Cylapinae is one of the poorly studied groups within the megadiverse family Miridae (Insecta: Heteroptera). In this paper, five monotypic genera from Australia are described as new to science. Two of those taxa, Dariellarubrocuneatagen. nov. and sp. nov., and Labriellafuscagen. nov. and sp. nov. are assigned to the tribe Cylapini. Three taxa, Callitropiscaflorentinegen. nov. and sp. nov., Laetifulviusmorganensisgen. nov. and sp. nov. and Micanitropisseisiagen. nov. and sp. nov. are placed into the tribe Fulviini. Habitus images, SEMs of external characters, illustrations of male and female genitalia, and distribution maps are provided for each species where possible. The systematic position and possible relationships of the newly described taxa are discussed. Miridae is one of the largest hemimetabolous insect families, currently comprising more than 11,000 species and with numerous taxa yet to be described. Cylapinae is among the smallest subfamilies within the Miridae with approximately 100 genera and 500 species. Currently this subfamily includes the followings tribes: Bothriomirini, Fulviini, Cylapini, Rhinomirini, and Vanniini. Additionally, the subfamily Psallopinae is sometimes considered within Cylapinae as a tribe  and accessible through https://www.discoverlife.org/. The USI code starts with “UNSW_ENT” prefix for all the labels, except otherwise stated. The specimens are deposited in the following collections:Eighty-two specimens were examined for this study. A unique specimen identifier (USI) was attached to each specimen, and collection event data were entered into the Arthropod Easy Capture Specimen Database  (Shorthouse and Davis 2010) and processed with Photoshop CS5.1.The maps were completed using Simplemappr website , Daria Namyatova. The gender is feminine.Dariella does not belong to any Cylapinae tribe. It is similar to Cylapini and Bothriomirini in having punctate body  and a very similar shape of the metathoracic scent gland evaporative area which is slightly longer than wide with distinct vertical grove behind peritreme , 15.95°S, 145.1333°E, 950 m, 05 Nov 1995–11 Jan 1996, Monteith, Cook, Roberts, 1♂ (00043357) (QM). Paratypes: Australia: Qld: Graham Ra, 17.28333°S, 145.95°E, 550 m, 08 Dec 1995–09 Dec 1995, Monteith, Cook, Thompson, 1♂ (00043361) (QM). Koombooloomba Dam, Upper Tully, 17.8353°S, 145.605°E, 08 Dec 1989, Monteith, Thompson and Janetzki, 1♂ (00043362) (QM). Millaa Millaa Falls, 17.46667°S, 145.6°E, 800 m, 17 May 1995, G. B. Monteith, 1♂ (00045284) (QM). Mt Boolbun Sth (summit), 15.95°S, 145.1333°E, 950 m, 05 Nov 1995–11 Jan 1996, Monteith, Cook, Roberts, 3♂  (QM).Head, pronotum and pleura mostly brown to dark brown, corium and embolium yellow to pale brown with brown or reddish areas; antennal segment I yellow, reddish apically; segments II–IV mostly brown, segment IV whitish apically; labium yellow with reddish tinge; embolium reddish apically; cuneus red or pale brown with distinct reddish tinge Fig. ; endosomMale. Body length 2.1–2.3. Coloration .iagnoses . The comiomirini . HoweverLabriella is similar to all Fulviini in that the total antennal length is shorter than the body, antennal segment II is as thick as segment I, and the labium is relatively long, the apex is reaching abdominal segments IV–V. However, Labriella differs from other Fulviini representatives in the possession of a vertical head , whereas in Labriella it is located just above the mandibular plate  (QM). Paratypes: Australia: Qld: 10 km SE El Arish, Laceys Creek nr Mission Beach, 17.86067°S, 146.08632°E, 40 m, 23 Jul 1982–05 Aug 1982, S. and J. Peck, 1♂ (00043320), 1 sex unknown (00043333) (AMNH). Bellenden Ker Range, 1 km S of Cable Tower 6, North Queensland, 17.23409°S, 145.86514°E, 500 m, 17 Oct 1981–05 Nov 1981, Earthwatch/QLD. Museum, 1♂ (00043312) (QM). Bellenden Ker Range, Cableway Base Stn, 17.271°S, 145.9°E, 100 m, 17 Oct 1981–09 Nov 1981, Earthwatch, 1 sex unknown (00043311) (QM). Cardwell Ra, Upper Broadwater Ck Valley, 18.3°S, 145.9333°E, 700 m, 17 Dec 1986–21 Dec 1986, Monteith, Thompson, Hamlet, 1♂ (00043317) (QM). Davies Ck Rd, 20 km SE Mareeba, 17.05°S, 145.6°E, 750 m, 04 Dec 1988–13 Dec 1988, Monteith and Thompson, 1♂ (00043319) (QM). Downey Ck, 25 km SE Millaa Millaa, 17.65°S, 145.7833°E, 400 m, 07 Dec 1988, G. Monteith and G. Thompson, 4♀ (00043291–00043294) (QM). Graham Ra, 17.28333°S, 145.9667°E, 550 m, 08 Dec 1995–09 Dec 1995, Monteith, Cook, Thompson, 3♀  (QM). Hughes Rd, Topaz, 17.43333°S, 145.7°E, 650 m, 06 Dec 1993–25 Feb 1994, Monteith, Janetzki and Cook, 2♂  (QM). Lake Eacham, 17.28796°S, 145.62616°E, 750 m, 09 Dec 1989–14 Jan 1990, Monteith, Thompson and Janetzki, 1♂ (AMNH_PBI 00201880), 1 sex unknown (00043306) (QM). Mossman Bluff, 2 km ESE, 9 km W Mossman, 16.65°S, 145.5667°E, 1000 m, 17 Dec 1988–19 Dec 1988, Monteith and Thompson, 1♀ (AMNH_PBI 00404490) (QM). Mossman Bluff Track, 5–10 km W Mossman, N. Qld, Site 6, 16.46667°S, 145.3667°E, 860 m, 20 Dec 1989–15 Jan 1990, Monteith, Thompson and ANZSES, 1♂ (AMNH_PBI 00202018) (QM). Mossman Bluff Track,5–10 km W Mossman (Site1), 16.46667°S, 145.3667°E, 250 m, 20 Dec 1989–15 Jan 1990, Monteith, Thompson and ANZSES, 1♀ (AMNH_PBI 00404484), 1♂ (AMNH_PBI 00404486) (QM). Mossman Bluff Track, 5–10 km W Mossman (Site 5), 16.46667°S, 145.3667°E, 760 m, 16 Dec 1988–30 Dec 1988, Monteith, Thompson and ANZSES, 1♂ (00043297) (QM); 01 Jan 1989–16 Jan 1989, Monteith, Thompson and ANZSES, 1♂ (00043298) (QM); 20 Dec 1989–15 Jan 1990, Monteith, Thompson and ANZSES, 3♂ (00043117–00043119) (QM). Mossman Bluff Track, 5–10 km W Mossman, Site 7, 16.46667°S, 145.3667°E, 1000 m, 20 Dec 1989–15 Jan 1990, Monteith, Thompson and ANZSES, 3♂ , 1♀ (AMNH_PBI 00404485) (QM). Mossman Bluff Track, 5–10 km W Mossman, site 6, 16.46667°S, 145.3667°E, 860 m, 16 Dec 1988–30 Dec 1988, Monteith, Thompson and ANZSES, 1♂ (00043295) (QM). Mossman Bluff Track, 9 km W Mossman, 16.44365°S, 145.29083°E, 1000 m, 17 Dec 1988, G. Monteith and G. Thompson, 1♂ (00043303) (QM). Mossman Bluff Track, 9 km W Mossman, Site 6, 16.44365°S, 145.29083°E, 860 m, 20 Dec 1989, Monteith and Thompson, 1♂ (00043302) (QM). Mossman Bluff Track, 10 km W Mossman, 16.45958°S, 145.27618°E, 1200 m, 17 Dec 1988, G. Monteith and G. Thompson, 1♂ (00043299), 2♀  (QM). Mt Finnigan summit, via Helenvale, 15.81667°S, 145.2833°E, 1100 m, 28 Nov 1985–30 Nov 1985, Monteith, Cook, Roberts, 1♂ (00043315) (QM). Mt Fisher, 7 km SW Millaa Millaa,Whiteing Rd, 17.55°S, 145.5667°E, 1200 m, 05 May 1983, G. B. Monteith, D. K. Yeates, 1♀ (AMNH_PBI 00404493) (QM). Mt Lewis Rd, 11 km from H’way (Site 1), 16.05°S, 145.2667°E, 1000 m, 18 Dec 1889–13 Jan 1990, Monteith, Thompson and ANZSES, 1♂ (00043304) (QM). Mt Lewis Rd,16 km from H’way (Site 2), 16.56667°S, 145.2667°E, 950 m, 18 Dec 1989–13 Jan 1990, Monteith, Thompson and ANZSES, 1♂ (00043305) (QM). Mt Spurgeon; 2 km SE, via Mt Carbine, 16.45°S, 145.2°E, 1100 m, 20 Dec 1988, Monteith and Thompson, 3♂ , 4♀  (QM). Mt Williams 0.5 km NW, 16.91667°S, 145.6667°E, 870 m, 28 Nov 1997, G. B. Monteith, 1♀ (AMNH_PBI 00404491) (QM). PEI road. Topaz, 17.4°S, 145.68333°E, 580 m, 06 Dec 1993–25 Feb 1994, Monteith, Janetzki and Cook, 1♂ (00043316) (QM). Paluma Dam Rd, Site 2, 19.23333°S, 146.2167°E, 720 m, 17 Nov 1990–08 Dec 1990, Monteith and Seymour, 1♂ (00043318) (QM). Polly Ck, (Hasenpusch property), 17.46667°S, 146.0167°E, 50 m, 25 Nov 1994–10 Jan 1995, Monteith and Hasenpusch, 1 sex unknown (00043332) (QM). Russell River at Bellenden Ker Landing, 17.25°S, 145.94°E, 5 m, 24 Oct 1981–09 Nov 1981, Earthwatch, 1♂ (AMNH_PBI 00404492) (QM). Tully R. Xing, 10 km S Koombooloomba Dam, 17.9318°S, 145.61902°E, 750 m, 08 Dec 1989, Monteith, Thompson and Janetzki, 1♀ (00043330) (QM).Body mostly brown to dark brown; clavus and corium with transversal stripe somewhat darker than rest of hemelytron Fig. ; labial Male. Body length 2.7–3.0. Coloration  (TMAG). Paratypes: Australia: Tas: 29 km WNW Maydena on Eleven Rd, Florentine Valley, 42.76667°S, 146.4°E, 460 m, 01 Feb 1980–06 Feb 1980, A. F. Newton, M. K. Thayer, 1♀ (00043068) (AMNH). Strahan, 42.15°S, 145.3333°E, 52 m, Lea and Carter, 1♀ (00043067) (SAMA).Characterised by head, pronotum, scutellum and pleura dark brown, and hemelytron brown; antennal segments mostly pale brown to brown; labial segment I red; hemelytron with whitish yellow stripes on clavus, along claval suture and on corium, and embolium whitish basally; coxa mostly reddish brown or reddish, fore- and middle femora mostly brown; foretibia pale brown, middle tibia reddish basally and yellow apically Fig. ; vesica Male. Body length 3.1. Coloration  (SAMA). Paratype. AUSTRALIA: South Australia: 51 km NW of Morgan, 33.58333°S, 140°E, 150 m, 01 Nov 1995, Schuh, Cassis, and Gross, 1 sex unknown (00042974) (AM).Head reddish brown, antennal segments I and II pale brown; segment II whitish yellow apically; labial segment I reddish brown, segments II and III pale brown to brown; pronotum uniformly brown; scutellum mostly yellow with reddish brown base; pro- and mesopleuron brown; metapleuron whitish yellow with reddish marking dorsally; metathoracic scent gland evaporative area whitish yellow; hemelytron mostly brown, corium with white oval marking posteriorly adjacent to cuneus; cuneus reddish brown; coxae mostly whitish yellow; femora reddish brown with whitish yellow apices; fore- and middle tibiae mostly pale brown; basal part of hind tibia reddish brown, its apical third or half whitish yellow Fig. ; endosomMale. Body length 3.0–3.1. Coloration  (QM). Paratypes: Australia: Northern Territory: Crocodile Ck nr Dorisvale M.T., 14.29°S, 131.22°E, 17 Nov 1984, M. B. Malipatil, 1♂ (00043059) (NTM). Kakadu National Park, Nourlangie Camp, 12.759°S, 132.659°E, 17 Nov 1979–18 Nov 1979, M. B. Malipatil, 1♀ (00043063) (NTM). Lake Bennett, 19 km SE off Stuart Hwy nr Manton Dam, 12.86449°S, 131.11889°E, 30 Mar 1979, M. B. Malipatil, 3♂ (00043052–00043054), 1♀ (00043055) (NTM), 1 sex unknown (00043056) (NTM). Tindal, 14.516°S, 132.383°E, 01 Dec 1967–20 Dec 1967, W. Vestjens, 1♂ (00043060) (NTM). Queensland: Clermont, 22.823°S, 147.638°E, Nov 1929, K. K. Spence, 1♂ (00043061) (AM). Proserpine, Thompson Creek, (site XY15), 20.51888°S, 148.55694°E, 21 m, 11 Nov 2007, C. J. Burwell, 1♂ (00043046) (QM). Proserpine, Thompson Creek, site XY15, 20.519°S, 148.557°E, 30 m, 11 Nov 2007, C. J. Burwell, 2♀  (QM). Western Australia: Kimberley Research Station, via Kununura, 15.70777°S, 128.69947°E, 25 Nov–26 Nov 1997, A. Postle and C. Brockway, 1♀ (00043062) (WAM). Roebuck Plains, via Broome, 17.96°S, 122.435°E, 30 Dec 1997–02 Jan 1998, C. Johnstone, 1♂ (00043057) (WAM).Head mostly brown to dark brown dorsally; antennal segment I yellow basally and reddish apically; segment II pale brown to brown, whitish yellow apically; segments III and IV pale brown to brown; pronotum, mesoscutum and scutellum brown to dark brown; scutellum whitish yellow to yellow apically; pleura mostly brown to dark brown or reddish brown; hemelytron mostly brown; clavus with three longitudinal whitish yellow stripes, inner stripe sometimes faint or indistinct; corium with two longitudinal whitish yellow stripes reaching or almost reaching middle of corium Fig. ; vesica Male. Body length 3.1–3.4. Coloration  Fig. .The specimens were collected with hands at night, at light, at MV light, and using pyrethrum knockdown of mango trees.Named after the town Seisia in the Cape York , where the holotype was collected Fig. .Cylapinae is characterised by long and narrow tarsi, as well as the combination of characters in the pretarsus, specifically the setiform and often asymmetrical parempodia, the lack of pulvilli, the slender claws usually toothed apically, and the three rows of tiles on the unguitractor with the tiles of the medial row acute , fragile and have the vertex width shorter than eye diameter . However, Cylapini have other genera which also have short antennae, and those taxa are similar to Dariella and Labriella. In particular, Dariella has the male genitalia and pretarsus structure very similar to another Australian genus Carvalhoma, and the metathoracic scent gland evaporative area similar to Schizopteromiris, which is also known from Australia. Therefore, we place Dariella and Labriella in Cylapini based on their affinities to other genera assigned to this tribe, although not its typical representatives. We are awaiting the phylogenetic study of Cylapinae to clarify the position of those two new genera.Cylapinae fauna now includes 26 genera and 48 species currently assigned to four tribes, Bothriomirini, Cylapini, Fulviini and Vanniini. The Cylapini fauna is composed of the genera Carvalhoma, Dariella, Labriella and Schizopteromiris. None of these genera fully fit the diagnosis of this tribe, and the position of those genera can be reassessed in the future.With five new monotypic genera, Australian


Entertainment-education (E-E) media can improve behavioral intent toward health-related practices. In the era of COVID-19, millions of people can be reached by E-E media without requiring any physical contact. We have designed a short, wordless, animated video about preventive COVID-19 behaviors that can be rapidly distributed through social media channels to a global audience. The E-E video’s effectiveness, however, remains unclear.This is a multi-site, parallel group, randomized controlled trial comparing the effectiveness of an E-E video on COVID-19 against (i) an attention placebo control (APC) video and (ii) no video. For our primary outcomes, we will measure knowledge about preventive COVID-19 behaviors. We will also use a list randomization approach to measure behavioral intent toward preventative COVID-19 behaviors. In each trial arm, participants will be randomized to a control list or a control list plus an item about social distancing, washing hands, cleaning household surfaces, sharing of eating utensils, and the stockpiling of essential goods. Using an online platform, we will recruit 17,010 participants (aged 18–59 years) from the USA, the UK, Germany, Spain, France, and Mexico.#DRKS00021582. Registered on May 12, 2020.German Clinical Trials Register This trial will utilize several randomization procedures, list experimentation methods, and state-of-the-art online technology to demonstrate the effectiveness of an E-E video to improve knowledge of, and behavioral intent toward, the prevention of COVID-19. Our results will inform future E-E video campaigns for COVID-19 and similar public health intervention needs. A large amount of information about novel coronavirus COVID-19) has been disseminated by the traditional mass media since the outbreak of the pandemic 9 has bee. HoweverArguably, one possible limitation of mainstream mass media is that it has been perceived as politicized and culturally localized, thus limiting the persuasiveness of messages about COVID-19 prevention , 5. It iTo improve knowledge and behavioral intent toward COVID-19 prevention, we have designed an animated, wordless, E-E video that can be rapidly distributed to a diverse and global audience through social media channels. With a short duration (approximately 2.30 min), the E-E video contains no speech and minimizes cultural signifiers to increase universality and appeal. The E-E video was released on Stanford Medicine’s YouTube channel on March 21, 2020, and went viral within 24 h. After 10 days, it had reached 332,000 views on YouTube, 220,000 views on Instagram, 294,000 views on Facebook, and 402,000 views on Twitter, with a cumulative count of 1.2 million views . The E-EThe E-E video’s effectiveness in improving knowledge of preventive COVID-19 behaviorsThe E-E video’s effectiveness in increasing behavioral intent toward COVID-19 preventionPeople’s voluntary interest to watch the E-E videoThe study aims to achieve the following objectives. To establish:The present study is a multi-site, parallel group, randomized controlled trial (RCT) comparing the effectiveness of the E-E video against an APC video or no video Fig.  9]. Ran. Ran9]. https://www.prolific.co) to enroll participants from the USA, the UK, Germany, Spain, Mexico, and France. We will host and deploy our study on an online platform called Gorilla™ (www.gorilla.sc)  Fig. .Fig. 2SRegistered participants on the ProA platform must be between the ages of 18 and 59 years , have current residence in the target countries, and speak English, German, or Spanish.Ethical approval was obtained from the Stanford University IRB on April 12, 2020, protocol #55820.Participants will undergo a process of informed consent on the ProA platform. The consent form explains the purpose of the study, the risks and benefits of the research, and how to contact the study investigators (or the Stanford University ethics review board) about problems experienced during the course of the study.We will not discontinue or modify the allocated interventions during the course of the study. Participants may choose to discontinue their participation at any time.https://www.youtube.com/watch?v=rAj38E7vrS8.The intervention is an E-E video about COVID-19 prevention, which we abbreviate to CoVideo. Developed by our co-author (MA) for Stanford Medicine, the CoVideo is animated with sound effects and has no words, speech, or text. The CoVideo shows how the novel coronavirus is spread  and recommends best practices to prevent onward transmission . The CoVideo also covers the mass media coverage of the outbreak and the public’s response to this media coverage, which includes a subplot on the stockpiling of essential goods, and the impact thereof on healthcare services and resources . The CoVideo can be viewed at https://www.youtube.com/watch?v=_HEnohs6yYw). The APC will enable us to quantify the attention effect of the CoVideo. APC conditions should mimic the “inactive” components of an intervention—the effect of watching the video—while not containing any of the “active” intervention components—the content delivered by the video [The comparators are an APC video (arm 2) or no video (arm 3). The APC video is similar in style to the CoVideo; it is also animated with a duration of 2.30 min and has sound effects but no words, speech, or text. The video message is about how small choices become actions, which become habits, which become a way of life .)We will assess participant’s behavioral intent to seek health information from online, animated videos. Because of social desirability bias, we will again use a list experiment with the same procedures described in Table We aim to measure participant engagement with the CoVideo. At the end of the survey, we will offer the APC and no-video arms the choice to watch the CoVideo or end the survey. The Gorilla platform will record this response. If the “Watch Video” button is clicked, Gorilla will record the time (in milliseconds) from the video start until the participant clicks the “Finish” button . This data will be used to assess objective 3.We calculated the sample size needed for pairwise comparisons between three groups using a one-way analysis of variance (ANOVA). The formula to calculate the sample size is :κ = 1, which is the matching ratio; μA and μB are the group A and B means; σA and σB are the group A and B standard deviations; α = 0.05 is the type-I error; β = 0.20 is the type-II error; Z is the quantile function; and τ = 2 is the number of comparisons to be made. To detect a small difference of 0.1 between the knowledge scores of two trial arms, we assumed a mean of μA = 14.0 and μB = 14.1 and σA = 1.5 and σB = 1.5. We select μ on the expectation that participants will get 14 out of 18 knowledge items correct. This gives a sample size of nA = nB = nC = 3,532, so N = 10,596. If we change our assumption about σ and increase it to σ = 1.8, then the required sample size becomes nA = nB = nC = 5,087 and N = 15,261. For the list experiment, we selected a sample size to detect a small difference of 0.05 between the control list group and the treatment list group. Because we framed the list questions to avoid floor and ceiling effects, we expect, on average, that the control group will agree with 2 out of the 5 items and the treatment group 2.05 of the 6 items. We selected σA = 0.7 and σB = 0.8, allowing the second σ to be larger because of the additional sensitive item. This calculation gives a sample size of nA = nB = nC = 3,548 and N= 10,644. If we change our assumption about σ and increase it to σA = 0.9 and σB = 1.0, then we have nA = nB = nC = 4,553 and N = 13,659. For this study, we will recruit 17,010 participants, more than the 15,261 calculated sample size, to ensure our study is sufficiently powered.To be recruited, a person must open an account on ProA and provide his or her personal information. Participants must agree to ProA’s data privacy terms and conditions. ProA will assign each participant a unique, anonymized ID. The study investigators will also open an account on ProA. We will instruct the ProA platform on how many participants need to be recruited. ProA will filter out all participants who do not meet the eligibility criteria. Participant recruitment will happen on a “first come, first served” basis until the recruitment number (sample size) is reached. We will compensate the participants an equivalent of £1 for the expected 10-min completion time.The Gorilla platform is designed to host and implement online experimental studies (implementation). Gorilla will randomly allocate participants to the intervention (CoVideo), placebo (APC), or control (no video) arm (sequence generation). Gorilla will use a web-based randomization algorithm, which is unknown to us .The study investigators and those involved in the data analyses and statistics will be blinded to the group allocation.Data will be collected on the Gorilla platform. Participants will submit data by clicking on the response buttons. We expect to collect the data over a 4-week period.Participants will automatically exit the study if they take longer than 45 min to complete the survey. The time-out is to ensure that participants do not clog up the system with incomplete surveys. Since the participants are anonymous to us, there is no way to initiate follow-up in the time limit.Gorilla will store the trial data on its cloud platform, hosted on Microsoft Azure in the Republic of Ireland. The Gorilla database is encrypted using industry-standard cryptography. The study investigators own the research data that has been collected using Gorilla and have complete control over it. The study investigators can generate and access the completely anonymized data from the Gorilla platform. The data will be downloaded and safely stored for statistical analysis on a computing system maintained by the University of Heidelberg in Germany.The participants, who are completely anonymous to us, will have no identifying information associated with their unique IDs. We will inform participants that if they email the study investigators then their names could be revealed to us. The study investigators will keep this information confidential.We will use descriptive statistics to obtain the mean and standard deviation of age, the proportion of participants by gender, and frequency distributions for country of residence and education status.kth trial arm, where k ∈ {v, a, c} such that v represents the CoVideo, a represents the APC, and c represents the control. We will use an ordinary least squares (OLS) regression model to estimate For each participant, we will sum the knowledge items that are correctly answered . We will then obtain the mean knowledge score for each trial arm. Let ith list experiment . We will then estimate the difference between the treatment and control list for each trial arm, denoted by ith treatment list and kth trial arm, where k ∈ {v, a, c}. Let Div − Dic; let Div − Dia; and let Dia − Dic. These analyses are analogous to difference-in-difference analyses, which can be implemented by specifying the appropriate main and interaction terms in an OLS regression.For each list experiment, we will calculate the mean score for the control list, denoted by Using the same statistical procedure described above, we will assess behavioral intent to seek health information with E-E media. To establish participant engagement with the CoVideo, we will use a logistic regression model to estimate the proportion of participants in the APC and control arms that chose to watch the CoVideo, adjusting for the knowledge scores and demographic factors. We will use either an OLS model or Cox proportional hazards model to model the time to when a person clicks “Finish Video” (right censoring) or when the CoVideo ends naturally (left censoring). We will use R statistical software to undertake the analysis.No interim analyses are planned.We will conduct both country-specific and cross-country pooled analyses, provided sufficient sample sizes can be recruited from each country.Participants will have a 30-s time limit to answer each knowledge item. This limit is to prevent participants from searching for answers on the Internet. If the participant times out, they will receive a missing value of 9. This missing value will be recoded as an incorrect answer to the knowledge item, since the participant could not correctly answer the question in the allotted time.This document is the full protocol. Anyone interested in other data or documentation should contact the corresponding author.The trial will be overseen by a trial steering committee (TSC). The TSC will have an independent chairperson and members but also includes the trial collaborators. Two TSC meetings are planned.It is unlikely there will be adverse events given the online format of the trial. The auditing of trial conduct will be addressed in the two TSC meetings.We will disseminate the study findings through journal publications and conference presentations.There is a critical need for public health actors to disseminate scientific information about the prevention of COVID-19, especially in the absence of a vaccine. To this end, we have produced a short, animated E-E video to improve knowledge of, and behavioral intent, toward preventive COVID-19 behaviors. In this study, we propose to evaluate the effectiveness of our E-E video using three innovative approaches.First, we will use state-of-the-art online technology to implement our multi-site randomized controlled trial. The ProA platform will enable us to rapidly recruit a large and diverse number of participants who speak different languages and live in different countries in Europe, North America, and Latin America. Second, we will implement the study on the Gorilla platform, which is designed to host and facilitate experimental trials in behavioral research. The Gorilla platform will enable us to randomize at two different levels: (1) participants will be randomized to the E-E intervention, the APC, or the control arm; (2) within each arm, participants will then be randomized to receive a control list or treatment list. Further, the list experiments will also be randomly ordered to avoid order effects. All randomization will be performed automatically by the Gorilla randomization algorithm, which demonstrates the platform’s potential to implement innovative trial designs and concepts.Third, we will use a list experiment as the primary outcome of this study. Given the unprecedented nature of the COVID-19 outbreak, and the media attention it has received, we assume that participants will already be primed to give socially acceptable responses to questions about COVID-19. In public, individuals will say they will adhere to social distancing recommendations. But in private, they may attend secret “corona parties” [We expect that our study will make important contributions to the E-E literature. Importantly, lessons learned can help us to improve the design of E-E videos to disseminate public health information for future pandemics. And we may hopefully demonstrate that our E-E video, which has been viewed more than a million times on social media thus far, will have contributed to current public health efforts to keep people safe and reduce the spread of COVID-19. Our results will also guide future E-E strategies to support the long-term COVID-19 response, as countries are easing first-wave lockdown or reimplementing second-wave lockdowns.www.drks.de) on May 12, 2020, with registration number #DRKS00021582.The trial is currently recruiting on the ProA website. The first 50 participants were randomized to the pilot phase of the trial on March 23, 2020. A structured summary of the protocol was published on June 3, 2020 . Full re


This review presents the main properties of hydroxycinnamic acid (HCA) derivatives and their potential application as agents for the prevention and treatment of neurodegenerative diseases. It is partially focused on the successful use of these compounds as inhibitors of amyloidogenic transformation of proteins. Firstly, the prerequisites for the emergence of interest in HCA derivatives, including natural compounds, are described. A separate section is devoted to synthesis and properties of HCA derivatives. Then, the results of molecular modeling of HCA derivatives with prion protein as well as with α-synuclein fibrils are summarized, followed by detailed analysis of the experiments on the effect of natural and synthetic HCA derivatives, as well as structurally similar phenylacetic and benzoic acid derivatives, on the pathological transformation of prion protein and α-synuclein. The ability of HCA derivatives to prevent amyloid transformation of some amyloidogenic proteins, and their presence not only in food products but also as natural metabolites in human blood and tissues, makes them promising for the prevention and treatment of neurodegenerative diseases of amyloid nature. Such socially significant diseases as Alzheimer’s, Parkinson’s, Huntington’s, prion diseases of humans and other mammals, and other neurodegenerative diseases, are associated with aggregation of disease-specific proteins, which leads to the formation of amyloid oligomers and fibrils ,2. TheseIn case of prion protein, interest in HCA derivatives as anti-amyloid compounds stems from their structural similarity to a “half” of the curcumin molecule. Curcumin is a natural polyphenolic compound with various prophylactic and medicinal properties. Curcumin has a wide spectrum of biological activities, including antioxidant, anti-inflammatory, antitumor, hepatoprotective, antifungal activities, inhibition of a number of enzymes, iron chelation and neuroprotective activity ,16,17,18In this review, we will discuss general information about HCA derivatives, and then present the main approaches for the production of various natural and synthetic HCA derivatives, which are useful for the investigation of mechanisms of their interaction with target proteins. Then we will discuss the results of molecular modeling of HCA derivatives’ binding to known structures of monomers and fibrils of amyloidogenic proteins. The main focus of the discussion will be on the influence of HCA derivatives and structurally close compounds on the amyloid transformation of PrP and α-synuclein.para-coumaric, caffeic, sinapic acids and 3,4-dimethoxycinnamic acid  are present in significant quantities in the cell wall of plants. In plants, these compounds are formed through the mevalonate-shikimate biosynthesis pathway, which allows plants to synthesize essential amino acids from the primary metabolites phosphoenolpyruvate and erythrose-4-phosphate triazolopyridine-1-ium 3-oxide hexafluorophosphate (HATU), and dicyclohexylcarbodiimide (DCC) have been used for the preparation of ferulic [Natural HCAs possess numerous biological activities that have been extensively reviewed in several publications ,82,83,84chloride . The firchloride . The samalcohols . Compounactivity . The synreaction . Both co ferulic  and caff ferulic . The nuc ferulic ,90,91 or ferulic ,93. Othe ferulic .As previously described, esters and amides of coumaric, ferulic and caffeic acid possess numerous biological activities, e.g., antioxidant ,94,95,96trans-cinnamic acids due to the extent of hydrogen bonding with water—a higher number of hydroxyl groups leads to increased association interactions with water [1) increases in the following order: orto < meta < para , whereas for phenolic group (pKa2) the m-coumaric acid is the least acidic (pKa2 = 10.39) [app) of trans-cinnamic, ferulic and caffeic acids were determined as 4.55, 4.61 and 4.77, respectively [The substitution on the aromatic ring has also a high impact on their physico-chemical properties. Among the main cinnamic acid derivatives, higher solubility was observed for caffeic acid, followed by ferulic and th water . The hydth water . For cou= 10.39) . On the ectively .Molecular modeling of small molecule interactions with target proteins is currently a method used first, and sometimes as a stand-alone, for the evaluation of new drug candidates. This approach is hard to apply in the case of many amyloidogenic proteins since they are either completely or partially naturally unfolded. The inability to crystallize proteins with intrinsically unfolded structure means there is no data available on their tertiary structure based on X-ray crystallography analysis. Nevertheless, a few studies have investigated the molecular modeling using specific structured parts of amyloidogenic proteins present either in monomers, oligomers, or fibrillar aggregates. Herein we will review works concerning molecular modeling of the interaction of HCA derivatives and similar compounds with PrP and α-synuclein, the proteins that are the main focus of our research.C, cellular form) has an α-helical structure. In certain conditions, i.e., in the presence of PrP in amyloid conformation or some metal ions, PrPC can be rich in β-structures , with a propensity for amyloid aggregation [PrP is only partially intrinsically unfolded. Although PrP has an unstructured region, its main physiological conformation :caffeic acid , curcumiFinally, docking of potential ligands can be done to the structure of the already formed α-synuclein fibrils, which have a few potential binding sites for small molecules in the β-structured NAC-domain and unstructured tails of the polypeptide chain  Figure b. This aPrP is an amyloidogenic protein whose amyloid conversion ultimately leads to the development of a number of neurodegenerative diseases of animals (mad cow disease) and humans  ,112. AltSc), which is resistant to proteinase K, in neuroblastoma cells infected by mouse prion, and even free these cells of prion infection [Sc [Interest in HCA derivatives arose after the work on the anti-amyloid action of the dye Congo red . Since 1nfection . Unfortunfection ,138. Sintion [Sc , scientition [Sc ,140.Sc in prion-infected neuroblastoma cells (IC50 10 nM) [Curcumin, similarly to Congo red, was shown to inhibit the accumulation of the dangerous form of PrP0 10 nM) , and com0 10 nM) , which i0 10 nM) .A study conducted in 2013 in a cell-free system on a mouse PrP showed that 20 μM curcumin is able to reduce the formation of amyloid fibrils. In addition, PrP aggregates obtained in the presence of curcumin were not susceptible to proteinase K, in contrast to the true amyloid forms of the protein that are known to be resistant. Moreover, 2.5 μM curcumin rescued mouse neuroblastoma (N2a) cells from apoptosis caused by the accumulation of amyloid structures [p < 0.01) [On the contrary, the results of in vivo studies have been contradictory. Caughey et al. found that a diet with unlimited food containing a 2% mass fraction of curcumin did not significantly affect the development of prion infection in hamsters . On the  < 0.01) .These curcumin deficiencies stimulated the search for compounds of similar structure, but with better water solubility and bioavailability. Given the “cumbersome” nature of the curcumin molecule and its symmetrical structure, it has been suggested that some HCA derivatives, which actually represent half the curcumin molecule, may also have an anti-amyloid effect. First of all, 3,4-DMCA was docked; 3,4-DMCA also has much better solubility in water—the apparent solubility of 3,4-DMCA is 5 mM against that of 0.5 mM for curcumin. Although the binding of 3,4-DMCA to the site found for curcumin cannot be excluded, a more energy-efficient site between H2 and H3 helices was found when modeling the binding of 3,4-DMCA to PrP, and the suggested binding mode is supported by hydrogen bonds and electrostatic interactions with R139 and N162 residues  with dG o-, m-, and p- positions of cinnamic acid were studied for anti-prion activity [Experimental studies confirmed the results of molecular modeling of the interaction of 3,4-DMCA with a prion monomer. Using various approaches, the effects of 3,4-DMCA, ferulic acid, and 7 chemical derivatives bearing different substituents in activity ,144. Amoactivity ,144.HCA derivatives can have another effect on the progress of neurodegenerative diseases, in addition to direct interaction with prion molecules and their aggregates. For example, it has been shown that caffeic acid can increase neuronal viability due to the inhibition of apoptosis induced by the PrP106-126 peptide . In thisThe development of drugs for prion diseases is fraught with a number of obstacles, such as the low incidence of spontaneous forms of prion pathologies in humans (in the absence of infectious outbreaks), the very long latent period before the onset of clinical symptoms and the incurability at clinically obvious stages due to practically irreversible molecular and cellular disorders. Therefore, the possibility of safe, regular and prolonged use, as in the case of 3,4-DMCA and ferulic acids from coffee and other dietary plants, looks promising for the prevention and inhibition of the rate of development of diseases at undetectable stages.α-synuclein is the main amyloidogenic protein implicated in the pathogenesis of Parkinson’s disease and other synucleinopathies. Parkinson’s disease is characterized by the formation of protein aggregates called Lewy bodies, mainly consisting of α-synuclein protein, in the nerve cells. For a long time, the accumulation of α-synuclein fibrils was believed to be the main cause of the pathological changes associated with this neurodegenerative disease. However, in recent years it has been shown that the toxicity of α-synuclein is the result of the formation of oligomeric intermediates formed in the process of amyloid aggregation . α-synucS. baicalensis (Scutellaria radix). Baicalein is actively used in traditional Chinese medicine due to its antioxidant, anti-inflammatory, and anticarcinogenic properties [Numerous epidemiological and experimental studies indicate that daily consumption of polyphenolic compounds with food protects against neurodegeneration ,153,154.operties ,158. Howoperties .Masuda et al.  tested 7The combination of nuclear magnetic resonance, circular dichroism spectroscopy, and electron microscopy methods has demonstrated that in the presence of polyphenolic compounds, the assembly of α-synuclein oligomers and fibrils is destabilized due to the presence of aromatic and hydroxyl groups on the phenyl ring of the ligands . This isMany authors especially emphasize the polyphenols baicalein and curcumin as inhibitors of α-synuclein fibrillation. For baicalein, the therapeutic effects in Alzheimer’s and Parkinson’s diseases  and the −5 M, affecting the configuration of the molecule and thus blocking oligomerization and fibrillation [The anti-amyloid effect of curcumin is associated with an increase in the solubility of α-synuclein monomers dose-dependently inhibiting protein oligomerization. According to published data curcumin binds to the α-synuclein monomer, with a dissociation constant of 10illation . Using iillation , which aillation .The effect of HCA derivatives, the structure of which is similar to a half of the curcumin molecule, and structurally similar compounds on the amyloid transformation of α-synuclein, was studied by several groups ,176,177 The most active in inhibiting α-synuclein fibrillation was ferulic acid with a half-maximal inhibitory concentration of 0.8–13 µM reported in different studies ,161. It Data on the interaction with monomers and inhibition of α-synuclein monomers is less comprehensive. In one study, no interaction of gallic acid with α-synuclein monomers was shown , while oA comparative analysis of the effect of 9 HCA and caffeic acid derivatives on the ability to prevent α-synuclein amyloid transformation was performed by our group: two naturally occurring  and seven synthesized compounds . SynthetConsidering the possible mechanism of action of HCA derivatives and structurally similar compounds, a correlation is noted between the number of hydroxyl groups in the compounds and their efficiency in inhibiting α-synuclein aggregation: the more groups, the stronger the effect, while identical molecules with a hydroxyl group replaced by a methyl group no longer inhibit fibrillation . Given tAs noted above, many HCA derivatives are found in black and especially green coffee beans ,43,44, aThe concentration of caffeine in the blood of volunteers who took coffee thrice a day (160 mg of caffeine per serving) reached 4 μg/mL 100 min after coffee consumption . In one The evidence reviewed above, including our findings, supports the notion that HCA derivatives are promising drug candidates for preventive and therapeutic use in neurodegenerative diseases of amyloidogenic nature. Although the main corpus of data on the application of HCA derivatives concerns their use in Parkinson’s and prion diseases, there are reasons to believe that they will be quite effective in other neurodegenerative pathologies. For example, a few studies have been published on anti-amyloid activity of HCA derivatives towards amyloid-β aggregates ,187 implNotably, despite a pronounced anti-amyloid effect of HCA derivatives on PrP and α-synuclein, there are significant differences in the mechanisms of interaction of these ligands with the two proteins. Probably, HCA derivatives do not bind to completely disordered polypeptide chains but interact with structured elements. Such structured regions are present in PrP but are absent in α-synuclein monomers. For these reasons, HCA derivatives bind to monomeric, oligomeric, and fibrillar forms of PrP, preventing the formation of amyloid structures and disrupting already formed aggregates. At the same time, HCA derivatives interact only with the preformed amyloid structures of oligomers and fibrils of α-synuclein, preventing their further pathological transformation, but not with unstructured α-synuclein monomers. Structural features of the binding sites present in monomeric PrP or amyloid aggregates of α-synuclein also lead to a varying effectiveness of HCA derivatives on the formation of amyloid structures by these proteins. Interestingly, ferulic acid was not active in preventing PrP fibrillation , while sHowever, the most promising compounds for the development of prophylaxis and treatment of amyloid neurodegenerative diseases are natural HCA derivatives. The advantage of natural HCA derivatives, contained in various foods and spices, is the centuries-old indication of their safety for the human body, as well as accumulated information about their ability to prevent or slow down a number of pathological processes. Moreover, there are pathways for the metabolism of certain HCA derivatives, which prevents their excessive accumulation in organs and tissues and, therefore, prevents overdose when taking such compounds as dietary supplements and medicines. It is also possible that a careful analysis of the content of HCA derivatives in various food products will reveal new compounds of this class. For instance, we have obtained preliminary data that synthetic 3-methoxy-4-acetamidoxycinnamic acid, which has a pronounced anti-amyloid effect against α-synuclein, is present in coffee extracts. It is possible that for some other synthetic HCA derivatives, there are naturally occurring analogs, which will facilitate the development of the drugs based on them.Synthesis of a variety of HCA derivatives to elucidate the fundamental aspects of the mechanisms of their influence on the pathological transformation of amyloidogenic proteins.Search for natural analogs of synthetic HCA derivatives in food products with a view to their further use for drug development.Assessment of the prevalence of HCA derivatives in different living organisms and elucidation of their metabolism, including in human organs and tissues.Expansion of the spectrum of amyloidogenic proteins, the pathological transformation of which is affected by HCA derivatives.Development of targeted preparations for the prevention and treatment of various amyloid neurodegenerative diseases based on synthetic and natural derivatives of HCA.Thus, further development of studies on HCA derivatives as anti-amyloid drugs can occur in the following areas:


A recent Alzheimer’s Association report noted that by year 2050, the number of Americans diagnosed with Alzheimer’s disease and related dementias (ADRD) will triple to over 15 million. The report referred to primary care as the front line for meeting this demand, yet the nation faces a severe shortage of ADRD trained, primary care professionals (PCPs). Louisiana Geriatric Workforce Enhancement Program (LA-GWEP) addresses this demand. The purpose of this study was to examine preliminary data respective to LA-GWEP effectiveness with interdisciplinary education and training seminars, primarily aimed at medical, nursing, and social work PCPs. Three seminars were conducted in south Louisiana: Seminars 1 and 2 addressed effective communication, verbal and nonverbal, among persons with ADRD and caregivers; Seminar 3 offered basic overview of dementia symptomology, stages, and behaviors. Pre- and post-training session data were collected on-site. Participants completed questionnaires that included a 10-item knowledge assessment and 20-item Dementia Attitudes Scale (DAS). These measures contained Likert response formats; higher scores indicating greater levels of ADRD knowledge, in patient and caregiver contexts. Paired sample t-tests were conducted to observe any significant pre-to-post improvement, Cohen’s d for effect size. Seminar 1 revealed no significant pre-to-post difference: t = -1.019, p = 0.320. Adjusting content from audience feedback, Seminar 2 revealed significant pre-to-post difference: t = -7.516, p < .001, Cohen’s d = 1.2. Seminar 3 yielded significant improvement on DAS scores: t = -2.96, p < .01, Cohen’s d = 0.34. Implications for seminars in future years of LA-GWEP are discussed.


Telemedicine has been used for decades. Despite its many advantages, its uptake and rigorous evaluation of feasibility across neurology’s ambulatory subspecialties has been sparse. However, the COVID-19 pandemic prompted health care systems worldwide to reconsider traditional health care delivery. To safeguard health care workers and patients, many health care systems quickly transitioned to telemedicine, including across neurology subspecialties, providing a new opportunity to evaluate this modality of care.To evaluate the accelerated implementation of video visits in ambulatory neurology during the COVID-19 pandemic, we used mixed methods to assess adoption, acceptability, appropriateness, and perceptions of potential sustainability.Video visits were launched rapidly in ambulatory neurology clinics of a large academic medical center. To assess adoption, we analyzed clinician-level scheduling data collected between March 22 and May 16, 2020. We assessed acceptability, appropriateness, and sustainability via a clinician survey (n=48) and semistructured interviews with providers (n=30) completed between March and May 2020.Video visits were adopted rapidly; overall, 65 (98%) clinicians integrated video visits into their workflow within the first 6 implementation weeks and 92% of all visits were conducted via video. Video visits were largely considered acceptable by clinicians, although various technological issues impacted their satisfaction. Video visits were reported to be more convenient for patients, families, and caregivers than in-person visits; however, access to technology, the patient’s technological capacity, and language difficulties were considered barriers. Many clinicians expressed optimism about future utilization of video visits in neurology. They believed that video visits promote continuity of care and can be incorporated into their practice long-term, although several insisted that they can never replace the in-person examination.Video visits are an important addition to clinical care in ambulatory neurology and are anticipated to remain a permanent supplement to in-person visits, promoting patient care continuity, and flexibility for patients and clinicians alike. Telemedicine has been used for decades, yet its uptake and rigorous evaluation of feasibility across neurology’s ambulatory subspecialties has been sparse ,2. StudiThe declaration of COVID-19 as a pandemic in March 2020 prompted health care systems worldwide to reconsider traditional health care delivery and quickly transition to telemedicine -21. In rIn this study, we evaluate the implementation of video visits in Stanford Health Care’s  ambulatory neurology clinics using mixed methods to assess adoption and explore clinicians’ perspectives on the acceptability, appropriateness, and sustainability of this broad expansion.This quality improvement project received a nonresearch determination by Stanford University’s Institutional Review Board (IRB-55644). It was conducted at Stanford University’s Department of Neurology and Neurological Sciences, which includes 11 ambulatory subspecialties staffed by 60 physicians and 8 advanced practice providers (APPs). As previously described , at the The primary implementation outcomes assessed were adoption, acceptability, appropriateness, and perceived sustainability of video visits , as descClinician-level scheduling data were extracted for all clinicians who had the opportunity to conduct video visits. The first week of the stay-at-home order  was considered a transition week where the physician champion onboarded physicians onto the video visit platform. To assess our primary outcome, adoption, scheduling data from the 8-week implementation period  was used for analysis; the transition week was excluded. Adoption was assessed in three ways: (1) proportion of clinicians who conducted video visits, (2) proportion of visits completed via video during the COVID-19 pandemic, and (3) proportion of all “expected” visits that were done via video, where “expected” was defined as the estimated number of visits completed had COVID-19 not occurred ..The number of visits completed during the implementation period  and comparator period  included visit types that could be feasibly conducted in-person or via video. Visit types inherently requiring in-person patient interaction, such as procedures and research visits, were excluded. The percentage of “expected” visits is shown for video and in-person visits separately, along with the percentage of lost potential visits. The proportion of all “expected” visits completed is a measure of the proportion of “saved” or “protected” visits attributable to video visits during the COVID-19 stay-at-home periodWe developed a 20-item survey informed by early interview findings and reflections from the clinical improvement team. The survey was administered via Stanford’s REDCap platform  and emaiAll quantitative data were processed and analyzed using SAS , R   and assoWe designed the interview guide  to encomInterview notes and transcripts were used for analysis. To ensure anonymity, identifiable information was removed from transcripts and subspecialties with <5 clinicians were grouped. Data were analyzed using both deductive and inductive approaches. Deductive codes were derived from the implementation outcomes of interest . During Quantitative and qualitative data were consolidated during analysis and interpreted in parallel to understand the impact of video visits in ambulatory neurology more comprehensively. This approach allowed us to harness strengths and offset weaknesses of the two methodologies ,39. We wOut of the 68 clinicians in the department’s 11 ambulatory subspecialties, 66 clinicians conducted regular video visits during the 8-week implementation period and were included in analyses (two clinicians were on leave and thus excluded). During the transition week, the clinician champion onboarded 30 of the 66 physicians included in this study, and 129 video visits were conducted. Prior to this transition week, clinicians in these ambulatory neurology clinics had not used video visits. During the 8-week implementation period, video visit adoption was high based on both percentage of clinicians using them, and percentage of visits completed via video. Within the first two weeks, 52 (79%) clinicians integrated video into their practice, increasing to 65 (98%) clinicians by week 6. Almost all (92%) visits were conducted via video and adoption of video visits was high for both new and return patient visits . The total number of completed visits, conservatively estimated, was almost 80% of expected visits based on the 2019 comparison period A. ClinicOverall acceptability of video visits was high, but clinicians experienced technological and scheduling issues, and identified additional needs. Two themes emerged related to acceptance: technology and workflow efficiency.While some clinicians experienced a smooth transition to video visits and seamless connection with patients, others dealt with numerous technical issues, jeopardizing their overall satisfaction. Indeed, technology was one of the top 3 concerns regarding video visits for 30 (63%) survey respondents .screen sharing to facilitate patient education and explain imaging results, (2) a waiting room function to replicate “stepping out of the room” when engaging with trainees, (3) a chat box for troubleshooting, (4) file sharing capabilities, (5) screenshot capabilities to support efficient charting, and (6) multiperson teleconferencing to include other members of the multidisciplinary team, interpreters, trainees, and family members in different physical locations. These functionalities were not available during the study period.Several video functionalities were suggested for a successful visit, including the following: (1) ...when we're discussing end-of-life care issues, to have the physician and respiratory therapist, social worker and palliative care physician, all present in the same ‘virtual room’, that would be really nice.MD19Engaging in education of trainees was one of the top 3 concerns for 21 (44%) surveyed clinicians . The iniPerceptions of workflow efficiency were mixed. Major issues included rigid video visit scheduling, note-taking efficiency, and previsit planning. Several clinicians mentioned that, provided there were no technological issues, video visits helped them stay on schedule. However, hard time limits set by the video visit platform caused frustration. Clinicians could not notify the next patient when running late nor initiate the next visit earlier than scheduled as they might do at the clinic.…it's much easier for someone to wait in a physical waiting room if you do happen to run over with a patient who’s before them. It’s a lot harder or less acceptable if someone is waiting to see you via video and staring at their computer screen for 10 or 15 minutes. … You can’t open up another video and say, ‘I'm here. I'm just with somebody else, and I'm going to switch back.’MD10Views on documentation during a video call also differed. Note-taking was considered easier by some during video visits, reducing after-hours charting time. Others were unable to document simultaneously, making them less efficient. Dictation was considered a possible solution.…unless you get the screen set up correct[ly], it actually can be really hard to document and type while doing the video visit. The typing can be noisy on the patient’s end…MD5However, most surveyed clinicians  agreed or strongly agreed that video visits allowed them to shift uncompensated to compensated work .The lack of integration of medical assistants (MAs) in the video visit workflow, resulting in a lack of previsit charting and medication reconciliation, was another concern. Incorporating MAs, or even involving the patient in their own previsit preparation, was deemed necessary for video visits to be sustained.I'd like to see it be more efficient… In advance of the visit, it would be nice if they [patients] could do their medication reconciliation. …enter in the last set of vitals that they took for themselves. …enter in their own review of symptoms and chief complaints.MD16Three themes emerged related to appropriateness of video visits: benefits and barriers, physical examination, and continuity of care, each of which are described below.Clinicians highlighted several benefits of video visits for patients and families/caregivers, including convenience, impact on travel and cost, and seeing the patient’s home environment. Barriers noted included access to technology, patient’s technological capacity, and language. Video visits were considered advantageous and convenient, saving patients time and money, particularly for older adults and those who travel long distances for appointments. Survey respondents  agreed that saving patients unnecessary travel was one of the top 3 benefits . Several…it's very convenient for our patients, especially those who are elderly or have neurologic issues. [It] Spares them unnecessary travel and costs...MD16Several clinicians saw value in seeing patients in their home. Not only did it allow more family involvement, but clinicians could also troubleshoot daily functioning issues or modify the patient’s environment by directly assessing fall hazards, medications, and home devices.…maybe you see … a lot of stuff strewn over the floor and that is why they're falling so much … you might observe things … that might impact their neurological disease on a day to day basis … or you don't think to ask about … in a clinic visit because you're not seeing the world that they're actually living in.MD25Even though increased access to vulnerable populations was rated as one of the top 3 benefits of video visits  surveyed clinicians indicated inclusion of interpreters was one of their top 3 concerns .Clinicians reported that video visits were superior to a phone call, allowing them to gather more information than just a medical history. Although exam needs varied by clinician and subspecialty, several clinicians described that despite challenges, they were pleasantly surprised to be able to perform several modified physical examinations over video. Nevertheless, many stated that the inability to perform a hands-on physical examination was a limitation of video visits that was best paired with a timely in-person follow-up. Several clinicians mentioned that virtual exams were more time-consuming and occasionally required assistance from a caregiver to position the phone to properly observe the patient, perform certain physician-directed exams, confirm what the patient says, or catch the patient if s/he is at risk of falling.You have to have a caregiver, you can’t check gait without it [a caregiver] or the patient needs some sort of stand or desk or something where they can put the computer down at the end of a hallway and then asking the patient to find a hallway that they can walk back and forth is really the best way to do it. But a caregiver probably works best.MD21Additional limitations were related to the patient’s immediate environment, including adequate space for the patient to move around, and sufficient lighting. Camera positioning was also critical. If positioned too close, the clinician lacked sufficient visual field to observe the patient’s entire body. Clinicians also noted that occasionally patients took their video call at inappropriate times , despite previsit counseling.Clinicians considered video visits beneficial to ensure continuity of care for chronic conditions. There was general agreement that video visits are best suited for established patients, especially those who are stable/uncomplicated, or for a quick checkup without extensive examination or testing. Although several clinicians felt that most patients were appropriate for video visits, the majority agreed that new patient visits, and patients with acute conditions and declining health, were less suited due to relative ease of the complete physical examination when conducted in person. Many preferred to first see the patient in person before determining whether further follow-up care can be provided, at least partly, over video. Clinicians also recognized that some patient populations encounter significant barriers to attending the clinic in person and that video offers an opportunity to continue care.We deal with progressive conditions, and once you get into that moderate to advanced stage of illness it just becomes not worth their effort to come anymore. It’s too difficult on the patient, it’s too difficult on the family, and so we lose contact with the vast majority of our patients as they become more advanced. ...telemedicine actually might allow continuity of care into the more advanced stages…MD12Most clinicians were positive toward video visits and believed they could incorporate video into their practice long-term, although several insisted that video cannot replace a full in-person examination. Moreover, 40 (83%) surveyed clinicians agreed or strongly agreed that video visits supported their overall well-being. The general view was that for long-term sustainability, patient video visits will need to be selected carefully to optimize care and respect preferences. Patients’ suitability for video visits would need to be determined during scheduling based on several criteria . However, previsit screening and triage to determine which patients are best suited for video was considered burdensome, which could compromise their sustainability. Seldom was the video visit itself considered a good tool for triage.I would like to be able to offer it for my patients who are a little less mobile and who come from far away. I don’t think it will completely replace in-person visits, but if we can alternate visits and do in-person versus telehealth, I think that’ll be huge.MD21Most survey respondents  agreed that video visits should be supplemented with in-person visits. The recommended frequency of supplemental in-person visits varied among the respondents: 6 (15%) recommended quarterly, 11 (28%) biannually, 17 (44%) annually, and 5 (13%) every 2 years. A concern mentioned by a minority of interviewees and 7 (15%) surveyed clinicians was that patients may find video too convenient and opt out of recommended in-person visits. In contrast, 9 (19%) survey respondents with representation from epilepsy, memory, headache, stroke, and neuro-oncology, indicated that an all-video practice would be feasible for their patient population.Video visits were rolled out rapidly at Stanford University’s Department of Neurology and Neurological Sciences during the COVID-19 pandemic. A high proportion of visits were conducted via video at volumes near prepandemic volumes, indicating robust and rapid adoption by both clinicians and patients. This necessary and widespread adoption allowed for thorough assessment of new opportunities and barriers in video-based care across almost all ambulatory neurology subspecialties.Clinicians recognized the patient benefits of video visits, including saving patients unnecessary travel and increasing access to vulnerable populations, as is well-documented ,3-8. As Clinicians reported that video visits were beneficial for seeing the patient’s home and meeting caregivers and family members. Observing patients at home is a documented benefit of video visits; it can reduce patient and caregiver anxiety, and allow assessment of fall hazards and habitual behaviors that are not always possible to capture during an in-person visit ,42. ThesPreviously, the perceived limitations of virtual physical examinations have been a source of hesitant incorporation of telemedicine into neurology practice -12; howeClinicians were keen about the ability to work remotely, reduction in uncompensated work, and flexible scheduling facilitated by video visit use. In the current configuration, video visits are not constrained by clinic spaces nor specific staffing needs, thereby allowing clinicians flexibility to vary timing and length of both their overall clinic session and individual patient appointments. This is a clear benefit, as lack of flexibility in work is a key driver of burnout , and evePerceived sustainability of video visits was high; clinicians emphasized a desire for video visits to remain a permanent fixture in their practice. However, the proportion of video visits and in-person visits within their practice was anticipated to change in their postpandemic practice and vary by individual providers and subspecialty. Most clinicians preferred to have a practice that uses both video and in-person visits, but more than half (57%) expressed a preference for less frequent in-person visits . Perhaps most surprisingly, nearly 20% of clinicians from a variety of neurology subspecialties indicated that an all-virtual practice was possible. This variation in preferences may reflect the wide variation in the nature and examination demands of neurologic subspecialties, with subspecialties known to be especially exam-dependent  notably absent from those indicating feasibility of an entirely virtual practice.The capabilities of mobile technology and remote monitoring have facilitated great advances in telemedicine ,6,8,14; Further analysis of the workflow around telemedicine in ambulatory neurology is needed as there is growing recognition that workflow is nontrivial and complex . In thisPerceptions of clinicians using video visits were captured in real time during early rapid implementation through interviews and/or a survey across many ambulatory neurology subspecialties. However, given its nascent state, operational scheduling data only captured data of video visits conducted via the EPIC Hyperspace Platform and did not consistently reflect visits conducted on other HIPAA-compliant software, such as Zoom. Therefore, the data presented herein likely underestimate the actual total number of completed visits. Further, when video visits were diverted to phone calls or other software during the 8-week implementation period, the scheduling system incorrectly categorized the encounter as cancelled, no show, or patient left without being seen. This limitation has been recently addressed, presenting an opportunity to investigate the impact of video visits on clinic utilization in future investigations. Finally, views of other essential health care staff, such as patient care coordinators and MAs, who performed essential activities , as well as residents and patients/caregivers, are not presented here.Video visit adoption was rapid at Stanford’s ambulatory neurology clinics. Almost all clinicians conducted video visits by the eighth week of implementation and achieved near-normal patient volumes during the COVID-19 pandemic stay-at-home order. Despite the sudden change in workflow, clinicians largely expressed positive views toward video visits; clinicians supported permanent integration of video visits and noted them to be conducive to physician well-being. However, overall clinician satisfaction was impacted by technological issues, limitations with the physical examination, and challenges accessing vulnerable patient populations. Although our mixed methods evaluation confirmed the success of video visits in all subspecialty neurology clinics across many dimensions, innovations must be developed to address their limitations. Additional solutions are also needed for the most vulnerable patient populations. A crucial next step for optimization is to understand patients’ experiences and preferences.


The current ecological understanding still does not fully explain how biodiversity is maintained. One strategy to address this issue is to contrast theoretical prediction with real competitive communities where diverse species share limited resources. I present, in this study, a new competitive coexistence theory-diversity of biological rhythms. I show that diversity in activity cycles plays a key role in coexistence of competing species, using a two predator-one prey system with diel, monthly, and annual cycles for predator foraging. Competitive exclusion always occurs without activity cycles. Activity cycles do, however, allow for coexistence. Furthermore, each activity cycle plays a different role in coexistence, and coupling of activity cycles can synergistically broaden the coexistence region. Thus, with all activity cycles, the coexistence region is maximal. The present results suggest that polyrhythmic changes in biological activity in response to the earth’s rotation and revolution are key to competitive coexistence. Also, temporal niche shifts caused by environmental changes can easily eliminate competitive coexistence. A simple mathematical theory predicts that, at equilibrium, the number of sympatric species competing for a shared set of limited resources is less than the quantity of resources or prey species4. This apparent paradox leads ecologists to examine mechanisms that allow competitors to coexist and has produced diverse coexistence theory7.Diverse species that coexist in an ecological community are supported by fewer shared limited resources than expected, contrary to theory9. Natural ecosystems, by non-linearity itself, can intrinsically generate non-equilibrium dynamics12. More fundamentally, externally imposed disturbances, such as seasonal and less predictable changes in environmental conditions, such as weather, also contribute to disequilibrium. Weather shows prominent seasonal cycles. Temperate regions have four obvious seasons, whereas other locations may have fewer or more seasons, and seasons can reflect changes in rainfall as well as temperature and food availability. In any case, our world is undoubtedly seasonal, and species interactions are constrained in a cyclical manner16.Non-equilibrium dynamics is considered as a major driver to prevent interacting species from going into equilibrium and violate the competitive exclusion principle5. For instance, resource fluctuations or activity cycles of consumers make otherwise impossible coexistence of competing species possible26. For example, fluctuation plays a role in temporal niche partitioning, which can allow competing species a period of competitive superiority and avoid any one species from being excluded. Yet, previous theories with predictable or deterministic fluctuation have mainly focused on changes occurring within a certain period, such as season15; more general environmental fluctuation has multiple periods/cycles.Earlier ecological theory predicts that temporal variation in environmental conditions and species abundance can create conditions for competitive coexistence27. Many organisms have circadian, circalunar, and circannual rhythms, in response to daily, monthly, and annual cycles in environmental conditions. The environment continuously changes over time, and organisms change activities, such as foraging, reproduction, and rest not only within a day but also across longer time scales32. Some species may sleep during the night, and some species may hibernate during winter. Marine organisms are well known to reproduce on a full or new moon. Besides seasonality, such short-term cycles can affect the strength and structure of species interactions32. Nevertheless, how the diversity of activity rhythms with different cycle periods affects competitive coexistence remains unclear.Generally, organisms are affected by earth cycles, such as earth rotation and revolutionY1, Y2, and X, respectively. Superior and inferior competitors display higher and lower prey capture rate, ai, respectively (a1 > a2). In this system, competitive exclusion always occurs, and coexistence is impossible. I consider multiple periodic cycles of foraging by predators. Daily, monthly, and annual cycles in foraging activity  are described by sine waves with different cyclical periods . The presence or absence of rhythms  is controlled by the amplitudes of the activity cycles, γd, γm, and γy, respectively  in the presence of a focal rhythm, otherwise 0). In earlier studies, each activity cycle enabled species to coexist if times in activity peaks differed. In the default setting, a perfect difference in activity peaks in predators is assumed. However, depending on the combination of different cycles, the parameter space for coexistence can be greatly broadened. Not all combinations display this result. When all activity cycles are considered, the coexistence region is maximal. The present results suggest that polyrhythmic changes in biological activity are key to maintaining competing species.I present in this study a polyrhythmic competition model in which two predators with multiple foraging activity cycles share a single prey. The model considers simple exploitative competition in which two predators with linear functional response compete for a single prey. Population sizes of the superior predator, inferior predator, and prey are represented by γi = 0), competitive exclusion of the inferior species always occurs . However, phase differences in each activity cycles between predators affect coexistence. When time niches of predators are not perfectly different, coexistence is possible . Time niche overlap has a qualitatively similar effect on the coexistence as does lack of any activity cycle  . It was revealed that multiple activity cycles allow for otherwise impossible coexistence, thus greatly broadening the coexistence parameter regions in both systems . Hence, coexistence may be most favored by an intermediate activity cycle. However, this finding may not be important in nature since organisms should show multiple activity cycles.Temporal niche partitioning is a classic concept for explaining the coexistence of competing speciesThe present theory suggests that multiple activity cycles have complementary and synergistic effects for species coexistence. Weak interaction is a key factor in coexistence. As demonstrated by the effects of cycle amplitude  is capture rate ; gi is conversion efficiency, which relates the predator’s birth rate to prey consumption (gi = g is assumed for simplicity); and di is the death rate of predator species i.Consider two competing predator species that share a single prey species. The simplest two predator–one prey system is defined by the following ordinary differential equations:ai = ai0ci(t), where ai0 is the basal capture rate. ci(t) is a time-varying function, which represents daily, monthly, annual cycles of foraging activity, or polyrhythmic cycles made by combinations of cycles. Each basal biological cycle is described by the following sinusoidal functions24:Tj and uij are cycle period and timing of activity peak . Here, Td = 1, Tm = 30, and Ty = 365. For the daily cycle, uid may be 0 or 1/2, defined as diurnal or nocturnal, respectively. For the monthly cycle, uim may be 0 or 30/2, each defined as full moon or new moon type, respectively. For the yearly cycle, uiy may be 0 or 365/2, each defined as summer or winter type, respectively. In this study, uj1 = 0, and the default values of ud2, um2, and uy2 are 0.5, 15, and 365/2, respectively. This restrictive assumption is later relaxed).Here, γj is the parameter that controls presence (γj = 1) or absence (γj = 0) of cycles.Models with either two or all cycles are given by the product of each cycle function with different cycle periods.γd = 1, γm = 1, γy = 0), ci(t) = [1 + sin{2π(t − uid)/Td}][1 + sin{2π(t − uim)/Tm}], and in the case with all cycles, ci(t) = [1 + sin{2π(t − uid)/Td}][1 + sin{2π(t − uim)/Tm}][1 + sin{2π(t − uiy)/Ty}]. Single cycles are assessed with Eq. , ci(t) = 1, the system is a well-known Lotka–Volterra type two predator–one prey system. This system produces no coexistence equilibrium. That is, one competing species is always competitively excluded. The system converges to one of the following equilibria: X* = d1/a1, Y1* = r(a1 − d1/K)/a12, Y2* = 0 or X* = d2/a2, Y1* = 0, Y2* = r(a2 − d2/K)/a22.Without activity cycles  after sufficient time (t) t = 5 × 103, which corresponds with the time taken for community persistence to reach an asymptote, it is evaluated as competitive coexistence (otherwise competitive exclusion).Models with activity cycles are analytically intractable. To examine the population dynamics of three species and evaluate competitive coexistence, I performed a numerical simulation of the differential Eqs. –3) by u by u3) bSupplementary Information.