In this paper I study semantic and pragmatic properties of elevational demonstratives by means of a typological investigation of 50 languages with elevational demonstratives from all across the globe. The four basic verticality values expressed by elevational demonstratives are UP, DOWN, LEVEL, and ACROSS. They can be ordered along the elevational hierarchy (UP/DOWN > LEVEL/ACROSS), which reflects cross-linguistic tendencies in the expression of these values by demonstratives. Elevational values are frequently co-expressed with distance-based meanings of demonstratives, and it is almost always distal demonstratives that express elevation, whereas medial or proximal demonstratives can lack elevational distinctions. This means that elevational demonstratives largely refer to areas outside the peripersonal sphere in a similar way as simple distal demonstratives. In the proximal domain, fine grained semantic distinctions such as those encoded by elevational demonstratives are superfluous since this domain is accessible to the interlocutors who in the default case of a normal conversation are located in close proximity to each other. I then discuss metaphorical extensions of elevational demonstratives to non-spatial uses such as temporal and social deixis. There are a few languages in which elevational demonstratives with the meaning UP express the temporal meaning future, whereas the DOWN demonstratives encode past. This finding is particularly interesting in view of the widely-debated use of Mandarin Chinese spatial terms ‘up’ for past events and ‘down’ for future events, which show the opposite metaphorical extension. I finally examine areal tendencies and potential correlations between elevational demonstratives and the geographical location of speech communities in mountainous areas such as the Himalayas, the Papuan Highlands and the Caucasus. I tentatively conclude that languages spoken in similar topographic environments do not tend to have similar systems of elevational demonstratives if they belong to different language families. The expression of space in grammars of natural languages is ubiquitous and ‘spatial language’ has been investigated for decades within many different linguistic subdisciplines and by means of various approaches and frameworks. However, research on the spatial category of elevation is just at the beginning and typological studies are lacking so far. Elevation refers to the expression of a location of a figure with respect to the ground on the vertical axis. Many languages have words for ‘up’ and ‘down’ or ‘higher’ and ‘lower,’ but not all languages have this semantic distinction grammaticalized as part of certain closed class items, most notably demonstratives, which are the topic of this paper, but also spatial preverbs and case systems. Elevational meanings have repeatedly been grouped together with grammatical items that refer to salient landmarks . Such systems have been called ‘environmental space deixis’ , ‘spatiaIn this paper, I concentrate on the semantic and pragmatic properties of elevational demonstratives, more specifically, adnominal, spatial adverbial, and pronominal demonstratives. This study therefore goes beyond general cross-linguistic studies of demonstratives, which devote only a few sentences to demonstratives with elevational meaning. It also goes beyond more specific surveys such as 1 The three axes and planes through the human body provide the ground for three pairs of (linguistic) concepts, namely UP/DOWN, BACK/FRONT, and LEFT/RIGHT  or transverse (left/right) axes or do not employ them regularly and in the same fashion as familiar European languages . Locations in front of X or left of X are potentially ambiguous because they can depend on the relative viewpoint: By contrast, normally we unambiguously understand above/over X or below/under X if we know the position of X. Because of this  unambiguity of locations along the vertical axis, the anchor point of an observer can shift without difficulty . Levinson summarizes the distinctiveness of the vertical axis by stating that “the intrinsic , the relative (perception from an upright stance) and the absolute  tend to coincide”   for one see also . Positiooincide” , p. 348 north of X). By contrast, in a relative frame of reference there is a ternary relation because in addition to the figure and the ground (relatum or ground object) there is an anchoring point (=the origin of the coordinate system).The intrinsic frame of reference entails that the ground and the origin of the coordinate system that serves as anchoring point are identical and the spatial relation between the figure and the ground is binary. In an absolute frame of reference, there is also a binary relation, but this time between the ground and independently given salient geographical landmarks or cardinal directions that serve as anchoring points  or absolute frame of reference as determined by gravity.3 We make use of an intrinsic frame of reference when we refer to object A, which is located at the same elevation of the head of the person and aligned with it along the same horizontal axis, as over the head. However, in none of the languages in my sample I encountered examples illustrating an elevational demonstrative used with an intrinsic frame of reference . From a logical point of view there is no reason to exclude such usages, but their actual existence has yet to be proven by future research.4As was just said, the vertical axis is special because of its natural grounding in gravity. However, we can ‘escape gravity’ in the sense that we can change the frame of reference from absolute to intrinsic or relative. The peculiarity of the vertical axis has also been examined in psychology. Vertical spatial relations among objects remain largely constant with respect to a moving observer whereas on the transverse  plane spatial relations change more frequently. Therefore, human beings are faster at retrieving the names of objects located along the vertical axis than along the other two axes .here vs. there), or in combination with a pointing gesture  of demonstratives. Following  gesture , p. 65.  gesture , around I will discuss the interaction of deixis with elevation in the Section “The vertical dimension and its relation to deixis” after having described in more detail elevational meanings.For this paper I surveyed elevational demonstratives in 50 languages from 20 language families plus one isolate. My sample is a convenience sample because elevational demonstratives are not particularly frequent in the world’s languages. Many of the languages have been identified through the works by The elevational demonstrative systems of the 50 surveyed languages have been coded for a number of formal and semantic properties. The list of languages, schematic overviews of the elevational demonstrative systems together with genealogical and geographical information on the area where the languages are spoken and references are given in the 5 In other words, elevational demonstratives are often morphologically and always semantically complex expressions that constitute single word forms. Based on these considerations, the items under investigation can be divided into three basic types:6In general, demonstratives can be bound and unbound forms, whereby the bound forms are normally clitics and not affixes ((i)Co-expression of elevational and demonstrative meaning in a single morpheme.(ii)Obligatory co-occurrence of demonstrative morphemes with elevational morphemes in a single word-form.(a)No occurrence of elevational morphemes outside these forms.(b)Occurrence of elevational morphemes outside these forms.(iii)Optional co-occurrence of demonstrative morphemes with elevational morphemes in a single word-form.(a)No occurrence of elevational morphemes outside these forms.(b)Occurrence of elevational morphemes outside these forms.The elevational morphemes that obligatorily or optionally co-occur with demonstrative morphemes are bound roots, affixes or clitics. Based on the descriptions it is not always possible to distinguish between the subtypes (ii) and (iii) because not all grammars explicitly state whether the elevational morpheme also occurs in some other parts of speech .tatu) co-expresses the elevational meaning UP and the deictic meaning distal. Only when occurring in opposition with tatu, the neutral distal demonstrative watu can also mean DOWN or LEVEL.Co-expression of elevational and basic deictic demonstrative meaning at the synchronic level occurs in Muna , Daga T, Yakkha DISTAL. The second subset, which contains the intensifier d-, expresses additional distance or contrast.Eipo  has two subsets of demonstratives . The eler- and the verbalizer , Central Alaskan Yupik, Kurtöp (9), (22), and Galo (19).Languages with morphologically complex elevational demonstratives in which the elevational meaning is expressed by bound roots or affixes and regularly combines with demonstrative stems are Blagar, Tauya, Tanacross , KoyukonThe demonstratives in the East Caucasian language Andi  are particularly transparent and consist of stems that express distance- and person-based deixis, followed by a range of further optional suffixes such as an emphatic marker, the elevational morphemes and gender suffixes  and (b) subtypes, whereby the (a) subtypes refer to elevational morphemes that only combine with demonstrative morphemes, whereas the (b) subtypes of elevational morphemes also occur outside the demonstrative systems. In Andi and Manambu, the elevational markers are only used with the deictic demonstratives and thus belong to the (a) subtype. By contrast, in Dyirbal they can also be added to verbs to form verbs of motion .up. English up can co-occur with adverbial demonstratives (up there) and verbs (climb up). However, no linguist has ever claimed that English has an elevational demonstrative although such a claim would perhaps be imaginable if we wrote up-there or upthere instead of up there. This means that among the languages studied for this paper there might be languages that are actually not extremely different from English, but for which the author of the grammar has reasons to assume that a morphologically and semantically complex expression translates with, e.g., up-there or upthere, constitutes a single lexical item.For the (b) subtypes, the question can be asked what the nature of the elevational morpheme is, in particular, whether they are themselves deictic or non-deictic. However, for this paper the answer to that question is largely irrelevant, because I am only interested in the combined forms, i.e., the co-occurrence of demonstratives and elevational morphemes. This touches upon a problem I encountered during this study. I had to rely on the often implicit assumptions of the linguists whose descriptions I consulted that the items classified as ‘elevational demonstratives’ represent single lexical units. In languages such as Manambu, Sougb, or Nêlêmwa-Nixumwak, in which the morphemes with the elevational semantics can be readily identified and are sometimes also used with lexical items other than demonstratives , the elevationals resemble English non-deictic expressions such as Most of the elevational demonstratives take further optional or obligatory derivational and/or inflectional suffixes . They are part of paradigms or subparadigms that consist of three (Andi) to five  items on average, but more than seven members are not exceptional (Daga). For instance, Tanacross has nine items , and MovThe last context (iv) has several subtypes . Copular demonstratives are cross-linguistically rare  ‘like that/those up there (not necessarily visible)’ , (24). Makalero and Tidore do not have genuine elevational adverbial demonstratives, and the adverbial function is fulfilled by demonstrative verbs (5). Blagar, Galo (26) and all East Caucasian languages in my sample  have not only spatial elevational demonstratives, but also a further class of elevational demonstratives that function as manner adverbs, e.g., Blagar isible)’ , p. 159.All languages expect for Tanacross and Maale employ elevational demonstratives in the adnominal context, and this is therefore the second most commonly attested type of usage. In Usan and Eipo, elevational demonstratives can be used as modifiers within a noun phrase , but not in the syntactic function of determiners. Instead, they co-occur with determiners.The degree to which the syntactic contexts are expressed by specialized, formally distinct elevational demonstratives varies. I did not come across any language that always distinguishes all four types formally. Nungon makes formal distinctions between the first three syntactic contexts .8 The term LEVEL includes a more specific term ACROSS:Semantically, elevational demonstratives are deictic expressions that also convey elevational or verticality distinctions. Following I further adopt and simplify the classification of (i)General elevational demonstrative systems:•The location is determined according to an imagined vertical  axis that runs through the ground .(ii)Topographic elevational demonstrative systems:•The location is determined with respect to the geophysical environment.The first type  corresponds to Burenhult’s ‘verticality proper’ and ‘global elevation,’ and the second term (‘topographic’) to his ‘geophysical elevation.’ General elevationals are used in accordance with the gravitational axis. They can have very local meanings, which means that they can be applied, for instance, to refer to positions close to the speaker, inside a room or in the immediate environment (7), (8) but they are also used to denote locations in the geophysical environment (9).10 The vertical dimension of rivers might not be obvious at first glance. But what connects rivers with what was said before about the vertical axis is the fact that gravity causes the flow of the water in a certain direction and the direction is absolute and independent of an anchoring point. I did not find any other types of landmarks defining topographic elevational demonstratives.Genuine topographic elevationals refer on the basis of the geophysical environment. There are two types of landmarks outside and generally further away from the speaker that naturally expand along the vertical dimension, namely topographical contour  and hydrological contour .Topographic elevational demonstratives basically mean something like ‘uphill’/‘downhill,’ ‘upriver’/‘downriver’ and the like. For instance, Dyirbal has an elaborated set of twelve so-called ‘spatial indicators’ that are added to demonstratives or other noun markers and express topographic elevation, e.g., ‘downhill,’ ‘uphill,’ ‘downriver,’ ‘upriver,’ and ‘across river’ , p. 98. UP and DOWN meanings but also to LEVEL and ACROSS. For instance, terms that express ACROSS can be topographic and refer to locations across a valley at the same altitude of the opposite mountain as in Yakkha (12), or across the river as in Tanacross (13). They can also be general as in Usan and applied in the local domain (14).The distinction between general and topographic elevational demonstratives applies not just to the UP and what as DOWN independently of an observer or an intrinsic orientation of the ground. This type of absolute frame of reference is also entailed in many usages of adverbs or adjectives such as English up vs. down or high vs. low :(i)The local domain: the minimal local scale is the peripersonal sphere, but it extends to the area inside a house or its immediate surrounding; locations within this area are often visible.(ii)The local larger, but delimited environment, e.g., a village, a valley, or an island; locations within this area can be visible or not.(iii)The global scale, e.g., locations on other continents that are never visible from the location of the speaker.Since general elevationals can normally be used both in the local domain and in the larger domain , they have to be carefully distinguished from topographic elevationals that are projected into the minimal local domain.UP or DOWN demonstrative based on the permanent location of her house within the village, which is mentally divided into an upper part and a lower part, and not on the location of that person with respect to the speaker or another spatial anchoring.Metaphoric usage extensions, projections onto the horizontal plane and conventionalized uses can create problems for the correct categorization of elevational demonstratives as general or topographic because they might obscure the basic elevational meanings. For example, Sanzhi Dargwa has a general elevational system clearly based on an abstract vertical axis . HoweverElevational demonstratives that are characterized as ‘topographic’ in grammars can be used at the local scale such as within a house or close by a house or, with respect to a tree. For instance, Tanacross and other Northern Dene languages have genuine topographic elevational systems  that conventionally extend to the micro level. This means that within a house there are four directions/locations, namely ‘upstream,’ ‘downstream,’ ‘inland,’ and ‘across’ because traditionally houses have been built with the door toward the water , p. 298.Similarly, by means of the second topographic system of Yakkha the ‘uphill’ and ‘downhill’ elevationals can be mapped onto the human body and teeth are then referred to as uphill, i.e., ‘upper teeth’ and downhill ‘lower teeth’ irrespectively of their actual position .The two systems  as portrayed so far are idealized prototypes. Based on the descriptions that I consulted it is not always possible to determine if an elevational system falls into the one or the other category. In addition, it seems that there are systems that cannot be categorized as truly belonging to the one or to the other type, or should be analyzed as combining both types. For instance, the elevationals of Galo are translated as given in (16) , the larger local scale (18) and the global scale (26). Only when the referent is potentially visible  the relevant items encode elevational and riverine meanings.LEVEL items can be used as default demonstratives.When the referent is not potentially visible and also not located on the path of a nearby river, but is separate from the speaker by at least a mountain range , then the same items function as labels for cardinal directions (19), and elevational differences are ignored. For instance, the speaker who uttered (19) is located in a village at around 100 m above sea level and Itanagar, where he would like to go, is situated at around 440 m and thus higher, and to the south but not visible from his village. In such a context, the anchor point can be the actual location of the speaker, or her/his home village can serve as conventionalized anchor point . For unknown locations, the UP, DOWN, and ACROSS) and general elevational morphemes only two (UP and DOWN)  . Grimes nd DOWN) , p. 170 11 For instance, Kurtöp elevational demonstratives have been glossed as deictic with the speaker as deictic center. However, in (22) the UP-demonstrative occurs together with the hearsay evidential, which means that the speaker has acquired her/his information from the speech of others. This is a clear indication that the speaker cannot be the deictic center that serves as the point of anchoring for the location of the woman. The location of the woman is rather described as being higher than before after she had climbed up to the top of the roof.As stated in Section “Verticality Within the Domain of Spatial Language” above, demonstratives are deictic and express distance-based meanings with the speaker (ego) as deictic center or person-based meanings that additionally consider the position of the hearer. Verticality is not inherently deictic because the ground or anchoring point is not exclusively the speaker  for elevational demonstratives can easily shift, e.g., in a story it shifts to a protagonist or to another salient inanimate anchor point [Tulil as analyzed by ABOVE or BELOW can, in principle, be employed within intrinsic and relative frames of reference, it is desirable in future research on elevational demonstratives to systematically test if there are any elevational demonstratives that can also be used in that way.Furthermore, as illustrated by means of In (6), I introduced the basic terms for verticality values. These values can be ordered along the elevational hierarchy that reflects cross-linguistic frequency of occurrence (23):UP and DOWN are more commonly found than those with the meanings LEVEL or ACROSS . The more specific value ACROSS (8 languages) occurs only around half as often as LEVEL (19 languages).Elevational demonstratives with the meanings r ACROSS . All lanUP and DOWN , but only one for DOWN (mu)  are either obligatorily co-expressed or optionally combined with elevational items if the elevationals are morphemes that are formally independent of the distance-based deictics. There are languages in which all distance-based deictics can be combined with all elevationals. For example, in Manambu , three person-based deictic stems take gender, number and the current relevance suffix, followed by the topographic and general elevational morphemes  with the elevational values UP, DOWN, and LEVEL, and four more encode only elevational meanings , for instance, has a particularly rich system with 14 demonstratives, of which two are merely person-based, eight co-express three distance-based meanings  has a rich set of 13 demonstratives of which nine co-express elevational meanings, and relative distance and at the same time additional distance from the speaker (‘away from the speaker’) (UP).13 Thus, it seems that elevational demonstratives largely refer to areas outside the peripersonal sphere in a similar way as simple, non-elevational distal demonstratives , but not with the distal or anaphoric demonstratives  proximal demonstrative meaning.14The only language I found so far that contradicts this otherwise robust cross-linguistic tendency is Yakkha. This language has two cognate sets of basic adverbial elevational roots, which are classified in the grammar as ‘topographic.’ The first set, which in the grammar is called ‘/u/-forms’ based on their stem vowel, is given in the lower part of tratives . Thus, iThis type of co-expression or combination of distance and elevation in demonstratives is not obligatory because there are languages such as Makalero , Hatam, I encountered only very few cases of elevational demonstratives that combine with person-based deictic systems and therefore express person-based elevational meanings, e.g., Manambu (24) .If languages have elevationals and person-based deictics, these meanings are more commonly separately expressed as, for instance, in Muna, Daga  or SanzhFURTHER/NEARER (or FRONT/BACK) along the sagittal axis . The same kind of projection is applied at the global scale on an imagined map, e.g., Estonians are located UP with respect to Latvians because Estonia is further to the north . In Sougb the equation is the opposite, namely UP = west and DOWN = east (26). In Iaai, the elevationals are in complementary distribution with other items that also convey compass points.There are a number of languages whose elevational demonstratives also encode cardinal directions, but these meanings seem not to be available within the local domain. Examples were given in (16) and (19) from Galo. Other languages are Makalero, Bantawa, Baskeet, and Sougb. Usually only two opposite cardinal directions are encoded. Which elevational expresses which compass direction depends on the local position of the mountains that serve as anchor points and thus varies from language to language. For instance, as (25) shows, in Galo we have UP-demonstratives carry the temporal meaning FUTURE, whereas the DOWN-demonstratives encode PAST . The languages are spoken in Papua New Guinea, but in different areas of the country, and they belong to two different language families. In Iaai, an Oceanic language from New Caledonia, only the second equation, i.e., DOWN = PAST exists. In the following, I will provide examples from the four languages and discuss this type of spatial metaphor. I will also mention a few other languages in which spatial verticality metaphorically maps onto time.In three languages of my sample, the Tulil (Taulil-Butam) has three morphologically complex demonstrative stems with elevational meaning that can be used for temporal expression  past.’•bo ‘up, uphill, upstream’ > pbo ‘front, up near’ > ‘(near/far) future.’•mu ‘far from speaker and hearer’ + mə ‘down’ > mumə ‘down distal’ > ‘far past/future.’vənu(=a) ‘day,’ atade(=e) ‘week,’ vəgam(=e) ‘month,’ or laləng(=a) ‘year,’ whereby demonstratives can precede or follow the noun (27). They are also used as independent demonstrative pronouns. The temporal meaning of the first two elevational demonstratives can be schematized as DOWN = BACK = PAST and UP = FRONT = FUTURE, and it is possible that the temporal meanings are, in fact, based on the ‘front’/‘back’ meanings. It is well known that words for ‘front’ and ‘back’ are commonly used as temporal metaphors in a wide range of different languages and cultures , but it has been translated with a temporal meaning.Note that in the following example the elevational morpheme is actually an adverbial demonstrative with originally spatial function (due to the locative prefix DOWN/UP/LEVEL), in contrast to Tulil, which has only terms for UP and DOWN, co-expressed with distance such that we arrive at six items , has a three-level contrast in elevation ’ can express the meaning ‘past’ (32), and also serves to introduce relative clauses with past time reference. According to DOWN = PAST.In Iaai  the deictic particle 16 Yupno speakers have been found to consistently use topographic  gestures toward the ground for referring to the present, uphill for reference to the future and downhill for past (omo-ropmo bilak (down.there.other.side year) ‘a couple years ago, a few years ago.’ In Avar, the adverbials ʁorƛisa ‘last year’ and t’adejaɬːu ‘next year’ originate from the adverbs ʁorƛ ‘down(ward), under’ and t’ade ‘up(ward),’ respectively, and in Lak jalunè’in ‘next year’ is derived from jalu(w) ‘up(ward).’ Finally, in Tzeltal, which does not have elevational demonstratives, the topographic terms -ajk’ol ‘uphill’ and -anil/alan ‘downhill’ are also employed with the meanings ‘later’ and ‘ahead of time, before.’ There are three other languages in my sample that do not employ their elevational demonstratives with temporal meaning, but make use of the same or a very similar type of metaphor, namely Yupno (which belongs to the same language family as Tulil), Avar, and Lak.for past . The lanDOWN) whereas in the future s/he will be taller (=UP). The same applies to many other animals and plants with an upright position .17I take the examples (27)–(33) as metaphors that map spatial expressions onto a temporal dimension: the future is located above or higher than the deictic center, and the past below. The metaphor can be explained by the direction of the biological growing process of upright human beings in the course of time. During the first years of their life human beings become taller as they get older, which means that if we compare one and the same person across time in the past the same person was smaller  corresponds to EARLIER and BACK (or NEARER) to LATER. This metaphorical correspondence is said to result from the fact that if human beings moved by crawling on the ground their head would be in front and their feet would come last. The same applies to other animals that move with legs – the head is normally in front and turned into the direction of movement. Yu adds that in Western cultures family trees are arranged in a similar fashion: the oldest (earliest) generations are placed on the treetop and the last generation on the bottom. These findings are particularly interesting in view of the widely debated use of Mandarin Chinese spatial terms on e.g., . Yu  and lobino tora ‘early evening, shortly after the sunset prayer’ (lit. night downward). In these expressions, the demonstratives most likely refer to the path of the sun with its apparent rising and setting. In Daga, there seems to exist a correlation such that FUTURE/PAST = UP because yampoa utu-pa (third up.there-out.of.sight) means ‘next Wednesday’ and wataget utu-p (before up.there-out.of.sight) means ‘long ago’ . The correlation between the UP-elevational and the conventional position of a powerful person represents an example of the metaphor CONTROL/POWER IS UP, for which cognitive evidence has been found by psychologists and psycholinguists , in which the elevational with the meaning inguists .UP-directional da ‘up’ . Bril further writes that it is generally improper to address others by name. Directional are used instead, e.g., hey! the man up there.a-da-wur du (DEM.DST-M.SG-UP man) (a-na-wur numa-də du (DEM.DST-CURR.REL-UP big-M.SG man)  , p. 53 a.SG man)  are used19 Other semantic distinctions with which elevational demonstratives are combined or are in complementary distribution in languages with rich demonstrative systems areDemonstrative systems that encode elevation are, in general, already larger than the more common systems that express only (person-based) distance. A number of languages in my sample have not only elevational demonstratives but some more terms.•TOWARD vs. AWAY FROM20Direction/movement: –Toward .–Yonder/away .–Ahead (Tanacross and Koyukon).–Transverse (Nêlêmwa-Nixumwak).•INWARD vs. OUTWARD (or INTERIOR vs. EXTERIOR)–Exterior (Jahai).–In/out .–Out-of-field (Eastern Canadian Inuktitut).–Out in front .-Outward (Manambu).•Position (standing vs. non-standing) (Movima).•Perception.–Invisible .–Visible (Daga).–Audible .•Other topographic meanings.-Seaward/landward .-Off-river (Manambu).•Temporary possession (Movima).•Non-past vs. past (Movima).•Referential or confidential (Dawro).Most of the meanings are well-known from the literature on demonstratives . It is thus possible to suggest some generalizations concerning the areal distribution of elevational demonstratives.There are clear areal hotspots in which there is a particular dense concentration of languages with elevational demonstratives. These areas are the New Guinea Highlands, the Himalayas, the Ethiopian Highlands and the Eastern Caucasus. Furthermore, a number of languages spoken on volcanic islands of Southeast Asia have elevational demonstratives. However, only on the island of New Guinea and immediately adjacent islands, in particular in the New Guinea Highlands, elevational demonstratives are found across a large range of different language families. In the Himalayas, only Sino-Tibetan languages have elevationals. If we consider the entire greater Hindu Kush Himalayan Region, we have to add some more Indo-Aryan languages. In the Caucasus, only East Caucasian languages, and in Ethiopian Highlands only some Omotic languages possess elevational demonstratives. By contrast, the mountainous areas of the Americas largely lack languages with elevational demonstratives with the exception of Cora and Pacaraos Quechua. The other American languages in my sample that have elevational demonstratives are spoken in rather flat areas .It has been hypothesized several times that there is a correlation between the presence of elevational demonstratives and the location of the speech community, more specifically, that the respective languages are spoken in hilly or mountainous areas e.g., . With reUP/DOWN > LEVEL/ACROSS) that reflects cross-linguistic tendencies in the frequency of the respective elevational values. Furthermore, the importance of the peripersonal sphere is linguistically reflected by elevational demonstratives because they predominantly co-express distance as opposed to proximity to the speaker. Another important finding of this study concerns the metaphorical extension of spatial elevational demonstrative meanings to the domain of time: the future is metaphorically located higher than the deictic center, and the past below. This metaphorical extension is the opposite of what has been found in Mandarin Chinese. I have proposed that the metaphor can be explained by the direction of the biological growing process of humans, many animals and plants.In this paper, I have examined elevational demonstratives, mainly focusing on their semantic and pragmatic properties. The main results of this study can be summarized as follows. The basic semantic values that elevational demonstratives encode can be ordered along a hierarchy  location, but simply relational and needs an anchor point, which can be a location that is independent of speaker or addressee. Items expressing elevational meaning can combine with deictics, in particular with demonstratives. If the combination is tight such that the items are synchronically monomorphemic, this leads to the deceptive impression that the elevational component is also deictic. Second, elevational demonstratives only rarely refer to geomorphic landmarks and they do not make use of an absolute frame of reference comparable to cardinal directions. They seem to be ‘absolute’ because normally gravity determines the direction and thus what is up and down, but the same is true for relational adverbials referring to the vertical axis.In addition, I have also shown that elevational meaning Topographic Correspondence Hypothesis. The latest version of the Topographic Correspondence Hypothesis, which is called Sociotopographic Model, states that languages spoken in similar topographic environments tend to have similar systems of absolute spatial reference, whereby social and cultural factors also play a role . New Guinea is the only area in which a wide range of languages with different genealogical affiliations that are spoken in mountain settlements have elevational demonstratives and thus geography or even language contact might have played a role in the development of those systems. In relation with that finding one possible direction for future research is to clarify whether the languages with elevational demonstratives, which were discussed in this paper, confirm the y a role . The hypy a role , and twoy a role . What coThere are many other open questions left for future studies of elevational demonstratives. In this paper, I have largely ignored the morphological and syntactic properties of elevational demonstratives as well as their use in discourse . In order to be able to accomplish a detailed typological study we need more comprehensive descriptions of language-particular systems that are based on natural corpus data such that not only formal properties are covered but also the actual use and possibly frequency estimations can be detected. Another fruitful direction of research are various experimental approaches. The role of demonstratives in spatial cognition has been mainly investigated with respect to peripersonal space and distance as well as pointing, and the vast majority of controlled, experimental studies that I am familiar with examine languages with small demonstrative systems . In the future, this line of research should be extended to languages with rich demonstrative systems such as the languages discussed in this paper.All datasets generated for this study are included in the article/The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation, though no other collaboration, with the author DF at the time of the review.


This study aimed to investigate the effects of morin on cerebral damage and blood–brain barrier (BBB) integrity in a middle cerebral artery occlusion (MCAO) and reperfusion model. Wistar rats were exposed to MCAO for 2 h, followed by reperfusion. Thirty mg/kg of morin was administered via intraperitoneal injection at the different time points: before ischemia, during ischemia, and at reperfusion. The rats were divided into five groups, including sham, vehicle, and three groups of morin. Twenty-four hours after reperfusion, the rats were tested for neurological deficits, and the brains were harvested to assess brain damage. In addition, brains were harvested 72 h to determine BBB disruption. We found that morin significantly reduced reactive oxygen species production and lipid peroxidation. It also decreased inflammation via reducing the expression of Toll-like receptor 4, nuclear factor kappa-beta. Morin ameliorated cerebral damage and reduced apoptosis through decreasing the cerebral infarct size, including apoptotic cell death. Moreover, morin decreased the BBB damage via reducing Evans blue extravasation, neutrophil infiltration, and increasing tight junction protein expression. Therefore, morin protected against cerebral and BBB damage by attenuating oxidative stress, inflammation, and apoptosis in MCAO and reperfusion models. Cerebral ischemia is the most common type of stroke; it arises from a sudden interruption of the blood supply to the brain by thrombus or embolus4. Nowadays, administration of tissue-plasminogen activator (t-PA) is approved for cerebral ischemia treatment. However, to restore blood flow in the brain with t-PA would encourage the excessive production of reactive oxygen species (ROS), which would lead to cerebral ischemia/reperfusion (I/R) injury7. Moreover, ROS overexpression also triggers an inflammatory response mediated through toll-like receptor 4 (TLR4), a transmembrane protein that plays a key role in inflammation. TLR4 is expressed mainly on the membrane of neurons and glial cells to recognize the intracellular components known as damage-associated molecular patterns (DAMPs), which are released from neuronal cell damage induced by ROS9. TLR4 activation stimulates the nuclear factor kappa-beta (NF-κB) signaling pathway, which regulates the synthesis of pro-inflammatory cytokines to stimulate neuronal inflammatory such as tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-9 (MMP-9)10. MMP-9 release leads to blood–brain barrier (BBB) disruption. The BBB plays a principal role in brain homeostasis and protection against various toxins. BBB disruption causes infiltration of neutrophil from blood circulation to the brain, a phenomenon that results in brain damage and leads to the high morbidity and mortality of cerebral I/R injury. Thus, ameliorating brain damage and BBB disruption following cerebral I/R would prove advantageous for the improvement of functional outcomes after stroke13.Stroke, the most frequent trigger of permanent disability, is the third leading cause of death in adults worldwideMaclura cochinchinensis (“kae lae” in Thai) that belongs to the Moraceae family. Compelling evidence has demonstrated that morin is a bioactive compound that exhibits multiple pharmacological and physiological effects, including anti-oxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activity18. Moreover, morin has been reported to improve transient global cerebral ischemia model and also reduce oxidative stress, apoptosis, and inflammation in middle cerebral artery occlusion (MCAO) model19. However, its benefits on BBB disruption after cerebral I/R have not been reported. In the present study, we investigated the protective effects of morin during the acute phase of rats subjected to MCAO and reperfusion injury via attenuation of BBB and cerebral damage.Morin  is a flavonol isolated from We examined parameters during pre-ischemia, ischemia, and reperfusion. Morin treatment did not affect the rat’s body temperature, oxygen saturation, body weight, or heart rate compared with vehicle-treated rats Fig. A–D. In ap < 0.001; Fig. To investigate the neuroprotective effects of morin on brain injury in MCAO rats, we first evaluated the neurological deficit scores at three different time points: before occlusion, before reperfusion, and during reperfusion. Morin-treated rats at these time points exhibited significantly reduced cerebral infarction, as indicated by decreased the infarct area and the percentage of infarct volume Fig. A,B compaTo investigate whether morin reduces oxidative stress, we utilized the 2′,7′-dichlorofluorescin diacetate (DCFDA) assay and malondialdehyde (MDA) assays. Our results showed that ROS production and MDA level was significantly increased in vehicle-treated rats. However, morin administration in all groups tended to decrease, but with no significant differences when compared to I/R group Fig. A,B.FigurTo investigate which cells are the source of oxidative stress, we performed western blotting analysis to examine the expressions of Iba1 and glial fibrillary acidic protein (GFAP). Expression of both proteins was significantly increased in vehicle-treated rats compared to the sham group. Morin treatment significantly decreased the expression in all groups compared with vehicle group. Fig. A–C. ThesTo investigate the mechanism underlying the ability of morin to reduce inflammation mediated by NF-κB activation in I/R rats, we first examined the expression levels of inflammatory cytokines, including TNF-α and IL-1β, by Western blotting analysis Fig. A, D, E. We further investigated the role of morin in neuroinflammation in I/R injury to determine whether it was mediated by the TLR4 pathway. As shown in Fig. 21. We found that morin treatment significantly decreased MMP-9 expression compared to vehicle-treated rats  breakdownp < 0.01 and p < 0.05; Fig. We investigated inflammation at 72 h after reperfusion by examining neutrophil infiltration; we performed an MPO activity assay. MPO is a peroxidase enzyme that is most abundantly expressed in neutrophil granulocytes. We found that MPO activity in the vehicle group was significantly increased, but morin treatment significantly decreased this activity in all groups compared with the vehicle  staining. TUNEL-positive cells appeared as dark brown particles, which are indicative of apoptotic cells Fig. D. There p < 0.001; Fig. After 24 h of reperfusion, we assessed morphological changes in the cerebral cortex and striatum with hematoxylin and eosin (H&E) staining. Neuronal cells with pyknotic nucleus and vacuoles around their nucleus were widely represented in the vehicle group. There were no changes in the sham group, and the morin-treated groups presented reduced changes in neuronal cells Fig. F. The reAnti-TLR4, anti-TNF-α, and anti-IL-1β were purchased from Abcam . Anti-MMP-9 was purchased from Cell Signaling . Anti-NF-κB, anti-iNOS, anti-caspase-3, anti-occludin, anti-claudin-5, anti-GFAP, anti-Iba1, and anti-actin were purchased from Millipore . All other reagents were obtained from Sigma-Aldrich .M. cochinchinensis (5.0 kg) was extracted successively with n-hexane, ethyl acetate (EtOAc) and methanol (MeOH) at room temperature. The filtered solution from each extraction was evaporated to dryness under reduced pressure at 40–45 °C to give the hexane extract (6.2 g), the EtOAc extract (800.8 g), and the MeOH extract (524.3 g). To the EtOAc extract (800.5 g), MeOH–H2O (1:1) was added with stirring. The solid, which was separated out, was collected by filtration and recrystallized from MeOH–H2O (1:1) to give pure morin (5.5 g). The spectroscopic  data were in agreement with the structure of morin and were consistent with those of the reported values22.The dried, pulverized heartwood of We obtained male Wistar rats weighing 300–350 g from the National Laboratory Animal Center, Mahidol University, Salaya, Nakorn Pathom, Thailand. All animals were kept on a 12/12 h light/dark cycle with a constant ambient temperature (25 ± 1 °C). All animals were given a standard pellet rat diet and water ad libitum. All experiments in this study were approved by the Institutional Animal Care and Use Committee at the Faculty of Medicine, Chiang Mai University (Permit number: 33/2559), in compliance with National Institutes of Health (NIH) guidelines. Briefly, we randomly divided the 120 rats into five groups (n = 24) as follows: (1) Sham group; (2) MCAO group ; (3) MB group (MCAO rats treated with morin 30 min before occlusion); (4) MD group (MCAO rats treated with morin 30 min before reperfusion); and (5) MA group (MCAO rats treated with morin at reperfusion). We chose the morin dosage, 30 mg/kg body weight (BW), based on our pilot study. We dissolved morin in dimethyl sulfoxide (DMSO) and subsequently diluted it in 2-hydroxyethyl cellulose. The vehicle group received the same volume of 2-hydroxyethyl cellulose by intraperitoneal (i.p.) injection.23 In brief, we identified the right common carotid artery (CCA) and external carotid artery (ECA). We introduced 4–0 filament  into the internal carotid artery and advanced it until we felt a slight resistance. Importantly, we measured the sudden drop in cortical perfusion  by laser Doppler flowmetry 24. After 120 min of MCAO, we carefully removed the filament to permit MCA reperfusion. After surgery, we transferred the rats to a room temperature environment (25 ± 1 °C) until sacrifice.We anesthetized rats using zoletil (30 mg/kg) and xylazine (10 mg/kg) i.p. We conducted MCAO on the rats with the use of an intraluminal monofilament technique, as previously described23. The scale is as follows: 0 = no neurological deficits; 1 = failure to extend contralateral forepaw fully; 2 = circling to the ipsilateral side when held by the tail; 3 = falling to the contralateral side; and 4 = did not walk spontaneously and has a depressed level of consciousness.Twenty-four h after reperfusion, we assessed 6 rats from each group for neurological deficits, according to a 5-point scale system, as previously described25.Three whole brains from each group were harvested 24 h after reperfusion, and the brain tissues were processed to six 2-mm-thick slices. We incubated the slices in 1% 2,3,5-triphenyltetrazolium chloride (TTC) at 37 °C for 20 min and then fixed them in 4% buffered formaldehyde solution overnight. We determined the infarct volume by measuring the area of the ischemic lesion in each section by using ImageJ software. The infarct volume (%) was calculated as follows: 100% × [/contralateral hemisphere volume]26. The average value was used to compute the apoptotic index (Apoptosis index (AI) = number of positive cells/number of total cells).We detected apoptotic cell death by TUNEL staining on the basis of DNA fragmentation. We sacrificed rats from each group 24 h after reperfusion and fixed the brains in 4% paraformaldehyde (PFA). Next, we processed the brain tissues into 4-μm-thick slices. We deparaffinized the sections and then rehydrated them. We performed TUNEL staining according to the manufacturer’s instruction for the TUNEL assay kit , with nuclei stained in brown particles. Finally, we observed the total cells and TUNEL-positive cells under a light microscope . We randomly chose five fields (× 20 and × 40 magnification) of a coronal section of the cerebral cortex at the same level and counted the number of apoptotic cells and the number of total cells of five adjacent sections20. Briefly, at 72 h after reperfusion, rats from each group were anesthetized and administered 2% Evans blue solution (4 ml/kg) via intravenous injection into the jugular vein. Thirty min after EV injection, the rats were perfused intracardially with cold phosphate-buffered saline . Then, we harvested the brains, homogenized them in DMSO, and incubated the homogenates at 50 °C. We centrifuged the samples at 12,000g at 4 °C for 30 min and collected the supernatants. We measured the absorbance at 620 nm by using a spectrophotometer .We investigated BBB leakage by Evans blue injection, as previously describedWhole brains from each group were harvested and fixed for 48 h in 4% PFA. Next, the brain tissues were commonly embedded in paraffin, processed to 4-μm-thick slices, and stained with H&E. We observed morphological changes in the cerebral cortex and the striatum at the same level in each group were observed using a light microscope .  × 100).3 of the cerebral penumbra of the ischemic hemisphere with 2.5% glutaraldehyde in 0.1 phosphate buffer (pH 7.3) at 4 °C overnight. After dehydration, we saturated the samples with epoxy resin and sectioned them. We double stained the brain sections with lead citrate and uranyl acetate and then obtained images with a JEM-2200FS TEM26.At 72 h after reperfusion, whole brains from each group were harvested and fixed with 4% PFA. Subsequently, we fixed 1 mm2 and 10 mM KCl. We homogenized the samples, centrifuged them at 12,000 rpm for 10 min at 4 °C, and collected the supernatants. We placed the supernatants were placed in a 96-well plate and mixed them with 10 µl of H2DCF-DC solutions, followed by incubation in the dark for 25 min. We measured the samples with a microplate reader  at the excitation wavelength 480 nm and the emission wavelength 530 nm.We used oxidation-sensitive 2ʹ,7ʹ-dichlorofluorescein diacetate (DCFH-DA) dye to investigate intracellular ROS. Twenty-four h after reperfusion, we harvested the cerebral penumbra from each group and processed them to 2-mm-thick slices at the same level. We added total lysis buffer with protease inhibitor cocktail, including 10 mM HEPES (pH 7.9), 1.5 mM MgClTwenty-four h after reperfusion, we determined the MDA level using a calorimetric assay. MDA is the end-product of lipid hydroperoxide decomposition. In brief, we harvested the cerebral penumbra from each group and homogenized them in lysis buffer. The samples were mixed with 10 µl of butylated hydroxytoluene, 250 µl of 1 M phosphoric acid, and added 250 µl of 2-thiobarbituric acid. All reactions were mixed and incubated at 60 °C for 1 h. Then, the samples were centrifuged at 12,000 rpm for 5 min. The supernatants were transferred into a 96-well plate for measuring the absorbance by a microplate reader  at 532 nm.MPO is a peroxidase enzyme that is most abundantly expressed in neutrophil granulocytes. Evaluating MPO activity is crucial to understanding its effects on inflammation. Briefly, the brain tissues of each group were collected from the ipsilateral hemisphere at 72 h after reperfusion. The MPO activity was measured following the myeloperoxidase (MPO activity assay kit) .The assay is based on detection of cleavage of substrate DEVD-AFC, which is cleaved by caspase-3. Twenty-four h after reperfusion, we collected the cerebral penumbra from each group and homogenized the samples in lysis buffer. Then, we measured caspase-3 activity using an assay kit .Twenty-four or seventy-two hours after reperfusion, cerebral penumbra of each group was harvested and stored them at − 80 °C until use. To extract total proteins, we homogenized the brains and determined the total protein concentrations using the Bradford protein assay  with bovine serum albumin (BSA) as the standard. We applied 25 µg of total protein in each sample were applied into the lanes of a 10–15% sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) gels. Then, we transferred isolated proteins to polyvinylidene difluoride (PVDF) membrane  and blocked them in a fresh blocking buffer  for 3 h at room temperature. Subsequently, the membranes were incubated with the primary antibodies  overnight at 4 °C. Next, the membranes were washed with Tris-buffer saline and Tween-20 (TBST) and incubated them with anti-rabbit IgG or anti-mouse peroxidase-conjugated secondary antibody. The membranes were incubated with Immobilon Western  and exposed them to X-ray film. Densitometric analysis was performed by a scanning films with a densitometer the results were normalized using β actin by image J analysis.t-test. Other data were analyzed using a one-way analysis of variance (ANOVA), followed by Dunnett’s post hoc test. However, the data with non-normal distribution were analyzed using Kruskal–Wallis test. A p value < 0.05 was considered a statistically significant difference between experimental and control groups.The data are presented as mean ± standard error of the mean (SEM). Statistical differences between the two groups were determined by using Student’s 27, a phenomenon that can activate a cascade of pathophysiological processes, including oxidative stress, inflammation, and neuronal apoptosis30. A previous study demonstrated the anti-inflammatory and anti-oxidant activity of morin in a transient cerebral model. Morin acts as a powerful anti-inflammatory agent by suppressing activation of NF-ĸB and the expression levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and iNOS19. However, its benefits toward preventing or ameliorating BBB disruption after cerebral I/R have not been reported. Hence, in the present study, we first investigated the ability of morin to attenuate BBB and cerebral damage following cerebral ischemia/reperfusion injury during the acute phase of rats subjected to MCAO and reperfusion injury. We focused on three different time points: pre-ischemia, during ischemia, and during reperfusion. Our results demonstrated that morin treatment had no effect on body temperature, oxygen saturation, body weight or heart rate in the rats. Further, morin decreased NF-ĸB activation, whereas TNF-α, IL-1β, and iNOS expression decreased. The major findings showed that morin inhibited NF-ĸB activation which, in turn, decreased the expression of proinflammatory cytokines. Moreover, morin suppressed MMP-9 expression, which improved BBB disruption by reducing TJ protein degradation and BBB permeability at pre-ischemia, during ischemia, and during reperfusion.Cerebral I/R injury leads to the excessive production of ROS31. The mechanisms occur extremely rapidly in the ischemic core, and thus this area is difficult to protect. However, preservation of the penumbra by residual or collateral blood flow and salvaging the area can help to prevent the continued growth of the ischemic core or decrease the infarct size. Our results showed that at all time points morin treatment improved the neurological outcome and attenuated the cerebral infarct size. When cerebral perfusion is re-established (reoxygenation), a high oxygen surge occurs in the penumbra. This event leads to marked increase in ROS generation. Many studies have reported that a large quantity of ROS causes subsequent oxidative stress and neuronal cell injury7. Following the oxidative stress of cerebral ischemia, inflammation, BBB disruption, and apoptosis are induced. Therefore, suppression of oxidative stress might prevent neuronal injury in cerebral I/R. A decrease of ROS may reduce neuronal cells death by attenuating lipid peroxidation and oxidative stress. Many studies have reported that morin has strong antioxidant properties. Morin prevents lipid peroxidation, scavenges intracellular ROS, and protects the antioxidant system34. Moreover, a previous study reported that morin plays an antioxidant role in the MCAO model. Our results confirmed that morin-treated groups tends to decrease ROS production and reduce lipid peroxidation, as observed by the MDA level. These outcomes are related to the levels of Iba1 and GFAP expression, markers that represent microglia and astrocytes, respectively. This study showed that microglia and astrocyte were the source of ROS and oxidative stress in cerebral I/R injury.Cerebral ischemia leads to cerebral infarction via mechanisms that cause irreversible damages and neuronal cell death36, and activation of TLR4 leads to neuronal inflammation through an NF-ĸB signaling pathway9. NF-ĸB activation plays an important role in pro-inflammatory cytokine regulation, including TNF-α, IL-1β, and iNOS. Therefore, TLR4 inhibition downregulates activation of the NF-ĸB signaling pathway, in addition to reducing pro-inflammatory cytokines production. Our studies found that morin attenuated TLR4 expression and also decreased NF-ĸB activation, which is closely related to reducing TNF-α, IL-1β, and iNOS expression. Furthermore, MMP-9, a pro-inflammatory cytokine produced by NF-ĸB activation, is also released to induce BBB disruption20. MMP-9 directly degrades the extracellular matrix, basal membrane, and TJ proteins, such as occludin and claudin, all of which lead to BBB breakdown37. Subsequently, the BBB disruption allows neutrophil infiltration from the blood into the brain at 72 h after cerebral I/R12. However, previous research suggested that suppressing MMP-9 expression improves BBB disruption by reducing TJ protein degradation and BBB permeability in a cerebral I/R model38. Our results revealed that morin administration suppressed MMP-9 expression. In addition, morin decreased the degradation of TJ proteins, like occludin and claudin, and reduced the infiltration of neutrophils, correlated with decreased MPO activity at 72 h after reperfusion. These results, related to the Evans blue assay, showed that the leakage of Evans blue dye in morin-treated groups was significantly decreased compared with the vehicle group. These findings suggest that morin decreases BBB permeability and BBB leakage. Moreover, we further studied the ultrastructural changes of the BBB using TEM. We found that the cerebral microvascular was altered in morin-treated groups. Sham rats showed mostly vascular lumen alterations and the formation of microvilli. These results suggest that morin reduces inflammation and enhances BBB integrity after cerebral ischemia/reperfusion in the MCAO model.ROS overexpression also triggers neuronal inflammation, which includes the contribution of TLR4. TLR4 is upregulated after cerebral I/R injury to recognize the intracellular components from neuronal cell death was known as DAMPs39. Previous studies demonstrated that apoptosis plays an important role in the pathogenesis of cerebral I/R and leads to cerebral infarction. Decreasing caspase-3 expression reduces apoptotic cells and cerebral infarction after MCAO. A previous study revealed that morin-treated rats subjected to MCAO showed caspase-3 downregulation19. In our study, morin treatment at each time point decreased caspase-3 expression and activity. In addition, we noted fewer TUNEL-positive cells in the ischemic brain of morin-treated groups, data that indicate a decrease in apoptotic cells. Our results also showed histological changes in the cerebral cortex and striatum. We found that the number of neuronal cells was decreased in the vehicle group, and neuronal cells exhibited pyknotic nuclei and overall shrinkage. Hence, our data indicated that morin can reduce apoptosis in the acute phase of cerebral ischemia/reperfusion.Several death receptor ligands, such as TNF-α and IL-1β, can markedly induce neuronal apoptosisIn conclusion, our study provided evidence that morin has a neuroprotective effect on cerebral ischemia/reperfusion. It improved cerebral damage and neurological outcomes by attenuating oxidative stress, inflammation, and apoptosis. Here, we found that morin improved BBB disruption and enhanced BBB integrity.Supplementary file 1.Supplementary datasets.


IntroductionMaternal near-miss and maternal mortality cases have common characters, especially in terms of risk factors. Both of them are indicators of the quality of health care services provided to pregnant women. Our center is a tertiary care center in a rural area of western Uttar Pradesh (U.P.) so we get a large number of referred cases from most of the rural areas of western U.P. and the adjoining areas of other states too, which sometimes end up in mortality. Thus this study was planned to find out the incidence of maternal near-miss events and compare the nature of near-miss events with maternal mortality.Goal and objectivesThe main objectives of the study were to determine the frequency of maternal near-miss events, observe the trend of near-miss events, and compare the nature of near-miss events with maternal mortality.Materials and methodsIt was a retrospective study conducted in the department of obstetrics and gynecology at Uttar Pradesh University of Medical Sciences (UPUMS), Saifai, Etawah, from July 2018 - June 2019, over a period of one year. Potentially life-threatening conditions and maternal mortalities were noted from the records of the hospital after taking ethical clearance from the institute. Near-miss cases were noted based on the Health and Family Welfare Government of India guidelines 2014. Data were collected and statistical analysis was performed using the Statistical Package of the Social Sciences (SPSS) version 21 .ResultsThe maternal near-miss incidence ratio was 16.6/1000 live births, the maternal near-miss to mortality ratio was 1.9:1, and the mortality index was 0.34%. Hypertensive disorders of pregnancy were the most common causes of near-miss events (45.8%) followed by hemorrhage (23.6%) in this study.ConclusionsHypertensive disorders in pregnancy and hemorrhage were the two leading causes of near-miss events and mortality followed by sepsis. As the near-miss analysis indicates, the quality of health care and causes are almost similar to maternal mortality, so its registry should be done along with maternal mortality. Maternal near-miss (MNM) is a condition in which a woman nearly dies from complications of pregnancy or childbirth within 42 days of termination of the pregnancy regardless of location or duration but survives either due to the good care she receives or due to chance . MaternaOur center is a tertiary care center in a rural area of western Uttar Pradesh so we get a large number of referred cases from most of the rural areas of western U.P. and the adjoining areas of other states too, which sometimes land up in mortality so we planned this study to find out the frequency of maternal near-miss events and compare the nature of near-miss events with maternal mortality. It was a retrospective study conducted in the department of obstetrics and gynecology, UPUMS, Saifai, Etawah, from July 2018 - June 2019 over a period of one year. Potentially life-threatening conditions related to pregnancy, delivery, and maternal mortalities were noted from the records of the hospital after taking ethical clearance from the institute. Near-miss events were noted based on the Health and Family Welfare Government of India Guideline 2014. Data were collected. Statistical analysis was done by using the Statistical Package of the Social Sciences (SPSS) version 21 . The following indices were calculated:Maternal near-miss incidence ratio-total no of near-miss cases/total no. of live births X 1000Maternal near-miss/maternal mortality ratioMortality index = no. of maternal deaths /no of maternal deaths + no of near-miss casesMaternal mortality rateThe maternal near-miss to maternal mortality ratio and the mortality index tell about the quality of care given at a particular institute. The higher the maternal near-miss to maternal mortality ratio, the better is the care at the given institute. A lower mortality index signifies better care at the institute.In the study period of one year, the total number of deliveries was 8793 and the total live births were 8638. The total no of near-miss cases or SAMM was 144, and 77 maternal mortalities occurred during the study period of one year. The maternal near-miss incidence ratio was 16.6/1000 live births, maternal near-miss to mortality ratio was 1.9:1, and the mortality index was 0.34%.Table As shown in Table Out of all near-miss cases, 92 (63.8%) patients required ventilatory support, 35 (24.3%) patients required vasopressors, 12 (8.3%) patients required hysterectomy for different indications like rupture uterus, placenta accrete, and intractable post-partum hemorrhage not responding to medical and other surgical management, 58 (40.2%) patients needed > 5 units of blood transfusion, and two (1.3%) patients required dialysis for acute renal failure.In Uttar Pradesh, the maternal mortality ratio is higher than the national maternal mortality ratio. So this study was conducted to find out the incidence of near-miss events based on the Government of India Health and Family Welfare Guidelines 2014 and to compare common causes responsible for maternal near-miss with maternal mortality at a rural tertiary care center that is in Uttar Pradesh, which can help in further improvement.A study by Bansal et al.  in BastaIn this study, the age group of 20 to 35 years was most commonly affected both by MNM and maternal mortality due to the fact that it is the most common reproductive age group so mostly complications occur in this age group. It is similar to the study by Bansal et al.  in BastaMaternal mortality was significantly high  in unbooked women as compared to near-miss cases in this study. It may be because high-risk cases remain undiagnosed till complications develop and lead to mortality if not managed timely.In this study, most of the near-miss cases were in the third trimester of pregnancy, post-partum and maternal mortality also mostly occurred in the same gestational age group, and near-miss cases were higher, which was statistically significant. It may be because most complications develop during the third trimester of pregnancy and our center is in a rural area and covers a large rural population so patients from all referral centers come to us. Sometimes, they deliver at other centers or at home and are then referred to our center or come on their own if any complication occurs. The study conducted at Ahmadabad by Mansuri et al.  and in KThe most common cause of a maternal near-miss was hypertensive disorder in this study, which was similar to the study done by Jain in 2019  and the Hypertensive disorders in pregnancy and hemorrhage were the two leading causes of near-miss events followed by sepsis. Causes in near-miss and maternal mortality are almost similar. Our center provides good care. Maternal mortality mostly occurred in cases that reached delayed or moribund. It is necessary to boost referral services so that patients can reach the hospital in time and lives can be saved. Awareness-raising programs should be conducted for increasing the knowledge regarding antenatal check-ups needed, the need for blood investigation, and all the morbid conditions that can occur in pregnancy so that patients can contact the healthcare facility in time. As the near-miss analysis indicates the quality of health care and causes are almost similar to maternal mortality, its registry should be done.


Design, setting, and participants. A total of 90 laypersons were randomized into three groups: the mobile video call-guided, voice call-guided, and non-guided groups. Participants were exposed to simulated cardiac arrest to use an AED, and guided by video calls, voice calls, or were not guided. We recorded the simulation experiments as a videoclip, and other researchers who were blinded to the simulation assessed the performance according to the prespecified checklist after simulations. Outcomes measure and analysis. We compared the performance score and time intervals from AED arrival to defibrillation among the three groups and analyzed the common errors.  To investigate the feasibility of mobile videocall guidance to facilitate AED use by laypersons.  There was no significant difference among the three groups in terms of baseline characteristics. Performance scores in the checklist for using AED were higher in the mobile video call-guided group, especially in the category of “Power on AED” and “Correctly attaches pads” than in the other groups. However, the time interval to defibrillation was significantly longer in the mobile video call-guided group.  Mobile video call guidance might be an alternative method to facilitate AED use by laypersons. Therefore, further well-designed research is needed to evaluate the feasibility of this approach in OHCA. Ventricular fibrillation is one of the major causes of out-of-hospital cardiac arrest (OHCA), and the time from the onset of cardiac arrest to electrical defibrillation is critically related to the survival rate of OHCA patients , 2. The Despite these efforts, however, less than 5% of OHCA patients receive defibrillation before the arrival of paramedics following emergency calls to 119 . HoweverTherefore, we aimed to determine whether instructions via video call helps laypersons to use the AED more accurately than in those via the voice call or in the absence of instructions.This prospective randomized simulation study was conducted to determine whether video call guidance can help a layperson to correctly use the AED in a hypothetical cardiac arrest situation. We enrolled adult college students (age ≥ 18 years) and selected 90 participants who did not have formal training, such as the AHA Basic Life Support (BLS) course, in CPR and AED. In June 2019, we performed a simulation experiment using a mannequin while assuming a cardiac arrest situation. The control group included participants who performed CPR without any guidance (non-guided group), and the two intervention groups were divided into those that received researcher-conducted guidance through a voice call  or a video call . All participants were randomly assigned to three groups and then simulated according to the study protocol . After rThe study population was uniformly and randomly assigned to the non-guided, voice call-guided, and video call-guided groups through a computer-based random number program. Before the simulation, participants were blinded as to which group they had been assigned. To reduce the impact of the preceding simulations by other participants, the participants were not permitted to communicate with other participants after the simulation and asked to return home without individual feedback. The simulation operation, data collection, and postassessment process were described in the study protocol based on the preliminary research meeting. The non-guided group had to independently apply the AED to the mannequin under the assumption of an OHCA situation without any questions or guidance during the simulation. The voice call-guided group was instructed to use an AED via a call with a person who was assigned the emergency medical dispatcher's role in a separate room. The participants could communicate with the dispatcher via a voice call, but the dispatcher has standardized to explain only the predefined contents of the script, without sharing any personal opinions. The video call-guided group proceeded similarly as the voice call-guided group, except that the video call group was instructed through a mobile video call. The AED use was recorded with a cellphone camera by another assistant, and the instructor supervised it in real time via video calls. The entire process was filmed, and each process was evaluated with a score by using the performance checklist. The AEDs used in the simulation were educational AEDs  where no actual shock was transmitted. After all simulations were completed, all participants received training on the correct use of AEDs.The simulation process was recorded as a videoclip using a camera. Video recording was performed under controls to ensure that the participants' personal information was not revealed, and the file was saved with a preassigned serial number such that the participants could not identify the assigned group. The performance score evaluation through the checklist was conducted independently by three different emergency medical specialists who did not participate in the simulation; in case of disagreement, the final performance score was confirmed after discussion among the specialists. The main outcome variable was defined as the AED performance of each group. Therefore, the AED checklist of the 2015 AHA Basic Life Support (BLS) course was incorporated as an evaluation tool . AHA's AU test and Bonferroni calibration were performed with multiple-comparison post hoc tests. Continuous variables are expressed as the mean and standard deviation or median and quartile range, and categorical variables as the frequency and percentage. Statistical analysis was performed using SPSS version 18.0 , and p < 0.05 was considered to indicate statistical significance.In the pretest, the average scores of the non-guided, voice call-guided, and video call-guided groups were 6.2, 6.8, and 7.1, respectively. Based on this, 81 samples were deemed necessary to calculate the table fractions with a significance level of 0.05 and a statistical power of 0.8. A total of 90 samples were finalized, factoring in a 10% dropout rate. The analytical method was determined by performing a normality test for each outcome variable. One-way analysis of variance was performed in case of normality among continuous variables, and the Kruskal–Wallis test was used in case of nonnormality test. If necessary, the Mann–Whitney p = 0.87). The median age was 24.0, 22.0, and 22.5 years in the non-guided, voice call-guided, and video call-guided groups, respectively, without any significant difference (p = 0.07). The experiences of CPR and AED education and the number of education in the last 2 years among the groups were not significantly different . Most of the participants had no experience in using real AEDs (n = 60) and police administration (n = 30). But there were no differences in the previous CPR and AED education experiences according to their majors .There were 18 (60%) women in the non-guided group, 19 (63.3%) in the voice call group, and 17 (56.7%) in the video call group, with no significant differences among the three groups . All participants in the video call group scored 2 points in the “Powers on AED” category compared to the non-guided (0.73 ± 0.91 points) and voice call-guided (1.93 ± 0.37 points) groups. Moreover, the video call-guided group (1.97 ± 0.18) showed a significant difference in the “Correctly attached pad” category than the non-guided (0.77 ± 0.57 points) and voice call-guided (0.73 ± 0.74 points) groups. Both, the non-guided group and voice call-guided groups, only received 1 point in the checklist of “Clears to analysis” and “Clears to safely deliver a shock”; however, the participants in the video call-guided group had scores of 1.3 ± 0.47 and 1.17 ± 0.38 (p < 0.001 and 0.005), respectively. Furthermore, the scores in the non-guided and the voice call-guided groups were 0.8 ± 0.41 in the “Safely delivered a shock and resumed compression,” although the score in the video call-guided group was 1.03 ± 0.12 (p = 0.017) (p < 0.001).The defibrillator performance scores of each group were 4.3 ± 1.21, 5.47 ± 0.94, and 7.47 ± 0.82 in the non-guided, voice call-guided, and video call-guided groups, respectively. The scores in the video call group were significantly higher than those in the other two groups (= 0.017) . To evalp = 0.004). The time taken to power on was significantly longer in the non-guided group  than in the other groups, whereas the time from powering on to attaching the pads was significantly shorter in the non-guided group   . The com< 0.001) .The participants who did not have formal training were included in this study. However, in the results, more than 70% of the participants had an experience of CPR education and more than 20% has AED education. In Korea, CPR education has been mainly conducted in school, military, workplace, etc. Furthermore, men were educated CPR at least once during compulsory military service. But this type of education was frequently done as a lecture form without practice sessions, in a large group, in a short time, and using only video clips or slides. Because the participants remember such an experience, they might answer like that way.The overall performance score of the AED simulation ranged from high to low in the video call-guided, voice call-guided, and non-guided groups. In the post hoc analysis, both the voice and video call-guided groups showed higher scores in the category of “Power on AED,” and the video call-guided group showed significantly higher scores than the other two groups in the category “Correctly attaches pad.” Despite significant intergroup differences in the categories of “Clears to analysis,” “Clears to safely deliver a shock,” and “Safely delivers a shock and resumes compression,” there was no significant difference in pairwise comparisons between the two groups. In a meta-analysis, the proportion of laypersons who knew how to correctly use an AED was reported to be 7-26% . In thisThe score of the non-guided group in the category “Powers on AED” was relatively low, but the difference between the voice call and video call-guided groups was not significant, which may be because pressing the power button is an easy step to follow in the dispatcher's instruction. In contrast, this may be a difficult step for laypersons unfamiliar with AED use. The step of attaching the pads to the correct position could be performed more precisely in the video call-guided group because the dispatcher could direct the laypersons through real-time interactive communication. To date, few clinical studies have evaluated whether AED pad placement in the right location actually affects the survival rate and recovery of spontaneous circulation in OHCA patients. However, some animal studies have reported that maximizing the current through the myocardium by correctly attaching the pads is critical for successful defibrillation –16; therThe total time to AED use was the longest in the video call-guided group and the shortest in the non-guided group. Thus, as the cessation of chest compression is inevitable when using a defibrillator, it is important to perform defibrillation as soon as possible , 18. AltIn the qualitative video analysis, most of the participants in the groups did not ensure that no one was touching the person before delivering a shock. However, some participants did not know how to remove the AED pad cover or how to power on the AED, possibly because they had no experience in the stepwise education for AED practice. To reduce the abovementioned errors, CPR training, including not only the lecture but also AED practical training, is needed. Furthermore, laypersons could not competently use the AED in accordance with the dispatcher's instruction despite being in the voice call-guided group, possibly because they did not understand the anatomical directional terms or hear the advice clearly because of ambient noise. Accordingly, the dispatcher should also consider the possibility of communication errors between dispatchers and laypersons, and video call guidance could be an alternative method to facilitate AED use in CPR.This study has several limitations. First, because it is a relatively small study of university students in a specific area, it cannot represent the general characteristics, such as age, regional distribution, and accessibility of video calls, of the general public, and the results may not be easily generalizable. Second, this is a simulation study that dealt only with AED use for the virtual OHCA situation, which can be quite different from the actual OHCA situation. During actual CPR, the chest compression quality and minimizing of interruptions are important , 21. HowIn summary, this simulation evaluation confirmed that the AED performance of the laypersons improved in the video call-guided group than in the control or voice call-guided group. When using an AED alone, the AED could not be turned on quickly and the pad could not be properly placed; therefore, a video call could be considered as a feasible alternative in layperson CPR for OHCA.


To assess the associations of problem drinking with wellbeing and mortality in Chinese men.Population‐based prospective cohort study.Ten diverse areas across China.A total of 210 259 men aged 30–79 years enrolled into China Kadoorie Biobank between 2004 and 2008.Self‐reported alcohol intake and indicators of problem drinking  were assessed by questionnaire at baseline, along with stressful life events  and wellbeing‐related measures . Problem drinking was defined as reporting at least one of the drinking problem indicators. Follow‐up for mortality and hospitalized events was through linkage to death registries and national health insurance systems. Multivariate logistic regression models assessed cross‐sectional relationships between problem drinking and stressful life events/wellbeing. Cox proportional hazards regression models estimated prospective associations of problem drinking with mortality/hospitalized events.P < 0.01).A third of men were current regular drinkers , 24% of whom reported problem drinking: 8% of all men. Experience of stressful life events in the past 2 years, especially income loss , was associated with increased problem drinking. Compared with low‐risk drinkers , men with problem drinking had poorer self‐reported health, poorer life satisfaction and sleep problems, and were more likely to have symptoms of depression and anxiety. Men with two or more problem drinking indicators had an approximately twofold higher risk for all‐cause mortality as well as mortality and morbidity from external causes (i.e. injuries), respectively, and 15% higher risk for any hospitalization, compared with low‐risk drinkers (all Eight per cent of men in China are problem drinkers, and this is associated with significantly increased risk of physical and mental health problems and premature death. Alcohol drinking is a well‐recognized risk factor for the global burden of disease In China, the patterns of drinking differ importantly from western populations, including a lower prevalence of regular drinking especially among women, and the Chinese custom of drinking spirits and drinking alcohol with meals Given the cultural differences in drinking patterns and the growing alcohol‐attributable disease burden, assessment of the relationships between problem drinking and health consequences in Chinese populations is needed to inform treatment and prevention strategies. This study uses data from the prospective China Kadoorie Biobank (CKB) of 0.5 million adults  to (1) examine the prevalence and correlates of problem drinking; (2) assess the cross‐sectional relationships of problem drinking with experience of stressful life events and wellbeing; and (3) explore the prospective associations of problem drinking with all‐cause mortality, hospitalizations and events due to external causes. As few women (~2%) drink alcohol regularly in CKB Details of the CKB study design and methods have been previously reported Self‐reported alcohol drinking patterns and indicators of problem drinking at baseline were recorded by questionnaire, with details described previously http://www.ckbiobank.org).Experience of stressful life events in the past 2 years and wellbeing‐related measures  were assessed by baseline questionnaire. The 10 stressful life events  are common stressors often examined in epidemiological research of stress and alcohol Cause‐specific mortality was monitored through China's Centre for Disease Control (CDC) Disease Surveillance Points (DSP) system, with annual active confirmation through local residential, medical, health insurance and administrative records. Non‐fatal outcomes of major diseases and any episodes of hospitalization were collected through linkage with disease registries and the Chinese National Health Insurance claim databases. All events were coded using International Classification of Diseases (ICD)‐10 by trained staff blinded to baseline information. The follow‐up outcomes in this study were all‐cause mortality, any episode of hospitalization and all fatal and non‐fatal events due to all external causes (ICD‐10: V01‐Y98). By 1 January 2016, 21 545  men had died and 1792 (0.9%) were lost to follow‐up.Means and percentages of baseline characteristics were adjusted for age and region where appropriate by direct standardization to the age and region structure of the cohort. The statistical associations between problem drinking categories and baseline characteristics were tested using multinomial logistic regression for categorical variables, logistic regression for binary variables and linear regression for continuous variables. Logistic regression was used to calculate odds ratios (ORs) of problem drinking associated with exposure to stressful life events, and ORs of wellbeing‐related measures associated with exposure to problem drinking and individual problem drinking indicators, in cross‐sectional analyses among current regular drinkers adjusted for age group, region, education, income and smoking. For analyses of problem drinking and wellbeing‐related measures, marital status, prior chronic diseases and body mass index (BMI) were additionally adjusted for   of log ORs or log HRs for all categories including the reference group, which reflected independent variability within each group. It enabled comparison between any two categories rather than simply pairwise comparisons with the reference category Sensitivity analyses were conducted to explore the associations of problem drinking with depression and anxiety after removing the negative emotions indicator from the definition of problem drinking. Analyses of the associations of problem drinking with stressful life events, wellbeing and mortality risk with further adjustment for potential confounding factors, e.g. prior chronic diseases for stressful life events, physical activity for wellbeing and prior psychiatric disorders for all analyses, were performed. Further analyses on the associations of problem drinking with wellbeing and mortality risk were repeated among all male participants.SAS version 9.4 was used for performing statistical analyses and R version 3.4.0 was used for producing figures. The analyses were not pre‐registered and the results should be considered exploratory.n = 69 904) drank alcohol regularly, among whom the mean age was 51 years and 50% were from urban areas (Table P < 0.001). Problem drinkers reported the following indicators: morning drinking (55%) and unable to stop drinking (47%), which increased with age (P < 0.001), unable to work due to drinking (15%), negative emotions after drinking (7%) and having shakes when stopping drinking (2%), which decreased with age (P < 0.001)   and were more likely to drink daily (1) Table . High‐ri1) Table . The hig1) Table . Those r1) Table .Experience of any stressful life events was associated with an adjusted OR of 1.24 (95% CI = 1.16–1.33) for problem drinking Table .P < 0.001). The associations were stronger for other wellbeing‐related measures, i.e. an approximately 2–2.4‐fold higher risk for panic attacks, symptoms of depression and anxiety . The associations of problem drinking with MDE and GAD were similar to those with symptoms of depression and anxiety respectively, although the ORs were less extreme for MDE. Among problem drinkers, there were significant dose–response relationships of poor wellbeing with the number of indicators reported  for low‐risk drinkers, 1.28 (95% CI = 1.21–1.35) for high‐risk drinkers, 1.37 (95% CI = 1.28–1.46) and 1.91 (95% CI = 1.71–2.13) for drinkers with one and two or more problem drinking indicators, respectively Fig. . The risThe main results from the cross‐sectional and prospective analyses persisted after further adjustment for other relevant covariates such as prior chronic diseases, physical activity and prior psychiatric disorders  in CKB suggested that the burden of harmful alcohol use is likely to be highly skewed towards Chinese men. The overall prevalence of problem drinking in men 8%) in this study is broadly consistent with a previous meta‐analysis of 38 cross‐sectional studies, most of which focused on a single geographical region, including 1 304 354 individuals conducted during 1987–2013 in China, which reported a prevalence of AUD of 10% in men and 0.1% in women % in thisPrevious studies of mainly western populations have reported the associations of stressful life events, particularly financial‐related events, e.g. job loss, with alcohol craving and problem drinking per se, but to the negative consequences of, or the genetic predisposition to, problem drinking Although the evidence is limited in China, previous studies which are mainly from western populations have shown associations of problem drinking with various measures of poor wellbeing, including lower life satisfaction, sleep problems, depression and anxiety The associations between problem drinking and depression and anxiety disorders have been established previously among western populations, in both cross‐sectional and prospective studies For long‐term health outcomes, our findings were generally consistent with previous studies world‐wide Several possible mechanisms have been proposed to explain the pathway linking problem drinking and poor mental health, including the self‐medication theory ; substance‐induced pathway ; a reciprocal causal relationship ; or causation by a common factor  The chief strengths of this study were the large sample size, the wide range of geographical areas covered and detailed data collected on drinking patterns and wellbeing‐related measures. However, the study has several limitations. First, CKB was not designed to be nationally representative and, given the overall response rate of ~30%, the present study may have underestimated the prevalence of problem drinking, as individuals with severe problem drinking may have been less likely to participate in the CKB. However, the associations of problem drinking with stressful life events, wellbeing and health outcomes are likely to be generalizable to the general population, given the large size and diversity of CKB. Secondly, the low prevalence of regular drinking among women precluded reliable exploration of associations in women. Thirdly, full clinical diagnostic standard assessment for AUD (i.e. DSM‐5) was not used. Nevertheless, the construct of alcohol‐related problems used in our assessment was comparable to the major domains of AUD diagnostic criteria  with wellbeing in male current regular drinkers.Figure S8. Prospective associations of problem drinking with all‐cause mortality, all hospitalisations and events due to all external causes in male current regular drinkers without prior chronic diseases, by rural and urban regions.Figure S9. Cross‐sectional associations of problem drinking with wellbeing‐related measures in men.Figure S10. Prospective associations of problem drinking with all‐cause mortality, all hospitalisations and events due to all external causes in men without prior chronic diseases.Table S1 Definitions of main alcohol drinking categories, pattern and problem drinking.Table S2 Details of main analytic models.Table S3 Drinking characteristics by problem drinking status in male current regular drinkers, by rural–urban regions.Table S4 Drinking characteristics by specific problem drinking indicators in male current regular drinkers.Table S5 Cross‐sectional associations of stressful life events with problem drinking in male current regular drinkers, by rural and urban regions.Table S6 Adjusted odds ratios (ORs) associated with an increase in the number of problem drinking indicators in men with at least one problem drinking indicator.Table S7 Cross‐sectional associations of problem drinking with sleep problems in male current regular drinkers.Table S8 Cross‐sectional associations of problem drinking indicators with wellbeing‐related measures in male current regular drinkers.Table S9 Adjusted hazard ratios (HRs) associated with per an increase in the number of problem drinking indicators in men with at least one problem drinking indicator.Table S10 Prospective associations of problem drinking indicators with all‐cause mortality, all hospitalisations, and events due to external causes in male current regular drinkers.Table S11 Cross‐sectional associations of stressful life events with problem drinking in male current regular drinkers in sequentially adjusted models.Table S12 Cross‐sectional associations of problem drinking with wellbeing‐related measures in male current regular drinkers in sequentially adjusted models.Table S13 Prospective associations of problem drinking with all‐cause mortality, all hospitalisations, and events due to external causes in male current regular drinkers in sequentially adjusted models.Table S14 Baseline characteristics of men by alcohol drinking and problem drinking status.Table S15 Comparison of problem drinking and AUD definitions in the China Kadoorie Biobank and commonly used screening tests and diagnostic criteria.Click here for additional data file.