and 124 applicants completed the respective follow-up surveys. Our survey finds that factors associated with matching included a higher US Medical Licensing Examination (USMLE) Step 1 score, having a home dermatology program, and a higher number of interviews offered and attended. Some demographics had varying USMLE Step 1 scores but similar match rates.

Patient Use of Physicians' First (Given) Name in Direct Patient Electronic Messaging.

This cohort study examines factors that may contribute to whether patients address physicians differently through electronic messaging.

Adhesive Tape to Guide Injection Depth of Botulinum Toxin for Axillary Hyperhidrosis.

OnabotulinumtoxinA for treating axillary hyperhidrosis requires a 2- to 3-mm depth of injection. This small depth is difficult to accurately estimate once the needle tip is in the skin. We have found that measuring 2 to 3 mm on the needle tip and then wrapping a piece of adhesive tape at that point acts as a depth guide.

BRAF V600E Expression in Primary Melanoma and Its Association With Death: A Population-Based, Retrospective, Cross-Sectional Study.

Approximately 50% of melanomas contain BRAF mutations; the effects on survival are unclear. We aimed to determine whether mutant BRAF expression in melanoma differs according to age, sex, and melanoma-specific survival. A total of 638 patients who resided in Olmsted County, Minnesota, with a first lifetime diagnosis of melanoma between 1970 and 2009 were identified from the Rochester Epidemiology Project (REP). Available tissue was analyzed for a BRAF V600E mutation with immunohistochemistry.

The role of race and ethnicity in the dermatology applicant match process.

OBJECTIVE: The field of dermatology is one of the least racially diverse specialties. We aimed to identify ways in which minorities become underrepresented within dermatology. METHODS: We surveyed dermatology applicants who applied to Mayo Clinic in Scottsdale, AZ during the 2018-2019 application cycle and Mayo Clinic in Rochester, Scottsdale, and Jacksonville during the 2019-2020 application cycles. Underrepresented minorities (URM) were defined as Latino/Latina, African American, American Indian/Alaska Native, or Native Hawaiian/Pacific Islander. RESULTS: In total, 149 and 142 dermatology applicants completed the initial 2019 and 2020 surveys, 112 and 124 completed the follow-up surveys. The racial breakdown was 69.9% Caucasian, 23.7% Asian, 5.4% African American, 0.4% American Indian/Alaska Native, and 0.7% Native Hawaiian/Pacific Islander. Eight percent identified as Hispanic/Latino. Median Step 1 scores were lower for URM (p<0.01). URM had more publications (p=0.01). There were no observed differences in away rotations or interviews attended. URM were less likely to match (76.7%) vs. Whites (88.4%) and Asians (96.0%; p=0.03). CONCLUSION: URM are taking out more loans, pursuing research fellowships more often than their White counterparts, publishing more, completing the same number of away rotations and interviews, yet have lower match rates leading to underrepresentation in the field. It is important to realize how Step scores might reflect and reproduce disparities between different racial/ethnic backgrounds, in turn influencing the racial composition of dermatology residency programs.

Recurrence and mortality rates with different treatment approaches of Merkel cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: Comprehensive treatment recommendations for Merkel cell carcinoma are complex. We aimed to systematically review the published data on recurrence and mortality rates associated with various treatment approaches for Merkel cell carcinoma. METHODS: Search of MEDLINE, Embase, Web of Science, and Scopus from inception to August 2015. Studies were included that reported comparative survival and recurrence data for two or more treatment modalities. Two reviewers independently reviewed and abstracted recurrence and mortality rates. Event rates for individual treatment arms in each study were pooled and meta-analyzed across studies using a random-effects model. RESULTS: Fifty-two retrospective studies met inclusion criteria, revealing a total of 1,804 patients with primary Merkel cell carcinoma with data available for analyses. The recurrence rate was higher for surgery alone (55.0%) versus a combination of surgery and radiotherapy (39.0%) (odds ratio, 2.089; 95% CI, 1.374-3.177; P < 0.001). Combination therapy including surgery, radiotherapy, and chemotherapy had a higher mortality rate (44.6%) than did combined surgery and radiotherapy (23.2%) (odds ratio, 2.688; 95% CI, 1.196-6.037; P = 0.02). CONCLUSIONS: The treatment of Merkel cell carcinoma with surgery plus adjuvant radiotherapy may produce lower recurrence rates.

The role research gap years play in a successful dermatology match.

BACKGROUND: A new trend includes taking a dedicated year away from medical school to complete a research fellowship. There is minimal data on the benefit of a gap year. We aimed to identify if a gap year makes a dermatology applicant more successful in The Match. METHODS: Dermatology applicants who applied to Mayo Clinic Arizona for the 2018-2019 application cycle and Mayo Clinic Rochester, Arizona, and Florida for the 2019-2020 application cycle were surveyed. RESULTS: In total, 291 dermatology applicants completed the initial survey, and 236 completed the follow-up survey. Ninety applicants took a gap year, 198 applicants did not. There was no significant difference in match rates. When comparing match rates at top dermatology residency programs, 40.6% of gap-year applicants matched to these residencies versus 19.0% of no gap-year applicants (P < 0.01). CONCLUSION: Applicants should weigh the opportunity costs before pursuing research gap years as they may not be universally helpful. Applicants who want to match at a top dermatology program may benefit from a research gap year. This data may have limited generalizability outside of the United States.

Survival and glycemic control in patients with co-existing squamous cell carcinoma and diabetes mellitus.

AIM: This study examined the impact of diabetes mellitus (DM) on survival in squamous cell carcinoma (SCC) patients, and the impact of SCC on glycemic control. MATERIALS & METHODS: Patients with newly diagnosed SCC with and without DM were matched 1:1 (2007-2017). Overall survival and recurrence-free survival were estimated using the Kaplan-Meier method. Hemoglobin A1c (HbA1c) and glucose level during the year following cancer diagnosis were compared using mixed models. RESULTS: HbA1c decreased over time in DM patients (p = 0.04). The 5-year overall survival was 61% in DM patients, compared with 78% in patients without DM (p = 0.004). CONCLUSION: The presence of co-existing DM adversely impacted survival in patients with SCC. SCC did not affect glycemic control.

Substantial and sustained reduction in under-5 mortality, diarrhea, and pneumonia in Oshikhandass, Pakistan: evidence from two longitudinal cohort studies 15 years apart.

BACKGROUND: Oshikhandass is a rural village in northern Pakistan where a 1989-1991 verbal autopsy study showed that diarrhea and pneumonia were the top causes of under-5 mortality. Intensive surveillance, active community health education and child health interventions were delivered in 1989-1996; here we assess improvements in under-5 mortality, diarrhea, and pneumonia over this period and 15 years later. METHODS: Two prospective open-cohort studies in Oshikhandass from 1989 to 1996 (Study 1) and 2011-2014 (Study 2) enrolled all children under age 60 months. Study staff trained using WHO guidelines, conducted weekly household surveillance and promoted knowledge on causes and management of diarrhea and pneumonia. Information about household characteristics and socioeconomic status was collected. Hurdle models were constructed to examine putative risk factors for diarrhea and pneumonia. RESULTS: Against a backdrop of considerable change in the socioeconomic status of the community, under-5 mortality, which declined over the course of Study 1 (from 114.3 to 79.5 deaths/1000 live births (LB) between 1989 and 1996), exceeded Sustainable Development Goal 3 by Study 2 (19.8 deaths/ 1000 LB). Reductions in diarrhea prevalence (20.3 to 2.2 days/ Child Year [CY]), incidence (2.1 to 0.5 episodes/ CY), and number of bloody diarrhea episodes (18.6 to 5.2%) seen during Study 1, were sustained in Study 2. Pneumonia incidence was 0.5 episodes /CY in Study 1 and 0.2/CY in Study 2; only 5% of episodes were categorized as severe or very severe in both studies. While no individual factors predicted a statistically significant difference in diarrhea or pneumonia episodes, the combined effect of water, toilet and housing materials was associated with a significant decrease in diarrhea; higher household income was the most protective factor for pneumonia in Study 1. CONCLUSIONS: We report a 4-fold decrease in overall childhood mortality, and a 2-fold decrease in childhood morbidity from diarrhea and pneumonia in a remote rural village in Pakistan between 1989 and 2014. We conclude that significant, sustainable improvements in child health may be achieved through improved socioeconomic status and promoting interactions between locally engaged health workers and the community, but that continued efforts are needed to improve health worker training, supervision, and the rational use of medications. TRIAL REGISTRATION: Not Applicable.

Acute Upper-Limb Complications Following Radial Artery Catheterization for Coronary Angiography.

PURPOSE: The radial artery is becoming the vessel of choice for performing cardiac catheterization. Transradial catheterization can impose risks on the upper extremity, and hand surgeons should be aware of the most frequent complications. The purpose of this study was to determine the frequency, timing, and scope of upper-limb complications shortly after transradial catheterization. METHODS: A retrospective review was conducted of the medical records of patients who underwent catheterization between 2009 and 2016. Complications were assessed for up to 60 days. The Cox model was used to assess risk factors for complications. RESULTS: A total of 10,540 patients were included in the analysis (68.5% male), median age 67 years. There were 79 patients who experienced at least one complication within 60 days (0.84% of procedures; 95% confidence interval, 0.65% to 1.02%). The most common complications were hematoma (n = 39) and radial artery occlusion (n = 28). Other complications included pseudoaneurysm (n = 7), arteriovenous fistula (n = 3), carpal tunnel syndrome (n = 4), arterial perforation (n = 3), persistent vasospasm (n = 2), and compartment syndrome (n = 1). The complications were diagnosed a median of 1 day after catheterization. Female sex was at increased risk for developing a complication. Diabetes, age, body mass index, and catheter size were not associated with an increased risk for developing a complication. Ten patients underwent surgical management of a complication. Reasons for surgery included symptomatic radial artery occlusions, pseudoaneurysm formation, arteriovenous fistulas, and compartment syndrome. No identifiable risk factors were associated with patients who underwent surgical intervention. CONCLUSIONS: The frequency of upper-limb complications after radial artery catheterization is small. They include arterial occlusion, bleeding, compartment syndrome, arteriovenous fistula, and pseudoaneurysm. Most complications presented within 1 week of the procedure and occurred more frequently in the female sex. Operative management of complications was infrequent. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Measles outbreaks and public attitudes towards vaccine exemptions: some cautions and strategies for addressing vaccine hesitancy.

Today, the United States and countries throughout the world are experiencing measles outbreaks that have sickened thousands of children. From the Disneyland outbreak in 2014 to today, some states have responded with changes in laws on vaccine requirements and exemptions. In this article, we examine the history of vaccine laws, and using our 2015 survey data, explore to what extent the news coverage of the Disneyland outbreak altered parents' attitudes toward required vaccination and non-medical exemptions. We explore those results in the context of today's increasing polarized and politicalized battle over vaccine laws, and consider how health care providers and policy makers can work to improve public attitudes about vaccines.

Improving Access to Care Through the Establishment of a Local, Teledermatology Network.

Introduction: Access to dermatologic care is a major issue in the United States, especially within the un- and underinsured populations; technology, including teledermatology, will pay a role in improving access to care. Methods: We performed a prospective study between November 2016 and September 2017. We leveraged a partnership between Mayo Clinic and Mountain Park Health Clinic, a community clinic that primarily serves un- and underinsured populations. We implemented a mobile phone-based store and forward (SAF) teledermatology service, which integrated an external community health clinic to an existing electronic health record (EHR) using standardized data capture forms, real-time support, and simple workflows. Results: Thirty-seven patients were enrolled in the study, 65% female and 35% male with an average age of 47.9 (SD = 15.9). The ethnic breakdown was: 81.1% Hispanic, 13.5% Caucasian, and 5.4% African American. The majority, 62.2%, did not have a high school education, 45.9% were unemployed, and 51.4% were uninsured. 64.9% earned less than $25,000 for annual household income. Teledermatology consultation increased the absolute diagnostic and management concordance by 36.6% (p = 0.01, 95% CI 12.2%-61.0%) and 34.2% (p < 0.01, 95% CI 11%-57%), respectively. Primary care providers had a significant increase in mean confidence in the diagnosis and management of dermatology conditions pre and poststudy (3.60 vs. 3.70 and 3.21 vs. 3.60, respectively; p < 0.01). Ninety-six percent of the primary care providers agreed (52.0%) and strongly agreed (44.0%) that they would send another patient for teleconsultation.Conclusion: We successfully implemented a SAF teledermatology consultative service in a community health clinic outside our EHR. A similar approach can be used by other large health care organizations to provide integrated, high-quality consultation to clinics with rural, un- and underinsured populations.

Frequency of Bleeding Complications After Percutaneous Core Needle Biopsy and the Association With Aspirin Usage and Length of Aspirin Discontinuation.

OBJECTIVE. The purpose of this study is to report the frequency of major bleeding after percutaneous image-guided core biopsy and its association with aspirin usage and duration of prebiopsy aspirin abstinence. MATERIALS AND METHODS. A retrospective review of percutaneous image-guided core biopsies performed at our institution between September 1, 2005, and September 1, 2016, was performed (n = 30,966). Patients were excluded if aspirin usage data were missing (n = 633). Bleeding complications were defined using the Common Terminology Criteria for Adverse Events and were considered significant if they were grade 3 or higher. Multivariate models were adjusted for age, sex, platelet count, international normalized ratio, and biopsy target. Three categorizations of aspirin use were examined: any use within 10 days before biopsy, duration of abstinence (> 10 days or no aspirin, 8-10 days, 4-7 days, and 0-3 days before biopsy), and use on the day of biopsy. Associations with bleeding complications were modeled using logistic regression models. A p < 0.05 was considered significant. RESULTS. The study included 30,333 biopsies in 21,938 subjects (57% male; median age, 60 years; interquartile range, 49-70 years). Of the biopsies, 7921 (26.1%) were performed in patients who received aspirin within 10 days of biopsy, and 3761 (47.5%) of those biopsies were performed in patients who took aspirin within 3 days. Ninety-eight (0.32%) significant bleeding complications occurred overall, including 34 (0.43%) in patients who used aspirin within 10 days before biopsy (odds ratio, 1.5; 95% CI, 0.96-2.3; p = 0.08). Duration of abstinence was associated with a significantly increased bleeding risk only between 0-3 days versus more than 10 days or no aspirin (odds ratio, 2.1; 95% CI, 1.3-3.6; p = 0.004). Aspirin use on the day of biopsy showed the greatest increase in risk (1.9%; odds ratio, 6.6; 95% CI, 3.8-11.5; p < 0.001). CONCLUSION. Significant bleeding complications after biopsy remain rare even among patients with recent aspirin usage, although shorter duration of prebiopsy abstinence increases bleeding risk, most significantly if aspirin is taken the day of biopsy.

Pain, psychiatric comorbidities, and psychosocial stressors associated with Klippel-Trenaunay syndrome.

BACKGROUND: Klippel-Trenaunay syndrome (KTS) is characterized by the triad of capillary malformation, venous malformation with or without lymphatic malformation, and limb overgrowth. Patients with KTS have lower scores in general in mental health, physical function, and quality of life than the general population. OBJECTIVE: To determine the prevalence of pain and psychiatric comorbidity in patients with KTS. METHODS: A retrospective review of 410 patients with KTS evaluated during 1976-2012 was conducted to identify the presence of pain, psychiatric comorbidities, and psychosocial stressors. RESULTS: Pain was reported by 260 patients (63.4%) and was associated with any KTS complication (P < .0001) and venous malformations of the lower extremities (P = .0008) and feet (P = .0007). Ninety-five patients had a diagnosed psychiatric condition (23.2%), most commonly depression (15.1%) and anxiety (5.1%). Pain (P = .0016), superficial thrombosis (P = .0269), deep embolic/thrombotic events (P = .0005), gastrointestinal complications (P = .0085), genitourinary complications (P = .0163), and capillary malformation of the hands (P = .0040) were associated with having a psychiatric diagnosis. LIMITATIONS: This is a retrospective study that relied on physician detection and reporting of variables. CONCLUSION: Pain and psychiatric conditions, particularly depression and anxiety, are common in patients with KTS. Awareness of the psychosocial impact of KTS and appropriate screening are important.