No abstract

ImportanceCase reports describe persistent erectile dysfunction (PED) associated with exposure to 5α-reductase inhibitors (5α-RIs). Clinical trial reports and the manufacturers’ full prescribing information (FPI) for finasteride and dutasteride state that risk of sexual adverse effects is not increased by longer duration of 5α-RI exposure and that sexual adverse effects of 5α-RIs resolve in men who discontinue exposure.ObjectiveOur chief objective was to assess whether longer duration of 5α-RI exposure increases risk of PED, independent of age and other known risk factors. Men with shorter 5α-RI exposure served as a comparison control group for those with longer exposure.DesignWe used a single-group study design and classification tree analysis (CTA) to model PED (lasting ≥90 days after stopping 5α-RI). Covariates included subject attributes, diseases, and drug exposures associated with sexual dysfunction.SettingOur data source was the electronic medical record data repository for Northwestern Medicine.SubjectsThe analysis cohorts comprised all men exposed to finasteride or dutasteride or combination products containing one of these drugs, and the subgroup of men 16–42 years old and exposed to finasteride ≤1.25 mg/day.Main outcome and measuresOur main outcome measure was diagnosis of PED beginning after first 5α-RI exposure, continuing for at least 90 days after stopping 5α-RI, and with contemporaneous treatment with a phosphodiesterase-5 inhibitor (PDE5I). Other outcome measures were erectile dysfunction (ED) and low libido. PED was determined by manual review of medical narratives for all subjects with ED. Risk of an adverse effect was expressed as number needed to harm (NNH).ResultsAmong men with 5α-RI exposure, 167 of 11,909 (1.4%) developed PED (persistence median 1,348 days after stopping 5α-RI, interquartile range (IQR) 631.5–2320.5 days); the multivariable model predicting PED had four variables: prostate disease, duration of 5α-RI exposure, age, and nonsteroidal anti-inflammatory drug (NSAID) use. Of 530 men with new ED, 167 (31.5%) had new PED. Men without prostate disease who combined NSAID use with >208.5 days of 5α-RI exposure had 4.8-fold higher risk of PED than men with shorter exposure (NNH 59.8, all p < 0.002). Among men 16–42 years old and exposed to finasteride ≤1.25 mg/day, 34 of 4,284 (0.8%) developed PED (persistence median 1,534 days, IQR 651–2,351 days); the multivariable model predicting PED had one variable: duration of 5α-RI exposure. Of 103 young men with new ED, 34 (33%) had new PED. Young men with >205 days of finasteride exposure had 4.9-fold higher risk of PED (NNH 108.2, p < 0.004) than men with shorter exposure.Conclusion and relevanceRisk of PED was higher in men with longer exposure to 5α-RIs. Among young men, longer exposure to finasteride posed a greater risk of PED than all other assessed risk factors.

Medical professionals have long used algorithmic thinking to describe and implement health care processes without the benefit of the conceptual framework provided by a programming language. Instead, medical algorithms are expressed using English, flowcharts, or data tables. This results in prescriptions that are difficult to understand, hard to debug, and awkward to reuse. This paper reports on the design and evaluation of a domainspecific programming language, POP-PL, for expressing medical algorithms. The design draws on the experience of researchers in two disciplines, programming languages and medicine. The language is based around the idea that programs and humans have complementary strengths, that when combined can make for safer, more accurate performance of prescriptions. We implemented a prototype of our language and evaluated its design by writing prescriptions in the new language and administering a usability survey to medical professionals. This formative evaluation suggests that medical prescriptions can be conveyed by a programming language's mode of expression and provides useful information for refining the language. Analysis of the survey results suggests that medical professionals can understand and correctly modify programs in POP-PL.

A medical prescription is a set of health care instructions that govern the plan of care for an individual patient, which may include orders for drug therapy, diet, clinical assessment, and laboratory testing. Clinicians have long used algorithmic thinking to describe and implement prescriptions but without the benefit of a formal programming language. Instead, medical algorithms are expressed using a natural language patois, flowcharts, or as structured data in an electronic medical record system. The lack of a prescription programming language inhibits expressiveness; results in prescriptions that are difficult to understand, hard to debug, and awkward to reuse; and increases the risk of fatal medical error. This article reports on the design and evaluation of Patient-Oriented Prescription Programming Language (POP-PL), a domain-specific programming language designed for expressing prescriptions. The language is based around the idea that programs and humans have complementary strengths that, when combined properly, can make for safer, more accurate performance of prescriptions. Use of POP-PL facilitates automation of certain low-level vigilance tasks, freeing up human cognition for abstract thinking, compassion, and human communication. We implemented this language and evaluated its design attempting to write prescriptions in the new language and evaluated its usability by assessing whether clinicians can understand and modify prescriptions written in the language. We found that some medical prescriptions can be expressed in a formal domain-specific programming language, and we determined that medical professionals can understand and correctly modify programs written in POP-PL. We also discuss opportunities for refining and further developing POP-PL.

MicroRNA-29 is an anti-fibrotic miRNA whose expression is downregulated in multiple fibrotic indications including in cutaneous scars and keloids. Its target genes include numerous collagens and other extracellular matrix molecules, suggesting that restoration of miR-29 expression in a skin wound or at the site of an excised scar could have a therapeutic benefit by reducing scarring and/or preventing scar regrowth. An oligonucleotide mimic of miR-29b (MRG-201) was studied in vivo in mouse, rats and rabbits as well as in vitro in human skin fibroblasts to identify a set of conserved pharmacodynamic biomarkers in the skin. MRG-201 was then evaluated in a Phase 1 double-blinded within-patient randomized clinical trial in 53 normal healthy volunteers (NCT02603224). Expression of miR-29b and its pharmacodynamic biomarkers was assessed in untreated skin incisions and following single or multiple administrations of MRG-201 at the site of a sutured skin incision. miR-29b expression was significantly decreased and direct miR-29 target genes were significantly upregulated with incision alone. Intradermal administration of MRG-201 resulted in a high local concentration of miR-29b with low systemic exposure and good safety/tolerability at all doses tested. Pharmacodynamic activity was seen after MRG-201 treatment: single and multiple doses of MRG-201 reduced collagen mRNA expression as compared to a placebo injected incision in the same subject. Additionally, multiple administrations of MRG-201 reduced fibroplasia as assessed by histopathology (p < 0.01). These findings support further investigation of MRG-201 as a novel therapeutic to inhibit scar formation or prevent hypertrophic scar or keloid recurrence following excision.