Takotsubo syndrome is a cardiomyopathy that can mimic an acute heart attack, in terms of clinical presentation, electrocardiographic changes, and findings on echocardiogram. Point-of-care-ultrasound (POCUS) can be used to detect this condition, even though the definitive diagnosis is made angiographically. We present the case of an 84-year-old woman with a subacute coronary syndrome and high levels of myocardial ischemia markers. The POCUS performed on admission showed characteristic left ventricular dysfunction involving the apex but sparing the base. The coronary angiography ruled out significant arteriosclerotic in the coronary arteries. The wall motion abnormalities were partially corrected in the 48 hours after admission. POCUS might be a useful tool to establish an early diagnosis of Takotsubo syndrome at time of admission.  The markers for myocardial injury were positive, with an ultrasensitive Tnl of 3832 ng/l (nanograms per liter). The patient is an 84-year-old woman with a medical history of hypertension and hypercholesterolemia on a type II angiotensin receptor antagonist (ARAII) and ezetimibe, who presented with an episode of mid-thoracic pain which radiated to her neck. The pain lasted for two hours and persisted as a slight to moderate discomfort until the patient finally went to the Emergency Room 24 hours later. The electrocardiogram (ECG) done at admission showed sinus rhythm of 61 beats per minute (bpm), with an axis of 30Since the patient was completely asymptomatic at this point, the case was interpreted as an anterolateral infarction in its subacute phase. Acetylsalicylic acid (ASA) and clopidogrel were administered and anticoagulant treatment with heparin of a low molecular weight was started. The patient was admitted to the Intensive Care Unit. Upon arrival, the patient was still asymptomatic, with a stable sinus rhythm and without a sign of cardiac failure. In the physical exploration an audible systolic heart murmur that radiated to the neck could be heard. An advanced cardiac POCUS was performed (Video S1) and revealed the following: Non-dilated left ventricle, with an eccentric hypertrophy affecting the basal part of the interventricular septum. Severe hypokinesia of the apex and most apical segments of the anterior and lateral surfaces of the heart. • Compensating hyperkinesia in the basal segments. Slightly depressed ejection fraction. Sclerosis and calcification of the mitral-aortic ring and of the valves. Abnormal pattern of relaxed diastolic filling. Moderate mitral regurgitation. Slight aortic regurgitation. In the study done with color-doppler, a turbulent flux appeared in the left ventricular outflow tract. When pulsed-doppler was applied, it had the characteristic knife shape of sub-valvular dynamic stenosis. The gradient peak was about 63 millimeters of mercury (mmHg). .In the two-dimensional image (2D) the movement of the anterior valve towards the septum during the systole  could be clearly seen (Video S2). The maximum peak of ultrasensitive Tnl was reached at 5298 ng/l. In the ICU, anticoagulants, antiplatelets and beta-blockers (bisoprolol) were started. The following morning coronary angiography did not show any coronary lesions . Incidentally, the descending anterior artery was abnormally long, and wrapped around the apex and continued along the diaphragmatic surface. The diagnosis of Takotsubo syndrome was made, and the clopidogrel was stopped, while continuing the AAS and the bisoprolol. On the ECG done prior to discharge, 18 hours after the coronary angiography, elevation of the ST segment was still present while the T waves in V3, V4, V5 and V6 were beginning to become negative. The follow up echocardiography showed evidence of a substantial decrease of the dynamic systolic gradient of the left ventricular outflow tract (LVOT) which was attributed to the beta-blockers. The Takotsubo syndrome was first described in 1990 by Sato et al.The usual clinical presentation is indistinguishable from that of an acute coronary syndrome, since it produces the typical central thoracic pain, elevation of the ST segment in the ECG and an elevation of the markers for myocardial ischemia The echocardiographic image is very characteristic. The severe apical hypokinesia appears together with hyperkinesia in the basal segments which gives the heart the appearance of an inverted vase, the type traditional Japanese fishermen used to capture octopuses (tako-tsubo) The hallmark of Takotsubo syndrome is that on coronary angiography the coronary arteries will show no significant lesions.The etiology of the syndrome is still not definitively known. It has been observed that often the symptoms are triggered by a situation which causes emotional distress, and it has been postulated that the syndrome might be explained by the toxic effect of catecholamines amidst the excessive local sympathetic response On the echocardiography, a dynamic obstruction of the LVOT with systolic anterior movement of the mitral valve (SAM) can be seen in 20% of cases, generating an intraventricular gradient greater than 30 mmHg This gradient could be important in the genesis of the syndrome, because the obstruction elevates the intraventricular pressures of the apical area and diminishes myocardial perfusion (Video S2). In some series of coronarography the anterior descending artery has shown a longer than average length with a longer diaphragmatic course  After diagnosing Takotsubo and confirming it angiographically, antiplatelet treatment can be stopped, but beta-blockers must still be used, specially, in cases where an LVOT obstruction exists. Even though alterations in the left ventricular ejection fraction are characteristically transitory and functional recovery is the norm, some patients can present very severe cases of heart failure and even cardiogenic shock and death. For the emergency or ICU physician that uses POCUS, it is important to know the cardiac POCUS and echocardiographic characteristics of Takotsubo cardiomyopathy in order to raise the index of suspicion in patients presenting with chest pain. None Video S1 Video S2


The successful occupation of the eastern Eurasian Steppe in the Late Pleistocene improved cultural connections between western Eurasia and East Asia. We document multiple waves of lithic technological transmission between the eastern Eurasian Steppe and northern China during 50–11 cal. ka BP. These waves are apparent in the sequential appearance of three techno-complexes in northern China: (1) the Mousterian techno-complex, (2) the blade techno-complex mixed with Mousterian elements, (3) and the microlithized blade techno-complex. These lithic techno-complexes were transmitted under different paleoenvironmental conditions along different pathways through the eastern Eurasian Steppe. The Mousterian techno-complex and the blade techno-complex mixed with Mousterian elements were only dispersed in the north and west peripheries of northern China . We argue that these techno-complexes failed to penetrate into the hinterland of northern China because they were not well suited to local geographical conditions. In contrast, the microlithized blade technology which diffused from the eastern Eurasian Steppe was locally modified into a Microblade techno-complex which was highly suited to local environmental conditions, and proliferated across the hinterland of northern China . The subsequent spread of microblade technology over vast regions of Mongolia and Siberia indicates that the Pleistocene inhabitants of northern China not only adopted and modified technologies from their neighbors in the Eurasian Steppe, but these modified variants were subsequently transmitted back into the Eurasian Steppe. These episodes of technological transmission indicate complicated patterns of population dispersal and technological interaction across northern China and the eastern Eurasian Steppe. Geographical obstacles and great distances impacted the cultural transmission of lithic technologies between western Eurasia and East Asia . In contComparing the lithic developmental patterns between the eastern Eurasia Steppe and northern China is crucial for understanding the increased level of lithic technological connection between western Eurasia and East Asia at the end of the Paleolithic. The Eastern Eurasian Steppe is mainly composed of the Mongolia Plateau and the eastern part of South Siberia. It is located to the northeast of West and Central Asia, and borders west, north and east margins of northern China. Unlike the formidable desert and mountainous Inner Asian regions situated directly between western Eurasia and East Asia, the eastern Eurasian Steppe poses less geographical obstacles and could serve as a relatively convenient corridor of technological transmission between western Eurasia and East Asia in the Late Pleistocene . The litBased on the cross-regional comparison of lithic techno-complexes over time, we have identified multiple episodes of technological transmission between the eastern Eurasian Steppe and northern China at the end of the Late Pleistocene . Through synthetic and comparative studies of the characteristics and distributions of lithic remains associated with different waves of technological transmission under different paleoclimatic circumstances, we further examine the nature, spread and possible routes of these transmissions and evaluate their impacts on local cultural adaptation.Various methods were employed to reconstruct the transmission of lithic techno-complexes and contextualize these within broader climatic and environmental trends. Firstly, we temporally contextualize archaeological sites in the eastern Eurasian Steppe and northern China based on chronometric data and temporally diagnostic lithic features , S1 FileTo understand the mechanisms underlying different waves of lithic technological transmission and identify why each episode of transmission differed, we reconstruct the respective paleoenvironmental context associated with each major transmission. We then examine technological organization to identify the conditions and human responses which prompted changes in lithic technological transmission. Paleoenvironmental reconstruction is based on climate proxies derived from loess, stalagmites, and pollen. Investigation of technological organization is based upon the selection and integration of strategies for making, using, transporting, and discarding lithic tools and materials . Our exaFor the purposes of this article, the eastern Eurasian Steppe refers specifically to the areas east of the Altai Mountains, including the Mongolian Plateau and regions across South Siberia, like the Altai Mountainous region, the Yenisei River valley, Cis-Baikal, and the Transbaikal regions. We define Northern China as the area encompassing the modern territory of China, the eastern part being north of the Qinling Mountain- Huai River line and the western part being north of the Tibetan Plateau . To faciOf these regions, Northwest and Northeast China are closer to the eastern Eurasian Steppe than North China. The climate in Northwest China is dry because it is situated largely outside of the monsoon climate zone . The cliOur main temporal focus is the end of the Late Pleistocene, ranging from about 50 to 11 cal. ka BP. This period is temporally divided into several periods and there is no unified scheme applied both in the eastern Eurasia Steppe and northern China. In northern China, the Upper Paleolithic is often divided into two phases by a time line between 30 and 20 cal. ka BP , 13, butThe waves of technological transmission between the eastern Eurasian Steppe and northern China which are our focus occurred during two different paleoclimatic stages: MIS 3  and MIS 2 . MIS 3 was an interglacial period in which conditions in the northern hemisphere were warmer and wetter than those during the preceding and following glacial maxima periods. The eastern Eurasian Steppe is part of the Mammoth Steppe biome, which is composed of steppe and patchily distributed woodlands . The cliIn contrast, MIS 2 comprises the Last Glacial Maximum and the beginning of the Post-Glacial period. The climate of the northern Hemisphere in this period was drier and colder than today. The tundra area in the eastern Eurasian Steppe was larger. The Mammoth Steppe biozone was more open and homogeneous with less patches of temperate forest and therefore less biodiversity . In nortThe eastern Eurasian Steppe was likely occupied comparatively later than neighboring parts of western Eurasia and northern China as it was a challenging adaptive environment. Situated in the mid-to-high latitudes of the continental northern hemisphere, the eastern Eurasian Steppe has a fluctuating climate with extreme seasonality. The short growing seasons, long and cold winter, and fewer edible plant resources poses serious challenges to survival. People could not permanently occupy this area until they had developed efficient means to cope with these challenges, these means took time to develop .The oldest known site in the eastern Eurasian Steppe is the Karama site located in the Altai Mountains, which dates to 800 kya . HoweverArchaeological evidence of human occupations is more abundant in the eastern Eurasian Steppe from the Middle Paleolithic period. The Middle Paleolithic sites in this area are mainly distributed in the Altai Mountains of South Siberia and the western and central parts of the Mongolian Plateau. In the subsequent Upper Paleolithic period, the number of sites increased and these became more widely distributed across the landscape. Regions which were devoid of any Middle Paleolithic occupation became infilled with Upper Paleolithic occupations, indicating population increase and further eastward expansion into the Eurasian Steppe , 42. MidThe increased intensity of occupation in the eastern Eurasian Steppe by the Upper Paleolithic is closely associated with technologies which people developed to adapt to the high-latitude environment. Tools associated with the Mousterian and Blade techno-complexes increased hunting efficiency by providing regularized formal end products . MoreoveThe Middle Paleolithic remains in the eastern Eurasian Steppe are characteristic of the Mousterian techno-complex found in Central and West Asia , 49. OnlIUP remains were stratigraphically situated above the TMP techno-complex at multi-component sites in Siberia and Mongolia. The earliest layer of IUP techno-complex materials from the Kara-Bom site in the Altai Mountains dates to ~43 ka BP . NonetheThe appearance of blade technology was once considered to be a cultural marker of modern human behavior . AlthougThe IUP techno-complex was a widespread cultural phenomenon distributed across several regions of East-Central Europe, West Asia, Central Asia, and the eastern Eurasian Steppe. Despite beginning later in the eastern Eurasian Steppe than Central and West Asia, the IUP techno-complex lasted longer in this region, with IUP remains dating to as late as ~30 cal. ka BP . The IUPThe typical Mousterian techno-complex was long considered absent from China due to a lack of convincing evidence . HoweverIn Northeast China, the Mousterian techno-complex was also identified at the Jinsitai and Sanlongdong caves. A typical Levallois core, a few Levallois flakes and points, and a considerable amount of the debitage associated with Levallois reduction sequences were recently found at the Jinsitai cave site . In assoThe newly excavated Sanlongdong cave site in the Chifeng region of Inner Mongolia represents the easternmost site in northern China in which Mousterian assemblages, including points and Quina scrapers have been found . DetaileExcept for the three cases mentioned above, none of the other Middle Paleolithic sites in China show clear Mousterian features. This general absence of Mousterian assemblages at this time suggests that the Mousterian techno-complex only diffused along a linear stretch on the periphery of northern China, which stretched more than 2000 km from the northwest to northeast . The disThe IUP techno-complex intruded even further southward than the TMP Mousterian techno-complex. The Shuidonggou site complex located on the margins of the semi-arid Ordos Basin in eastern Northwest China  a wide range of size variation in cores and end products ; (2) bladelets proportionally outnumber large blades (forming the predominant end products); (3) the use of both broad-faced and narrow-faced cores for producing blades but not Levallois cores .Chronometrical studies show that stratigraphic layers containing an admixture of microblade and blade assemblages in North China date to 27–25 cal ka BP . The proThe lithic assemblage of the Xishantou site in the western part of the Northeast China Plain shows similarities with the assemblages of the Xishi and Dongshi sites. Bladelet production and the incorporation of early-stage microblades as subordinate end products predominate in the Xishantou site lithic assemblage . In contAnother site with blade remains is the Shibanzhan site in the Greater Khingan Mountainous region. A tabular-shaped blade core with bidirectional flaking along the narrow face was found, accompanied with four blades. OSL dating indicates that this cultural layer dated to ~25 ka BP . No micrAround 27–23 cal. ka BP, microblade remains became more widely distributed in Northeast China and its eastern surroundings. This growing prevalence of microblade remains is indicated by the dating of the earliest microblade assemblage layers at sites like Dadong in the Changbai Mountainous Area of Northeast China, Ust-Ulma in the Russian Far East, Kashiwadai-1 and Pirika-1 in Hokkaido, Hopyeond-dong and Sinbuk on the Korean Peninsula, and Ogonki-5 on Sakhalin Island –118. UnlWe argue that the compilation of this evidence suggests that microblade technology in Northeast China emerged from the narrow-faced blade core production strategy of the MUP techno-complex. The initial microblade technology differs from blade technology mainly because smaller cores and perhaps pressure flaking methods were used. Later in time, innovative methods were applied to core pre-forming. As a result, overall core shape still resembled narrow-faced cores, but the whole reductional sequence from core pre-forming to consecutive microblade production differs remarkably from any of the blade production methods.According to the analysis and overview above, the earliest microblade remains often coexisted with blades and show strong technical affinity with them. Subsequently, microblade technology became further developed with a higher level of stylization of core pre-forming. The specific methods of microblade core-preforming in North China remain very similar to the core-preforming techniques employed for blade production. However, in Northeast China and its eastern surroundings more innovative types of core-preforming developed. These novel core-preforming techniques resulted in greater differences between blade and microblade traditions in Northeast China than in North China. Hence, microblade technology in northern China can be considered a localized innovation based upon blade technology. Different trajectories of localized innovation can be found across North China and Northeast China, leading to the formation of different types of microblade technology.As discussed above, the microblade technology was likely based upon the introduced MUP techno-complex. Two additional lines of evidence support this inference and exclude the possibility that microblade technology emerged out of the earlier IUP techno-complex. Firstly, the IUP techno-complex only appeared ephemerally in a spatially restricted fashion in specific regions of northern China and the IUP techno-complex materials in some of these contexts was superseded by the core-flake techno-complex before 30 cal ka BP, leaving a temporal gap between the IUP and the microblade/blade techno-complexes . SecondlMicroblade technology is characterized as being prevalent across northern China and Mongolia-Siberia during the LUP period  121]. T. T121]. in situ from the IUP and MUP techno-complex [The development of two divergent reductional trajectories of microblade production are apparent in North and Northeast China at 28–23 cal. ka BP (as discussed above). Yet during the time period between ~23–11 cal ka BP, a microblade techno-complex with a predominant reliance on narrow wedge-like cores for production expanded into vast areas of Siberia and Mongolia . The tim-complex , 127. Ot-complex , 128–130-complex . The sit-complex .Due to the rarity of sites with clear stratigraphy, it is difficult to ascertain when the oldest microblade technology appeared in Mongolia. Nonetheless, unequivocal microblade remains coming from the definite cultural layers was found in the horizon 3 and 4 of the Tolbar-15 site, which is dated to around 18–17 cal. ka BP. Like those in Siberia, these microblades were fashioned from narrow wedge-like cores .Outside of Mongolia and Siberia, the expansion of microblade technology centered on the use of narrow wedge-like cores (the Yubetsu technique) is also identified in the Nihewan Basin of northern North China . A numbeMultiple episodes of technological transmission can be identified from the distributional patterns of lithic techno-complexes, indicating consecutive cultural communication between the eastern Eurasian Steppe and northern China from the TMP to the end of the Upper Paleolithic. Each episode shows distinct patterns of technological transmission as summarized in The TMP and IUP lithic techno-complexes, which are characterized by the prevalence of Mousterian or blade and Mousterian mixed techno-complex assemblages, only spread into the north and west peripheries of northern China and did not penetrate into North China. The indigenous core-flake techno-complex still thrived in most parts of northern China. There was no pronounced geographical distance between the distributional area of the core-flake techno-complex and the TMP and IUP techno-complexes . MoreoveThe TMP and IUP lithic techno-complexes involve the use of large and fine-grained raw materials, complicated core pre-forming procedures, sequential flaking of regular pieces of end products and intensive retouch of tools. They not only demand higher lithic reduction skills but also require a more restricted array of raw materials , 137. ThTherefore, it is reasonable to assume that unless Mousterian and blade technology provided urgently needed benefits which could not be offered by the core-flake technology, they would not be widely adopted in northern China. Compared to core-flake technology which involves mostly expedient tools, one benefit of Mousterian and blade technology was the creation of formalized end products with pre-planned forms , 139. ThWhile more detailed paleoenvironmental reconstruction is needed, the current paleoenvironmental research implies that broad regions of northern China, especially its southern part, did not conform to the environmental conditions mentioned above during the relatively warmer and wetter MIS 3 period , 33, 144In contrast to the episode of transmission associated with the TMP/IUP techno-complex during the relatively warm and humid MIS 3 period, the MUP blade technology diffused into northern China just before the LGM when the climate was colder and drier . This epMicroblade technology was more suitable for the local environment in northern China because it lowered the cost of raw material acquisition and better allowed people to cope with the climatic changes associated with the LGM period. Although Microblade technology also involved sophisticated flaking procedures and high demands for quality raw materials, the use of small cores to produce extremely small end products enabled people to use just tiny nodules or flakes of quality raw materials. Therefore, although quality raw materials were only scarcely distributed in most parts of northern China, they could be fully exploited in the most economical way.Moreover, from the perspective of technological organization, microblade technology provided adaptational benefits for dealing with environmental changes during the LGM period. Firstly, microblades were often used as insets slotted into different organic handles or shafts to form composite tools for different purposes  . The staThe shift to a drier and colder environment right before and during the LGM period caused the southward movement of ecological zones. The retreat of forests and the expansion of desert-steppe, steppe, and meadow-steppe across northern China, made large portions of the region more ecologically similar to the Eurasian Steppe . This siFurthermore, the performance of microblade technology in coping with resource stress might explain why it then diffused into Siberia and Mongolia after the peak of the LGM. The scarcity of sites and chronological records between 25–23 cal. ka BP implies that the higher latitude eastern Eurasian Steppe was probably an extremely harsh place to live during the peak of the LGM . While wWhether the episodes of cultural transmission between the eastern Eurasian Steppe and northern China indicate direct population dispersal or cross-regional technological communication between different social groups remains unresolved. Equifinality exists because both of these behaviors would generate the cross-regional cultural similarities which we document in lithic assemblages. If we assume that population dispersal would lead to close similarities in lithic technologies between an original area and a new area, whereas technological communication between different groups would result in either intentional adjustments or unintentional changes to the original techno-complexes in the transmitted area, then the episodes of lithic transmission of the TMP, IUP, and LUP techno-complexes between the eastern Eurasian Steppe and northern China could be seen as resulting from population dispersal. In contrast, the development of microblade technology, based on the modification of MUP blade technology, could be characterized as the adoption of ideas. Local people adopted blade technology from the north and made their own modifications to increase suitability for local conditions. Admittedly, these are just tentative inferences rather than solid conclusions. Other lines of evidence, especially ancient DNA studies are needed to clarify whether similarities in technology might reflect dispersal of people, the uptake of ideas, or the combination of the two.The site distributional pattern suggests that while the TMP/IUP techno-complex diffused into northern China from the west or northwest, the MUP blade technology probably diffused into North China from the north, along the corridors at the eastern edge of the Gobi-Steppe. The reason why technological transmission happened along different routes was probably also related to paleoenvironmental changes. While no obvious geographical barriers existed between the Eurasian Steppe and higher-latitude Northeast China, the desolate Gobi Desert situated between the core area of the Eurasian Steppe and North/Northwest China posed geographical obstacles for mutual cultural transmission. Only specific corridors comprising chains of oases could be passed through, which potentially served as important routes of technological communication. Therefore, the ameliorated MIS 3 period climatic conditions in arid Inner Asia facilitated southeastward cultural transmission from the west part of the eastern Eurasian Steppe into northern China.Compared to the warmer and wetter MIS 3 period, the climatic change to colder and drier conditions during MIS 2 led to the expansion of dry desert areas situated between the eastern Eurasian Steppe and northern China , 150. ThEpisodes of cultural transmission can be identified between northern China and the eastern Eurasian Steppe after the Middle Paleolithic human migration into the latter region. Since the eastern Eurasian Steppe is culturally connected with western Eurasia in terms of lithic technology, the appearance of typical western lithic techno-complexes in northern China resulted from trans-regional technological transmission through the eastern Eurasian Steppe. From TMP and the beginning of the Upper Paleolithic, the Mousterian and blade technologies probably spread through the central Mongolian Steppe corridor into Northeast China, and through the foothills and along the oases corridor (across the Gobi Desert) into eastern Northwest China. The relatively wet and warm MIS 3 period ameliorated the environmental conditions in the dry Gobi Desert and facilitated cultural transmission from west to east. Nonetheless, both TMP Mousterian and IUP blade/Mousterian mixed techno-complexes were only confined to the northern periphery of northern China and did not penetrate into and replace the core-flake techno-complex in the hinterland of northern China. The higher costs of these sophisticated techno-complexes and the fact these technologies did not pose any real advantage over the simpler core-flake technology, given the environmental context, might explain why the transmitted Mousterian and blade technology did not thrive in northern China at this time.Climatic changes to drier and colder conditions after MIS3 made the arid Gobi Desert increasingly impassable. In the MUP period, technological transmission probably occurred along the east margin of the Gobi Desert, connecting the eastern part of northern China and the eastern Eurasian Steppe. The spread of MUP blade technology between 28–25 ka BP impacted lithic technological development in a much broader region of northern China than the earlier TMP/IUP technology. Yet the broad spread of this technology was mainly achieved due to the development of microblade technology from the modification of previously introduced MUP blade technology, rather than the direct wholesale adoption of the MUP techno-complex in its original form. The microblade technology was well suited to the drier and colder environments of the LGM since it facilitated more efficient and intensive resource exploitation in high mobility contexts. As a result, it became further developed and gradually replaced the core-flake technology which once thrived across northern China.The advantages of microblade technology for adapting to challenging environments might explain its widespread distribution across Northeast China and its eastern surroundings  and vast regions of Mongolia and Siberia right after the peak of the LGM. This scenario suggests that people in northern China did not only receive lithic technologies from the eastern Eurasian steppe, but ultimately modified these technologies in ways which saw them subsequently spread back into the eastern Eurasian Steppe.The various transmitted techno-complexes impacted different regions of northern China in different ways. In the north and west periphery of northern China, each episode of technological transmission can be detected, and the introduced techno-complex often, but not always remained in its original form, as it was close to the source area of diffusion. In contrast, less episodes of technological transmission left traces in the southern and central hinterland of northern China. In these regions, introduced technology was often modified from its original forms. Such a pattern suggests that distance from the eastern Eurasian Steppe and differences in ecological and geological conditions played important roles in shaping the distribution and adoption of waves of technological transmission between the eastern Eurasian Steppe and northern China.Whether or not technological transmission between these two broad geographical units resulted from direct population dispersal or the exchange of ideas is open to discussion. We argue that both mechanisms, or some combination of them, could lead to the types of technological transmission evident in the archaeological record. Multidisciplinary research is needed to examine population migration, cultural interaction, technological evolution and how these processes related to patterns of cross-regional technological transmission between the eastern Eurasian Steppe and northern China.S1 TableThe radiocarbon dates are calibrated by using OxCal 4.4 and the IntCal20 calibration curve. The references of the dating for each site are listed in (XLSX)Click here for additional data file.S1 FileThe dating information and the identification of the types of lithic technology for each site discussed in the paper are based upon the references listed in this file.(DOCX)Click here for additional data file.


Despite extensive efforts over the past 40 years, there is still a significant gap in knowledge of the characteristics of elastic fibers in the intervertebral disc (IVD). More studies are required to clarify the potential contribution of elastic fibers to the IVD  function and recommend critical areas for future investigations. On the other hand, current IVD in-vitro models are not true reflections of the complex biological IVD tissue and the role of elastic fibers has often been ignored in developing relevant tissue-engineered scaffolds and realistic computational models. This has affected the progress of IVD studies  and translation into clinical practice. Motivated by the current gap, the current review paper presents a comprehensive study (from the early 1980s to 2022) that explores the current understanding of structural , biological , and biomechanical properties of the IVD elastic fibers, and provides new insights into future investigations in this domain. The intervertebral disc (IVD) is a three-component connective tissue that consists of a central gel-like nucleus pulposus (NP) which is surrounded by concentric annulus fibrosus (AF) layers, peripherally, and two cartilaginous endplates that interface with the vertebral bodies a 1]. Th. Th1]. TIVD degeneration is characterized by progressive mechanical and biological mechanisms, leading to irreversible structural failure that impairs IVD function. There is a subtle relationship between the biological and mechanical pathways during progression to IVD degeneration, and their interconnection amplifies the process . The IVDThe current review was prepared by performing a comprehensive search (from the early 1980s to 2022) using PubMed and Web of Science online databases, including papers that were published in peer-reviewed journals. The keywords searched were “intervertebral disc” and/or “elastic fibers”. In addition, the bibliographies of selected papers were employed to find other relevant publications that were not found in the keyword search.From a structural point of view, revealed by microscopy studies, elastic fibers in soft tissues are composite structures comprising core elastin proteins surrounded by microfibrils a 20]. T. T20]. TWhile the structural organization and mechanical role of elastic fibers in different soft tissues, including lungs, tendons, vessels, and skin, have been widely studied, our understanding of their characteristics in the IVD is still limited ,29,30,31Efforts to identify elastic fibers as a structural component of the IVD date back to 1952. However, the main challenge faced was identifying their presence using light microscopy, which remained unsuccessful . BuckwalThese results suggest that the arrangement and distribution of elastic fibers may change between different species and depend on the IVD level. In addition, the results from these studies confirmed the presence of elastic fibers throughout the IVD  and concurrently shattered randomly amongst the collagen fibers. The concept of sparse elastic fibers in the IVD had come to an end in 2002 when Yu et al. reported an abundant and organized distribution of elastic fibers in different regions of bovine IVDs .Within the NP, radially orientated elastic fibers appeared straight with more than 200 µm in length a. In addWithin the AF region, a lower density of elastic fibers was observed in the lamella compared to the ILM and PB spaces c–e. The A comprehensive review study by Tavakoli et al. (2016) explained the multi-scale hierarchical structure of the elastic fibers in the ILM and identified several unknown characteristics, including the ultrastructural organization of elastic fibers in the ILM, their mechanical properties, and their contribution to the AF structural integrity and delamination . In 2017Recent IVD microstructural studies using scanning electron and light microscopes have shown that elastic fibers are well organized across different regions of the IVD and generate a continuous and integrated elastic network. This network seems to play a critical role in the structural integrity and mechanical properties of the IVD as previously predicted, and therefore, its clinical role has to be identified in detail.In 1985, Johnson et al. utilized light microscopic and histological techniques to quantify the relative number of elastic fibers (percentage) in the AF of human IVDs a and estStudies have shown that elastin content correlates with disc degeneration and other diseases. Cloyed and Elliott (2007) found a significant increase in IVD elastin content (dry weight term) for degenerated (grades > 2.5) compared to healthy IVDs. The largest amount of elastin was found in the inner AF (9.3%) compared to the outer AF and the NP b 54]. S. S54]. SThe biological development of elastic fibers in the IVD is not very well known; however, general studies have shown that the early development of elastic fibers involves tropoelastin deposition on a fibrillin-rich microfibril scaffold . SimilarMelrose et al. (2011) reported colocalization and interaction between elastin and perlecan during elastic network assembly, indicating the important role of elastin in the development of AF in human fetal and newborn ovine IVDs . ElasticStudies have shown that fibulin-5 protein regulates elastic fiber organization and plays a role in binding cells to elastic fibers through colocalization with elastic microfibrils and interaction with integrin cell receptors ,71. UsinThe relationship between the structure of IVD elastic fibers and cell morphology is not very well understood. Few studies have identified different cell morphologies in the ILM compared to the lamellae. Cord-like, spherical, and flattened cells were observed in the ILM region of the AF, moving from the outer towards the inner AF, respectively, with the ILM’s cells creating a connective network in the outer AF. The ILM’s cells rarely form a network in the inner AF ,78,79. TEarly IVD structural studies at the micro-level have identified low density with a random distribution of elastic fibers and therefore thought that the role of elastic fibers was not substantial in the overall IVD mechanical properties. However, biochemical research has revealed a higher concentration of polar amino acids in elastin extracted from IVD than in ligamentum nuchal, suggesting a strong crosslink between elastic fibers and extracellular components; hence, their contribution to the IVD mechanical function. In addition, recent studies have found a highly organized elastic network across the IVD with different regional distributions. The presence and colocalization of Versican with the elastic network in the ILM, reported by Melrose et al. (2001), suggested an anchoring role of elastic fibers connecting adjacent AF lamellae . MoreoveThe first approach has been the evaluation of structural connectivity between IVD components at the fibrillar level in the presence of ECM  5,47]. ,47. 5,47Furthermore, Tavakoli et al. (2018) performed a multiscale biomechanical and structural study to understand the role of the ILM elastic fibers during progression to herniation and suggested that the ILM biomechanical properties (such as modulus and maximum stress) were significantly reduced compared to the lamella during progression to herniation. Their study confirmed that the ILM, compared to the AF lamella, was the weaker AF component during the progression of herniation in the posterolateral region of the IVD. This study proposed a stress threshold above which the ILM fails mechanically . While tEnzymatic treatment to eliminate elastic fibers has been the second most frequently used strategy for measuring the IVD mechanical properties in the absence of elastic fibers . This stDigestion of all IVD components except for elastic fibers has been the third strategy that provided an opportunity for direct measurement of the mechanical properties of elastic fibers in the IVD . One stuThis strategy was successfully applied to the ILM and has a great potential to directly measure the mechanical properties of the elastic fibers in different regions of the IVD. It is expected that the third strategy will be used for future investigations to understand the relationship between IVD disease  and the mechanical properties of elastic fibers. Understanding the structure–function relationship of the IVD components, at different scales from micro (collagen and elastic fibers) to macro , plays an important role in developing new tissue engineering strategies ,104,105.Regeneration of IVD requires deep knowledge about mechanisms of IVD degeneration and is a challenge at the intersection of IVD biology, biomaterials, and biomechanics which would benefit from having a reproducible and adaptable 3D scaffold able to recapitulate the relevant complexity of the IVD ,123,124.The fabrication of integrated biphasic AF-NP scaffolds has been the second strategy to develop full IVD scaffolds. Researchers have often employed three approaches, including 1—chemical routes to integrate the AF and NP during fabrication, 2—acellular matrix-derived biomaterials, or 3—naturally aligned plant-based platforms, to create a fully integrated IVD scaffold ,139,140.The third strategy has been the cellularization of acellular animal IVDs ,147,148.The application of additive manufacturing in the fabrication of full IVD scaffolds will provide opportunities for creating more realistic IVD scaffolds with defined regions and gradient areas between AF and NP, replicating the composition and structural organization of the native IVD ,153. It Finite element models have significantly contributed to our understanding of IVD functional biomechanics. They have played an essential role in minimizing the use of animal and human IVD models in experimental biomechanics and pre-clinical studies. Various assumptions and degrees of complexity have been employed to model IVD or its components (mainly the AF and NP), where IVD was considered a homogeneous, heterogeneous, or fiber-reinforced composite entity ,159,160.Furthermore, the refined representation of fibers, including the contribution of fiber-matrix interaction (structure-based finite element modeling) in computational models, demonstrated superior results to homogenized models . These mFew computational studies have considered the mechanical role of the ILM using homogenized IVD models that include the ILM region in the studies. In 2011, Nerurkar et al. considered a hyperelastic model for interlamellar interactions in angle-ply biologic laminates based on a tissue-engineered construct to understand how the ply angle changed with uniaxial extension. They found a reinforcing role of interlamellar shearing and characterized the contributions of extrafibrillar matrix, fibers, and interlamellar interactions . Labus eTo the best of the authors’ knowledge, a full IVD computational model to represent the contribution of the elastic network to the mechanical properties and structural integrity of the IVD is still lacking. Since our understanding of how elastic fibers are organized in the different regions of the IVD has been enhanced and several studies have identified the mechanical properties of the IVD elastic fibers, the development of more physiologically relevant computational IVD models is expected.The purpose of this literature review was to address the current knowledge about the role of elastic fibers in the intervertebral disc. During the early studies, the function and the structural organization of elastic fibers in soft tissues such as lungs, blood vessels, and skin were examined in detail, whereas their characteristics in the IVD did not get enough attention. However, recent studies demonstrate that elastic fibers play a crucial role in the mechanical function of IVD. These new studies have given us a new understanding of the multi-scale hierarchical structure of the elastic fibers and their mechanical role in the structural integrity of the IVD. Recently, there have been a few attempts to develop IVD scaffold designs using different fabrication techniques. Unfortunately, these IVD models often lacked the ability to display gradient composition and the structural organization of elastic fibers. Future IVD models should represent the role and structural organization of elastic fibers to represent more physiologically relevant models.On the other hand, the mechanical contribution of elastic fibers has been ignored inevitably in most computational models, as the role of elastic fibers in the IVD was not well understood. As our understanding of the characteristics of elastic fibers has enhanced over time, better multi-scale computational models can be introduced. From a clinical point of view, future studies should aim at identifying the role of elastic fibers in the pathophysiology of lower back pain.


Professional self-concept is one of the important outcomes of nursing professionalism. There is a lack of adequately planned curriculum may limit nursing students’ practical knowledge, skills and professional self-concept in providing comprehensive geriatric-adult care and promoting nursing professionalism. Professional portfolio learning strategy has allowed nursing students to continue professional development and enhance nursing professionalism in professional clinical practice. However, there is little empirical evidence in nursing education to support the use of professional portfolios in blended learning modality among internship nursing students. Therefore, this study aims to examine the effect of the blended professional portfolio learning on professional self-concept among undergraduate nursing students during Geriatric-Adult internship.A quasi-experimental study two-group pre-test post-test design. A total of 153 eligible senior undergraduate students completed the study (76 in the intervention group and 77 in the control group). They were recruited from two Bachelor of Sciences in Nursing (BSN) cohorts from nursing schools at Mashhad University of Medical Sciences (MUMS), in Iran, in January 2020. Randomization was undertaken at the level of school via a simple lottery method. The intervention group received the professional portfolio learning program as a holistic blended learning modality, though the control group received conventional learning during professional clinical practice. A demographic questionnaire and the Nurse Professional Self-concept questionnaire were used for data collection.The findings imply the effectiveness of the blended PPL program. Results of Generalized Estimating Equation (GEE) analysis was indicated significantly improved professional self-concept development and its dimensions  with high effect size. The results of the between-group comparison for professional self-concept and its dimensions at different time points  showed a significant difference between groups at post-test and follow up test (p < 0.05),while at pre-test there was no important dissimilarity between two groups (p > 0.05).The results of within-group comparison for both control and intervention showed that there were significant differences in professional self-concept and for all its dimensions across the time from pre-test to post-test and follow-up (p < 0.05), and also from post-test to follow-up it was significant (p < 0.05) for both groups.This professional portfolio learning program demonstrates as an innovative and holistic blended teaching-learning approach to improve professional self-concept during professional clinical practice among undergraduate nursing students. It appears that the use of a blended designed of professional portfolio can promote a link between theory and the advancement of geriatric adult nursing internship practice. The data obtained from the present study can be useful for nursing education to evaluate and redesign a curriculum for development of nursing professionalism as a quality improvement process and groundwork to develop new models of teaching-learning and assessment. Nursing professionalism envelops a set of values that are basic to raising the quality of patient care whereas making strides the educational learning strategies, benchmarks, and judgments that direct nursing practice each day . The desOver the past two decades, the studying clinical environment in nursing practice education has received a bigger interest , 14, 15.Given the lack of empirical evidence in the PPL in Geriatric-Adult internship program with blended teaching-learning strategy and concerning the urgent attention to improving PSC among Iranian nursing students, to the best of our knowledge, this has not been studied in the nursing education of Iran. Therefore, development of blended PPL can engage professional development activities such case studies, reflective practice, group discussions, and simulation debates seminar during the blended program sessions in professional clinical practice and so can lead to promoting nursing professionalism in nursing students and improving quality of care in geriatric/adult patients. The evidence on the effectiveness of existing portfolio approaches also remains limited, which in turn restricts the ability of nursing educators to incorporate such approaches into the curriculum. Therefore, this study aims to examine the effect of the blended professional portfolio learning on professional self-concept among undergraduate nursing students during Geriatric-Adult internship.This quasi-experimental study was conducted in 2020 using a two-group, pre-test post-test design.The senior undergraduate nursing students were recruited from two Bachelor of Sciences in Nursing (BSN) cohorts from Mashhad School of Nursing & Midwifery at Mashhad University of Medical Sciences (MUMS), in Iran, in January 2020, in the North-East Province of Iran, who finished the academic program and take their first professional clinical practice in Clinical Geriatric-Adult Nursing (CGAN) Course. Probability-sampling methods of cluster random sampling were used to recruit participants. Cluster random sampling involves selecting groups rather than selecting individuals. Randomization via a simple Lottery method was undertaken at the level of school rather than with individual students to avoid contamination from the intervention group to the control group. Therefore, two schools randomly allocated to intervention or control groups. The calculation of sample size was based on the effect sizes of similar studies by  & 8] th th8] theThe Inclusion criteria were signing up for this course and having no previous experience of PPL. Had a smartphone with internet access in their residence and be able to use it effectively (intervention group) and should attend professional internship clinical practice for sixteen weeks during the program and fulfill all of the activities. The exclusion criteria failed to accomplish the requirement of the PPL program, and students were excepted if they partially responded to study questionnaires or had more than one absence from the course sessions. The eligible senior nursing students in intervention and control groups had 16 weeks of professional clinical practice during the intervention period. All students provided written informed consent to participate. All methods were carried out in accordance with relevant guidelines and regulations or declaration of Helsinki.Firstly, the qualified nursing students were recognized from the authoritative record and they were inquired to take an interest in this to consider through the welcome letter Fig. . At thatThe professional portfolio learning (PPL) program in the blended learning modality was a holistic structured intervention and consists of four professional development modules; portfolio learning, case study, reflective witting, and simulation seminar. Therefore, this holistic program involved a systematic combination of face-to-face and online teaching-learning approach mediated interactions between students, facilitators, researcher, and learning resources. In this light, blended learning offers the chance to perform asynchronously, allowing novel kinds of communication and teamwork. Also, the instructor has the chance to track and accompany the student learning process during the way and in the ending, to assess it based on various basics as the contribution, reflections, learning products, and feedback .The intervention program was implemented in three phases according to some theories and models as its theoretical framework. Face-to-face activities guided through principles of Bandura’s Social Learning Theory (SLT). The learning process takes put through observation, imitation, and modeling that’s arranged by four standards process to be attention, retention, motor reproduction, and inspiration process . MoreoveAlso during the clinical practice, the case study activity was implemented based on Continuing Professional Development (CPD) Model, and reflective writing activity was performed based on Holistic Reflection Model (HRM) by Bass et al. (2017) and to support reflective practice  and learAt the beginning of the intervention in the orientation session, the overall and the daily syllabuses of the Geriatric-Adult Nursing Course were delivered to students in both groups, then researcher in the intervention group created the online Telegram groups of each eight students in a group named Portfolio Learning Group (PLG). Ten clinical facilitators who directed and guided the students’ clinical practice were welcomed to go to a one-day workshop preparing session. The preparing was expecting to clarify the PPL and disseminate rules on how to convey it in clinical practice to assure their tasks and parts during the PPL program.The professional portfolio learning (PPL) program has consisted of two-part preclinical and clinical. Part one  was teaching; the four-day workshop was run for nursing students teaching modules activities of PPL at week 1 before entering the clinical practice. This four-day workshop consists of four blended modules; portfolio learning, case study, reflective writing, and simulation seminar oriented them to PPL concepts including definition, benefits, and techniques of portfolio learning. Also, reviewing the definition and importance of PSC promotion and strategies provided. They were also needed to simulate and practice the modules that would be completed during their sixteen weeks of professional clinical practice. The workshops were held twice a day for a duration of four-day from 1 to 4 February 2020. The briefing notes and teaching contents remained available in the online groups for students’ reference.Part two  was implementation the intervention; Implementing modules activity during the professional clinical practice for Geriatric-Adult Nursing Course from week 2-week 16 and nursing students practice activities and developed their PP under face to face supervision and guidance from the facilitators. Besides, they received online teaching, activity assessment, and written feedback from the researcher. Clinical facilitators were assigned to oversee the PPL for a PLG during the course, in addition to fulfilling their usual student advising responsibilities. Case studies had chances to lead the student from a holistic perspective of the patients’ needs of nursing, they could see clear benefits and were satisfied with the case study analyzing . CreatinBased on the clinical program schedule, students were responsible for the care of their assigned both geriatric and adult patients and implemented a case study in their group based on the principles of the CPD model that comprised of six processes consists of; briefing, identifying learning needs, reflection, developing a plan and carry out, record and review, analyses, and evaluation to develop the professional portfolio in practice. Each student in PLG is expected to do at least two care plan activities for two patients (one geriatric and one adult) per week. Also, nursing students in PLG performed two reflective writing based on steps of the Holistic Reflective Model (HRM) . In weekThus, five sessions of PPL  were performed by the students during week2-week6. The students also implemented four individual sessions of PLP during weeks 7–10 of clinical practice. On the last day of each week, professional activities of PPL were posted to the discussion online group were reviewed by the researcher after the students finished each section, and relevant feedback and responses were posted for the group to see. Week 11 researcher asked students to improve their PP constantly and they reviewed their activities regularly with a serious consideration of the researcher feedback and gained submitted their revised PP to the researcher (summative assessment). In week 12 students worked on the posttest assessment section.From week 13–15 as a follow-up part, students independently continue to utilize case studies and reflective practice writing as well as other features to compile their PP. Students to aim improve PSC were needed to reveal and share their interactions with patients and family, to estimate (and perhaps revise) their nursing care plan, and to assess learning results in professional practice. The researcher invited the PLG to share their complete PP with the online group for a comprehensive assessment. Then, students completed all professional development activities of the PPL program, revised, and compiled the PP items. Finally, students developed their professional portfolios. Figure Students in the control group undertook the clinical practice using the conventional learning system and were responsible to complete and submit their logbooks. The control group participants were given online access to the content of the PPL program upon completion of the study.The data were analyzed utilizing the SPSS software program Form 25.0. Descriptive statistics, Chi-Square test, and Independent T-test were conducted to compare both groups for “participants’ characteristics” and study outcomes at baseline. The Generalized Estimating Equations (GEE) was utilized to assess the impact of the PPL program over time, between the interventional and control groups, and within the interaction between the time and group. Due to the significant differences in the PSC and its dimensions at pre-test and age for intervention and control groups, this variable was considered as a covariate in the analysis, therefore a GEE analysis was applied to assess whether there were groups and times differences in respondent’s PSC and its dimensions.The number of qualified students was 153 and none of them were excluded from the study. There were no any drop out across the study. Therefore the response rate was 100%. The results of the Chi-Square test and Independent t-test  had significantly increased in the intervention group. Results of Generalized Estimating Equation (GEE) showed that there was a significant interaction between time and group on total PSC, self-esteem ,caring ,staff relation, communication, knowledge and leadership indicating that the score of PSC and its dimensions were significant across the time  between two groups, therefore post hoc test using Bonferroni test was employed to compare the mean scores between and within groups. The results of the between-group comparison Table  for PSC Further, the results of within-group comparison for both control and intervention Table  showed tThis study was the first to be demonstrated the blended PPL program among undergraduate nursing students in Iran. This study aimed to examine the effect of the PPL program on PSC among undergraduate nursing students during Geriatric-Adult internship clinical practice. The outcomes showed significantly improved PSC development with high effect size and findings imply the effectiveness of the blended PPL program.The PPL is one method for enhancing nursing professionalism . The resGaps between theory and clinical practice mean challenges for nursing students through their learning strategies. Professional portfolio learning (PPL) may assist nursing students to improve in knowledge, skills, attitudes, self-learning, study satisfaction, critical thinking, problem-solving skills, and professional competency –26. The However, the leadership dimension was least improved compared with the rest of the PSC dimension, but it was a significant difference. This result was consistent with results of recent studies indicated students who participated in purposeful workshops and clinical activities such as the reflective practice and simulation scenarios  improvedIn contrast, results presented no important growth in the mean scores of total PSC and its dimensions in the control group. The conventional learning strategy was seemed not to simulate the Iranian undergraduate nursing students to expand their PSC during their professional practice and thereby learners make a little attempt for fulfilling their educational needs. The discrepancy could be due to the dissimilar ways of bringing the learning program. There are many criticisms of conventional learning. Through conventional learning, instructors give students an enormous sum of information in a brief sum of time without the capability to proficiently interface with them, hence, they ordinarily confront challenges .particularly in caring of geriatric patients with different health issues, in making a strong clinical environment for the development of PSC. However, the control had experienced a slight increase in the total mean score of PSC. The possible explanation may be changes in the work environment situation, communication between the students, peers, staff at work, or the inspiration and activity of the control group through using a logbook. Both learning strategies offered and allowed the students to practice PSC as they were exposed to the related conditions in the clinical setting. Nonetheless, the effect of each education strategy was different. Therefore, incorporating a blended teaching-learning approach in this study was a very effective approach and so the outcomes attained were in line with those found in the researches of some studies by , 22. ButOne of the strengths of the study was using the PPL as one approach for enhancing nursing professionalism  and moniThe current study was limited to fourth-year nursing students only. Since the self-report questionnaires do not describe the real situation of participants so may present bias to study outcomes, they might rate higher or lower than the real condition. However, using the self-reported questionnaire in the current study provides a basis for professional self-concept among the Iranian undergraduate nursing students and there is no information about them previously. Another limitation of the study is the participants in the groups are fully aware of their participation in the current study and this may have introduced bias to results, but the researcher reminded them to maintain behavior naturally. Last, the current study was a quasi-experimental study with quantitative research methods, further research with qualitative or mixed research methods can be carried out to examine the effects of PPL with blended learning in more depth. Besides research employing a qualitative study can be utilized to investigate in detail the most excellent conveyance strategy for the PPL program, and the components that influence the nursing students’ learning process with the intervention.This professional portfolio learning program demonstrates as an innovative and holistic blended teaching-learning approach to improve professional self-concept and its dimensions during professional clinical practice among undergraduate nursing students. The blended teaching-learning approach of delivering the PPL (face to face and online) during the workshops and clinical practice is a practical, cost-effective, and less time-consuming way to train professional development activities of PPL to nursing students with busy schedules during internship professional clinical practice. It appears that the use of a blended designed of professional portfolio can promote a link between theory and the advancement of geriatric adult nursing internship practice. The data obtained from the present study can be useful for nursing education to evaluate and redesign a curriculum for development of nursing professionalism as a quality improvement process and groundwork to develop new models of teaching-learning and assessment.


A congenital cystic eyeball is an extremely rare condition, with only 52 cases reported in the literature to date. An orbital cyst replaces the eyeball which occurs due to the complete or partial failure in invagination of the primary optic vesicle during the fourth week of gestation. We discuss a case of a congenital cystic eyeball in a 14-year-old female who presented to us for a cosmetic blemish due to a large swelling in the right eyelid with the absence of a right eyeball since birth. She underwent removal of the cyst followed by an orbital implant and later prosthesis. Diagnosis of the congenital cystic eyeball was made based on the clinical and ultrasound B-scan features, intraoperative findings, and histopathology report. This article adds one more case to the existing literature on the congenital cystic eyeball. Orbital implant with prosthesis after excision of the cyst provided definitive diagnosis and a good cosmetic outcome in our case. The congenital cystic eyeball (CCE) was first reported by Taylor and Collins in 1906 . Mann alA 14-year female presented with a complaint of cosmetic disfigurement caused by a large swelling in the right eye (RE) since birth which was gradually increasing with her age. The patient was aware of no vision from that eye. There was no history of perinatal complications or consanguineous marriage. On examination, the vision in RE was no perception of light (NPL) whereas the vision in the left eye (LE) was 1/60 on the Snellen distant visual acuity chart. RE examination revealed a large cystic swelling predominantly in the lower eyelid but no visible eyeball in the palpebral aperture . The sweA congenital cystic eyeball occurs because of a developmental anomaly occurring during the third week of embryogenesis. An arrest in the invagination of the primary optic vesicles during the 2 mm-7 mm stage is attributed to this rare congenital anomaly . Though Cases are usually unilateral, although few bilateral cases have been described in the literature. A case of bilateral congenital cystic eyeball was reported by Sacks and Linderberg. In two cases reported by Hayashi et al., one had bilateral involvement although the nature of the lesion was not established . The patDiagnostic workup for a case of CCE starts from the examination of the eyes and orbits and extends to the whole body to rule out systemic associations which may be life-threatening. In infants, the cyst can be examined properly using eyelid retractors, such as Desmarre's, to look for the presence of a microphthalmic eye which is the most important differential diagnosis. Where congenital cystic eyeballs have the complete absence of a globe, microphthalmos with cyst usually has a small eyeball and the cyst is attached to the sclera or choroid , 16. IncThe fellow eye in our case had microcornea with an inferior corneal scar and, iris, and fundal coloboma. As anophthalmos and microphthalmos (with or without cyst) and uveal coloboma—all are congenital abnormalities occurring due to the failure of invagination of optic vesicle at various stages of development of ocular structures, these are often found in association. Tucker et al. found abnormal second eye in 21% cases of unilateral anophthalmos without a cyst . AlthougRadiological investigations such as B-scan ultrasonography (USG), computed tomography (CT) scan, or magnetic resonance imaging (MRI) form the logical next step in the diagnosis of CCE. B-scan USG is usually readily available at the ophthalmology outpatient department and gives valuable information about the cyst, absence or presence of an eyeball, and an associated optic nerve-like stump. Cysts may be replaced partially or even completely by neuroglial tissues . BaghdasThe mainstay of management of the congenital cystic eyeball is excision of the cyst followed by an orbital implant. Morselli et al. reported a case of the congenital cystic eyeball where they followed up the case serially from 20 weeks of gestation till birth . The casAn irregularly shaped cyst with a connective tissue layer externally and an inner neuroglial tissue layer is the common histopathological picture in CCE. There is no presence of epithelial linings of cysts in the CCE and microphthalmos with cyst, and thus, they are similar in histopathology . HoweverAlthough CCE usually does not have associated nonocular abnormalities, some bilateral congenital cystic eyes , 29 and Clinical assessment and radiological investigations aid in the confirmation of the diagnosis of CCE. However, a definitive diagnosis can only be made through histopathology. Removal of the cyst followed by an orbital implant, conformer, and later on ocular prosthesis seems to be the appropriate management approach for CCE.


Our case highlights leukocytoclastic vasculitis as a potential side effect of the elasomeran COVID-19 vaccine. As the elasomeran vaccine becomes more widely available to the public, cutaneous reactions should be noted and looked for as potential side effects of the vaccine. Our patient had a history of immune thrombocytopenic purpura, making this a potential predisposing condition to the development of vasculitis following elasomeran administration. The case of vasculitis in our patient, although diffuse in distribution, was self-resolving. Our patient was counseled of the potential risk of worsening reaction to the second dose of the vaccine and instructed to proceed at their own risk. He elected to receive the second vaccination dose without any further reaction or side effects. Primary teaching points from this case include the potential of developing leukocytoclastic vasculitis following the elasomeran vaccination. Patients who develop LCV following the first dose should be counseled of the risks associated with receiving the second dose, including progression to systemic organ involvement. Leukocytoclastic vasculitis refers to inflammation of small blood vessels resulting from immune-complex deposition within blood vessel walls leading to tissue destruction . InfectiWe present a patient with leukocytoclastic vasculitis that developed 72 hours after administration of the first dose of the Spikevax (elasomeran) vaccination developed by Moderna. This vaccination is a two-part vaccination that utilizes mRNA technology to promote an immunological response to the spike protein of the Sars-CoV-2 virus. While the efficacy and safety of mRNA vaccination technology have been studied at length, the COVID-19 pandemic is the first time in which widespread utilization of this vaccine technology has been employed. This case highlights leukocytoclastic vasculitis as a potential rare side effect of the COVID-19 vaccination.An 80-year-old male with a history of immune thrombocytopenic purpura (ITP) presented for evaluation of multiple small, red, violaceous petechiae involving the bilateral dorsal feet, legs, thighs, buttocks, and arms Figures and 2 thaHistology showed a perivascular lymphocytic infiltrate with extravasated red blood cells suggestive of vascular injury Figures  and 4. FThe patient was managed supportively and seen for follow-up 10 days after the initial biopsy was taken. Physical examination at that time revealed nearly complete resolution of the initial lesions. The patient was counseled of the potential risks associated with receiving the second vaccine dose including worsening cutaneous reaction or potential for more severe systemic involvement and instructed to proceed at their own risk. The patient elected to receive the second dose of the elasomeran and denied any skin reactions.Leukocytoclastic vasculitis (LCV) is caused by the deposition of immune complexes within blood vessels leading to immune system activation and fibrinoid necrosis, resulting in characteristic vasculitic skin lesions . The etiMessenger RNA vaccine technology has been studied at length and offers strong safety advantages compared to traditional vaccine technology . The priLCV presents clinically as symmetrically distributed palpable purpura or infiltrated erythema most commonly on the bilateral lower extremities , 3. DepoLCV is diagnosed by punch biopsy preferably within 18–48 hours of lesion onset. After this time frame, dissipation of immune complexes and recruitment of various mononuclear cells in addition to neutrophils makes the histopathological findings less specific for LCV . In addiTreatment for a primary episode of cutaneous vasculitis is aimed at avoidance of suspected triggers , as well as supportive treatment such as leg elevation, antihistamines, and NSAIDs. For mild refractory LCV, antineutrophilic agents such as colchicine and dapsone are considered first-line agents . Severe Our case highlights LCV as a potential novel side effect of the elasomeran vaccination. The case of LCV in our patient was self-limiting, however, the potential for a more severe immunological reaction with systemic involvement should be considered a possibility, and patients should be counseled of the risks associated with receiving the second dose of the elasomeran vaccine. In the case of our patient with a history of ITP, a predisposition for an amplified immunological response is considered as a potential confounding variable. Further research is required to isolate specific compounds within the vaccination associated with a high risk for an immunological reaction.


Two hydrogeologic cross-sections of basin-scale identify the W-E and N-S regional groundwater flow directions, with the lower Yellow River catchment becoming the discharged region. The hierarchically and steadily nested flow systems containing coal mining claims are influenced by coal mining activity. The groundwater depression cone in a shallow coal measure aquifer is caused by mine water drainage whereas the groundwater mound in Liujiagou Formation is generated by mine water injection activity. The numerical simulation revealed that the groundwater head rebound is slightly decreased and will not recover to its initial baseline within 500 years due to its low porosity and permeability. This study elucidates the deep groundwater flow patterns induced by mine water injection and provides a practical methodology for the management and pollution monitoring of mine water injection activity.Mine water injection into deep formations is one of the effective approaches for reducing the drainage from coal mines in the arid and semi-arid region of the Ordos basin, China. Many coal mines are attempting to execute the related projects. Under the influence of groundwater protection, the understanding of regional groundwater flow is becoming highly important to the mine water monitoring, whereas quite few academic research teams focus on the deep groundwater flow pattern by mine water injection. This paper reveals the spatial distribution of Liujiagou Formation that is in positive correlation with the terrain, and its local thickness is influenced by the dominant W-E and NE-SW directions of geological structures. Only a part of sandstone rocks consists of aquifers, the rest 61.9% of relatively dry rock provide the enhanced storage space and partial mudstone aquicludes decrease the possibility of the vertical leakage for mine water. The dynamic storage capacity is evaluated at 2.36 Mm It is common in the eastern margin of Ordos Basin. The deep storage aquifer of Liujiagou Formation shows a very high TDS concentration at 65,111 mg/L with the hydrochemical Cl-Ca·Na type and pH value at 5.35. Therefore, the approximative “Brackish Water Injection and Storage” of treated mine water is practicable for brine aquifers and it is interesting to quantify the geochemical evolution of groundwater induced by mine water injection. Additionally, a large number of oil-gas field injection wells are distributed in this region, and their successful application is also useful for mine water injection. Several million cubic meters of mine water has already been injected into the deep and tight sandstone voids. Mine water injection has been feasible by the current technique. Until now, however, deep groundwater flow patterns and geochemical evolution induced by mine water injection activities has not ever been properly studied. Deep groundwater flow regime and complex water-rock interaction are the fundamental challenge for hydrogeologists.Groundwater is an important part of the global hydrologic cycle ; it is gDue to the limitations to approaching and investigating deep groundwater systems, the results of studies of deep groundwater >1500 m) flow evolution are poorly reported. Mine water is a niche area of research. Previous studies did not refer to the field of mine water and focused mainly on regional contaminant identification 00 m flow, climate2 in deep rock formations at Tokyo Bay showed that carbon dioxide storage activity has caused considerable pressure perturbation and significantly affected the regional groundwater system. Groundwater pressure buildup, migration to the land surface and discharged to the shallower aquifers is examined [Furthermore, the research focusing on water injection for the unconventional oil and gas recovery  at Williexamined . The degexamined .Deep groundwater characteristics not only indicate the valuable information of hydrosphere, but also an effective tracer for groundwater evolution including dissolution, sedimentation, evaporation and mixing . AccordiHowever, how mine water injection activities influence the deep groundwater flow and geochemical evolution have not been studied by the previous literature. Understanding this basic theoretical research in the field of mine water injection will be the fundamental advancement and significant progress.In this study, collected drill hole information, geophysical technique and numerical simulation are proposed to identify the spatial distribution, horizontal and vertical heterogeneous characteristic of Liujiagou Formation. The original deep regional groundwater flow cross sections that are disturbed by mine water drainage and injection activities will be elaborated to describe the effect on the regional groundwater flow pattern and the long-term rebound of the groundwater head to its initial baseline. The industrialization management for mine water injection in the coal mining claims would be a novel expectation.The study area is located in the eastern margin of Ordos Basin, which is the ecologically fragile area in the western arid and semi-arid region of China. It is rich in coal, trona, mirabilite, oil and gas resources. Many large coal mines with high production are located here. A total of 1.223 billion tons of coal was produced in Ordos city and Yulin city in 2021. As shown in LFm is the lower of Triassic and characterized with little porosity, low permeability  and highTwo dimensional simulations of different cross-sectional models through the basin-scale could be governed by both hydraulic water-table and stream function in the steady flow equations  is expreaquifers , which aThe surface of the finite element mesh is approximately consisted with the groundwater table generally following the topography  with theAccording to the data mining and analysis for the identified 37 wells from salt and coal mines, oil and gas fields, we generalized the spatial geodata in the study area of LFm as shown in Geophysical exploration methods including 3D seismic, gravity , magnetiThe comparison of Therefore, the combination of drillhole, gravity and magnetic methods were able to describe the regional thickness and banded heterogeneous characteristics for LFm. The dominant W-E and NE-SW directions may influence the groundwater flow direction and the circulation rate. The faults zone with the derived fractures has a relatively high porosity and conductivity for mine water injection.Based on the few available papers, drill holes and the high cost of deep exploration, as well as the approximately horizontal geologic structure in the study area, we took the MC-1 well as the example to characterize the vertical heterogeneity of LFm.3, the high density means that its sonic properties are lower than in other formations due to low porosity and fracture ratio. When focusing on the green natural gamma curve, a relatively higher content of argillaceous mud may enhance this performance due to the main source of gamma-ray from the minerals of mud fraction [According to the geophysical log as shown in fraction . The avefraction , which wBy combining the systematical analysis of the above geophysical log, 35 original sub-aquifers were identified. We evaluated the thickness of sandy mudstone, medium sandstone, interlayered siltstone, fine sandstone, coarse sandstone, mudstone and siltstone that are 27.53%, 23.97%, 21.28%, 13.81%, 6.52%, 4.24% and 2.65% of the whole LFm thickness, respectively. Not all aquifers have the lithology of sandstone with particle granularity over fine stuff; only 38.1% of LFm was identified as the watered rocks. Dry sandstone containing gravitational water was not detected . The staJust for the vertical aquifers shown in 3 of mine water had been injected and stored in LFm, with the wellhead pressure always fluctuating around 8.0 MPa. The empirically evaluated radius of influence was 635 m, and the specific mine water storage capacity of rocks near the MC-1 well was 1.06 Mm3 per 1 km2. According to the volumetric calculation method [3), −1), The previous performance of the MC-1 well indicated that 1.347 Mmn method , the fol3 in the study area. Based on the proportion of confirmed sandstone aquifers in LFm of the MC-1 well was 36.1% and the specific porosity of pore diameter over 10 μm was 0.0224, the estimated dynamic storage capacity was 25.10 billion m3 for the total area of 106,240 km2 in this study area. The calculated volume of 2.36 Mm3 per 1 km2 in the study area was found to be larger than the measured specific data of the MC-1 well. This indicates that the potential storage capacity of LFm may be higher than expected, so more pre-treated mine water could be transferred and disposed in the deeper aquifer through the projects in coal mines. As shown in The total volumetric of LFm was evaluated at 3,103.77 billion mThe deep groundwater regime within the large hydrogeological basin is controlled both by geology and topography . StudyinSimilarly, 2D simulations of W-E and S-N cross-sectional models through the basin-scale in the study area, as shown in Regional basin-scale hydrology was generally characterized by gravity-driven flow and considered as steady state. The hierarchically and steadily developed nested flow systems of basin asymmetry  for W-E The regional hydrodynamic regime of LFm was in the focus of this study aimed to evaluate the potential capacity and influence resulting from mine water injection activity. The overlaying low-permeability sandstones and mudstones aquitards limit the groundwater flow between the shallow and LFm systems. Deep groundwater in LFm passes and flows slowly, sometimes is under a nearly stagnant state, toward its outcrop in the Kuye River and Tuwei River, which were also the discharge zone of regional LFm groundwater. Therefore, the higher heads in the western recharge area than the eastern lower discharge area constituted the driving force for the groundwater circulation in LFm aquifers, but the nonlinear relationship between topography and the water table might have been influenced by local variability in epeirogenetic geology and climate ,59.The S-N cross-section with the larger extension than the W-E cross-section has the groundwater flow regime that can be described by the same classical gravity-driven model with local, intermediate and regional patterns , as showWe found that coal mining activities, including massive drainage, pumping and mine water injections, generated new flow subsystems which covered capturing zones in the coal measures of mining area (depression cone) and releasing zone in the deep mine water injection aquifers (groundwater mound), as shown in As for mine water injection activity around coal mining claims (the MC-1 well), the emergence of streamlines clearly showed that the groundwater in shallow Jurassic aquifers was pumped and drained to the surface. Extensive coal mining resulted in the appearance of the new fractures generation in overlying rocks. With the influence of complicated water-rock  interaction, water mixing, microbial, geothermal and human activities, groundwater quality was obviously affected when water flowed along those fractures into the panels, roadways and eventually became the mine water. Large basin-scale mine water drainage prompted the downtrend of the regional water table, especially many local depression cones and subsystems of groundwater were distributed over coal mines.Mine water injected into the tight and low permeability LFm aquifer may move downdip into the deeper zone and the Wuding River  in the lK value was obtained from the repeatedly pressure decaying tests of MC-1 well. Porosity changes induced by the pressure increase were not considered. The specific storage was inversed by the observation well of MC-1. The other region parameters were valued at 0.0001 m/d, 0.000009 and 0.05; they were obtained from the lab test, original groundwater table recovery test and high pressure of hydraulic fracturing.The LFm confined aquifer boundary was set as the weak-flow condition due to low permeability and the characteristic of regional-scale low porosity. Laterally extensive low-permeable layers were particularly common in the Ordos basin . Most of3/d for each well. The long-term evolution of different groundwater fields is shown in The natural and original region-scale groundwater field of LFm was presented in 2 Capture, Utilization and Storage Program in Shenhua experimental site in Ordos Basin. Relatively low porosity and permeability LFm was favorable for fluid storage due to the wellbore storage effects would clearly separate the hydraulic fracturing region and originally undisturbed LFm. Therefore, mine water injection activities in Hujierte and Nalinhe coal mining regions had significantly increased the water pressure, flow velocity and altered local groundwater subsystem for LFm. The external region around the above coal mining region was not showed high groundwater contours. Only the groundwater gradient zone with high dense isolines was distributed between them. With the continuous constant injection rate at the initial period of 1 month, the system response of groundwater pressure to injection is very rapid, with the notable increases in groundwater contour [Low groundwater velocity and the rock properties of LFm constrained the migration scope of mine water injection, which was similar to the CO contour . The cha contour . The fra contour  applied The groundwater level of the deep part of LFm reached the steady condition before injection activity, as shown in Simulation results suggested that the proper injection management and concept would significantly reduce the unwanted pressure variation and associated effects . The monMine water is not only the unconventional groundwater resource, but also can be reserved in the deep saline aquifers for emergency. The arid and semi-arid region of the Ordos basin in China was menaced by the massive drainage of mine water and scarce groundwater resource. In contrast to the current mine water treatment techniques and other methods, the new and novel approach of mine water injection and storage has significant advantages, and is able to alleviate the currently grim situation as the scientific in-situ experiment of mine water injection in the area of LFm succeeded. The mine water injection activity by coal enterprises would be effectively operated in the study area, but has been poorly studied. Hence, studying the regional deep groundwater pattern was quite necessary for the management and monitoring of mine water injection and groundwater quality evolution. Geophysical technique of gravity and magnetic anomaly, 37 deep wells, logging data of MC-1 well, cross-sectional and numerical models were all combined and focused on revealing the hydrogeological characteristic and deep groundwater flow pattern induced by mine water injection activity.The main conclusions and findings of this study can be summarized as follows:The top and bottom interface of LFm were similar to the terrain features due to the stable Yishan Slope in the sedimentary Ordos Basin. The characteristics of thickness and local groundwater systems were mainly influenced by the dominant W-E and NE-SW directions of faults as it follows from studying the geophysical gravity and magnetic anomaly. The horizontal heterogeneity was helpful for justifying well site selection.Geological logging of MC-1 well revealed more than 35 sub-aquifers in LFm, with 38.1% of its thickness being considered as aquifers. The vertical distribution for the aquiclude of mudstone weakened the vertical leakage and inter-aquifer flow in LFm. The majority of relatively dry sandstone was able to be transformed into effective aquifers during mine water injection and enhanced the storage space for water.3 per 1 km2 was set as one of the criteria for well design. The estimated mine water storage capacity was 25.10 billion m3 in this study area. The analysis of two hydrogeologic cross-section models in basin-scale allowed us to suggest that the regional groundwater flow is directed from the west to east and from the north to the west; the lower elevation zone of the rivers’ catchment is located in the discharged region. Compared with the previous literature, the hierarchically and steadily nested flow systems affected by coal mining activity provide insights into the dynamics of basin-scale in the study area.As a result of studying regional volumetric and dynamic storage capacity the calculated volume of 2.36 Mm2 collaboratively.Mine water drainage in the shallow aquifer formed the groundwater depression cone whereas mine water injection in LFm generated the groundwater mound located in the coal mining claims with a low ability to migrate further. The groundwater simulation based on the flow field calculation revealed that the recovery of groundwater head slightly decreased and the head is not expected to recover to its initial baseline within 500 years. This was beneficial to the geological storage of mine water and management for coal enterprises, as well as the fundamental findings to storage mine water and CO


Environmental contamination with antibiotic residues and antibiotic resistance genes is increasing due to human and animal use of antibiotics. Various anthropogenic sources, such as wastewater treatment plants, effluents and biosolids, reclaimed water, animal manures, and farm runoff, are largely responsible for the diffusion of antibiotic residues and resistant bacteria and genes in soil and water, including drinking water . This antibiotic is an emerging alternative treatment for multidrug-resistant pathogens. Because it is used only when other antibiotics are ineffective, it is very important to monitor the development of resistance against it. The study describes a rapid assessment  of the resistance against fosfomycin that can occur in managed bacterial wastewater communities or in natural microbial communities. Fosfomycin was tested at two concentrations, 10 and 268 mg/L. The latter was considered the 50% maximal effective concentration (EC50) for fosfomycin for wastewater microbial communities. They also used the bio-augmented Pseudomonas putida KT2440  as a model and marker organism, but it was outcompeted in all experiments. The authors demonstrated that the complex WWCs may tolerate a low fosfomycin concentration, but higher antibiotic presence caused a turnover of community structure and promoted resistance.The paper by Pesce et al. evaluated the chronic effects of sulfamethoxazole (SMX) and sulfamethazine (SMZ) in river sediment microcosms over 28 days. The SMX and SMZ effects on five potential activities involved in C , N , and P (phosphatase) cycles were variable depending on the antibiotic, treatment dose , and measured activity, with a strong influence of exposure duration. Whereas, the SMZ treatments resulted in only transient effects on the five microbial activities investigated; a significant stimulation of β-glucosidase activity over the 28 days in the communities exposed to the high concentration of SMX was observed. Moreover, a stimulation of aerobic respiration at low SMX concentrations and a reduced concentration at the end of the experiment suggested a potential biodegradation of sulfonamides by sediment microbial communities. The findings suggest that contamination of sediments by sulfonamides is likely to affect biogeochemical cycles, with possible impacts on ecosystem functioning.Matviichuk et al. measured the concentration of 20 antibiotics and analyzed resistome and microbial taxonomic composition in river biofilms collected upstream (UPS) and downstream (DWS) (at the point of discharge) from a wastewater treatment plant (WWTP). The results showed significant differences between microbiome compositions in biofilms collected UPS and DWS. According to Procrustes analysis, microbial community composition and antibiotics content (sub-minimum inhibitory concentration) may be determinants of antibiotic resistance gene (ARG) composition in samples collected DWS. However, network analysis showed that the occurrence and concentration of antibiotics measured in biofilms did not correlate with the occurrence and abundance of antibiotic resistance genes and mobile genetic elements. The complex matrix of environmental biofilms likely affects the bioavailability and bioaccessibility of antibiotics, which may limit their impact on microbial communities. Specific studies are necessary to better characterize the interactions of biofilm and antibiotics, especially at the microenvironment scale within the biofilm.Tiwari et al. characterized ARGs and metal resistance genes (MRGs) in different drinking water distribution systems (DWDSs). Two of the waterworks employed artificially recharged groundwater and (ARGW) and used no disinfection in the treatment process. The other three waterworks (two surface and one groundwater source) used UV light and chlorine during the treatment process. Environmental DNA was extracted and then sequenced using the Illumina HiSeq platform for high-throughput shotgun metagenome sequencing. Overall, 430 ARGs were characterized among all samples with the highest diversity of ARGs identified from samples collected from non-disinfected DWDSs. Furthermore, non-disinfected DWDSs contained the highest diversity of bacterial communities. However, samples from DWDSs using disinfectants contained over double the ratio of ARG reads to 16S rRNA gene reads and most of them were MRGs (namely mercury and arsenic resistance genes). The total reads and types of ARGs conferred genes associated with antibiotic groups namely multidrug resistance, and bacitracin, beta-lactam, aminoglycoside, and mercury resistance genes increased in waterworks treating surface water with disinfection.Werner et al. evaluated the effect of 140 and 154 days of thermophilic composting on the microbial composition of human excreta and sawdust from dry toilets together with straw and green cuttings with and without the addition of biochar. The relative abundance of multiple ARGs, virulence factors, and genes associated with gene-encoding secretion systems  decreased during composting. Biochar at the concentration used had very little effect on the efficacy of composting.Microbial community response to antibiotics is a complex issue and it depends on a combination of site-specific abiotic and biotic factors which make each ecosystem unique. Further studies are desirable for obtaining a more exhaustive overview on this topic.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.