Comparison of Recreational Fish Consumption Advisories Across the USA

Purpose of Review Our comparative analysis sought to understand the factors which drive differences in fish consumption advisories across the USA — including exposure scenarios (acute and chronic health risk, non-cancer and cancer health endpoints), toxicity values (reference dose, cancer slope factor, acute tolerance level), and meal size and bodyweight assumptions. Recent Findings Fish consumption provides essential nutrients but also results in exposure to contaminants such as PCBs and methylmercury. To protect consumers from the risks of fish contaminants, fish consumption advisories are established, most often by state jurisdictions, to estimate the amount of a certain fish species a person could consume throughout their lifetime without harm. However, inconsistencies in advisories across the USA confuse consumers and undermine the public health goals of fish advisory programs. To date, no rigorous comparison of state and national fish consumption advisories has been reported. Summary Our work identifies discrepancies in key assumptions used to derive risk-based advisories between US states, reflecting differences in the interpretation of toxicity science. We also address the implications for these differences by reviewing advisories issued by contiguous states bordering two waterbodies: Lake Michigan and the Lower Mississippi River. Our findings highlight the importance of regional collaboration when issuing advisories, so that consumers of self-caught fish are equipped with clear knowledge to make decisions to protect their health.

Opioid Free Cardiac Anesthesia

Opioids are one of the effective forms of analgesia for acute pain in the perioperative period but, with overprescription, have become detrimental to public health. There has been a steady increase in opioid consumption and the number of opioid-related deaths, and the U.S. government has declared the opioid epidemic as a public health emergency. Anesthesiologists have a responsibility as the first exposure to opioids was during the perioperative period in the majority of cases. Acute tolerance and hyperalgesia are well known after opioid use in the postoperative opioid further increasing opioid consumption. More importantly, anesthesiologists have no control after the postoperative period, where the prescriptions continue to be repeated from general practice physicians. We have a moral responsibility to reduce opioid use to avoid it if feasible.

A phase I dose escalation trial using intensity-modulated radiotherapy with simultaneous integrated boost in pelvic chemoradiotherapy for metastatic rectal cancer

BackgroundIn unresectable metastatic rectal cancers, the surgery of the primitive tumor remains highly debated. Chemoradiotherapy (CRT) of the primitive could allow sufficient local control in order to avoid major and sometimes mutilating surgery. Dose escalation during CRT could increase this local control. The aim of this study was to evaluate the feasibility and tolerance of a CRT with radiation dose escalation delivered in intensity modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB), in metastatic low and middle rectal cancers.MethodsThis multicenter phase I study included six patients treated for unresectable synchronous metastatic low and middle rectal adenocarcinoma in two dose levels. Radiotherapy was delivered using IMRT with SIB. The dose escalation was 52.5 Gy (level 1) and 56.25 Gy (level 2) in the primary tumor, in 25 fractions of 2.1 Gy and 2.25 Gy, respectively. High-risk clinical target volume (CTV) and low-risk CTV received respectively 50 Gy and 45 Gy in 25 fractions in the two levels. Concomitant chemotherapy was oral capecitabine and CRT was performed after four cycles of mFOLOX6 chemotherapy. The dose-limiting toxicity (DLT) was defined by a toxicity requiring the interruption of radiotherapy for more than five consecutive fractions.ResultsAll six patients received the full course of treatment at scheduled doses. No patients had acute toxicity requiring interruption of radiotherapy therefore no DLT has been reported. No patients had acute toxicity ≥ 3. Concerning late toxicity, three patients experienced grade 3. After CRT, four patients had a partial response and one patient had a complete clinical response. Two patients were considered in local progression at 9.4 months and 20.4 months of inclusion.ConclusionsDose escalation at 56.25 Gy in the tumor lesion was possible with good acute tolerance. It needs to be evaluated in a larger study. It could allow sufficient local control in order to avoid mutilating surgery in these metastatic patients.Trial registrationNCT03634202. Registered 16 August 2018 – retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT03634202

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles

The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.