Recent Publications by CFE Educators

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low-density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%-65%), apolipoprotein B (48%-59%), and lipoprotein(a) (27%-50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk.

In sub-Saharan Africa, high burdens of HIV and unmet need for contraception often coexist. Research emphasises the need to engage men and couples in reproductive health, yet couples' negotiations around fertility and family planning in the context of HIV have been sparsely studied. This study examined the gendered power dynamics that frame women's and couples' negotiations of contraceptive use in western Kenya. We conducted 76 in-depth interviews with 38 couples, of whom 22 couples were concordant HIV-positive. Qualitative data were analysed using a grounded theory approach. Direct communication around contraception with men was often challenging due to perceived or expressed male resistance. A substantial minority of women avoided male reproductive decision-making authority through covert contraceptive use, with concern for severe consequences when contraceptive use was discovered. Many men assumed that family planning use signified female promiscuity and that infidelity motivated covert use. Men were more willing to use condoms to avoid HIV re-infection or on the recommendation of HIV care providers, which allowed some women leverage to insist on condom use. Our findings highlight the tension between male dominated reproductive decision making and women's agency and point to the need for gender transformative approaches seeking to challenge masculinities that negatively impact health.

INTRODUCTION

Congenital ventral penile curvature without hypospadias is often treated surgically in childhood. The history of untreated ventral curvature is unknown.

OBJECTIVE

This study's aim was to examine the association of untreated ventral penile curvature with various sexual and psychosexual outcomes.

STUDY DESIGN

An electronic survey was advertised to men older than 18 years on Facebook. Men with possible ventral penile curvature identified themselves by choosing sketches that most closely represented their anatomy. Outcomes assessed included: Sexual Health Inventory for Men, difficulty of intercourse because of curvature, International Prostate Symptom Score, Penile Perception Score, psychosexual milestones, paternity, infertility, sitting to urinate, and the CDC HRQOL-4 module.

RESULTS

Among participants, 81 out of 684 men (11.8%) reported untreated ventral penile curvature. Participants with self-reported curvature noted more difficulty with intercourse because of curvature (4.5 vs 4.9, p 0.001), more unhealthy mental days (8.6 vs 6.2, p = 0.02), and increased dissatisfaction with penile self-perception compared with men without reported curvature (8.6 vs 9.5, p 0.001).

DISCUSSION

Men with possible untreated ventral curvature reported worse penile perception scores, more mentally unhealthy days, and increased difficulty with intercourse secondary to curvature compared with men without curvature. A limitation to this study is selection bias; responses collected were self-reported from survey volunteers. Additionally, the question identifying ventral penile curvature is not validated but performed well in pretesting. Most questions were from validated surveys, but some were modeled after validated surveys and/or contained high face validity types of questions.

CONCLUSION

Men with possible untreated ventral penile curvature reported more dissatisfaction with penile appearance, increased difficulty with intercourse, and more unhealthy mental days. Given high success rates, low complications, and improved outcomes after surgical correction of penile curvature reported in the literature, our results support correction of congenital penile curvature in childhood.

BACKGROUND

Concerns have been raised about efavirenz reducing the effectiveness of contraceptive implants. We aimed to establish whether pregnancy rates differ between HIV-positive women who use various contraceptive methods and either efavirenz-based or nevirapine-based antiretroviral therapy (ART) regimens.

METHODS

We did this retrospective cohort study of HIV-positive women aged 15-45 years enrolled in 19 HIV care facilities supported by Family AIDS Care and Education Services in western Kenya between Jan 1, 2011, and Dec 31, 2013. Our primary outcome was incident pregnancy diagnosed clinically. The primary exposure was a combination of contraceptive method and efavirenz-based or nevirapine-based ART regimen. We used Poisson models, adjusting for repeated measures, and demographic, behavioural, and clinical factors, to compare pregnancy rates among women receiving different contraceptive and ART combinations.

FINDINGS

24,560 women contributed 37,635 years of follow-up with 3337 incident pregnancies. In women using implants, adjusted pregnancy incidence was 1.1 per 100 person-years (95% CI 0.72-1.5) for nevirapine-based ART users and 3.3 per 100 person-years (1.8-4.8) for efavirenz-based ART users (adjusted incidence rate ratio [IRR] 3.0, 95% CI 1.3-4.6). In women using depot medroxyprogesterone acetate, adjusted pregnancy incidence was 4.5 per 100 person-years (95% CI 3.7-5.2) for nevirapine-based ART users and 5.4 per 100 person-years (4.0-6.8) for efavirenz-based ART users (adjusted IRR 1.2, 95% CI 0.91-1.5). Women using other contraceptive methods, except for intrauterine devices and permanent methods, had 3.1-4.1 higher rates of pregnancy than did those using implants, with 1.6-2.8 higher rates in women using efavirenz-based ART.

INTERPRETATION

Although HIV-positive women using implants and efavirenz-based ART had a three-times higher risk of contraceptive failure than did those using nevirapine-based ART, these women still had lower contraceptive failure rates than did those receiving all other contraceptive methods except for intrauterine devices and permanent methods. Guidelines for contraceptive and ART combinations should balance the failure rates for each contraceptive method and ART regimen combination against the high effectiveness of implants.

FUNDING

None.

BACKGROUND & AIMS

As many as 50% of large sessile serrated adenomas/polyps (SSPs) are removed incompletely, which is significant because SSPs have been implicated in the development of interval cancers. It is unclear if endoscopic mucosal resection (EMR) is an optimal method for removal of SSPs. We assessed the efficacy and safety of removal of SSPs 10 mm and larger using a standardized inject-and-cut EMR technique.

METHODS

We performed a retrospective analysis of colonoscopy data, collected over 7 years (2007-2013) at 2 centers, from 199 patients with proximal colon SSPs 10 mm and larger (251 polyps) removed by EMR by 4 endoscopists. The primary outcome measure was local recurrence. The secondary outcome measure was safety.

RESULTS

At the index colonoscopy, patients had a median of 1 serrated lesion (range, 1-12) and 1 nonserrated neoplastic lesion (range, 0-15). The mean SSP size was 15.9 ± 5.3 mm; most were superficially elevated (84.5%) and located in the ascending colon (51%), and 3 SSPs (1.2%) had dysplasia. Surveillance colonoscopies were performed on 138 patients (69.3%) over a mean follow-up period of 25.5 ± 17.4 months. Of these patients, 5 had local recurrences (3.6%; 95% confidence interval, 0.5%-6.7%), detected after 17.8 ± 15.4 months, with a median size of 4 mm. No patients developed postprocedural bleeding, perforation, or advanced colon cancer, or had a death related to the index colorectal lesion during the study period.

CONCLUSIONS

Inject-and-cut EMR is a safe and effective technique for the resection of SSPs. Less than 5% of patients have a local recurrence, which is usually small and can be treated endoscopically.

INTRODUCTION

The objective is to evaluate the accuracy of medication dosing and the time to medication administration in the prehospital setting using a novel length-based pediatric emergency resuscitation tape.

METHODS

This study was a two-period, two-treatment crossover trial using simulated pediatric patients in the prehospital setting. Each participant was presented with two emergent scenarios; participants were randomized to which case they encountered first, and to which case used the National Park Service (NPS) emergency medical services (EMS) length-based pediatric emergency resuscitation tape. In the control (without tape) case, providers used standard methods to determine medication dosing (e.g. asking parents to estimate the patient's weight); in the intervention (with tape) case, they used the NPS EMS length-based pediatric emergency resuscitation tape. Each scenario required dosing two medications (Case 1 [febrile seizure] required midazolam and acetaminophen; Case 2 [anaphylactic reaction] required epinephrine and diphenhydramine). Twenty NPS EMS providers, trained at the Parkmedic/Advanced Emergency Medical Technician level, served as study participants.

RESULTS

The only medication errors that occurred were in the control (no tape) group (without tape: 5 vs. with tape: 0, p=0.024). Time to determination of medication dose was significantly shorter in the intervention (with tape) group than the control (without tape) group, for three of the four medications used. In case 1, time to both midazolam and acetaminophen was significantly faster in the intervention (with tape) group (midazolam: 8.3 vs. 28.9 seconds, p=0.005; acetaminophen: 28.6 seconds vs. 50.6 seconds, p=0.036). In case 2, time to epinephrine did not differ (23.3 seconds vs. 22.9 seconds, p=0.96), while time to diphenhydramine was significantly shorter in the intervention (with tape) group (13 seconds vs. 37.5 seconds, p0.05).

CONCLUSION

Use of a length-based pediatric emergency resuscitation tape in the prehospital setting was associated with significantly fewer dosing errors and faster time-to-medication administration in simulated pediatric emergencies. Further research in a clinical field setting to prospectively confirm these findings is needed.

BACKGROUND

A developmental and descriptive approach to assessing trainee intraoperative performance was explored.

METHODS

Semistructured interviews with 20 surgeon educators were recorded, transcribed, deidentified, and analyzed using a grounded theory approach to identify emergent themes. Two researchers independently coded the transcripts. Emergent themes were also compared to existing theories of skill acquisition.

RESULTS

Surgeon educators characterized intraoperative surgical performance as an integrated practice of multiple skill categories and included anticipating, planning for contingencies, monitoring progress, self-efficacy, and "working knowledge." Comments concerning progression through stages, broadly characterized as "technician," "anatomist," "anticipator," "strategist," and "executive," formed a narrative about each stage of development.

CONCLUSIONS

The developmental trajectory with narrative, descriptive profiles of surgeons working toward mastery provide a standardized vocabulary for communicating feedback, while fostering reflection on trainee progress. Viewing surgical performance as integrated practice rather than the conglomerate of isolated skills enhances authentic assessment.

Although neuroanatomical tracing studies have defined the origin and targets of major projection neurons (PN) of the central nervous system (CNS), there is much less information about the circuits that influence these neurons. Recently, genetic approaches that use Cre recombinase-dependent viral vectors have greatly facilitated such circuit analysis, but these tracing approaches are limited by the availability of Cre-expressing mouse lines and the difficulty in restricting Cre expression to discrete regions of the CNS. Here, we illustrate an alternative approach to drive Cre expression specifically in defined subsets of CNS projection neurons, so as to map both direct and indirect presynaptic inputs to these cells. The method involves a combination of Cre-dependent transneuronal viral tracers that can be used in the adult and that does not require genetically modified mice. To trigger Cre-expression we inject a Cre-expressing adenovirus that is retrogradely transported to the projection neurons of interest. The region containing the retrogradely labeled projection neurons is next injected with Cre-dependent pseudorabies or rabies vectors, which results in labeling of poly- and monosynaptic neuronal inputs, respectively. In proof-of-concept experiments, we used this novel tracing system to study the circuits that engage projection neurons of the superficial dorsal horn of the spinal cord and trigeminal nucleus caudalis, neurons of the parabrachial nucleus of the dorsolateral pons that project to the amygdala and cortically-projecting neurons of the lateral geniculate nucleus. Importantly, because this dual viral tracing method does not require genetically derived Cre-expressing mouse lines, inputs to almost any projection system can be studied and the analysis can be performed in larger animals, such as the rat.

BACKGROUND

The excess incidence of thyroid cancer in Ukraine and Belarus observed a few years after the Chernobyl accident is considered to be largely the result of 131I released from the reactor. Although the Belarus thyroid cancer prevalence data has been previously analyzed, no account was taken of dose measurement error.

METHODS

We examined dose-response patterns in a thyroid screening prevalence cohort of 11,732 persons aged under 18 at the time of the accident, diagnosed during 1996-2004, who had direct thyroid 131I activity measurement, and were resident in the most radio-actively contaminated regions of Belarus. Three methods of dose-error correction (regression calibration, Monte Carlo maximum likelihood, Bayesian Markov Chain Monte Carlo) were applied.

RESULTS

There was a statistically significant (p0.001) increasing dose-response for prevalent thyroid cancer, irrespective of regression-adjustment method used. Without adjustment for dose errors the excess odds ratio was 1.51 Gy- (95% CI 0.53, 3.86), which was reduced by 13% when regression-calibration adjustment was used, 1.31 Gy- (95% CI 0.47, 3.31). A Monte Carlo maximum likelihood method yielded an excess odds ratio of 1.48 Gy- (95% CI 0.53, 3.87), about 2% lower than the unadjusted analysis. The Bayesian method yielded a maximum posterior excess odds ratio of 1.16 Gy- (95% BCI 0.20, 4.32), 23% lower than the unadjusted analysis. There were borderline significant (p = 0.053-0.078) indications of downward curvature in the dose response, depending on the adjustment methods used. There were also borderline significant (p = 0.102) modifying effects of gender on the radiation dose trend, but no significant modifying effects of age at time of accident, or age at screening as modifiers of dose response (p>0.2).

CONCLUSIONS

In summary, the relatively small contribution of unshared classical dose error in the current study results in comparatively modest effects on the regression parameters.