Human sperm cells can form paracetamol metabolite AM404 that directly interferes with sperm calcium signalling and function through a CatSper-dependent mechanism.

STUDY QUESTION: Do paracetamol (N-acetyl-para-aminophenol (APAP) or acetaminophen) and/or its metabolites affect human sperm Ca2+-signalling and function? SUMMARY ANSWER: While APAP itself does not interact with Ca2+-signalling in human sperm, its metabolite N-arachidonoyl phenolamine (AM404), produced via fatty acid amide hydrolase (FAAH), interferes with human sperm Ca2+-signalling and function through a suggested CatSper channel-dependent action. WHAT IS KNOWN ALREADY: Studies have shown that adult men with high urinary levels of over-the-counter mild analgesic APAP have impaired sperm motility and increased time-to-pregnancy. STUDY DESIGN, SIZE, DURATION: This study consists of (i) an in vivo human pharmaceutical APAP exposure experiment to understand to what degree APAP reaches the sperm cells in the seminal fluid; (ii) in vitro calcium imaging and functional experiments in freshly donated human sperm cells to investigate CatSper channel-dependent activation by APAP and its metabolites; and (iii) experiments to understand the in situ capabilities of human sperm cells to form APAP metabolite AM404. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three healthy young males participated in the in vivo human exposure experiment after prior consent. Human semen samples were provided by healthy young volunteer donors after prior consent on the day of the in vitro experiments. MAIN RESULTS AND THE ROLE OF CHANCE: Pharmaceutical APAP exposure reaches the seminal plasma in high micromolar concentrations and accumulates in the seminal plasma between 3 and 5 days of exposure (P-value 0.023). APAP and its primary metabolite 4-aminophenol (4AP) do not interact with human sperm Ca2+-signalling. Instead, the APAP metabolite AM404 produced via FAAH interferes with human sperm Ca2+-signalling through a CatSper-dependent action. Also, AM404 significantly increases sperm cell penetration into viscous mucous (P-value of 0.003). FAAH is functionally expressed in human sperm cells in the neck/midpiece region, as evidenced by immunohistochemical staining and the ability of human sperm cells to hydrolyse the fluorogenic FAAH substrate arachidonyl 7-amino, 4-methyl coumarin amide in an FAAH-dependent manner. Importantly, human sperm cells have the capacity to form AM404 in situ after exposure to 4AP (P-value 0.0402 compared to vehicle-treated sperm cells). LIMITATIONS, REASONS FOR CAUTION: The experiments were conducted largely in vitro. Future studies are needed to test whether APAP can disrupt human sperm function in vivo through the action of AM404. WIDER IMPLICATIONS OF THE FINDINGS: We hypothesize that these observations could, at least in part, be responsible for the negative association between male urinary APAP concentrations, sperm motility and time-to-pregnancy. STUDY FUNDING/COMPETING INTEREST(S): D.M.K. is funded by the Lundbeck Foundation, grant number R324-2019-1881, and the Svend Andersen Foundation. A.R. is funded by a BRIDGE-Translational Excellence Programme grant funded by the Novo Nordisk Foundation, grant agreement number: NNF18SA0034956. All authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Using derivatives to hedge against the unexpected.

Derivatives--financial instruments with a rate of return derived from an underlying asset--have been used as investment instruments for decades. Many derivative products originally were created explicitly for the purpose of reducing financial risks and have become more widely used and more complex in recent years. Healthcare financial managers should have a basic understanding of derivatives as well as the ability to apply general guidelines for their appropriate use in healthcare financial management.

Model curriculum for forensic dentistry in US dental schools.

A model curriculum for forensic dentistry in US dental schools has been presented. This curriculum follows guidelines that will provide the dental student with practical training in specific forensic techniques, knowledge of general principles of forensic dentistry, and an appreciation for the dentist's responsibility within the legal community.

The teaching of forensic dentistry: a status report.

A survey was conducted to assess the current status of instruction and curricular content in forensic dentistry in United States dental schools. The dean of each of the 60 dental schools was asked to describe the formal teaching program in forensic dentistry in the predoctoral, postgraduate, resident, and continuing education curriculum. Faculty characteristics and the relationship of the faculty to extramural organizations dealing with forensic science were analyzed. Results indicate that 42 percent of the respondents do not offer formal courses in forensic dentistry at any level of dental education. The remaining 58 percent offer courses that are primarily didactic in nature. The diagnostic dental science departments are responsible for the organization and administration of forensic dental courses at the majority of respondent schools. A significant number of faculty teaching forensic dentistry hold advanced degrees in medicine and law, as well as other disciplines. Although forensic dental faculty are trained to assist law enforcement agencies, their consulting services are not generally used to the fullest extent. Based on the results of this survey, a series of recommendations for structuring the forensic science curriculum in dental schools is offered.

An evaluation system for preclinical and clinical endodontics.

One of the most difficult tasks, facing the dental educator is the evaluation of students' preclinical and clinical performance. This article describes the development of an evaluation system that eliminates some of the problems associated with the assessment of psychomotor skills including rater subjectivity and the validity of evaluation instruments. The evaluation system discussed is currently being used by the Department of Endodontics at the Louisiana State University School of Dentistry for both preclinical and clinical endodontics. The article focuses on the development of the system, use of the clinical rating scale, and an assessment of the system's effectiveness.

Survey of curriculum and instruction: oral medicine.

Oral medicine programs in U.S. and Canadian dental schools generally concern the nonsurgical management of oral and surrounding tissues as related to the total health of the patients. A survey was conducted to determine the current status of program administration, curriculum, graduate programs, and continuing education in oral medicine. A wide variance in responses received indicated a general lack of consensus on the teaching of oral medicine.