Meddygon Myddfai (recipes 1–188). Although the majority of Myddfai I recipes were based on the Mediterranean herbal tradition of Dioscorides and Macer Floridus, they preserved the unique herbal preparation signatures distinct from continental and Anglo-Saxon counterparts in increased use of whey and ashes as vehicles for formulation of herbal remedies. Six plants could be hypothetically attributed to the Celtic (Welsh) herbal tradition including foxglove , corn bellflower (Legousia speculum-veneris L.), self-heal (Prunella vulgaris L.), sharp dock (Rumex conglomeratus Murray), water pimpernel , and river startip (Scapania undulata L.) This review provides initial evidence for traces of Celtic framework in the Welsh herbal tradition and warrants further investigations of bioactivity and clinical applications of the described plant leads.The Celtic linguistic community dominated large spans of Central and Western Europe between 800 BC and 500 AD, but knowledge of their traditional medicine is very limited. Multiple progressive plant gains in Neolithic settlements along the Danube and up the Rhine valleys suggested that taxon diversity of gathered plants peaked at the Balkans and was subsequently reduced as crop and gathered plants packages were adopted and dispersed throughout Neolithic Europe. This process coincided with the Bronze Age migration of the R1b proto-Celtic tribes, and their herbal traditions were occasionally recorded in the classic Greco-Roman texts on herbal medicines. The provenance of Celtic  healing methods and magical formulas as recorded by Pliny, Scribonius Largus, and Marcellus Empiricus can still be found in the first part of the medieval Welsh (Cymry) herbal manuscript  In their footsteps, proto-Celts likely followed the Balkan (Danube) route of the Neolithic Anatolian farmers (ca. 2400 BC) and admixed with the late Bell Beaker groups (ca. 2200 BC) in Central Europe by forming a succession of Unetice (2300–1600 BC), Tumulus (1600–1200 BC), and Urnfield (1300–750 BC) cultures likely ancestral to the Celtic speakers. Proto-Celts also spread their influence into the British Isles sometime after 800 BC, perhaps in a very similar manner to how the Bell Beaker culture replaced the late Mesolithic populations of Britain , Gallic (200 BC–400 AD), and Celtiberian (200–100 BC) continental Celtic languages made no references to their medical tradition, while the earliest inscriptions in insular Celtic languages did not appear before 400 AD . As suchMyddfai I as one of the earliest known medical texts written in a Celtic language, the most pertinent Roman sources were reviewed in chronological order to observe species frequencies and gather facts relatable to Myddfai I. Conclusions are original to the authors and when possible corroborated by citations from other scholarly works. The criteria for the selection of antique works to compare plant species frequencies was based upon the lineage and historical popularity of each text, availability, and relevance to medieval Wales . Herbal preparation signatures were evaluated by calculating the frequencies of certain vehicles used to crush, dissolve, or extract plant material in order to discern how different cultures were uniquely using similar plants. Methods, including translation notes, are discussed in more detail where relevant.Middle Welsh, Anglo-Saxon, Roman, and Continental European sources were reviewed in their original languages with the aid of lexicons, dictionaries, as well as both antique and modern English translations. Using PubMed, Scopus, Google Scholar, ScienceDirect, JSTOR, and NCBI were used to find and review relevant modern research articles. The plantlist.org was used for aligning Scientific Binomials. Archaeobotanical literature was reviewed with a focus on samples taken from the contexts  likely to represent the accumulated debris from a range of intentional plant-related activities, including the processing of gathered plants and cultivated crops.lingua franca, the main communication language in the region  warlords. The survival of this social structure required continuous conquest and expansion into new territories. The evidence for this is seen in the Celtic migrations over much of Europe as far as the Ukrainian Carpathians, and seemingly universal acceptance of Celtic languages as e region . The conca. 25000 BC  mutations found on the non-recombinant portion of the Y chromosome . Haplogr25000 BC . Haplogr25000 BC . The lat25000 BC . As Yamn–3000 BC . While t–3000 BC . Prelimi–3000 BC .The subsequent Unetice culture of the Upper Danube and Upper Rhine basins Figure 1circa 7000–1500 BC) hold the first archaeological records of humans gathering wild plants. The Late Mesolithic Lepenski Vir site within the Iron Gates gorge on the Danube (Serbia) produced early traces of wild grass grains such as einkorn and emmer wheat (circa 6000 BC (Lithospermum arvense L.), alkanet , and bugloss (Anchusa sp.) (20000–11000 BC). Wild lentils (Lens sp.), vetch (Vicia sp.), pistachio (Pistacia sp.), almonds (Prunus dulcis Mill.), oats (Avena sp.), barley (Hordeum spontaneum K. Koch), and pear  were recovered from the next Mesolithic layer (11000–7000 BC). The cultivated emmer wheat (Triticum dicoccon Schrank) also appeared at this site circa 6000 BC, similar to that of the Lepenski Vir settlement, followed by the cultivated two-row hulled barley (Hordeum distichon L.) and lentil (Lens culinaris Medik.) (Triticum dicoccon Schrank), einkorn (Triticum monococcum L.), hulled barley (Hordeum vulgare L.), flax (Linum usitatissimum L.), and four pulses—lentil (Lens culinaris Medik.), pea (Pisum sativum L.), bitter vetch (Vicia ervilia L.), and chick pea (Cicer arietinum L.). The adoption of this crop package led to an immediate reduction in vegetational taxon diversity at the settlements  . The comtlements .Adonis, Alkanna, Anchusa, Calendula, Capparis, Colchicum, Fumaria, Lithospermum, Malva, Medicago, Phalaris, Salvia, and Silene), could be considered medicinal by modern standards , agrimony (Agrimonia eupatoria L.), nightshade (Atropa belladonna L.), henbane (Hyoscyamus niger L.), ribwort plantain (Plantago lanceolata L.), poppy (Papaver somniferum L.), and wild strawberry (Fragaria vesca L.) Further migrations in the direction of Benelux, Scandinavia, and Southern Britain regions correlated with a divergent pattern of gathered species losses  from the Neolithic Skara Brae site (3180–2500 BC) in Orkney, Scotland (Hyoscyamnus niger L.) seeds in Grooved ware pots at the Balfrag settlement (2900 BC) in Fife, Scotland (Filipendula ulmaria L.) was found at the Bronze Age cairn at Fan Foel, Carmarthenshire  as well as in a beaker at Ashgrove, Fife, and North Mains Strathallan (Scotland)  .Lithospermum purpurocaeruleum L.) present within the same pot, or 22,400 seeds of common gromwell  in a goblet within a larger pot, dated to the Neolithic Cucuteni-Trypillia culture  were found in a pot from the Neolithic settlement of Niederwil (Switzerland), as well as in the intestines of seven European Iron Age bog bodies (Corylus sp.) and crab apple  found in many in Neolithic assemblages and used to supplement everyday diets , hemlock (Conium maculatum L.), white violet , elderberry (Sambucus nigra L. and Sambucus ebulus L.), and broadleaf plantain (Plantago major L.) (No significant changes in gathered wild plant profiles were observed in the findings from the 15 late Neolithic settlements of the Funnel Beaker culture from northern Germany  or six lajor L.) . The hisThe east to west Paleogenetic trends of early Europe coupled with the emerging archaeobotanical pattern would suggest that the flora of the Thessalian Greece—Thracian Bulgaria and Macedonia—Central Europe axis along the Danube migratory route constituted the core pharmacy of proto-Indo-European medical traditions, predating the diversification of tribes into Italic, Celtic, Germanic, and Slavic. As history went on, this core tradition would be further diversified by the evolution of distinct ethnic groups, local oral knowledge, and plants gained and lost due to changes in environment. Ultimately these core plants, became fixed or standardized as “European medicine” by the written tradition of Greece and Rome as a result of Romanization, with small vestiges surviving in folklore and oral tradition.ca. 800 BC through a succession of Hallstatt C-D and La Tene cultures centered around iron trade and salt mines of Hallstatt and Hallein (Dürrnberg) (Daucus carota L.), wild strawberry (Fragaria vesca L.), celery (Apium graveolents L.), camelina (Camelina sativa L.), parsley (Petroselinum crispum Mill.), hazel (Corylus avellane L.), and dyer's weed (Reseda luteola L.)  and Villanova (proto-Etruscan) people rrnberg) Figure 1rrnberg) . Despiteeola L.) . The fir. 500 BC . While t Ukraine .Piper nigrum L.), nutmeg (Myristica fragrans Houtt.), sesame (Sesamum indicum L.), or cumin (Cuminum cyminum L.) were found predominantly within Roman military camps in the Rhine frontier zone (e.g. apple) were present in their native wild form in the Late Iron Age. Dates, almonds, pine nuts, lentils, mulberry, and grapes were also found in the ceremonial context as votive offerings exclusively in Roman London temples, burials, and shrines (Viereckschanzen) spread across Czech Republic to France and dated to 200–100 BC (Olea europaea L.), celery (Apium graveolens L.), coriander (Coriandrum sativum L.), and dill (Anethum graveolents L.) from the high status Silchester site, dated to 50 AD . Boii and other Cisalpine Gaulish tribes often allied with Etruscan and Carthaginian armies against Rome, and their social organization and military tactics were extensively recorded by Roman writers. The military conflict intensified after the defeat of Carthage in 202 BC and resulted in annexation of Gallia Cisalpina in 192 BC, Gallia Transalpina in 121 BC, Gaul in 52 BC, and Britannia in 43 AD , Theodorus Priscianus , Oribasius , and many more authors. Although the original Greek version of Dioscorides was continuously inscribed for the next several centuries, the text was also rearranged in the alphabetical order (i.e. Vienna Juliana Anicia Codex ca. 515 AD) and translated into Latin on multiple occasions. The early Latin translation was designated as Dioscorides longobardus, while the later translations were based upon the alphabetical version of the manuscript and often combined with information extracted from the Pseudo-Apuleius herbal (Dioscorides vulgaris)  . Subsequenturies   in multiple languages including Dacian and Gallic. Generally believed to be a later addition  used as an aphrodisiac, and fennel gum (Foeniculum vulgare Mill.) as a more effective eye medicine than the plant juice. Finally, Celtic nard  endemic to the Celtic Alps, was described as a tonic to the spleen, stomach, liver, and kidneys, that could be taken in wine with wormwood (Artemisia absinthium L.) as a “narcotic,” likely meaning a painkiller. Dioscorides reported very few superstitious practices, including the use of anchusa (Echium sp.) charms against bites.Dioscorides owes his universal acceptance to the development of an empirical tradition of herbal remedies throughout the Mediterranean region . In the addition , the lisaddition Table 1.Naturalis Historia, Book XIV). Special attention was given to mistletoe , especially when grown upon the English oak (Quercus robur L.), as medicine and religious sacrament of the Celts. Pliny described other Celtic plants including glastum or dyer's woad (Isatis tinctoria L.) as a source of blue dye, the use of beech (Fagus sylvatica L.) ashes for reddish hair, hellebore (Helleborus niger L.) as arrow poison, and selago similar to savin (Huperzia selago L.) for eye infections. Even though much of Pliny's material came from Theophrastus or from shared sources, he described several new herbs including britannica, a plant that grew on the islands off the Frisian coast and was used as a cure for scurvy, quinsy, and snake bites. This name could be possibly attributed to the extremophile English scurvygrass (Cochlearia anglica L.) rich in vitamin C  to treat inflammation, originated in the vicinity a Roman colony Ariminum , and their magical formulas were incorporated into the Latin works by direct geographical proximity and societal overlap of Roman and Celtic cultures after 250 BC.The herbal practices of Hellenized Anatolia prioritized a rational approach to making and prescribing remedies, therefore deliberately avoiding magical formulas. Latin herbal writers, however, continuously mention magical cures in the form of spells, charms, and incantations, even while being hostile to these practices, as in the case of Pliny. Among 27 magical remedies listed in his work, only four could be attributed to Greek and Latin origin. One of them, attributed to use of reseda  to heal multiple inflammatory and gastrointestinal disorders, the use of urine collected after cabbage ingestion, and underlined the higher therapeutic potency of wild cabbage compared to its cultivated relatives.A separate branch of herbal knowledge rather independent from Theophrastus, Pliny, and Dioscorides works was initiated by Marcus Cato of Tusculum, known for his conservatism and opposition to Hellenization. He recorded the folk knowledge related to the agricultural and herbal tradition of the Italic and Celtic tribes, including the use of offerings, charms, and incantations for healing practices. Cato advised on the use of cabbage  which, according to Pliny, was native to Narbonese Gaul  in preparation of an eye salve. This form of treatment (dry packaging in large batches) was rather unique to Gaul and the British Isles and could be possibly explained by limited and often difficult access to Eastern Mediterranean herbs required for these preparations . He listed 12 Celtic plant names, ten of which were accompanied by a Greek or Latin synonym. These plants included baditis , biricumus , calliomarcus , gigarus , gilarus , odocos , ratis , and visumarus . The two plants without synonyms were tentatively identified as vernetus or viridis  and blutthagio    , Cyprian (251–270 AD), and Justinian (541–542 AD) plagues that killed as much as 30–40% of the population in the affected areas, and devastated the Roman army. From here, we can only discuss the surviving Celtic herbal framework within the fringes of the British Isles .Macer Floridus), Matthaeus Platearius (Circa instans), John of Milano (Regimen sanitatis), Nicolai Salernitanus (Antidotarium parvum), and Rufinus (Liber de virtutibus herbarum)  by Constantine Africanus and other writers. Medical schools of Salerno and Padua also maintained the Greco-Roman herbal tradition of the existing herbal manuscripts and their interpretations such as Odo Magdunensis (erbarum) Figure 2th century Anglo-Saxon Bald's Leechbook , the 12th century Germanic Physica (Liber simplicis medicinae) by Hildegard of Bingen (1098–1179), and the 14th century Welsh Meddygon Myddfai as a part of the Red Book of Hergest . The latter was said to incorporate the healing tradition of Rhiwallon Feddyg, the physician to Rhys Gryg from the Cymry Celtic kingdom of Deheubarth (ca. 1234). The manuscript is divided in two parts: Myddfai I  and Myddfai II  and appealed to personal experiences in discovering and testing the herbal remedies.Away from the Mediterranean, the classical herbals and their translations were of ever decreasing relevance, which prompted a revision and fixation of a distinct and presumably independent vernacular herbal knowledge. It was the turn of the outskirts of Medieval Europe to develop their own herbals by synthesizing the classic sources and local tradition, as evident from reappearance of magic formulas, incantations, and vernacular plant names in these works. Three manuscripts that fall under this category include the 9radition . Both BaMyddfai I did not follow an obvious organizational structure and seemed to represent a loosely collected list of recipes that was developed over time. This also differed from the Bald's Leechbook, which preserved the classical head-to-toe order. The botanical descriptions in Myddfai I were often significantly reduced or eliminated altogether, suggesting that the manuscript was developed as a quick reference guide of directions (steps) to be performed by a person versed in the herbal tradition and medicine, rather than a medicinal text to be read and interpreted by a medieval scholar. Straightforward passages such as “for an illness…, take a number of plants…, crush them in a vehicle medium., set aside…, have a patient use…” differed drastically with other herbal collections, and did not intend to educate readers in the art of identification and collection of medicinal plants. Another two features that set Myddfai I aside from the contemporary and classical herbals were i) the use of numerous and diverse media for the preparation of herbal remedies, and ii) the emphasis on magic formulas, charms, and incantations. Both groupings garnered very little attention in past scholarly works, however they are more likely to preserve the original references and vernacular knowledge of Welsh belief systems and practices as it applies to Celtic medicine as a whole.In contrast to Dioscorides, whose treatments were organized by substances (earlier Greek and old Latin manuscripts), or revised into an alphabetical order (later Greek and Latin translations), th century) and it's Old English translation (9th century) despite multiple scribes, edits, rearrangements, and translation of the recipes. The signature is still evident in the work of Marcellus Empiricus , and multiple manuscripts of Italian and German tradition such as works attributed to Petrocelli (9th century) or Hildegard (12th century). It is interesting that Bald's Leechbook II manuscript also falls under this category, while Leechbooks I, III, and the Lacnunga maintained sets of remedies that used a different, presumably Anglo-Saxon, herbal preparation signature based on an increased use of milk, butter, and beer  and ashes (similar to Marcellus Empiricus). Myddfai II, in concordance with stipulation of being a recent 18th century compilation from multiple herbal sources, shows a mixed herbal preparation signature with multiple formulation media present at nearly equal frequencies, including an increased use of milk and beer typical to the Anglo-Saxon tradition and largely limited in Myddfai I. It would be very interesting to extend the analysis of the herbal preparation signatures to other herbal manuscripts from the European  and Arabic tradition, as well as different versions of the same manuscript scribed in the geographically distinct areas and time periods.Herbal preparation signatures can be easily evaluated in the herbal manuscripts by calculating the frequencies of certain vehicles (media) used to crush, dissolve, or extract plant botanical material during formulation of the remedies. As evident from Dioscorides, classical Greco-Roman herbal tradition relied heavily on using wine, vinegar, and oil in addition to water as media for preparation of plant remedies. This signature clearly survived in Pseudo-Apuleius  against herbal texts of various medical traditions  is not actually present in the Welsh text but is found in the English translations of recipe 19. Uncertain plant names of Welsh origin were further checked against Davies' Welsh Botanology (1813), Richard's Antiquae linguae Britannicae thesaurus (1815), and Pughe's Dictionary of the Welsh Language (1832). In some cases, the common name was too general to resolve, such a redyn for “fern” or credega for “liverwort”. Plant names not found to match Dioscorides were also corroborated against other sources, including Dunbar's A New Greek and English Lexicon (1844) and the Natural History of Pliny.In an attempt to further distinguish the Welsh herbal tradition, we performed a systematic analysis of plant species and the target health conditions described in the aditions Figure 2De viribus herbarum shared the most extensive overlap with Myddfai I  were also mentioned in Myddfai I)  was mentioned in Regimen sanitatis, thus bringing the total number of Myddfai I plant species of classic Mediterranean herbal tradition to 120. Of those, only 5–6 species had to be imported in dried form from the warmer regions, suggesting that the manuscript was intentionally developed to exclude the most exotic species due to cost and/or lack of availability. The remaining nine plant species could be hypothetically allocated to the herbal medical tradition of the British Isles and Ireland. Three plant species were derived from the Bald's Leechbook or the common shared sources between the two manuscripts, including silver birch (Betula pendula Roth), woodruff , and fir clubmoss (Huperzia selago L.). The remaining six plants  Figure 4The plant is native to west and west-central Europe, including the British Isles. Foxglove is likely the closest claim to success for the Celtic and subsequent Welsh herbal tradition, as the plant was historically used to treat dropsy  and the decoction of its leaves was introduced into medical practice by the Scottish doctor William Withering in 1775. Chemical analysis revealed that foxglove contains a number of cardiac glycosides, including digoxin and digitoxin, that inhibit the activity of the Na/K-ATPase in the myocardium . In the Campanula hybrida, the plant is found in chalky cornfields of the British Isles and other parts of Europe. Due to its status as a weed, corn bellflower has been subjected to ecological and molecular phylogenetic studies, however there is no current scientific evidence of its medicinal properties, and its bioactive principles remain to be elucidated. Myddfai I cited it as a remedy for quinsy or tonsillar abscess.Formerly known as Although self-heal is common throughout Britain, Europe, Asia, and North America, it's traditional use was generally restricted to Asia, where it forms a part of traditional Chinese medicine targeting liver function, thyroid swellings, and inflammation. Flowering spikes of this plant contain up to 6% rosmarinic acid, one of the highest sources of this ingredient among plants . Otherwilabada, was used for treatment of purgative disorders and dysentery. The use of docks in Europe is predominantly restricted to the British Isles and the Carpathian basin  in general is often referred to as tafolen. Species follow such, R. sanguineus (tafolen goch), R. crispus (tafolen grych), R. acutus (tafolen mair), etc. The Welsh name turth appears to only have been attributed to R. conglomeratus.Sharp dock is another plant of a wider Eurasian distribution that was utilized for its medicinal properties mostly outside of Western Europe. In Turkey, the plant locally known as an basin . The rook plants . There iThe plant is found in a variety of wet habitats all over Europe and other parts of the world. Due to a unique cosmopolitan distribution, water pimpernel has been subjected to extensive molecular phylogenetic studies , howeverScapania undulata, contain highly specialized oil bodies enriched with sesqui- and diterpenoids, many of which have not been found in higher plants , suggesting a more detailed knowledge of this particular species. However, it is possible that this refers to the entire genus Scapania. This translation was corroborated by Davies, 1813.Moss-looking leafy liverworts are the second largest group of plants, and their traditional use for addressing abdominal and liver disorders stemmed from a magical doctrine of signatures that believed in beneficial effects of plants to heal certain organs and body parts by resembling their shapes . Traditir plants . Scapanisimples) into a pharmacologically-relevant treatments, Myddfai I herbal preserved the tradition of Roman and Celtic writers to incorporate magical formulas, scoring charms, evil spirits, and incantations into their healing practices. The reason could be argued that a later and often incomplete conversion to Christianity at the Celtic fringes of the British Isles preserved syncretism with pagan rituals including recognition of the fourfold principle, the luck of white cattle, eels, and roosters, lucky and unlucky days, as well as the legend of the Lady of the Lake—in which the authors described the way which they received healing powers—from what was essentially a water spirit.While the medicine of Greece and Hellenized Anatolia made great strides to separate formulations, vehicles, and single herb preparations , sustains three wounds, and is cured by three drinks of milk. Welsh mythology similarly abounds with the appearance of the number three, the deity Llyr has three children, and there are often three demons or plagues found in myths. The theme of threefold death is found in the Welsh Myrddin Wyllt, and this concept may be supported by the remains of the c. 1st century AD Lindow bog body which sustained a hanging, head wound, and cut throat and was found with mistletoe pollen grains in his stomach .Many herbal preparations also preserved the significance of numbers 3 and 9 in selection of ingredients, number of manipulations, and frequency of dosing—often a medicine made of three components was taken thrice daily for 9 days. The number 3 (and thus 9 = 3x3) was significant in Celtic religion prior to Christianity and in syncretic Celtic Christianity (Arthurian legends), symbolizing the trinity. However, the trinity itself predates Christianity in Indo-European religions including Roman, Celtic, Germanic, and Hindu polytheism and may be supported by the trifunctional hypothesis of Dumezil. Triple deities such as the Matronae , the Morrigan (Irish), and Brigid (Irish), are prominent examples of the significance of three in Celtic culture along with symbols such as the triskele. In  stomach . InteresA description of the Western Islands of Scotland (ca. 1695). Neil Beaton of Skye was said to treat “Lilium Medicinæ, and some other practical pieces that he has heard of, with contempt. The success attending his cures was so extraordinary that people thought his performances to have proceeded rather from a compact with the devil, than from the virtue of simples. To obviate this, he pretends to have had some education from his father, though he died when he hurnself was but a boy.” A more contemporary account of a direct oral transmission of herbal tradition of the Western Isles can be also found in the Maclagan Manuscripts (1892–1903) collected throughout the Highlands and the Inner Hebrides , Tess Darwin , and Bridgewater & Milligan .A distinctive Celtic ethnographic framework of traditional healing beliefs and practices also survived in part with local population and a network of hereditary scholarly physicians of the Western Isles of Scotland  . A peculHebrides . More ofBald's Leechbook (Myddfai I (Sorbus arranensis Hedl.). These findings, however, only further strengthen the critical need for correct translations, botanical identification of vernacular and old language plant names, understanding changes in formulation, biochemical composition, and efficacy of medicinal plants that varies tremendously based on plant species, environmental location, and tissues used in the preparation.Contrary to magic formulas, charms, and incantations which may exert beneficial results on human body by affecting the neurobiological mechanisms of individual expectations and psychosocial placebo effects , herbal eechbook  and Myddyddfai I , with thChelidonium majus L.) (The Celtic fringe flora of the British Isles subsequent to the last glaciation shares a lot of common species with Scandinavian plants (those that likely survived glaciation in the southern or mountaintop refuges), and the incomers from the Germanic and Mediterranean flora that spread over the land bridges that existed at the time . As suchajus L.) .Digitalis purpurea L.) and several other plants. While the extent to which the later Welsh 14th century text (Myddfai I) manifest an earlier oral tradition is uncertain due to overlaps with the classical writers, later scribes, additions, and even forgeries of the manuscript (Myddfai II), as well as dubious translations of plant identities and human diseases. Recipes from Myddfai I, however, carry distinct herbal preparation signatures (use frequencies of certain formulations and vehicles), which are vastly different from earlier Greco-Roman and contemporary Anglo-Saxon and Germanic traditions. The old practices also persisted in the Celtic fringes of the British Isles  till very recently, but were rarely incorporated into the written tradition until the late 18–19th centuries. Consequently, many herbal remedies remained an integral part of prevention and treatment of human diseases until modern times, some were rediscovered as botanical drugs and incorporated into pharmacopeias, while the other neglected recipes can be further explored for novel interactions and pharmacological applications.Traces of Celtic framework of traditional herbal remedies can still be found in classical and medieval herbal collections largely dominated by Mediterranean plants, as was shown for the foxglove (CW translated Welsh text, identified plant names, health indications, and performed descriptive statistics of the herbal texts. SK developed the concept of herbal preparation signatures. CW, JD, and SK conceived, designed, and developed the framework of the study. CW and SK drafted and wrote the manuscript. JD edited the manuscript. All authors read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Newborn screening is a public health program facilitated by state public health departments with the goal of improving the health of affected newborns throughout the country. Experts in the newborn screening community established a panel of eight quality indicators (QIs) to track quality practices within and across the United States newborn screening system. The indicators were developed following iterative refinement, consensus building, and evaluation. The Newborn Screening Technical assistance and Evaluation Program (NewSTEPs) implemented a national data repository in 2013 that captures the quality improvement metrics from each state. The QIs span the newborn screening process from collection of a dried blood spot through medical intervention for a screened condition. These data are collected and analyzed to support data-driven outcome assessments and tracking performance to improve the quality of the newborn screening system. Newborn screening (NBS) began in the United States in 1963 when four states began using blood drops collected on filter paper to detect Phenylketonuria (PKU) .The newborn screening test has moved beyond bloodspot testing to include hearing and congenital heart point of care testing. National policies over the past several decades have safeguarded funding while the establishment of federal programs at the Centers for Disease Control and Prevention (CDC) and the Health Resources and Services Administration (HRSA) have enhanced the system by establishing quality assurance, quality improvement, evidence review, advisory committee, and technical assistance related programs .This simple, life-saving/quality of life enhancing test—the newborn screen—is backed by a complex system comprised of laboratory testing, follow-up, diagnosis, treatment or management, evaluation, and education . Every sThe recording, analyzing, and sharing of screening observations and measurements becomes necessary when evaluating the successes, gaps, and areas for data-driven improvements in a dynamic system that operates uniquely in each state, with factors such as fees and budgets, operating hours, screening methodologies, disorders screened, staffing workflows, and reporting algorithms varying from program to program. Acknowledging the unique qualities of each NBS program, in 2012, NewSTEPs took the lead in facilitating stakeholder engagement and consensus building to refine a set of uniform QIs, allowing programs to use standardized metrics to track performance, identify outliers, initiate data-driven improvements, perform gap analysis, and to engage in national and peer benchmarking. These NewSTEPs QIs are a reflection of the quality of the national NBS system where uniform measures were otherwise previously lacking.The process of establishing, defining, and collecting uniform quality measures that would allow inter- and intra-program comparisons across multiple years required significant consensus-building and engagement from the newborn screening community, including representatives from the NBS laboratory, follow-up, and medical specialists. A meeting of subject matter experts to establish an initial set of QIs followed by pilot testing in one state’s newborn screening system yielded a framework from which the final eight QIs emerged. The final QIs- incorporate measurements from the full spectrum of the newborn screening system, from dried blood spot collection and specimen delivery to the laboratory, to point of care screening, diagnosis, and tracking missed  cases. Structured group communication methodologies, including the Delphi process, public comment, and World Café, were employed by NewSTEPs ,7. This In June 2011, APHL, in collaboration with the Genetic Alliance, convened 38 newborn screening experts representing a range of geographically diverse states at varying levels of screening complexity. In this instance, screening complexity referred to the number of disorders screened, the number of screens performed on each newborn (one versus two), and the number of annual births in each state  identification and categorization of existing state-specific quality metrics; 2) harmonization of definitions of existing quality metrics; 3) summarization of the utility of state-specific performance measures and identification of new, standardized quality measures; 4) identification of common metrics collected by all participating states to be incorporated into the development of uniform national newborn screening QIs; and 5) definition of key QIs useful for measuring operational and outcome-based newborn screening processes.In defining the ten QIs  establisIn fall 2011, the New Jersey Newborn Screening Program and its divisional Quality Assurance Program participated in a pilot study to collect the 10 QIs  developeIn July 2012, NewSTEPs convened the second meeting of 57 subject matter experts , as well as previously unengaged stakeholders from the newborn screening community, including Laboratory Information Management Systems (LIMS) vendors  tasked its Laboratory Standards and Procedures Workgroup with investigating the timeliness of newborn screening in the United States. The result was a series of recommendations later adopted by the Secretary of Health and Human Services, on the timeliness goals for newborn screening programs . NewSTEPIn mid-2017, several newborn screening programs entering QI data into the NewSTEPs data repository notified NewSTEPs staff that a bias may exist when reporting timeliness measured in units of hours versus days. The bias occurs when reporting the following: 1) time elapsed from specimen collection to specimen receipt at the laboratory, 2) time elapsed from specimen receipt to reporting results, and 3) time elapsed from birth to reporting results. NewSTEPs staff assessed the severity and impact of this potential bias by analyzing data from three newborn screening programs that utilized different recording methods to acknowledge specimen receipt at the NBS laboratory. Results of the analyses confirmed that a bias does exist. Specifically, newborn screening programs that do not currently collect timestamps  will enter data in integer values of whole units of days as opposed to units of hours for programs that do incorporate timestamps for laboratory receipt. To address this, NewSTEPs sought feedback from the subject matter experts who had been convened in February 2016  and ultiFollowing the voting process, 16 proposed measures received more than five votes each, with some measures combined into subcategories of a larger measure . Based upon the outcome of each potential QI, its ability to track improvements in the newborn screening system, scientific merit, relevance to stakeholders, and feasibility of collection, a final list of ten QIs were selected by the meeting attendees as viable options for inclusion in a standardized, national set of performance measures . The subThe New Jersey Newborn Screening (NBS) Program concluded that all 10 QIs proposed during the June 2011 subject matter expert meeting  were relAs a result of the pilot study, the New Jersey NBS program also noted that it was likely that the feasibility of any given newborn screening program to provide data for each QI will vary on how the program information management systems are configured, how data are stored, and how data can be retrieved. The pilot study in New Jersey also revealed a need for additional education around each QI and its corresponding definition, as well as broader system based quality improvements that should be addressed, such as developing a better understanding of gaps in data around parent refusals for a newborn screen.n = 57) of all respondents. An average of 44% ) of the respondents indicated that data on the majority of the proposed QIs would be challenging to collect. Further, the percentage of participants that found that the QI definition required changes ranged from 27–95%  definitions , when apm 27–95% .The January 2013 subject matter expert meeting resulted in a consolidated list of QIs, reducing them from 10 to eight, with an accompanying purpose and definition articulated for each one. This was achieved by combining QI 3  and QI 9 , into a new QI 3 ) while removing QI 10  of out-of-range screening results) .In July of the same year, the NewSTEPs program sought public comment on the eight refined QIs from the newborn screening community . NewSTEPThe December 2015 and February 2016 subject matter expert meetings yielded more comprehensive and uniform definitions for the eight QIs, as well as a source document that provided a description, purpose, list of denominators, and definition for each quality indicator.In 2016, NewSTEPs adopted the final set of eight National Newborn Screening QIs  followinThe nuances associated with each QI, including numerator and denominator data, as well as sub-components were incorporated by NewSTEPs in a Quality Indicator source document. The source document also includes detailed definitions and a glossary of terms to eliminate any ambiguity regarding frequently used terminology . QI quicTo achieve consensus with national standardized QIs, the engagement of multiple stakeholders within the newborn screening community has been a necessary step. Numerous meetings for engagement coupled with utilizing a variety of communication and consensus-building techniques proved valuable in reviewing, refining, establishing, and operationalizing national performance measures for the newborn screening system. The lengthy process required six years of community engagement and resulted in very detailed and complex QIs. The complexity of these quality measures, however, make it necessary to ensure that ambiguity and misinterpretation of definitions are minimized, thereby assuring that data reported across all programs is comparable and is measuring the same processes across newborn screening systems.NewSTEPs’ mission is to achieve the highest quality newborn screening systems. The program will continue to review and monitor the national newborn screening QIs every five years to ensure continued feasibility and relevance. Quality indicator data is collected on an annual basis within the NewSTEPs data repository. State newborn screening programs are requested to provide data at least annually for each prior year, with submission accepted via either manual or automated data entry mechanisms. NewSTEPs has made data import templates available to newborn screening programs for ease of data entry as well as free data visualizations that NBS programs can utilize for quality improvement initiatives. The governance of all QI data submissions is overseen by a data use agreement or memorandum of understanding (MOU) between the Association of Public Health Laboratories and each state newborn screening program.A recent demonstration of the utility of the standardized national newborn screening QIs is their use in a federal report developed by the US Government Accountability Office (GAO) on Newborn Screening Timeliness . NewSTEPAs newborn screening programs submit data, NewSTEPs welcomes feedback from NBS programs on the national newborn Screening QIs. NewSTEPs will use this feedback to ensure that the QIs continue to measure, in a harmonized fashion, the critical areas where quality improvements can be initiated within newborn screening systems. NewSTEPs plans to engage key stakeholders in an in-person meeting in the fall/winter 2019, in part to review feasibility of data collection and how this process can be made easier.Despite significant efforts to elaborate all nuances and definitions in a Quality Indicator Source Document, there remain data elements that are open to interpretation or that may not be measured in a harmonized fashion across programs . These idiosyncrasies of programs will be realized and acknowledged as QI data and feedback is collected from all states and reviewed. As these areas for improvement are identified, they will be addressed and incorporated into modified QIs at five-year intervals.Similar quality indicators or metrics are found in use by the Healthcare Improvement Scotland in a document titled “Pregnancy and newborn screening indicators” . The docThe efforts by newborn screening stakeholders between 2011 and present resulted in the first collection of a highly reviewed, consensus-based, refined set of national newborn screening QIs for use in newborn screening programs. These QIs can be used to evaluate and benchmark performance, make comparisons across programs that perform similar activities differently and allow for focused quality improvement initiatives. National newborn screening QIs are a necessary and useful tool in recording, analyzing and sharing observations and measurements within the newborn screening system, for tracking outcomes, and for implementing quality improvements.


Nathan Ford and co-authors discuss global priorities in the provision of HIV prevention and treatment services. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), in 2018, an estimated 37.9 million people were living with HIV worldwide. There were also 1.7 million new infections and 770,000 deaths.At the end of June 2019, 24.5 million people were receiving antiretroviral therapy (ART). Nonetheless, increased access to high-quality ART services is needed to further reduce mortality and new infections and to optimize long term outcomes.In this article, we summarize priorities for HIV service delivery research and guidance identified through a World Health Organization (WHO) consultation held at the end of 2018.The priorities identified include linkage from HIV testing to care; rapid initiation of ART (including out-of-facility ART initiation); task sharing and decentralization, including children and patients on second line; ART delivery for stable clients; adherence, retention, and reengagement in care; management of advanced HIV disease; provision of welcoming health services; and strengthening of service integration, particulary for NCDs and family planning.Ongoing evaluation is needed to determine the net effects of introducing differentiated service delivery models, in terms of health service inputs and long-term outcomes for people living with HIV.To support delivery of antiretroviral therapy (ART) at scale, the World Health Organization (WHO) has promoted a public health approach to HIV treatment and care. Recognizing the critical importance of streamlined, standardized approaches to scaling up HIV services in settings with limited resources, the public health approach emphasizes strategies such as task sharing, decentralization and integration of HIV services with other public health programs, and patient and community empowerment. The public health approach also prioritizes streamlined clinical and laboratory monitoring, standardized first- and second-line treatment regimens, and harmonized monitoring and evaluation strategies ,2. In hiSince 2013, WHO has developed evidence-based recommendations aimed at addressing the key steps in the HIV care cascade from HIV testing and linkage to care to initiation of ART and adherence and retention . By resphttp://lawsandpolicies.unaids.org/.In November 2018, WHO held an expert consultation on future priorities for HIV treatment service delivery. The consultation included national HIV program managers from 11 countries, implementation partners, and representatives from civil society and academia. To support this consultation, WHO conducted a survey to assess the implementation status of current guideline recommendations . InformaWe discuss the findings of the consultation for implementing key service delivery interventions and priorities for future guidance . PrioritBarriers to access to care, although critical, are beyond the scope of this review.Globally, only 65% of HIV-positive individuals are receiving ART, and the proportion of HIV-negative individuals at high risk of HIV acquisition who have access to HIV prevention services is unknown . ApproxiUpdated WHO HIV testing guidelines, including recommendations on linkage to care, were released in December 2019. These guidelines emphasize that wherever HIV testing is provided, the person or organization doing the testing should be responsible for supporting clients and linking them to treatment and prevention services . EffectiAnother potential strategy is to initiate ART in the community and then refer patients to the health facility for follow-up. A study from Lesotho found that people offered same-day ART start at home were more likely to link to care following an HIV-positive diagnosis than those referred to a health facility to initiate ART .Research and program experience has shown that losses to care prior to starting ART can be reduced by reducing time to ART initiation ,16. WHO Rapid initiation of ART, including starting ART on the same day as HIV diagnosis, can lead to improved retention in care and increased viral suppression . ConcernSome program reports suggest an increased risk of loss to care following ART initiation, highlighting the importance of focusing attention on adherence challenges during the initial period following ART initiation . This isGuidance is needed to identify the type, frequency, and duration of interventions that can improve treatment outcomes following rapid ART initiation, particularly for asymptomatic patients.Community-based testing and rapid ART initiation have been implemented in several countries, but support is needed to ensure that ART is safely and successfully started outside of health facilities. A trial from Malawi found that more people started ART at home than those referred to a health facility . Another3, access to the WHO recommended package of care for advanced HIV needs to be improved, and consideration should be given to adapting the package to cover region-specific comorbidities [Out-of-facility ART initiation is another promising intervention for future WHO guidance. Benefits may vary according to context . More research is needed to determine the optimal quantity of ART provided at initiation and the frequency and approach to ensure adherence counseling and appropriate clinical review, including laboratory testing and staffing needs. For patients with a CD4 cell count less than 200 cells/mmbidities .Task sharing to support ART initiation by nonphysicians has been strongly recommended by WHO since 2013 and is supported by most national guidelines surveyed . HoweverART coverage remains low for children—52% as of the end of 2017 . Task shTask sharing also can support expanded access to key diagnostic interventions, including HIV testing and other simple diagnostic tests. WHO recommends HIV testing by lay providers , and tasA related recommendation is the decentralization of HIV treatment and care to peripheral health centers and community sites to increase the number of facilities providing ART, bring care closer to where people live, and decongest hospitals. Decentralization of ART to lower-level health centers has been widely adopted, but community ART provision remains limited .Since 2016, WHO has recommended reducing the frequency of clinic visits and ART refills for stable clients . This apIn 2016, WHO recommended reducing the frequency of clinic visits for stable ART clients to once every 3–6 months. Data from UNAIDS up to the end of 2019 show that of 120 countries surveyed, the majority (104) have adopted these recommendations .A study from Zambia found that visits every 6 months were associated with decreased adverse outcomes  and improved retention in care . Some coFor children and adolescents, visits every 3 months are recommended more frequently in national guidelines than visits every 6 months, and several countries still require monthly visits for adolescents . Young cThe 2016 WHO guidelines also recommend ART refills once every 3–6 months for stable clients, and these recommendations have also been widely adopted by the majority of countries . In EthiFuture guidance could help clarify the optimal frequency of clinic visits and ART refills. Policies could consider accommodating patient preferences and the need to simplify and align clinic visits and drug refills for patients with comorbidities.Adherence to ART is critical to ensuring successful treatment outcomes and to reducing the risk of drug resistance. Although studies have suggested that 95% adherence is optimal, recent studies suggest that lower levels (80%–90%) may be sufficient with newer regimens .VL is the preferred way to measure adherence, and viral suppression is high: above 80% among people retained in care . AlternaPeer counseling, adherence clubs, and mobile text messaging and reminder devices are recommended by current guidelines to support adherence and retention in care . ReasonsEstablishing peer support groups for stable ART patients both in health facilities and in the community fosters support and facilitates access to treatment . SeveralOptimal approaches are needed to trace people who disengage from care and support return to care. Effective return to care includes rapid reinitiation of ART, clinical assessment, prophylaxis and management of opportunistic infections for patients with advanced HIV disease, and VL testing to assess need for regimen switch. Counseling also should be provided to understand reasons for disengagement and to offer any support required to facilitate return to care.Tracing and reengagement programs can be effective ,51. A stFuture guidance should recommend effective, feasible, and acceptable approaches to support tracing and reengagement with care and clarify who should perform the tracing and the type  and frequency of interventions. Tracing should be prioritized for patients with high mortality risk, such as those who do not attend scheduled follow-up visits after hospital discharge .A growing number of patients presenting with advanced HIV disease had previously started ART and then disengaged from care . GuidancThe use of national-level unique identifiers for patients would support effective tracing across the health system and improve return to HIV treatment as well as management for complex cases in decentralized clinical settings, via consultation or referral.A study from Zambia assessing patient preferences found that although longer ART refill intervals were preferred, patients were willing to accept shorter refills to access nice (as opposed to rude) providers . This fiShame and fear of negative attitudes can lead people to be reluctant to return to care following disengagement . In Sout3). Patients with advanced HIV disease should be screened for TB and cryptococcus and provided with prophylaxis, given the high mortality rates associated with these coinfections. Future guidance should consider whether additional interventions should be included, especially to reduce the risk of mortality associated with severe bacterial infections [WHO recommends a package of care for people presenting or re-presenting to care with advanced HIV disease . Baselinfections ,60 and tfections .Currently, WHO recommends service integration for common coinfections and comorbidities. These include providing both HIV and TB treatment, including TB preventive treatment in settings with a high burden of both diseases, providing ART in settings that offer opioid substitution therapy, integrating sexually transmitted infections (STIs) and family planning services within HIV care settings, and assessing and managing cardiovascular risk and depression . Most coSeveral studies have assessed the impact of integrating care for HIV, hypertension, and diabetes , and intWHO recommends integrating family planning into ART services as a one-stop service, and future guidance could consider integrating family planning in differentiated service delivery models for stable clients. Many countries face persistent challenges, such as lack of supplies and trained health workers to providing long-acting, reversible contraception options such as implants and intrauterine devices. In Malawi, approximately 20% of women received family planning during ART consultations in 2018, and 69% of last pregnancies were unintended, which highlights the unmet need for family planning in women receiving ART. The high proportion of women who became pregnant while using contraception was ascribed to inconsistent condom usage or poor patient adherence to hormonal contraception . In a paIntegration of HIV and noncommunicable diseases and sexual and reproductive health are key areas for future WHO guidance to support service integration. Service integration across a range of comorbidities should aim to align clinical follow-up and drug refill schedules as far as possible, adapted to the reduced frequency of contact with health services for the majority of clients who are stable on therapy.Recommendations for HIV service delivery in WHO guidelines have been informed by evidence and experience of successful scale-up of ART across a range of settings and populations. Key areas requiring clarification within existing recommendations include task sharing and decentralization of services for pediatric populations and second-line ART prescription as well as prioritization of linkage to care interventions. New areas that require guidance include community-based ART initiation, patient tracing, and reengagement of people lost to follow-up.HIV services could consider integrating the broad range of health needs of people living with HIV into models of care that may require less interaction with the health system while ensuring successful long-term outcomes of HIV treatment. Country experience of implementing differentiated service delivery models at scale has provided further evidence of the short-term impact of specific models for stable clients, those who may be at risk of advanced disease, and for specific populations. Ongoing evaluation would facilitate understanding of the net effects of introducing differentiated service delivery models on health service requirements and long-term outcomes for people living with HIV.S1 Text(DOCX)Click here for additional data file.S2 TextART, antiretroviral therapy.(DOCX)Click here for additional data file.S3 TextART, antiretroviral therapy.(DOCX)Click here for additional data file.S4 TextART, antiretroviral therapy.(DOCX)Click here for additional data file.S5 TextART, antiretroviral therapy.(DOCX)Click here for additional data file.S6 Text(DOCX)Click here for additional data file.


Over the past 10 years, knowledge about several aspects of fruit metabolism has been greatly improved. Notably, high-throughput metabolomic technologies have allowed quantifying metabolite levels across various biological processes, and identifying the genes that underly fruit development and ripening. This Special Issue is designed to exemplify the current use of metabolomics studies of temperate and tropical fruit for basic research as well as practical applications. It includes articles about different aspects of fruit biochemical phenotyping, fruit metabolism before and after harvest, including primary and specialized metabolisms, and bioactive compounds involved in growth and environmental responses. The effect of genotype, stages of development or fruit tissue on metabolomic profiles and corresponding metabolism regulations are addressed, as well as the combination of other omics with metabolomics for fruit metabolism studies. The growth and ripening of fruit are multifaceted and highly regulated developmental processes which yield colorful and flavorful tissues for organisms that consume and disperse the seeds therein . Fruits The number of teams involved in, and of articles published on, fruit metabolomics has been regularly and progressively increasing. Searching for articles in the Web of Science core collection for metabolomic(s) or metabolome, and fruit in the last decade  revealedThis Special Issue focuses on applications of metabolomics within the field of plant sciences for the study of fruit. It contains 12 original research articles and one review article. The contributed research articles are exemplary studies covering primary research applied to fruit species from a basic understanding of metabolism regulation to applications for phenotyping for breeding or defence priming .This Special Issue covers a range of fruit species, including model fruit tomato ,13,14), ,14, 13,1The original research articles can be classified according to scientific domains: biochemical phenotyping of genetic resources for collection maintenance or intraspecific classification, generating knowledge about fruit growth, ripening and post-harvest, understanding metabolism, characterizing defence priming, identifying bioactive compounds for human nutrition and health.Biochemical phenotyping of cashew apple based on LC-MS and near-infrared spectroscopy  allowed Fruit are complex organs constituted of different tissues. The distribution of metabolites throughout the different fruit tissues, pericarp, placenta, and seeds, was described in chilli pepper . PericarThe mechanisms underlying fruit growth during kiwifruit development were investigated using phytohormone profiling with transcriptomics under two carbon supply levels . The resConcerning metabolism regulation, a cross-species study using LC-MS was performed to clarify the metabolic regulation of fruit phenolics among three Solanaceae crops, tomato, eggplant and pepper . It alloMetabolic correlation networks covering a variety of metabolic traits such as lipophilic and volatile compounds in tomato fruit have shown how the individual metabolic classes are related to yield-related phenotypic traits . MoreoveFruit metabolism is tuned in interaction with the abiotic and biotic environments. Immune priming of tomato fruit by the defence inducer ß-aminobutyric acid (BABA) was investigated against three different fruit pathogens using a combination of targeted and untargeted metabolomics . While BIn relation to human health, in white and black mulberry fruits, combining an LC-MS method with assays for (i) α-glucosidase inhibitory activity and (ii) antioxidant activity , allowedVitis vinifera cv. Pinot noir putative-clones grown in identical field environments [Wine is a famous product derived from fruit for which a range of metabolomic studies have been performed ,25. Hereronments . In addiOverall, these 13 articles demonstrate that metabolomics is a powerful and insightful tool to address numerous biological issues that link to fruit biology before or after harvest. The future improvement of metabolite annotation workflows will certainly help to decipher more ambitious questions when metabolomics biomarker discovery broadens our understanding of fruit processes. A greater number of fruit metabolomics studies, especially for tropical species or species other than major crops, will allow for a better depiction of fruit mechanisms that govern development and responses to environmental fluctuations.To conclude, we would like to thank each of the authors who contributed to this Special Issue on fruit metabolism and metabolomics, the peer reviewers who allowed for improving the quality of submitted manuscripts, and the staff members of the Metabolite Editorial Office for their support.


Public schools in the United States are the main providers of mental health services to children but are often ill equipped to provide quality mental health care, especially in low-income urban communities. Schools often rely on partnerships with community organizations to provide mental health services to students. However, collaboration and communication challenges often hinder implementation of evidence-based mental health strategies. Interventions informed by team science, such as Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS), have the potential to improve treatment implementation and collaboration within schools.The objective of this study is to improve communication and collaboration strategies among mental health and school staff by adapting an evidence-based team science intervention for school settings. We present a protocol for a hybrid effectiveness-implementation study to adapt TeamSTEPPS using stakeholder feedback, develop a tailored implementation plan, and pilot the adapted content in eight schools.Study participants will be recruited from public and charter schools and agencies overseeing school mental health services in the local metro area. We will characterize current services by conducting a needs assessment including stakeholder interviews, observations, and review of administrative data. Thereafter, we will establish an advisory board to understand challenges and develop possible solutions to guide additional TeamSTEPPS adaptations along with a complementary implementation plan. In aim 3, we will implement the adapted TeamSTEPPS plus tailored implementation strategies in eight schools using a pre-post design. The primary outcome measures include the feasibility and acceptability of the adapted TeamSTEPPS. In addition, self-report measures of interprofessional collaboration and teamwork will be collected from 80 participating mental health and school personnel. School observations will be conducted prior to and at three time points following the intervention along with stakeholder interviews. The analysis plan includes qualitative, quantitative, and mixed methods analysis of feasibility and acceptability, school observations, stakeholder interviews, and administrative data of behavioral health and school outcomes for students receiving mental health services.Recruitment for the study has begun. Goals for aim 1 are expected to be completed in Spring 2021.This study utilizes team science to improve interprofessional collaboration among school and mental health staff and contributes broadly to the team science literature by developing and specifying implementation strategies to promote sustainability. Results from this study will provide knowledge about whether interventions to improve school culture and climate can ready both mental health and school systems for implementation of evidence-based mental health practices.ClinicalTrials.gov NCT04440228; https://clinicaltrials.gov/ct2/show/NCT04440228DERR1-10.2196/26567 Youth living in poverty experience internalizing and externalizing mental health disorders at considerably higher rates than higher socioeconomic status peers. One in five children living below 100% of the federal poverty level has a mental, behavioral, or developmental disorder ,3. ApproDue to a lack of internal capacity to adequately meet student mental health needs, districts often have contracts with community agencies for services. A comprehensive national survey found that about half of school districts in the United States had contracts with community organizations for student mental health services, typically provided in school with a combination of school and community staff . RegardiEffective collaboration among interdisciplinary personnel is a necessary yet understudied aspect of providing school-based mental health services. Supporting school-aged children with mental health needs often requires a team of providers, including teaching and nonteaching staff, paraprofessionals, mental health clinicians, case managers, and physicians . CollaboTeam science literature has the potential to inform implementation efforts and improve collaboration within school-based mental health teams -23. One As TeamSTEPPS was developed for health care settings, it requires modifications for the school mental health context. Our team has previously adapted the intervention for mental health teams working in schools and has examined the feasibility and acceptability of the adaptation . RelevanThis study will expand the adaptation of TeamSTEPPS using additional stakeholder feedback, develop a tailored implementation plan, and pilot the new adapted version. The Consolidated Framework for Implementation Research (CFIR) provides an overarching framework for the project to guide implementation . The CFIThe specific aims of this project are to (1) characterize the use of school mental health services in urban districts within the United States, including challenges and successes, using multiple sources of information; (2) identify interorganizational challenges and required components of TeamSTEPPS to adapt ; and (3) explore the feasibility, acceptability, and impact of TeamSTEPPS plus tailored implementation strategies on interprofessional collaboration, teamwork, and student outcomes. Primary implementation outcomes  of interThis study has a mixed methods effectiveness-implementation hybrid design. The effectiveness of TeamSTEPPS will be examined while knowledge of implementation barriers and facilitators are incorporated into an implementation plan .We aim to characterize the use of urban school mental health services, including challenges and successes, using multiple sources of information .Participants will be recruited from public and charter schools and agencies implementing and overseeing school mental health services in the local metro area. Participants for needs assessment interviews will range from upper-level leadership to front line personnel. Schools are invited to participate via an introductory email sent to district and/or school leadership. Following approval from the district and/or charter entities, individual staff members will be invited to participate via an introductory staff meeting or email facilitated by our leadership partners.First, we will conduct a needs assessment with 15 key informants who represent clinical leadership, clinical and paraprofessional providers from the mental health team, teachers, and school administrators. Key informants will be asked about (1) the history of mental health services in their school/district, (2) successes, and (3) challenges or unintended consequences of previous models. We will ask interviewees to recommend additional key informants, and we will include as many individuals as appropriate to better our understanding of the district’s services. Key informant meetings will last approximately 1 hour.We plan to observe school mental health teams providing services. Study staff will spend one full day per school observing team dynamics, service provision, and interactions with school personnel in 10 schools drawn from our partner districts. In light of COVID-19, if in-school observations are not permitted, we will utilize a “think aloud” exercise in lieu of observations.To understand the impact of previous and existing mental health service models in our partner districts, we will examine students’ behavioral health and school outcomes using administrative data when available . These data may include (1) routine and acute behavioral health service use, (2) psychotropic medication use, (3) school absence, (4) grade promotion, (5) school suspension, (6) disciplinary referrals, (7) individualized education plan status, and (8) demographic data including sex and race/ethnicity. School-level data will include average annual school-level absence and suspension rates, average annual number of students with disciplinary school transfers, and annual number of students with an individualized education plan.We will use an adapted version of the Oxford Non-Technical Skills (NOTECHS) scale  as the fOne-way analysis of variance (ANOVA) will examine the mean differences between schools on the NOTECHS total and for each domain. We will synthesize previous local evaluations that provide insights into the characteristics of an urban setting school, including student demographics and school climate such as suspension and absence rates, as well as children’s behavioral health service use over time. The synthesis will inform key stakeholders about whether school mental health services have a positive effect on improving school outcomes and whether the school climate (school-level absence and suspension rates) moderates the effect of school mental health services on children’s school outcomes. We will share the results with key stakeholders and obtain their views on the successes and challenges of school-mental health service delivery.We will load all field notes into NVivo  for data management and analysis. Analysis will be guided by an integrated approach  that incWe will integrate the NOTECHS observation data and field notes using the following taxonomy: the structure is Quan → Qual, the design is Convergent , and the process is Connecting (to elaborate upon the quantitative findings to understand the process of implementation of school-based services as experienced by stakeholders) . To inteWe aim to adapt TeamSTEPPS in collaboration with an advisory board of diverse stakeholders and develop tailored implementation strategies to support the use of TeamSTEPPS.Building on aim 1, we will establish an advisory board guided by the recommendations of Southam-Gerow et al  for utilThe advisory board will meet regularly to consider issues as the adaptation proceeds module by module. Consensus on important points will be determined by a 70% majority, consistent with the literature . MeetingThe products of aim 2 will be (1) an adapted TeamSTEPPS, directed toward both school mental health and school-employed personnel, and (2) specific tailored implementation strategies to improve services in schools in conjunction with TeamSTEPPS. Based on previous experience, we expect the implementation plan will include established strategies  such as The precise schools and participants to include will be determined during aim 1 in collaboration with our district leadership partners. We anticipate 10 to 15 participants, which will likely include a variety of stakeholders, including school mental health providers, leadership from mental health organizations providing school-based services, teachers, school leaders/supervisors, and parents of youth receiving school-based mental health services. Participants will be formally invited by email or letter and asked to apply and agree in writing to participate to ensure they can commit for the duration of the research.We aim to explore the feasibility, acceptability, and utility of TeamSTEPPS plus the implementation strategies generated in aim 2 in terms of interprofessional collaboration, teamwork, and student outcomes.We will pilot test the adapted TeamSTEPPS and implementation strategies in eight schools. Participating mental health team members and school personnel will complete self-report assessments measuring interprofessional collaboration, teamwork, feasibility, and acceptability at baseline  and the school year following participation at two time points . ParticiDistrict leadership will provide guidance on the schools to invite for participation in the TeamSTEPPS pilot. We will recruit schools randomly without replacement from the pool of potential schools. We will compare the eight schools who agree to participate with those who decline in order to explore representativeness . We plan to enroll the first cohort of four schools during year 3 and the last cohort during year 4 of the study . We antiWe will work with schools to ensure that the initial TeamSTEPPS training is provided during regular professional development time to reduce burden for staff. We expect the initial training to be about 4 hours and to be delivered in person or online. The exact plans for ongoing support will be informed by the implementation plan developed in aim 2 with the advisory board.Feasibility and acceptability of the adapted TeamSTEPPS will be assessed using a combination of qualitative and quantitative methods. Exploratory outcomes include teamwork, interprofessional collaboration, and behavioral and academic outcomes for students receiving school-based services, as well as potential contextual predictors of implementation. Interprofessional collaboration will be assessed via observation and self-report.The Acceptability of Intervention Measure (AIM) and Feasibility of Intervention Measure (FIM) are each reliable and valid four-item tools to assess perceptions of the acceptability and feasibility of TeamSTEPPS ., a continuous measure of interprofessional collaboration in school mental health. Scores can be calculated individually or among groups working in the same school. For each subscale, an average score is calculated, with higher scores indicating strengths and lower scores indicating areas for improvement. The Cronbach α ranges from .81 to .94 for ESMHCI and .77 to .94 for ESMHCI-CV [Mental health and school staff will complete the Expanded School Mental Health Collaboration Instrument-Community Version (ESMHCI-CV) , a contiSMHCI-CV ,52The TeamSTEPPS Teamwork Perceptions Questionnaire (T-TPQ)  is a 35-The TeamSTEPPS Teamwork Attitudes Questionnaire (T-TAQ)  is a 30-The Evidence-Based Practice Attitude Scale (EBPAS)  is a 15-The Maslach Burnout Inventory Human Services Survey (MBI)  is a 22-Consistent with aim 1, a trained observer will spend one full day taking detailed field notes on team dynamics, service provision, and interactions among mental health providers, school personnel, and students along with using the adapted NOTECHS.We anticipate conducting 12 individual interviews of people randomly selected from all of the different stakeholder groups engaged in TeamSTEPPS, but will continue until saturation is achieved . The semIn districts where required data are available, behavioral and educational outcomes of students will be analyzed using deidentified administrative data as described in aim 1.We will use NVivo for analysis using the integrated approach as described in aim 1.Feasibility will be determined by the proportion of schools that enroll/those that are invited and the proportion of participants who attend TeamSTEPPS training/those who are eligible to participate. We will also examine the distribution of AIM and FIM scores.Collaboration and teamwork will be assessed observationally  and via self-report . The mean total and domain scores in the NOTECHS will be computed for each school. Individual and school scores will be calculated for self-report measures. A series of one-way ANOVA assessments will examine differences between schools at each time point to assess the impact of TeamSTEPPS plus implementation strategies. Repeated measures ANOVA will examine scores on these measures within schools over time. Relevant individual and team factors, including EBPAS and MBI scores and team size, will be explored and included in the models as covariates where appropriate.Behavioral and academic outcomes will be explored using administrative data as described in aim 1. These methods are described in detail elsewhere -67. Usin, self-report, and administrative data with the interviews and field notes following best practices [We will integrate the NOTECHSractices . The strractices . We willRecruitment for aim 1 of the study has begun. Goals for aim 1 are expected to be completed in Spring 2021. This project has been reviewed by the University of Pennsylvania (protocol 834488) and City of Philadelphia Institutional Review Board (study #2020-31).This study will examine the acceptability and feasibility of an adapted team training intervention, TeamSTEPPS, within school mental health. Our previous trial demonstrated both the preliminary acceptability and challenges of implementing TeamSTEPPS with school mental health service providers ,34. ResuThis study has three main innovations. First, few implementation studies focus on improving interorganizational functioning . Specifi


Climate change and food security are critical topics in sustainable agricultural development. The climate-smart agriculture initiative proposed by the Food and Agriculture Organization of the United Nations has attracted international attention. Smart agriculture (SA) has since been recognized as an influential trend contributing to agricultural development. Therefore, encouraging farmers to adopt digital technologies and mobile devices in farming practices has become a policy priority worldwide. However, the literature on the psychological factors driving farmers’ intentions to adopt SA technologies remains limited. This study investigated how farmers’ knowledge and attitudes regarding SA affect their adoption of smart technologies in Taiwan. A total of 321 farmers participated in a survey in 2017 and 2018, and the data were used to construct an ordinary least squares regression model of SA adoption. This study provides a preliminary understanding of the relationship between psychological factors and innovation adoption of SA technologies in a small-scale farming economic context. The findings suggest that policymakers and research and development institutes should concentrate on improving market access to established and critical SA technologies. Climate change and food security have become critical topics in sustainable agricultural development. The Food and Agriculture Organization of the United Nations proposed the climate-smart agriculture (CSA) concept, which has attracted international attention for its innovative use of technology in addressing agricultural challenges ,2. The oThe SA strategy focuses on the use of digital technology to create precision farming solutions, especially when combined with the application of information and communication technologies and other new interconnected equipment and techniques. The internet of things (IoT), drones, robots, big data, cloud computing, and artificial intelligence are all new resources that are expected to be applied to novel farming practices . The intSeveral similar but inconclusive concepts were used in different studies, such as agriculture 4.0, precision agriculture, smart farming, digital agriculture, virtual agriculture, big data in agriculture, IoT in agriculture, and interconnected agriculture ,12. ThesTaiwan’s agricultural sector is characterized by small-scale holdings and has been identified as a global disaster hotspot  . The AgrHuman resource development is a key factor in developing SA; thus, encouraging farmers and agribusinesses to adopt innovative digital technologies and intelligent mobile devices in their farming practices is becoming a policy priority in Taiwan. Therefore, the COA and National Taiwan University collaborated to create and design a series of SA training programs to develop human resources in smart agriculture. The educational objectives of the SA training program were to confer trainees with a positive attitude and practical competences, and to enhance their SA-related knowledge. Four types of training courses were offered, comprising of indoor lectures providing general SA education, on-site visits and training, international visits and exchanges, and individual tailor-made technical assistance provided by SA service teams for each pilot SA industry . HoweverThe following research problems regarding SA knowledge, attitude, and adoption were addressed. What types of SA technology are crucial for farming practices and are better understood by farmers? What are the driving factors in SA adoption behaviors? To what extent do sociodemographic variables, knowledge, and attitude affect the adoption of SA technologies?Studies have focused on the effects of psychological factors on individual behaviors, such as social learning theory, the theory of reasoned action, and the theory of planned behavior ,19. Few The data used in this study were drawn from a survey of trainees of the SA training program conducted in the summers of 2017 and 2018. The training program was sponsored by the COA in Taiwan. All participants were asked to complete the survey through face-to-face interviews as a reference for training course planning. The sample characteristics are presented in The main purpose of this study was to explore the knowledge, attitudes, and practices of SA trainees. The questionnaire design was developed based on previous research, as discussed in the literature review section. The dependent variable was SA adoption, which refers to the self-reported adoption level of SA technology in farming practices. To ensure the dependent variable measurements were valid and reliable, photographs of common SA technologies were presented in the interview. Respondents were thus provided with a framework from which to rate the adoption level of the SA technology from 0 (the lowest adoption) to 100 (the highest adoption).The principal independent variables in this study were the levels of knowledge and the perceived importance of each type of SA technology. The Smart-AKIS inventory of SA technologies  indicateRespondent knowledge of eight types of SA technologies was assessed. Reference answers were as follows: “Never heard of it (=1)”, “Heard of it but do not know much about it (=2)”, “Have a general understanding of it (=3)”, “Understand it well and can explain it to others (=4)”. The same scale was used to measure respondents’ perceptions of the importance of adopting SA technology. The level of perceived SA importance was measured by asking “To what extent do you think that SA technology is important for improving the management of your farm?”All responses were scored on a 4-point Likert scale, with a larger score indicating a higher degree of knowledge and perceived importance  of SA technology. The sociodemographic variables measured were gender, age (in years), education level, and farmer type. Moreover, the farm features recorded were farm size (in hectares) and average annual turnover.iSA_Adoption is individual i’s self-reported score for SA adoption behavior; iKnowl is the SA knowledge score of individual i; iImp is the SA perceived importance score for individual i; iZ is a set of sociodemographic characteristics; and iR represents a set of farming features. The random error term The primary purpose of this study was to investigate the effect of psychological factors on the adoption behavior of SA technology, after individual sociodemographic and farm characteristics were controlled for. The empirical analysis was performed in two steps. First, this study explored the associations between farmers’ knowledge, perceived importance, sociodemographic characteristics, and adoption of SA technology behavior. The second stage of the analysis focused on investigating the effects of exogenous determinants on farmers’ adoption of SA technology behaviors. The following equation is the SA adoption function, which was used to calculate the relationship between the adoption level and SA knowledge, SA perceived importance, and sociodemographic and farm characteristics. The corresponding ordinary least squares (OLS) regression equation is specified as follows:The descriptive statistics of the knowledge, importance, and adoption level of SA technologies are illustrated in r = 0.306), cloud and big data analysis services (r = 0.296), and biological image detection and recognition techniques (r = 0.286). The results of the correlation matrix support the hypothesis of a positive relationship between SA knowledge and SA adoption behavior, which is consistent with the findings of studies on innovation adoption [The correlations between different indicators of SA knowledge, attitudes, and practices were investigated. Significant and positive associations were observed between all the KAP indicators. es r = 0.96, and bSimilar results were revealed in the correlation matrix of SA importance and adoption behavior. Estimated results for the OLS multiple regression model of SA adoption are reported in As illustrated in The relationships between other determinants and SA adoption behavior were also briefly discussed. The farm characteristics significantly affected the adoption level of SA technologies. For example, farmers working in the agribusiness sector exhibited higher adoption levels of SA technologies than self-employed farmers, as was expected . FurtherThis study investigated SA-related knowledge, attitude, and adoption among farmers in Taiwan. The sociodemographic characteristics of the respondents were collected, and the effects on the adoption of SA technologies were determined. Survey data from 321 farmers who participated in the SA training program were collected. The results revealed significant and positive correlations between SA knowledge, perceived importance, and adoption behavior. Of the eight SA technologies, the automatic environmental control systems were the most well-understood and were perceived as being the most important, whereas biological image detection and recognition techniques were ranked as the least understood. SA knowledge and perceived importance significantly affected the adoption of SA technologies. Therefore, lower adoption levels of SA technologies may be attributed to inadequate information, missing knowledge, lack of awareness of the technologies, and lack of perceived practical value. We thus recommend the intensification of R&D and SA technologies, such as IoT and big data analysis, to satisfy farmer requirements under current farming conditions and management.These findings provide policymakers and agricultural educators with important insights that can be used to more accurately target interventions that promote or facilitate the adoption of SA technologies. Furthermore, these findings suggest that agricultural R&D institutes should concentrate on improving market access for established and valuable SA technologies. Additionally, providing systematic training courses related to the applications of IoT and big data in agriculture may enable farmers to engage more effectively in SA practices. However, the research limitations should be considered when these findings are being interpreted. First, KAP strengthens the theoretical foundation of this study, however, it also limits its depth. Agriculture policy, organizational support, computer efficacy, perceived effectiveness, perceived usefulness, and trust toward SA ventures should be considered in future models. Second, in methodologies used to analyze the collected data, the mediating role of attitude on the relationship between knowledge and practice could have been investigated. Furthermore, the moderating effects of gender and prior experience could have also been examined.


The aging of the United States population has led to an increase in the prevalence of Alzheimer’s Disease and Related Dementias (ADRD). Many individuals with ADRD receive care from family members and friends who, themselves, experience poor health outcomes. ADRD family caregivers from diverse backgrounds are frequently underserved by health and social service systems. However, research suggests that diverse caregivers possess culturally-based strengths that serve as protective factors against poor outcomes. This presentation reports findings from a study to develop and validate a community assessment of the needs, assets, and resources of rural Latinx and Native American ADRD family caregivers. Initial assessment items were based upon validated measures developed for diverse ADRD and comparable caregiver populations. A Delphi process was used to obtain ratings from a 9-member expert panel  about the degree to which the assessment was: (1) inclusive of different cultural groups; (2) respectful of cultural values and norms; (3) comprehensive with respect to needs, assets, and resources, and; (4) relevant to the lived experiences of diverse rural caregivers. Experts also provided qualitative feedback about modifying phrases to make the assessment more relevant to diverse respondents, removing sections, and adding items and response options to better reflect rural life. After two formal rounds of review and multiple iterations, between 77% and 100% of experts agreed that all sections of the assessment met criteria. Findings highlight the benefits of a systematic process for developing and validating community assessments for diverse, rural populations.