Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study.

OBJECTIVE: To investigate the use of repurposed and adjuvant drugs in patients admitted to hospital with covid-19 across three continents. DESIGN: Multinational network cohort study. SETTING: Hospital electronic health records from the United States, Spain, and China, and nationwide claims data from South Korea. PARTICIPANTS: 303 264 patients admitted to hospital with covid-19 from January 2020 to December 2020. MAIN OUTCOME MEASURES: Prescriptions or dispensations of any drug on or 30 days after the date of hospital admission for covid-19. RESULTS: Of the 303 264 patients included, 290 131 were from the US, 7599 from South Korea, 5230 from Spain, and 304 from China. 3455 drugs were identified. Common repurposed drugs were hydroxychloroquine (used in from <5 (<2%) patients in China to 2165 (85.1%) in Spain), azithromycin (from 15 (4.9%) in China to 1473 (57.9%) in Spain), combined lopinavir and ritonavir (from 156 (<2%) in the VA-OMOP US to 2,652 (34.9%) in South Korea and 1285 (50.5%) in Spain), and umifenovir (0% in the US, South Korea, and Spain and 238 (78.3%) in China). Use of adjunctive drugs varied greatly, with the five most used treatments being enoxaparin, fluoroquinolones, ceftriaxone, vitamin D, and corticosteroids. Hydroxychloroquine use increased rapidly from March to April 2020 but declined steeply in May to June and remained low for the rest of the year. The use of dexamethasone and corticosteroids increased steadily during 2020. CONCLUSIONS: Multiple drugs were used in the first few months of the covid-19 pandemic, with substantial geographical and temporal variation. Hydroxychloroquine, azithromycin, lopinavir-ritonavir, and umifenovir (in China only) were the most prescribed repurposed drugs. Antithrombotics, antibiotics, H2 receptor antagonists, and corticosteroids were often used as adjunctive treatments. Research is needed on the comparative risk and benefit of these treatments in the management of covid-19.

Mapping the origins and expansion of the Indo-European language family.

There are two competing hypotheses for the origin of the Indo-European language family. The conventional view places the homeland in the Pontic steppes about 6000 years ago. An alternative hypothesis claims that the languages spread from Anatolia with the expansion of farming 8000 to 9500 years ago. We used Bayesian phylogeographic approaches, together with basic vocabulary data from 103 ancient and contemporary Indo-European languages, to explicitly model the expansion of the family and test these hypotheses. We found decisive support for an Anatolian origin over a steppe origin. Both the inferred timing and root location of the Indo-European language trees fit with an agricultural expansion from Anatolia beginning 8000 to 9500 years ago. These results highlight the critical role that phylogeographic inference can play in resolving debates about human prehistory.

Species-specific responses of Late Quaternary megafauna to climate and humans.

Despite decades of research, the roles of climate and humans in driving the dramatic extinctions of large-bodied mammals during the Late Quaternary period remain contentious. Here we use ancient DNA, species distribution models and the human fossil record to elucidate how climate and humans shaped the demographic history of woolly rhinoceros, woolly mammoth, wild horse, reindeer, bison and musk ox. We show that climate has been a major driver of population change over the past 50,000 years. However, each species responds differently to the effects of climatic shifts, habitat redistribution and human encroachment. Although climate change alone can explain the extinction of some species, such as Eurasian musk ox and woolly rhinoceros, a combination of climatic and anthropogenic effects appears to be responsible for the extinction of others, including Eurasian steppe bison and wild horse. We find no genetic signature or any distinctive range dynamics distinguishing extinct from surviving species, emphasizing the challenges associated with predicting future responses of extant mammals to climate and human-mediated habitat change.

Pomegranate juice and extracts provide similar levels of plasma and urinary ellagitannin metabolites in human subjects.

Pomegranate juice (PJ), a rich source of polyphenols including ellagitannins, has attracted much attention due to its reported health benefits. This has resulted in the consumption of liquid and powder pomegranate extracts as alternatives to PJ. Therefore establishing the bioavailability of polyphenols from these extract preparations is necessary. Sixteen healthy volunteers sequentially consumed, with a 1-week washout period between treatments, PJ (8 ounces, Wonderful fruit variety), a pomegranate polyphenol liquid extract (POMxl, 8 ounces), and a pomegranate polyphenol powder extract (POMxp, 1,000 mg). The three interventions provided 857, 776, and 755 mg of polyphenols as gallic acid equivalents, respectively. Plasma bioavailability, judged based on ellagic acid levels over a 6-hour period, did not show statistical differences in area under the curve for the three interventions: 0.14 +/- 0.05, 0.11 +/- 0.03, and 0.11 +/- 0.04 micromol . hour/L for PJ, POMxl, and POMxp, respectively. The time of maximum concentration was delayed for POMxp (2.58 +/- 0.42 hours) compared to PJ (0.65 +/- 0.23 hours) and POMxl (0.94 +/- 0.06 hours). Urolithin-A glucuronide, a urinary metabolite of ellagic acid, was not significantly different with the three interventions, reaching levels of approximately 1,000 ng/mL. This study demonstrates that ellagitannin metabolites, delivered from pomegranate fruits, as PJ, POMxl, and POMxp, reach equivalent levels with a delay in time of maximum concentration of POMxp compared to PJ and POMxl.

Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland.

Our group has shown in a phase II clinical trial that pomegranate juice (PJ) increases prostate specific antigen (PSA) doubling time in prostate cancer (CaP) patients with a rising PSA. Ellagitannins (ETs) are the most abundant polyphenols present in PJ and contribute greatly towards its reported biological properties. On consumption, ETs hydrolyze to release ellagic acid (EA), which is then converted by gut microflora to 3,8-dihydroxy-6H-dibenzo[b, d]pyran-6-one (urolithin A, UA) derivatives. Despite the accumulating knowledge of ET metabolism in animals and humans, there is no available data on the pharmacokinetics and tissue disposition of urolithins. Using a standardized ET-enriched pomegranate extract (PE), we sought to further define the metabolism and tissue distribution of ET metabolites. PE and UA (synthesized in our laboratory) were administered to C57BL/6 wild-type male mice, and metabolite levels in plasma and tissues were determined over 24 h. ET metabolites were concentrated at higher levels in mouse prostate, colon, and intestinal tissues as compared to other tissues after administration of PE or UA. We also evaluated the effects of PE on CaP growth in severe combined immunodeficient (SCID) mice injected subcutaneously with human CaP cells (LAPC-4). PE significantly inhibited LAPC-4 xenograft growth in SCID mice as compared to vehicle control. Finally, EA and several synthesized urolithins were shown to inhibit the growth of human CaP cells in vitro. The chemopreventive potential of pomegranate ETs and localization of their bioactive metabolites in mouse prostate tissue suggest that pomegranate may play a role in CaP treatment and chemoprevention. This warrants future human tissue bioavailability studies and further clinical studies in men with CaP.

Physician knowledge of herbal toxicities and adverse herb-drug interactions.

OBJECTIVE: To determine how knowledgeable physicians are regarding the toxic effects and drug interactions of herbal remedies. METHODS: An anonymous voluntary demographic survey and 16-question, multiple-choice quiz was distributed at educational meetings of emergency medicine and internal medicine physicians. The primary outcome measures were to determine whether significant associations existed between quiz scores and the amount of clinical experience, or between quiz scores and self-assessed familiarity with the topic of herbal toxicities and adverse herb-drug interactions. RESULTS: A total of 142 surveys and quizzes were completed by 59 attending physicians, 57 resident physicians, and 26 medical students. The mean subject score on the quiz was only slightly higher than would have occurred from random guessing. Neither the amount of the subjects' clinical experience, nor their self-assessed familiarity with herbal toxicities and drug interactions correlated significantly with the score on the quiz. CONCLUSION: The physicians and medical students surveyed had little training in herbal toxicities and drug interactions. They generally rated their familiarity with these topics as 'poor', and their scores on the quiz bore out this assessment as correct. Educational efforts might improve physician knowledge of the adverse effects of herbal remedies.

Early nodal response as a predictor for necessity of functional neck dissection after chemoradiation.

PURPOSE: Chemoradiation is increasingly becoming the standard of care for node-positive squamous cell cancer of the head and neck. Response to chemoradiation for clinically node-positive disease in the neck is often difficult to ascertain because clinical response may or may not be predictive of pathological response. This often leads to uncertainty about the necessity of a functional neck dissection after chemoradiation. In this study, we retrospectively analyzed a cohort of node-positive patients to examine pathological response as well as clinical outcome after chemoradiation with or without functional neck dissection. METHODS: Using the radiation oncology records from 1993 until 2003, a population of 420 patients with squamous cell cancer of the head and neck were identified. Of these, 34 patients were clinically node positive at the time of diagnosis and under went chemoradiation as their primary therapy. All patients received a concurrent platinum-based regimen. Median radiation dose to gross neck disease was 68.4 Gy (range: 50.4-73.8 Gy). RESULTS: Median follow-up time was 25 months (range: 4-88 months). Patients with a complete response (17/34, 50%) after receiving 50 Gy finished the full course of therapy but did not undergo functional neck dissection. Only one patient (1/17) in this observation group experienced relapse in the neck. Patients with a partial response who received 50 Gy (17/34) completed therapy and under went functional neck dissection, regardless of response at the end of therapy. Fifty percent (3/6) with positive pathology had a regional relapse in the neck, whereas only 1/11 patients with negative pathology relapsed in the neck. This result compared favorably with those who were observed after chemoradiation. CONCLUSIONS: Clinical response at 50 Gy can be an effective means of selecting patients for functional neck dissection. Patients with complete response at 50 Gy may be observed with a low regional recurrence rate. Those patients with a partial response should undergo adjuvant neck dissection.