Additive manufacturing (AM) is one of the recently studied research areas, due to its ability to eliminate different subtractive manufacturing limitations, such as difficultly in fabricating complex parts, material wastage, and numbers of sequential operations. Laser-powder bed fusion (L-PBF) AM for SS316L is known for complex part production due to layer-by-layer deposition and is extensively used in the aerospace, automobile, and medical sectors. The process parameter selection is crucial for deciding the overall quality of the SS316L build component with L-PBF AM. This review critically elaborates the effect of various input parameters, i.e., laser power, scanning speed, hatch spacing, and layer thickness, on various mechanical properties of AM SS316L, such as tensile strength, hardness, and the effect of porosity, along with the microstructure evolution. The effect of other AM parameters, such as the build orientation, pre-heating temperature, and particle size, on the build properties is also discussed. The scope of this review also concerns the challenges in practical applications of AM SS316L. Hence, the residual stress formation, their influence on the mechanical properties and corrosion behavior of the AM build part for bio implant application is also considered. This review involves a detailed comparison of properties achievable with different AM techniques and various post-processing techniques, such as heat treatment and grain refinement effects on properties. This review would help in selecting suitable process parameters for various human body implants and many different applications. This study would also help to better understand the effect of each process parameter of PBF-AM on the SS316L build part quality. Additive manufacturing (AM) offers plenty of advantages over the conventional manufacturing process, due to the layer-by-layer deposition of materials. The applications of additive manufacturing are increasing exponentially, especially in the medical  and aeroThe entire study covers the effect of process parameters on mechanical properties, parameter effect on corrosion, and residual stress behavior. The literature collected over the past 10–15 years is on powder-based additive manufacturing of SS316L. The main four process parameters, i.e., laser power, scanning speed, hatch spacing, and layer thickness, and their influences on mechanical properties are considered. In the first section, the effect of the process parameters on tensile strength, hardness, and porosity with microstructure evolution is explained. In the second section, the corrosion and residual stress behavior of additively manufactured SS316L with process parameters are described. To conclude, all the reported process parameters on AM-SS316L and their influences are considered. This study will help to define the process parameter window for future applications to obtain desired strength and hardness. This study also helps by collecting all the process parameters effects reported till date for LPBF AM of -SS316L, this collected data can be used for future work in machine learning for the optimization of process parameters.3 and observed that a finer particle of around ~16 µm gives the highest tensile strength in the range of 610 MPa as shown in 2,B2) also implies the ductile failure of the sample.Tensile strength is one of the important factors considered to evaluate the quality of the build part. In AM, many parameters are involved at a time. Hence, it is essential to observe the effect of each parameter on tensile strength. This section covers powder selection, all the AM input parameters, the optimization of parameters, chamber environment, post-processing techniques, and comparison of tensile strength with other manufacturing processes in terms of properties and microstructural point of view. The selection of powder size plays a crucial role in the output mechanical properties. The smaller powder particles produce a denser product with minimal porosity and decreased chance of internal defects. Chen et al.  examined3, the highest tensile strength around 590 MPa was achieved. The fracture morphology at different energy density is shown in 3, more densification can be observed in The layer-by-layer deposition gives sequential heating and cooling, which results in a finer austenitic grain structure, compared to other conventional manufacturing processes. Hajnys et al.  investig3 to 105 J/mm3.The data of the effect of different process parameters on the as-built tensile strength of SS316L are collected from the literature as shown in The microstructure evaluation has a vital role in the mechanical properties in particular; the strength of the component depends on grain size and dislocation density. The refined grain structure greatly influences the porosity, residual stress, and strength of the components. The SLM process generates a finer microstructure, compared to the direct energy deposition (DED) process, due to more grain refinement. The SLM microstructure contains a higher dislocation density, compared to DED and other conventional processes. The dislocation hinders the movement of discontinuity. The heat treatment reduces the strength from 671 MPa to 616 MPa in the SLM part and 645 MPa to 600 MPa in the DED build part . The heaThe build orientation and location in the build plate also affect the strength of the component, as the fracture behavior is different when horizontal vs. vertical ,19. Casa3 to 105 J/mm3. The other individual parameters that play an important role are the scanning speed and layer thickness. The maximum tensile strength of SS316L obtained is 712 MPa with powder-based AM. However, commonly, the tensile strength varies from 600 MPa to 650 MPa. A significant improvement in the tensile strength can be obtained with grain refinement processes rather than heat treatment.The effect of various process parameters on the tensile strength of the building part is discussed in the above section. The overall most influencing factor is energy density for SS316L, and the highest tensile strength is found at in the energy density range of 50 J/mmHardness is the most important surface property considered in many industrial applications. In this section, each process parameter’s influence on hardness is discussed. The influences of the powder particles, laser power, energy density, build direction, scanning pattern, hatch spacing, porosity, and build chamber environment as well as the effect of various post-processing techniques are covered.3 and 50 J/mm3, respectively. The hatch spacing also affects the hardness level; the minimum hatch spacing of 80 µm gives the maximum hardness for the 80 J/mm3 energy density. The data of the effect of different process parameters on as build hardness of SS316L are collected from the literature as shown in The particle size alone does not show much effect on hardness; rather, it more depends on the scanning pattern and varies in each build direction. Chen et al.  found thThe layer thickness also influences the hardness value in the building part and at the lower layer thickness level; the bond between each layer is stronger, which leads to higher hardness. The maximum hardness reported at the layer thickness of 30 µm is shown in 3 and further increasing the energy density leads to a reduction in hardness. The overall effect of energy density on hardness from the collected literature data is shown in Wang et al.  also rep3. The hardness highly depends on the scanning speed, wherein the higher scanning speed leads to a faster cooling rate, which results in a finer grain and increases the hardness. Sun et al. [Tolosa et al.  also repn et al.  experimen et al. . Cherry n et al.  also repn et al.  investign et al.  reportedn et al.  stated tn et al.  also shon et al.  also stun et al.  also repn et al. ,32 invesn et al.  investign et al.  comparedn et al.  reportedn et al.  experime3 to 125 J/mm3. Hardness is the anisotropic property and varies in each different build plane direction. Heat treatment reduces the hardness value, due to recrystallization. The various surface modification techniques, which refine the grain structure, improve the hardness significantly.In this section, the influence of the process parameters on hardness is considered. The overall hardness with the powder-based AM of SS316L is achieved in the range of 220 HV to 270 HV depending upon the process parameters. The most affecting parameters contributing to hardness are hatch spacing, scanning pattern and layer thickness. The overall energy density range for optimum hardness is 80 J/mmThe porosity of the built part is one of the important properties to be considered, as, directly or indirectly, it influences all the mechanical and microstructure behaviors. In additive manufacturing, densification of the material is the most crucial factor to be considered. The optimum range of process parameters is required to obtain a denser product. In this section, the formation of pores, affecting process parameters and their influence, optimizes parameters in terms of mechanical and microstructural properties are discussed.The porosity is generally classified into two categories, namely, metallurgical pores and keyhole pores. The metallurgical pores are generated, due to the oxygen content and other inclusions, in 100 µm with a spherical shape. The keyhole pores occur at a higher scanning speed. Generally, keyhole pores formed irregular shapes of more than 100 µm in size as shown in The finer powder particles generate a denser product, as more surface area is available to absorb the laser energy, resulting in the complete melting of particles. The highest density 99.99%) is reported with a particle size range of 5 to 40 µm 9.99% is  demonstr3 and 50 J/mm3, respectively. The SEM images of porosity shown in 3 energy density.The optimum energy density is the critical parameter for the dense structure and is achieved by the essential selection of the laser power, scanning speed, hatch spacing, and layer thickness. The part produced with a lower energy density may have unmelted particles, which results in a porous structure. The higher energy density creates a steep “V” shaped melt pool, which leads to micro evaporation from the melt pool; that gas is trapped below the melt pool, which again results in porosity. Tucho et al.  experime3 and 41.81 J/mm3, respectively. The further increment in the energy density to 209.03 J/mm3 increases the porosity, due to the evaporation of microelements as shown in 3.Cherry et al.  also invLi  also obsThey reported that the most influential parameters on the density of AM build parts are the scanning speed, scanning pattern, and laser power . They vaThe porosity could also be due to the gas atomization of the powder material. Yusuf et al.  investig3 to 105 J/mm3. Each process parameter’s effect on a denser product is discussed; the scanning speed, laser power, and layer thickness are important parameters to be considered. The denser product above 99% density is observed at a 650 to 800 mm/sec scanning speed depending upon the energy density level. The general pore structure is still observed in powder-based AM in the range of 5 to 40 µm, even at a 99% dense structure.As discussed in this section, porosity is observed at higher and lower energy density levels. The optimum range for denser products is achieved in the range of 80 J/mmIn this section, the corrosion behavior of SS316L bio implants in additive manufactured parts is discussed. Musculoskeletal injuries and musculoskeletal diseases are increasing day by day in the human body. The estimated general surgeries of orthopedic implants are 1 million per year and are estimated to increase by 2 million per year in 2025 .Metal implants are used in different body parts, including as bone replacements, knee joint replacements, dental implants, screws, plates, etc., as shown in Lodhi et al.  comparedThe same group reported another study of corrosion behavior of AM SS316L in an acidic environment for less than 3 pH values. The microstructure of wrought alloy vs. AM is shown in Al-Mamun et al.  also comAnother study reported that AM part performs well in a corrosion environment, compared to wrought alloy, due to a layer-wise refined microstructure, the absence of MnS inclusions, and more robust passivity behavior ,62. Nie A similar study by Laleh et al.  also repThe overall scenario of an additively manufactured bio implant of SS316L is discussed. Corrosion is a major concern for the early failure of a bio implant. The manufacturing defects, critical environment, microstructure evolution, surface, and mechanical properties play an important role in the life of a bio implant. Additive manufacturing implants have a positive impact on corrosion behavior, as discussed. However, more research is required on microstructural evolution, the effect of different phases in the microstructure, parameter optimization for corrosion properties, and residual stress influences on corrosion behavior.In this section, the residual stress formation phenomenon in powder-based additive manufacturing explains their types and measurement techniques. The effect of process parameters, such as energy density, laser power, layer thickness, and build part orientation on the formation of residual stresses are elaborated. The various post-processing techniques and optimum parameters to reduce the amount of residual stress are explained.The main consequence of additive manufacturing is internal residual stress generation in the process. The layer-by-layer continuous heating and cooling cycle leads to generate thermal stress in the build component. This residual stress reduces strength, surface cracks, delimitation from the base plate, and distortion, and results in decreased overall quality of the part . There aThe maximum residual stress in the yield strength range generally occurs at a higher temperature gradient, i.e., joint of the base plate and first layer . When thThe lower laser power process involves a higher cooling rate, which eventually increases the temperature gradient and residual stresses . Tong etAs discussed in this section, residual stress cannot be eliminated in layer-by-layer manufacturing. Several techniques can be used to reduce the residual stresses, such as preheating of the base plate, re-scanning of the tracks , post-he3 to 105 J/mm3 to obtain significant tensile strength. The most influencing parameters affecting the tensile strength of the building part are scanning speed and layer thickness. The tensile strength can be improved with various post-processing techniques, such as grain refinement. The pre-heating of the powder bed also improves the tensile strength of the as-built sample.The tensile strength of PBF-AM of SS316L is found to be in the range of 600 MPa to 650 MPa. The maximum tensile strength reported for SLM builds part is 712 MPa. The energy density input is required in a range of 50 J/mm3 to 125 J/mm3. The most influencing input parameters for hardness are hatch spacing and the scanning pattern. The various grain refinement techniques can improve the hardness of an as-built sample.The hardness value of the as-built sample of the powder-bed AM of SS316L is observed in the range of 220 HV to 270 HV. Hardness is an anisotropic property, observed to be different in the different build directions. The energy density input for the better hardness of the as-built sample is observed in a range of 80 J/mm3 to 105 J/mm3. The most influencing parameters to obtain a denser product are scanning speed, laser power and layer thickness.In layer-by-layer manufacturing, higher relative density or lower porosity is the first objective to improve the overall strength of the building part. All the different mechanical properties and electrochemical behaviors are influenced by the amount and distribution of micro pores in the building part. The optimum range of energy density input in powder-bed AM can produce a denser structure. The optimum energy density window to obtain the maximum denser product is in the range of 80 J/mmThe different electrochemical behaviors of the PBF-AM build SS16L part are discussed. The corrosion behavior is observed to be different, due to layer-wise microstructure evolution in AM. The process parameters, environment, micro elemental segregation in AM, and different passivation behaviors play an important role to decide the life of a bio implant in the human body. The AM shows better corrosive resistance in the human body; however, the influence of each process parameter, microstructure evolution, the effect of different phases, and elements studied in this direction are required to better understand corrosion behavior of AM parts.Residual stress is the most affecting factor to degrade mechanical properties of an as-built part of AM. The formation of residual stresses and their influences was covered. However, further studies are required on the effect of residual stresses on corrosion behavior, wear rate, and different surface and structural properties for better understanding the correlation with other input process parameters.The powder-bed fusion additive manufacturing of SS316L for different process parameters and their influences on different mechanical and surface properties were extensively covered and critically discussed in this review. The effect of main input parameters of powder-bed fusion AM, such as laser power, layer thickness, hatch spacing, and scanning speed on build part properties is covered. The effect of post-heat treatment, grain refinement techniques on build properties were also discussed. Each parameter influences tensile strength, hardness, and relative density of the build part and are individually critically discussed. The microstructure evolution for AM-built parts and their properties comparison with different AM processes are also studied. This study helps to identify the process parameters window to obtain desired properties. The key concluding points from the entire literature are as follows:


Herniaria hirsuta L. (UV = 0.16), and the highest family use value (FUV) was assigned to Caryophyllaceae with (FUV = 0.163). Regarding the informant consensus factor (ICF), this index’s highest values were recorded for kidney stones (ICF = 0.72). The use of 45% of the selected plants were validated based on literature review. This study helped document and preserve crucial traditional plant knowledge of 121 plant species used to treat kidney problems that can be used in the search for new biologically active compounds through more upcoming pharmacological studies.Kidney disease is one of the most common health problems and kidney failure can be fatal. It is one of the health disorders associated with extreme pain and discomfort in patients. In developing countries, such as Morocco where socioeconomic and sanitary conditions are precarious, medicinal plants are considered the primary source of medication. In the present work an ethnobotanical survey was conducted in a remote area of North-Eastern Morocco and we focused on (1) establishing a record of medicinal plants used traditionally by local people to treat kidney diseases and (2) correlate the obtained ethnomedical use with well-studied pharmacological evidence. From February 2018 to January2020, information was gathered from 488 informants using semi-structured questionnaires. The data were analyzed using three quantitative indices: The use value (UV), family use value (FUV), and informant consensus factor (ICF). A total of 121 plant species belonging to 57 botanical families were identified to treat kidney diseases. The families most represented were Asteraceae (14 species), followed by Lamiaceae (12 species) and Apiaceae (10 species). The most commonly used plant parts were leaves, followed by the whole plant and they were most commonly prepared by decoction and infusion. The highest value of the (UV) index was attributed to  Nowadays, kidneys and their problems have gained increasing interest concomitant with life changes, industrialization and malnutrition. Plants have always played a significant role in traditional medicine in underdeveloped countries and have also been an integral part of local communities’ history and cultural practices . MedicinAs other regions of Morocco, people living in North-Eastern Morocco have a common cultural past that dates back to the Arab civilization in the seventh century. The original cumulative culture has maintained a well-developed traditional knowledge of medicinal plants’ uses that form the basis of the traditional medical system existing until now ,7. UnforRegarding, these ancestral medical practices in this country, we found that there are many investigations carried out in different regions of Morocco that deal with traditional use of medicinal plants for the treatment of renal diseases. In fact, an ethnobotanical survey conducted in the Fez-Meknes region was able to document traditional knowledge related to the 69 plant species belonging to 38 families, used as traditional remedies for the treatment of kidney diseases in this region . All theTo the best of our knowledge, no ethnobotanical survey on the use of medicinal plants used in treating kidney diseases has been conducted in North-Eastern Morocco, appealing this study to be conducted with the objective of (1) record, evaluate, and document medicinal plants and know-how related used by local people, in the control and healing of renal disorders, in six provinces of the North-Eastern region of Morocco, (2) make a quantitative analysis of traditional knowledge assigned to species inventoried, (3) provide pharmacological and toxicological data of the plant species listed in the present paper.In In this part of the text and for convenience, we divided medical practices, adopted by the population in North-Eastern Morocco, for treating renal diseases into three categories: those using only medicinal plants for these purposes, those using conventional medicine, and those using both traditional and conventional medicine. As indicated in Based on the information mentioned above, we deduced that informal health care approaches “traditional medication” have been reported to be shared among people living in this region, especially for renal diseases. Despite the population in this region’s lack of trust in the modern healthcare system, our findings confirm that patients still consider traditional medical practices a better option than conventional healthcare approaches.So, according to these observations, we can say that the socio-economic conditions, patients’ residence, culture, and tradition influenced the user’s decision to use traditional healthcare approaches.Among participants who chose informal healthcare as their first-choice treatment option, their subsequent decision to use standard healthcare options depended on their experiences or their initial interaction with the older and herbalists, when that exists. According to our results, most parts of ethnobotanical information generated from this inquiry were given by people living in remote areas. Based on this inquiry’s ethnobotanical information, we deduced that the accumulated experiences with age are the primary source of information at the local level. The highest age respondents provide more reliable information because they hold much of the oral tradition’s ancestral knowledge. However, the young generation detained less information related to traditional knowledge because they were influenced by modernization and exotic culture and the tendency to disinterest and the gradual mistrust of this herbal medicine. So, the present-day, the substantial holder of traditional knowledge, which is becoming very old, and the lack of interest among the younger generation as well as their tendency to migrate to cities to ensure their basic needs, could harm the transmission of the traditional know-how on medicinal plants of the elderly to the young people.Consequently, the traditional indigenous knowledge that has been transferred orally, which is fast disappearing, is in danger, and there is a possibility of losing this wealth of knowledge shortly. Indeed, this traditional knowledge on phytotherapy, which is transmitted from one generation to the next, is on the verge of extinction if no effort is made to save it .In the present study, 121 species of medicinal plants belonging to 57 families were used to treat kidney diseases. Ethnobotanical information related to these plants’ use was documented, including vernacular names, traditional uses, parts used, method of preparation, and route of administration .The dominated families that have been used to treat and relieve renal disorders were the Asteraceae 14 species), followed by the Lamiaceae (12 species), the Apiaceae (10 species), Rutaceae, Poaceae and Fabaceae (5 species) each, Cucurbitaceae with (4 species), Rosaceae, Myrtaceae, Brassicaceae and Amaranthaceae with (3 species for each), while the other families represent less than three species . The pre species,H. hirsuta with , followed by A. graveolens , P. crispum , and Z. lotus , Z. mays , Z. officinale , U. dioica , T. campylodes , T. microphylla , and R. officinalis . These ten species accounted for 60.78% of total use reports, and the remaining 101 species represent only 39.22% of total use reports. The frequent use of H. hirsuta, P. crispum, Z. lotus, and Z. mays against kidney pain are already confirmed in the results of a study conducted in the Fes-Meknes region of Morocco H. hirsutApium graveolens L. is ranked second, with a percentage of citations of . It is commonly used to treat several kidney problems: improved kidney performance, kidney swelling, kidney stones, kidney detoxification, kidney pain, diuretic, renal colic, and renal polycystic. The aerial part of Apium graveolens L. accentuates urinary excretion of Ca2+ in an experimental model of nephron-calcinosis in rabbits at an amount of 8 g/kg added to the animal feed [Apium graveolens L. demonstrated in vivo a protective effect on kidney damage in the model of rats with ischemia/reperfusion at a dose of 1000 mg/kg body weight [Apium graveolens L. have a diuretic effect in vivo in dogs at doses  for the ethanolic extract and  for essential oils [Apium graveolens L. is the reason why celery is the plant most used in traditional medicine [Apium graveolens L. are rich in bioactive compounds such as polyphenols and flavonoids [Apium graveolens L. have considerable pharmacological activities, suggesting that the activities mentioned below may be due to these secondary metabolites.mal feed . The ethy weight . The ethial oils . The premedicine ,181. Preavonoids ,183 . Another work, published recently by our team reviewed toxic plants in the region, indicated that out of 287 medicinal plants used by local people, 87 plant species had been identified as toxic [E. spinosissimus and B. cretica subsp. Dioica, used separately, could have toxic effects targeting the nervous system leading to excitement and convulsive effects; the consumption of L. usitatissimum could have some physiological turbulence such as colic, numbness, and/or respiratory acceleration; A. succotrina, when ingested, could have intense organic congestion, eczematous dermatitis, the bulbs of D. maritima, in decoction, causes digestive disorders with vomiting, the use of C. litoralis subsp. telephiifolia. at high dose could have intense diarrhea, and prolonged treatment with the aerial part of G. glabra can lead to the digestive system’s neuronal toxicity and disorders. The literature review revealed that among the seven species cited as toxic by the local population, three species were studied for their toxic effects on the laboratory. Hydroethanolic extract of the roots of C. litoralis subsp. telephiifolia. Showed toxicity in mice with the oral mean lethal dose (LD50) value of 14,000 mg/kg body weight [D. maritima showed a cytotoxic effect against cancer cells of different lines as in the cell line of non-small cell lung cancer A549 (NSCLC) with IC50 = 0.02 µg/mL and in human cervical cancer cell lines Siha and Hela, hosting HPV16 and HPV 18, respectively [B. cretica subsp. Dioica. showed cytotoxic and apoptogenic activity in Burkitt BL41 lymphoma cell lines at a dose of 125 g/mL [Several assumptions confirm these. Our team reported that some common plants used as medicine by people in North-eastern Morocco, such as toxicity . Accordias toxic . In the y weight . D. mariectively ,189. The125 g/mL .From these observations, we can deduce that although these plants were used traditionally by local people for the treatment of renal diseases and are considered to be safe, for some respondents, they may cause damage due to their unwanted side effects. Therefore, studying medicinal plants’ side effects would have an influential role in identifying and diagnosing the herbs’ safety profile. So, medicinal plants’ consumption without studies of efficacy and safety can result in several side effects that may affect people’s health.2, representing 12% of the national territory. Historically, North-Eastern Morocco people have a shared cultural past dating back to the Arab civilization in the seventh century. The cumulative traditional culture, related to ethnobotanical knowledge, has been maintained until now and constitutes the basis for the region’s traditional medical system [The study was conducted in North-Eastern Morocco . This rel system ,7.In order to collect the traditional knowledge about medicinal plants used by people living in the study area, an ethnobotanical survey was conducted from February 2018 to January 2020 in thirteen rural communes of the North-Eastern region of Morocco  spread ohttps://www.catalogueoflife.org/col/) (accessed on 13 April 2020), the Plant List (http://www.theplantlist.org/) (accessed on 13 April 2020) and African Plant Database (http://www.ville-ge.ch/musinfo/bd/cjb/africa/recherche.php) (accessed on 15 April 2020). Only the plant names accepted in these databases were retained. Following the Angiosperm Phylogeny Group IV (2016), the plant families listed in this paper were checked with database APG-IV 2016 [All local names of plants collected during this study were translated into botanical names, based on the following references ,190. For-IV 2016 .Once the name of each plant species selected was identified correctly, the whole or a part of the picked plants were pressed with a plant press and dried properly. A voucher number was attributed to each specimen and deposited in the Herbarium (HUMPOM), at Mohammed first University, Oujda, Morocco.To give the relative importance of each plant species known locally to be used in popular medicine, we calculated the use-value (UV) for each species. This index was calculated using the following formula :(1)UV=∑UThe value of UV will be higher if there are many reports of use for a plant, which implies that the plant is important, while they will be close to zero if there are few reports related to its use.In order to assess the relationship between botanical families and users of species belonging to these families, we used the index called Family Use Value (FUV) which is equal to the average total use value for each species in the family .(2)FUF=To know about informants’ agreement and consensus, we calculated Index Consensus Factor (ICF) by using the following formula :(3)ICF=NThe ICF values’ margin varies between 0 and 1, where values close to 0 show that the plants are randomly selected or that there is no exchange of information on their use among the informants. Values close to 1 are obtained when there is a well-defined selection criterion within the given community and/or if the information is exchanged between informants.A review of the available literature on the plants’ biological activities identified against kidney disease was undertaken using the following electronic databases: PubMed, Science Direct, Google Scholar, Scopus, and Web of Science using the following keywords “kidney disease”, “renal disease”, “renal insufficiency”, “nephropathy”, combined with the scientific name of the plant. Chemical structures of plant compounds were performed by Chem Draw 18.1 software.This survey showed that people living in North-Eastern Morocco’s remote areas still use medicinal plants to treat ailments, especially renal diseases. The choice of these people was based on their socio-economic and cultural conditions. This preference offered the best chance for them to manage renal sequelae. The people in the study region found that traditional uses of medicinal plants possess suitable healing properties. The results demonstrate the promising role of medicinal plants in managing this particular health problem for these users. However, this preference should be taken with great care. To confirm their therapeutic uses, more investigations are needed to approve the safety and efficacy of their bioactive compounds. Additionally, in predicting the traditionally believed effects of these herbs, researchers need to find out the actuality of their clinical effectiveness and active substances. Once the positive effects of these herbs were proved to be accurate, it is possible to produce drugs useful in the treatment of renal disorders.


Campylobacter spp., among small poultry flocks in Ontario, Canada. For each post-mortem submission to the Animal Health Laboratory, a pooled sample of cecal tissue was cultured for Campylobacter spp., and a husbandry and biosecurity questionnaire was completed by the flock owner (n = 153). Using both laboratory and questionnaire data, our objective was to investigate demographic, husbandry, and biosecurity factors associated with the presence of Campylobacter spp. in small flocks. Two multivariable logistic regression models were built. In the farm model, the odds of Campylobacter spp. were higher in turkeys, and when birds were housed in a mixed group with different species and/or types of birds. The odds were lower when antibiotics were used within the last 12 months, and when birds had at least some free-range access. The effect of pest control depended on the number of birds at risk. In the coop model, the odds of Campylobacter spp. were lower when owners wore dedicated clothing when entering the coop. These results can be used to limit the transmission of Campylobacter spp. from small poultry flocks to humans.This study is part of a 2 year disease surveillance project conducted to establish the prevalence of poultry and zoonotic pathogens, including  Birds submitted to the Animal Health Laboratory (AHL), University of Guelph for post-mortem examination were also tested for an array of pathogens using pre-set microbiology tests. Furthermore, for each submission, the flock owner was required to complete a husbandry and biosecurity questionnaire. Results of the surveillance project are presented in three companion papers ,27. Campmissions . This ister spp. . Thus, tCampylobacter has been described previously [C. jejuni and C. coli were detected in 18% and 20% of tested submissions, respectively. Chickens accounted for 84% of submissions, with approximately equal proportions of C. jejuni and C. coli. The majority (86%) of the Campylobacter-positive turkey submissions were C. coli.The species breakdown of eviously . In brieCampylobacter.The questionnaire had 41 questions ; howeverp ≤ 0.2) on univariable analysis are shown in bold, in p value.There were 44 demographic, husbandry, and biosecurity variables analyzed in the univariable analysis for the farm model . VariablCampylobacter spp. presence were higher in turkeys compared to other species  and when birds were housed in a mixed group with different species  and/or types  of birds . The odds of Campylobacter spp. presence were lower when antibiotics were used within the last 12 months  and when birds were housed inside with some free-range access  compared to when birds were housed indoors only; a similar, albeit non-significant trend was identified when birds were exclusively free-range . The effect of pest control on the presence of Campylobacter spp. depended on the number of birds at risk: the odds were lower in larger flocks (50–260 birds) in which pest control was used compared to smaller flocks (1–24 birds) in which pest control was not used . All statistically significant (p ≤ 0.05) contrasts for the number of birds at risk and pest control interaction are presented in The final multivariable model included: species: turkey; the number of birds at risk; pest control; an interaction between the number of birds at risk and pest control; medication: antibiotics; bird housing type; and mixed group . The odd2 = 40.85, p = 0.608). In the final model, there were two observations (belonging to the same covariate pattern) with large, negative, standardized residuals (−3.7) that were considered to be outliers and had a relatively large influence on the model. These were medium-sized flocks (25–49 birds) of chickens in which pest control was used; they were housed indoors in a mixed group and were not given antibiotics within the last 12 months, yet were Campylobacter-negative. When removed from the model, there were no major changes to any of the coefficients, so they were kept in the final model.The Pearson chi-square goodness-of-fit test indicated that the model fit the data (Χp ≤ 0.2) on univariable analysis are shown in bold, in p value.There were 15 indoor housing-related variables analyzed in the univariable analysis for the coop model . Variabln = 111) included only one significant variable: wearing dedicated clothing when entering the coop .After the backward elimination process was completed, the final model . Although commercial broiler chicken flocks are recognized as an important reservoir of Campylobacter spp., our finding suggests that turkeys can also be a reservoir and agrees with previous studies conducted on commercial turkey flocks. In Québec, Canada, the prevalence of Campylobacter-positive turkey flocks was 46% [Campylobacter spp. [Campylobacter spp. (mainly C. coli) [We found that the risk of  was 46% , and in ter spp. . AlthougC. coli) , stressiCampylobacter spp. was lower when antibiotics were used in the flock within the last 12 months, suggesting a potential relationship between antibiotic use and the gut microflora of the birds. The details of their use were not well-described by the flock owners, although tetracycline, tylosin, and penicillin were among those reported [Campylobacter spp. [C. jejuni and C. coli isolates in our study population were resistant to tetracycline [C. jejuni and C. coli isolates.We found that the risk of reported . At the reported . Althougter spp. . A high acycline , warrantCampylobacter spp. in small flocks. The risk of Campylobacter spp. was higher when birds were housed in a mixed group, and lower when birds had at least some free-range access compared to when housed indoors only. It is well known that poultry species, including chickens, turkeys, and ducks, are reservoirs of Campylobacter spp.; therefore, housing different poultry species together may lead to transmission between species through environmental contamination or direct contact [Campylobacter spp. was higher in the free-range flocks and broiler chickens with outdoor access compared to conventionally-raised flocks [Campylobacter spp. [Campylobacter spp. contamination [Campylobacter spp. in small flocks may be very different from those in commercial flocks.Our study found that housing factors likely play a role in the occurrence of  contact ,34. In ad flocks . Poultryter spp. ,37,38,39mination . This inCampylobacter spp. depended on the number of birds at risk: the odds were lower in larger flocks that used pest control compared to smaller flocks that did not use pest control. Indeed, the results of our comparisons indicate that for larger flocks, having pest control methods in place is especially important to reduce the risk of Campylobacter. There is limited knowledge on the relationship between flock size and pest control in small flocks; however, pests commonly found on livestock premises, including rodents and insects, are known vectors of Campylobacter spp. [Campylobacter spp. were found to be higher for commercial chicken flocks with professional rodent control compared to those without rodent control [Campylobacter spp. [In our study, the effect of pest control on the presence of ter spp. ,41. Inte control . Larger ter spp. ,42; howeCampylobacter spp. was lower for flocks in which the owner reported wearing dedicated clothing when entering the coop. This agrees with studies conducted on commercial broiler flocks, which showed that dedicated personal protective equipment (clothing) reduced the prevalence of Campylobacter spp. on farm staff and transporters [Campylobacter status of the flock [In our coop model, we found that the risk of sporters ,44. Howehe flock ,45,46.Campylobacter spp. that might be unique to small flocks, including the disposal method for dead birds, the presence of a wild bird feeder on the property, having a body of water on the property, and having additional domestic animals present on the property. However, only a few were significant on univariable analysis and none were significant on multivariable analysis. Overall, small flocks are very different from commercial flocks, making comparisons difficult. Small flocks have a different composition than commercial flocks, often with different bird species, breeds, and ages housed together. The average flock size in our study was 25 birds, whereas the average size of commercial layer and chicken flocks in Canada is approximately 22,000 and 14,000 birds, respectively [Campylobacter spp. presence in commercial flocks has been associated with numerous flock, barn, farm, and environmental exposures. Flock-level factors include: flock age; flock size; stocking density; antibiotic treatment; and feeding program [Campylobacter spp. in small flocks are similar to those for commercial flocks , whereas other factors  are indeed unique.The questionnaire included several questions related to potential environmental sources of ectively ,48. Furtectively ,15. Orga program ,42,45,46 program ,38,46,49 program ,51. Envi program ,49,50. OCampylobacter status) might have occurred due to errors in reporting by flock owners or grouping of categories, potentially resulting in conservative estimates of risk. Additionally, the submissions were all from sick or dead birds, and the occurrence of Campylobacter spp. might differ in healthy flocks. Future zoonotic disease surveillance studies that include healthy flocks would add valuable insight into our understanding of the epidemiology of this zoonotic pathogen in this sector of the poultry industry.A potential limitation of this study is sampling bias, as a relatively higher number of submissions were received from areas close to the two AHL locations in Guelph and Kemptville . HoweverCampylobacter spp. was conducted on pooled cecal tissues. Each pooled cecal sample (one per submission) consisted of cecal tissue from 1–5 birds , originating from flocks ranging in size from 1–299 birds  [Campylobacter spp. were identified using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF)  using a direct transfer method. Briefly, bacterial colonies were streaked on the stainless-steel target plate and overlaid with 1 μL of alpha-cyano-4-hydroxycinnamic acid (HCCA) [This study was part of a larger, cross-sectional, small-flock disease surveillance project that took place between October 2015 and September 2017. The project details and inclusion criteria have been described previously . In briemean 26) . All tesmean 26) . Colonied (HCCA) . Flock oThe details regarding the questionnaire design and data management have been described previously . In brieFor multiple-choice questions that were not mutually exclusive, all checked answers were tallied for each questionnaire; these were converted to individual, dichotomous variables in the analyses. Answers to questions pertaining to an indoor coop or barn were only tallied if the owner responded that the flock had some indoor access. The questionnaires had various numbers of unanswered and/or incomplete questions. As a result, the number of valid answers for each question varied.Campylobacter spp. For this model, the number of birds at risk reported on the AHL post-mortem submission form was used, as these data were considered to be more complete (n = 140) and reliable than data from the questionnaire pertaining to the number of birds of each production type.A farm model was built to investigate demographic, husbandry, and biosecurity factors associated with the presence of There were three questions on the questionnaire pertaining to drinking water for the flock: source ; whether the water was treated; and whether the water had been tested for bacteria. These were combined into a summary variable: drinking water risk level. Drinking water risk level was categorized as low risk , medium–low risk (well water that had been treated and/or tested for bacteria), medium risk (well water that had been neither treated nor tested for bacteria), and high risk (pond water). The isolation of new birds risk level variable was a summary variable derived from the isolation of new birds (yes/no) and the isolation duration variables to simplify the various responses given to the questions. It was categorized as low risk , medium risk (isolating for ≤2 weeks or isolating for an unknown amount of time), and high risk (no isolation).The continuous variables, number of birds at risk and the period of time the flock was present on the owner’s property, did not meet the linearity assumption and a quadratic term was not appropriate, so the variables were categorized using Lowess curves (described below). The number of birds at risk was categorized as 1–24 birds , 25–49 birds (medium-sized flocks), and 50–260 birds (larger flocks). The period of time the flock was present on the owner’s property was categorized as 0–19 months, 20–59 months, and ≥60 months.Campylobacter spp. The barn cleaning and/or disinfection variable had three categories: fairly frequently (when flock owners reported cleaning after each flock or cleaning more than once a year); infrequently ; and not applicable . The category ‘not applicable’ was excluded from the analysis because we were only interested in barns that had been cleaned and/or disinfected. Likewise, the ‘as needed’ category of the frequency of removing soiled litter and/or fecal material variable was excluded because it could have been interpreted in different ways by different flock owners, and the response of ‘never’ was combined with ‘yearly’ to eliminate a category that had only one response. There were several questions on the questionnaire pertaining to the use of dedicated shoes and clothing. These data were analyzed in a number of ways. First, as separate variables: wearing dedicated shoes when entering the coop; wearing dedicated shoes when cleaning the coop; wearing dedicated clothing when entering the coop; and wearing dedicated clothing when cleaning the coop. Next, by combining the shoes and clothing variables: wearing any personal protective equipment (PPE) when entering the coop; and wearing any PPE when cleaning the coop. Lastly, as a single, combined variable: wearing any PPE when entering and/or cleaning the coop. Flock owners were asked two questions pertaining to visitors: did they allow visitors into the coop (yes/no); and, if yes, were guests required to wear dedicated clothing. These data were analyzed in two different ways. First, as a simple, dichotomous variable: visitors were allowed (yes/no). Second, by combining responses from both questions into a summary variable with three categories: visitors were allowed into the coop and were required to wear dedicated clothing; visitors were allowed into the coop and were not required to wear dedicated clothing; and visitors were not allowed.A coop model was built to investigate indoor housing-related factors associated with the presence of Laboratory and questionnaire data were entered manually into Microsoft Office Excel 2016 , where they were visually inspected for errors and coded. The data were then imported into STATA IC 16  for statistical analyses.p-value ≤ 0.20 on univariable analysis were considered for further analysis. Lowess curves were used to assess linearity between the log odds of the outcome (presence/absence of Campylobacter spp.) and continuous variables that met the screening criterion. If the linearity assumption was not met, and a quadratic term was not appropriate, the variable was categorized based on cut points observed on the Lowess curve and then screened again. All pairwise correlations between independent variables that met the screening criterion were examined. When two variables were deemed to be highly correlated (rho ≥ |0.8|), p values, Akaike information criterion values, and biological plausibility were used to decide which variable would be offered to a multivariable model.Univariable logistic regression models were created to screen independent variables. Variables with insufficient variability (less than 10%) were excluded from the analysis, while variables that had a p-value of ≤0.05  indicating significance. When removed, if a variable changed the coefficient of any significant variable by ≥20%, it was considered to be a confounding variable and kept in the model regardless of statistical significance if the relationship was thought to be biologically plausible. Once a main effects model had been established, all possible two-way interactions were generated and assessed using the likelihood ratio test and Akaike information criterion. Using the lincom command in STATA, contrasts were built between interacting variables for all significant interaction terms.Significant, non-correlated variables from the univariable analysis were offered to a multivariable logistic regression model. To build the model, a manual backward selection method was used, with a p-value was >0.05, we accepted that the model fit the data. Standardized Pearson residuals that were ≥|3.0| SDs were considered to be outliers, and the raw data were checked for errors, corrected if necessary, and the model refit. If there were no errors in the raw data, the outliers were kept in the model. Influential observations were investigated, removed from the model, and the model was refit to determine if their removal resulted in any significant changes. However, regardless of their impact, the influential observations were kept in the final model.To assess the fit of the model, a Pearson chi-square goodness-of-fit was conducted, and if the Campylobacter spp., and although the birds are generally asymptomatic, it is an important zoonotic pathogen. We identified turkeys as having a higher risk of Campylobacter spp. than other poultry species, and described other demographic, husbandry, and biosecurity factors that were significantly associated with the presence of this pathogen in small flocks in Ontario. Our findings underline the importance of appropriate food safety and disease management methods by small flock keepers to prevent and control the zoonotic transmission of Campylobacter spp. via contact with infected poultry or ingestion of contaminated poultry meat.Poultry are reservoirs of


The aim of this study was to assess the electrophysiological and other influencing factors correlating with symptom severity in patients with major depressive disorder (MDD) under three different conditions: baseline, stress exposure, and relaxation following stress exposure.Symptom severity was assessed using the Beck Depression Inventory (BDI-II) in 89 inpatients  with MDD. Resting heart rate (RHR), heart rate variability (HRV), respiration rate (RR), skin conductance (SC), and skin temperature (ST) were recorded at baseline for 300 s, under stress exposure for 60 s, and under self-induced relaxation for 300 s. Age, nicotine consumption, body mass index, and blood pressure were evaluated as influencing factors.The BDI-II mean score was 29.7 points. Disease severity correlated positively with SC elevation under stress exposure and with a higher RR in the relaxed state, but no association was found between HRV and symptom severity. Age and higher blood pressure were both associated with lower HRV and higher RHR.The results indicate that, in patients with MDD, changes in the autonomic nervous system (ANS) are complex; and the assessment of ANS reactivity to stressors is useful. Elevated blood pressure might be underdiagnosed, although it is already relevant in patients with MDD in their early 50s. Major depressive disorder (MDD) has been repeatedly associated with dysregulation of the autonomic nervous system (ANS) . Heart rFurthermore, the use of other methods to assess sympathetic nervous system activity, such as noradrenaline spillover methodology  or direcDespite the rising popularity of HRV measurements in the assessment of stress/ANS, there are three main concerns regarding HRV studies in patients with MDD. First, there is a wide variety of HRV measurement protocols in the current research . Second,Furthermore, the current research suggests dysregulation in terms of abnormal autonomic responses to physical  stressors in patients with MDD compared with those in healthy controls , with auConcerning symptom severity and ANS function in patients with MDD, previous research is characterized by heterogeneity of results. While some studies have demonstrated the impact of disease severity on ANS dysfunction , others These diverse results can be explained by methodological shortcomings in the application of HRV assessment, exploring ANS functions, particularly by HRV, or by a narrow interpretation of this variable. The critical points mentioned in the literature include among others the incorrect use of low frequency/high frequency (LF/HF) as a marker of “sympatho-vagal balance” , the conA previous pilot study (unpublished data) of 32 patients with MDD and 32 healthy controls showed significantly higher RHR and respiration rate (RR) and significantly lower HRV parameters in patients with MDD than in healthy controls at baseline. The disease severity assessed using the Beck Depression Inventory (BDI-II) had no impact on the measured parameters. For that reason, we aimed to confirm the results on a larger sample size of depressed patients only with the same electrophysiological battery; however, we conducted the test under three different conditions: baseline, stress exposure, and relaxed state following stress exposure.This is of interest, as the findings of electrophysiological changes and symptom severity are inconsistent, and the use of a wider range of electrophysiological parameters under different conditions might help clarify the function of the autonomous nervous system in patients with MDD.We expected a negative correlation between SC response under the stress condition and symptom severity.A further aim of this study was to investigate the role of influencing factors, such as age, sex, and BP, on the different testing conditions.Ninety-eight inpatients were included in this study. The inclusion criteria for the MDD group were a diagnosis of MDD based on structural interviews and the International Classification of Diseases , as well as alcohol abstinence for 4 weeks. Only unipolar depression (first episode or recurrent) in the acute phase was considered; patients with bipolar affective disorder were excluded (one subject). Further exclusion criteria were diabetes mellitus (one subject), other manifest forms of psychiatric comorbidity (three subjects), manifest neurological disorder (one subject), and non-compensated hypertonia or heart disease, cancer, or other serious medical conditions. Patients with a pathological thyroid-stimulating hormone (THS) score (two subjects) or an elevated leukocyte count (one subject) were also excluded.The final sample consisted of 89 inpatients  with a diagnosis of MDD without any relevant comorbidities. Thirty-one patients were drug naïve, and 58 were on psychiatric medication. The most frequent antidepressants taken were selective serotonin reuptake inhibitors (SSRIs) , followed by venlafaxine (13), mirtazapine (13), bupropion (six), vortioxetine (two), and tianeptine (two).Other medications consisted of antihypertensive drugs , levothyroxine (six patients), proton pump inhibitors (pantoprazole in two and omeprazole in one case), acetylsalicylic acid (two cases), diclofenac (one case), and asthma spray (two patients).A comorbidity of arterial hypertension was observed in 15 patients, nine of whom were on medication. Previous or current hypothyroidism was observed in seven patients (six on medication). Minor injuries in the past had occurred in three participants, and six participants had allergies or asthma.All participants were introduced to the experimental protocols and provided written consent prior to participation. The experimental protocol was approved by the Ethics Committee of the institute  where the data were collected.To assess the severity of depressive symptoms, the German version of the BDI-II  was admi®, BioTrace+, Mind Media B.V., Herten, Netherlands) and were recorded at a sampling rate of 1,024 Hz.Electrophysiological data were acquired using the NeXus-10 system  position and in the same room. To reduce the impact of pretest movements, all subjects were asked to breathe normally and not move for 5 min prior to placement of the electrodes.For baseline, the subjects stayed in this sitting, slightly inclined position for 5 min with their eyes open and breathing normally, and were required not to talk and to avoid all unnecessary movements.Among emotion-induced stressors, various recall tasks designed to elicit specific emotions have been used . In our A relaxed state followed the stress exposure: patients were instructed to try to relax as much as possible, with their eyes either closed or open, staying in the same position, and avoiding all unnecessary movements.Recording and primary analysis of all electrophysiological parameters were performed using the BioTrace+ software. For the analysis of HRV, time- and frequency-domain parameters and records 5 min in length with a sampling rate of 1,024 Hz were used, according to recognized standards . The powPrior to the analyses, all parameters were visually controlled on a 15-s window, and artifacts in the RHR and HRV parameters due to movement were removed. Artifacts due to device failure in the SC or ST were also removed. Measurements with more than 5% artifacts were excluded; this was the case in four measurements of SC as well as in five measurements of RHR and HRV parameters.Statistical analyses were performed using R-Studio software (version 1.2). The normality of the distribution was assessed using the Shapiro test. To assess differences between groups, a Wilcoxon signed-rank test for non-normally distributed data was used. For normally distributed variables, a Pearson correlation analysis was used; non-normally distributed variables were assessed for correlation using Spearman’s correlation.The mean BDI-II score was 29.66, which corresponds to a severe depressive episode as a major diagnosis. Twenty-one subjects (23.6%) were smokers, the mean tobacco consumption was 4 pack-years (SD = 9.88), the mean BMI was 25.5  compared with the baseline  or relaxed state . The RR under stress was also significantly higher than that at baseline  or in the relaxed state . The RR in the relaxed state was significantly lower than that at baseline (p = 0.36 × 10–4). Regarding HRV parameters, SDNN was significantly higher in the relaxed state than under stress exposure ; VLF under stress exposure was significantly lower than that at baseline  or in the relaxed state ; the same constellation could be observed for LF  and HF .There were no between-group differences in SC and ST. A significantly elevated RHR was observed under stress exposure . A weak, but still significant, correlation was observed between the BDI score and RR in the relaxed state .Measured by BDI, symptom severity was positively associated with SC under the stress condition . The correlation between symptom severity and SC differences between baseline and stress conditions (r = –0.195) did not reach the significance level (p = 0.068), nor did the other ANS reactivity measures.In the next step, ANS reactivity was assessed as the difference between baseline and stress condition, stress condition, and relaxed state, as well as baseline and relaxed state. The differences in SC levels between stress and relaxed states correlated with symptom severity measured by the BDI-II ; the other parameters did not differ between the groups. Because of the small sample size, we decided not to run further analyses .Regarding medication with antidepressants, RR in the relaxed state was significantly lower in medicated subjects than in unmedicated subjects .Higher age was related to higher SC, higher RR, and lower HRV at baseline as well as in the relaxed state. Under stress conditions, no relationship between age and electrophysiological parameters was observed . Regardip = 0.022; mean 5.87 in men vs. 2.46 in women, p = 0.005; respectively).Significant sex differences were observed in the relaxed state only: LF and the LF/HF ratio were higher in men than in women .A higher BMI was associated with a higher ST at baseline, stress exposure, and relaxed state   .p = 0.074, p = 0.089, and p = 0.054).Similarly, positive correlations between diastolic BP and RHR, as well as RR at baseline and in the relaxed state, were found. Additionally, diastolic BP was inversely associated with RMSSD in the relaxed state . The negNo significant association was found between symptom severity and BP (systolic or diastolic).To eliminate the impact of age or the diagnosis of arterial hypertension as confounding variables, regression analyses with both parameters and BP were conducted. After correction for the diagnosis of arterial hypertension (18 subjects), systolic BP remained a significant factor for the following parameters: RR, VLF, and SDNN at baseline; RR under stress exposure; and SC, RR, SDNN, RMSSD, and VLF in the relaxed state (only HF at baseline was no longer significant after correction for hypertension). After correction for age, only VLF in the relaxed state remained an independent predictor; for all other parameters, age was the only independent predictor of the observed correlation between electrophysiological parameters and systolic BP.p = 0.056); all other correlations remained significant.Concerning diastolic BP, after correction for age, both age and diastolic BP remained independent predictors of elevated RR at baseline, but not in the relaxed state (with age as the only independent predictor). After correction for the diagnosis of arterial hypertension, diastolic BP was no longer an independent predictor for higher RR in the relaxed state (p = 0.037).The only difference between smokers and non-smokers that reached statistical significance was in the mean HF under stress exposure  and in the relaxed state .The mean lifetime tobacco consumption measured by pack-years correlated negatively with SDNN at baseline  valence. A distinct pattern of ANS reactivity might have been produced by a stressor task with a negatively valenced stimulus eliciting a different range of self-reported intensity . The ANSvia photoplethysmography . Some authors suggest it is more appropriate to use the term “pulse rate variability” (PRV) as a different biomarker than HRV  was reduced, and the RR and RHR were elevated under stress exposure compared with the baseline or relaxed state. Only RR values differed significantly between baseline and relaxed state, either suggesting the robustness of this parameter  or reflecting the use of slow breathing as a relaxation tool. Neither the SC nor ST values differed significantly between the three test conditions. The observed differences in age, sex, and tobacco use were consistent with those of previous studies .The positive correlation between SC response and symptom severity is contrary to the results of the literature review of Sarchiapone, with most findings showing a hypoactive electrodermal response in depressed patients . One posOn the other hand, our results indicate that age and BP do influence the ANS, especially in the relaxed state and at baseline. After regression analysis, age remained the most important influencing factor; however, for some parameters, BP remained more significant than age. Interestingly, almost no age- or BP-related changes under stress conditions could be found, which suggests impaired ANS reactivity. Our results are in agreement with previous findings of reduced HRV in subjects with elevated BP .In our study population, the mean BP was almost at the cut off point for a diagnosis of hypertension; however, only 14 of 89 patients had been diagnosed with arterial hypertension. Hence, we suggest, in accordance with The observed lower respiratory rate in medicated patients in the relaxed state was consistent with some findings pointing out the specific influence of antidepressants on respiratory activity . BecauseSymptom severity was associated with higher sympathetic arousal in an emotion-driven imaginative and retrieval-generated stressor condition and a higher respiratory rate in the relaxed condition.Heart rate variability indices were not significantly correlated with symptom severity (measured by BDI) in any of the stages of the protocol: baseline, stress, or recovery. ANS reactivity measured from HRV index differences between the stages was not significantly correlated with the BDI score.The present study demonstrates that the ANS changes in patients with MDD are complex, and the assessment of ANS reactivity by more parameters than HRV alone might be useful in understanding specific disease-related changes and their underlying mechanisms in depression. With respect to our results, respiratory rate can be considered a useful and easy-to-obtain marker of ANS reactivity in patients with MDD.Furthermore, our results indicate that influencing factors, such as BP or age, can have a greater impact on ANS than symptom severity, and should, therefore, be considered in the study design and data interpretation. Elevated BP seems to be an important but possibly neglected comorbidity in patients with MDD. The relationship between BP and depression should be investigated further.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ehitkommission, Landesärztekammer Baden-Württemberg. The patients/participants provided their written informed consent to participate in this study.JS, AS, and AK contributed to conception and design of the study. AK implemented the study in the clinical setting. JS collected the data, performed the statistical analysis, and wrote the first draft of the manuscript, supervised by AK. AS wrote sections of the manuscript. All authors contributed to the manuscript revision, read, and approved the submitted version.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.


To compare the efficacy of intravenous (IV) lidocaine with standard analgesics  for pain control due to any cause in the emergency department.The electronic databases of PubMed, Embase, ScienceDirect, CENTRAL, and Google Scholar were explored from 1st January 2000 to 30th March 2021 and randomized controlled trials (RCTs) comparing IV lidocaine with a control group of standard analgesics were included.I2 = 81% p = 0.59), 30 min , 45 min , and 60 min . There was no statistically significant difference in the need for rescue analgesics between the two groups , but on subgroup analysis, the need for rescue analgesics was significantly higher with IV lidocaine in studies on abdominal pain but not for musculoskeletal pain. On meta-analysis, there was no statistically significant difference in the incidence of side-effects between the two study groups .Twelve RCTs including 1,351 patients were included. The cause of pain included abdominal pain, renal or biliary colic, traumatic pain, radicular low back pain, critical limb ischemia, migraine, tension-type headache, and pain of unknown origin. On pooled analysis, we found no statistically significant difference in pain scores between IV lidocaine and control group at 15 min (MD: −0.24 95% CI: −1.08, 0.61 IV lidocaine can be considered as an alternative analgesic for pain control in the ED. However, its efficacy may not be higher than standard analgesics. Further RCTs with a large sample size are needed to corroborate the current conclusions. One of the most frequently encountered complaints in the emergency department (ED) is pain . Indeed,Lidocaine is a widely used amide local anesthetic that acts by blocking Na channels in the central and peripheral neurons of the nociceptive pathway . While lTo the best of our knowledge, to date, only a few systematic reviews have assessed the efficacy of IV lidocaine in the ED. Two studies by Silva et al.  and MasiThe PRISMA statement   and the A search strategy was designed with the help of the medical librarian wherein the electronic databases of PubMed, Embase, ScienceDirect, CENTRAL, and Google Scholar were explored. The search limits were set from inception to 26th October 2021. We also search clinicaltrials.gov for any ongoing trial. However, excluded databases with articles preprints that have not been peer-reviewed. A mix of MeSH and free keywords used for the literature search included: “lidocaine,” “lignocaine,” “emergency,” “pain,” and “analgesic.” The search strings used were “(((lidocaine) OR (lignocaine)) AND ) AND (emergency)” and “(((lidocaine) OR (lignocaine)) AND (pain)) AND (emergency).” Two reviewers carried out the electronic search independent of each other. The primary search results were assessed initially by their titles and abstracts to identify citations requiring full-text analysis. The full texts of the articles were reviewed by the two reviewers independently based on the inclusion and exclusion criteria. Any disagreements were resolved by discussion. Furthermore, we also hand-searched the bibliography of included studies for any missed references.Eligibility criteria for this review were structured using the PICOS  framework. Details are as follows:Population: Patients reporting to the ED for any kind of painIntervention: IV lidocaine in any doseComparison: NSAIDs or opioids via any route and any dose (Control group)Outcomes: Pain scores in the first 60 min, use of rescue analgesics, and/or side-effects of the drugs.Study design: Randomized controlled trials (RCTs) onlyExclusion criteria were: (1) Studies using IV lidocaine as an adjuvant to other analgesics (2) Studies not using a comparative analgesic drug or not using NSAIDS/opioids as a comparative drug (3) Non-RCTs and uncontrolled studies (4) Studies not reporting relevant outcomes (5) Editorials, review articles, and non-English language studies.Two reviewers extracted data independently using a data extraction sheet. Data regarding the first author, publication year, study location, cause of pain, inclusion criteria, sample size, mean age, gender details, the dose of IV lidocaine, type and dose of the comparative drug, and study outcomes were extracted. Primarily, we aimed to analyze the difference in pain scores in the first 60 min after drug administration. Secondary outcomes of interest were the need for rescue analgesics in the two groups and side-effects associated with the interventions. A descriptive analysis was carried out if sufficient data were not available for a meta-analysis. The corresponding authors were not contacted for any missing data.We used the recent Cochrane Collaboration's risk of bias assessment tool-2 to assess the quality of included RCTs . This waI2 statistic. I2 values of 25–50% represented low, values of 50–75% medium, and more than 75% represented substantial heterogeneity. However, irrespective of the heterogeneity we preferred to use a random-effects model for our meta-analysis as the included studies were conducted on different populations with significant methodological heterogeneity. Due to a limited number of studies in the meta-analysis (<10), funnel plots were not used to assess publication bias. Sub-group analyses based on the type of pain and type of comparative drug (opioid/NSAID) were also performed if there were at least 2 studies in each subgroup. We grouped studies reporting pain of abdominal origin  and musculoskeletal pain separately to separately assess the efficacy of IV lidocaine for each pain type.“Review Manager”  was used for the meta-analysis. Pain scores at different time intervals were summarized using mean Difference (MD) with 95% confidence intervals (CI). Need for rescue analgesics and side-effects were summarized using odds ratios (OR) with 95% CI. For studies reporting data only in graphical format, Engauge Digitizer Version 12.1 was used to extract data. Median, range and interquartile range data was converted into mean and standard deviation (SD) when required using the method of Wan et al. (The number of search results at each stage is summarized in I2 = 81% p = 0.59), 30 min , 45 min , and 60 min   . GRADE a = 0.18) . On subg = 0.18) . However = 0.18) .I2 = 41% p = 0.20)  . The cer = 0.20) . But on  = 0.20) . SubgrouI2 = 48% p = 0.78) (Details of side-effects reported by included studies are presented in  = 0.78) . The cer = 0.78) .The risk of bias summary of the included studies is presented in Treatment of pain is an important yet complex problem in an ED. While managing this symptom, the clinician has to not only make a quick diagnosis of the origin of pain but also take into account the past medical history, drug history, and severity of the problem to prescribe an optimal analgesic. On account of several apprehensions amongst healthcare professionals regarding the opioid epidemic , researcAs seen in our systematic review, with the availability of only 12 trials, IV lidocaine has not been widely researched for pain management in the ED. However, the drug has been used on a wide range of patients including both musculoskeletal and abdominal pain. On pooled analysis of the trials, we found no difference in pain scores between patients receiving IV lidocaine or standard analgesics at different time points in the first hour of drug administration. Interesting to note was that in the first 30 min, there was a significant but small reduction of pain scores with IV lidocaine in studies on musculoskeletal pain but not for abdominal pain. Nevertheless, this should be interpreted with the concept of minimum clinically important difference (MCID). In 1989, Jaeschke et al.  bought fFor comparing our results with prior literature, it can be noted that the use of IV lidocaine has been most commonly reported in a surgical setting . While tThe use of IV lidocaine as a potential analgesic in the ED is accompanied by its inherent complications. Due to the associated cardiotoxicity and neurotoxicity, IV lidocaine should be cautiously used in patients with comorbidities like heart block, cardiac failure, or epilepsy . FurtherOur review has some limitations. Foremost, the number of trials available in the meta-analysis was not high. Two studies had to be excluded from the analysis due to differences in reporting of outcomes. Secondly, there was significant heterogeneity in the included studies concerning the diagnosis, dosage of lidocaine, and comparative drug used. An attempt was made to explore this heterogeneity using a subgroup analysis for the type of pain and type of control group analgesic. However, this reduced the power of the analysis. Thirdly, not all studies were high-quality and free of bias. The certainty of evidence provided by the review was not high and ranged from moderate-low. Lastly, all the included trials were conducted in just two countries. This significantly limits the generalizability of the results of our review.Nevertheless, our study is the first meta-analysis to assess the efficacy and safety of IV lidocaine for pain control in an emergency setting. Unlike prior reviews , 16, we To conclude, our results indicate that IV lidocaine can be considered as an alternative analgesic for pain control in the ED. However, its efficacy may not be higher than standard analgesics. Further RCTs with a large sample size are needed to corroborate the current conclusions.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.JZ, JH, and LM: conceptualized and designed the study and analyzed the data. GY, KQ, and YZ: literature search. GY, KQ, and SH: writing—original draft preparation. YZ and SH: writing—reviewing and editing. All authors read and approved the final manuscript.This study was funded by Project of Shaoxing Municipal Science and Technology (2018C30078).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.


European Respiratory Journal was the leading journal in publications on tuberculosis studies with a total of 452 published articles, the WHO 2012 report was the most cited document with 2485 total citations while South Africa was the most productive country in tuberculosis publications as well as the leading country with the highest co-authorship collaboration. Analysis of top relevant authors revealed that Anonymous (133) and Dheda (44) were the two topmost relevant authors of tuberculosis publications, South Africa was the most relevant country by corresponding authors and the topmost cited country for tuberculosis publications. Furthermore, analysis of the university collaborations network showed that the University of Cape Town was the topmost university in Africa with the highest collaboration network, tuberculosis as a word had the highest co-occurrence network while the Three Field Plot diagram revealed the relations between universities, keywords and countries. This study provides a quantitative and qualitative analyses of the leading journals, most cited published articles, title word occurrences, and most relevant authors in published documents on tuberculosis and tuberculosis related studies from 2010–2019.Tuberculosis is one of the oldest known diseases and the leading communicable cause of deaths worldwide. Although several studies have been carried out on tuberculosis, no research has examined the publication trends in this area. Hence, this study aimed to fill the gap by conducting a bibliometric study in publications trends on tuberculosis and tuberculosis-related studies in Africa from 2010–2019 and explore the hotspots. Information in published documents on tuberculosis and its related studies from 2010 to 2019 were retrieved from the Web of Science (WoS) database. The bibliometric tool biblioshiny and Microsoft Excel 2016 were used to analyse the top leading journals, top cited documents, authors’ country production, country collaboration networks, most relevant authors, authors’ impacts, most relevant authors by corresponding author, most cited countries, university collaborations, most relevant affiliations, conceptual structural maps, title word co-occurrence networks, collaboration and significance of individual sources, university, country and keyword relations. A total of 3945 published documents were retrieved. The analyses showed that  Mycobacterium tuberculosis complex (MTBC) and it remains one of the global leading public health problems [Mycobacterium comprises of over 140 species [M. leprae and nontuberculous mycobacteria (NTM) other than MTBC and M. leprae [M. africanum, M. tuberculosis, M. pinnipedii, M. bovis, M. canettii, M. caprae, M. microti, M. bovis BCG vaccine strain and M. mungi infecting humans as well as animals [M. tuberculosis is an obligate human pathogen [Globally, the health of about 10.4 million persons is impacted yearly by tuberculosis (TB) resulting in approximately 1.7 million TB-related deaths with the majority of the deaths occurring in resource-limited nations [problems . The gen species  that are animals ,6. Of alpathogen  and is tpathogen . In 2018pathogen  and out M. tuberculosis MDR-MTB. MDR-MTB occurs when these bacteria become resistant to the drugs or agents used in the treatment of the disease; and this is a serious problem that is increasingly becoming prevalent worldwide [The main risk factors for tuberculosis include human immunodeficiency virus (HIV), older age, lower socioeconomic status such as homelessness, crowding, poor nutrition etc. . Other rorldwide . Drug reorldwide . In addiorldwide ,16.M. tuberculosis [TB is a major communicable disease with a global prevalence and about one-third of the worldwide population is infected with rculosis . Among trculosis , and therculosis . In Afrirculosis . In 2018rculosis , and amorculosis . TB poserculosis . Hence, rculosis .Moreover, numerous studies have been carried out on tuberculosis worldwide based on the infection incidence. Studies from such research have to help obtain data or information about the up-to-date state of research, measure current practice, and find gaps. To allows researchers to ascertain and commence new lines of research and help policymakers to evaluate and suggest approaches to improve on the research gaps, a method of statistical analysis called bibliometrics is used to measure or assess the major developmental trends and the characteristics of a given research subject based on published research . BibliomPublished documents in the Web of Science Core Collection (WoS) on tuberculosis between 2010–2019 were mined. The WoS consists of a wide conglomerate of quality and high-impact scientific studies with more than 12 million articles for bibliometric analysis . The WoSIn summary:i and j and 0 otherwise. In general, there is said to be a collaboration network connection between two nodes if they share at least one co-occurrence, and this can be explained by considering country or university collaboration networks. The networks analysis was grouped into (a) top papers, source, and authors relations; (b) title, keyword, and keyword plus analysis; (c) scientific collaboration mapping. The title words, keywords, and co-keyword analyses are methods used to visualize and describe the arrangement or structure of scientific fields of a certain group of publications [The weight is “A” if there is a collaboration network connection between the nodes ications , and theications . Hence, ications . FurtherA total of 3945 documents were retrieved from the WoS between 2010–2019, with average citations per documents of 4.512 and average citations per year per document of 0.7116. Articles (1395) are the most published document type, followed by meeting abstracts (1214), editorial material (311) and reviews (150), etc. The retrieved documents included 11,664 authors with 16,711 author appearances, 3.65 of collaboration index and 900 single-authored documents. European Respiratory Journal (452), American Journal of Respiratory and Critical Care Medicine (216), PLoS One (164), International Journal of Tuberculosis and Lung Disease (105), BMC Infectious Diseases (81) and African Medical Journal (79).The 21 topmost leading journals in publications on tuberculosis with their number of published articles between 2010–2019 are shown in Analysis of authors’ countries’ production outputs on tuberculosis and tuberculosis- related studies from 2010–2019 shows the top 20 most productive author countries in Africa on tuberculosis and tuberculosis-related studies. From the results, South Africa had the highest production output, with 2895 published documents on tuberculosis, followed by Ethiopia (877), Nigeria (533), Tunisia (475), Morocco (399). n = 4 each), Nigeria and Cameroon (3) and Kenya, Burkina Faso, Gabon, and Senegal as each country collaborated with two other Africa countries. Most of the other African countries in The country collaboration and study hotspots can be provided with the visualization of the collaborations of co-authorship countries. The network analysis illustrates co-authorship co-occurrences between countries in tuberculosis publications. The countries’ collaboration networks on tuberculosis publications/outputs and its related studies from 2010–2019 show different clusters with pathways ranging from 0 to multiples. Each node signifies different Africa countries and each node’s diameter, or size denotes or represents the number of occurrence of authors country collaboration strength with other African countries, while the lines signify the collaboration networks or pathways between each country. In the clusters , South An = 133), Dheda (n = 44), Walzl (n = 27), Ameni (n = 25), Na and Van Helden (n = 24 each) and Goussard and Warren (n = 22 each). Based on the number of published articles, the five topmost authors impact on tuberculosis publication outputs include Dheda, with 44 publications with an h-index of 15 followed by Walzl , Ameni , Na and Van Helen  and Goussard and Warren . The authors’ full details of authors impact with their h-index, g-index, m-index, TC, number of publications (NP), and the publication year (PY) are as shown in The top 20 most cited African countries in the retrieved documents from WoS database on tuberculosis related publications from 2010–2019 are shown in n = 716), University of Stellenbosch (n = 344), the University of Kwazulu Natal (n = 219), University of Witwatersrand (n = 198), University of Pretoria (n = 157) and University of Gondar, Ethiopia (n = 131) (n = 131) .M. tuberculosis etc. . In this instance, the significant features were represented in the diagram by rectangles with a different colour. The height of the rectangles in the diagram of the TFP depended on the rate or value of the summation of the relations arising between the component of the rectangle represents  and the diagram of other elements. The more relations the component or element had, the higher the rectangle representing it. Bibliometrics analysis is a scientific study field that has attracted more attention among the scientific community . CurrentEuropean Respiratory Journal (n = 452), American Journal of Respiratory and Critical Care Medicine (n = 216) and PLoS One (n = 164). In the same vein, the topmost cited documents on tuberculosis or tuberculosis-related studies were also published in high impact factor journals and the total citations was between 64 and 634. The most cited document on tuberculosis retrieved from the WoS was the WHO title ‘Global tuberculosis report 2012′ [Tuberculosis [Pediatric Infectious Disease Journal [This study analyzed publications trends on tuberculosis studies from Africa between 2010–2019. When studying the timeline for bibliometrics analysis, some vital factors need to be considered such as the inherent prejudice of bibliometrics against recently published articles or papers which might lead to some extremely vital papers not being involved or included in such analysis as it takes time to amass citations . Howeverrt 2012′  followedrculosis  with 151 Journal  with 124rnal n = 2, Americ Journal .As made evident by the statistical analysis, the total number of citations of topmost cited articles in this study is considered important because of the document’s quality. However, citation counts can vary due to the number of accumulated document or articles variable in diverse search engines . The autMycobacterium species involved in causing tuberculosis. The green cluster has pulmonary tuberculosis as an indicator of infection site, tuberculosis as an indicator of the type of bacterial infection, the red cluster has epidemiology as the study indicator, transmission as an indicator of disease spread, and the blue cluster has HIV as an indicator of co-infection, Africa as an indicator of the continent, South Africa as an indicator of country and drug-resistant tuberculosis (DR-TB) as an indicator of transmission of DR-TB strains. This result is in line with the reports of Calver et al. [These high citations of the published document originated from these African countries shows the impact of tuberculosis on these scientific communities. This result is in line with the report of Merigo and Yang , as theyr et al.  and Diarr et al.  as they Some of the major risk causes that have been linked with hospital-acquired DR-TB are lack of proper TB infection prevention and control measures, poor ventilation, delayed diagnosis, and overcrowded wards . In natiMycobacterium and pulmonary as the lines connecting these title words are thicker compared to other title words (Furthermore, analysis of co-word is used to identify the associations between subjects in a research field and, consequently, help trace science development. Analysis of co-word also focused on identifying the hierarchies among the focused subject areas of a research problem . The resle words . The anaOne of this study’s major strengths is that it is the first and only bibliometric study to the best of our knowledge that characterizes published documents on tuberculosis in Africa from 2010–2019. By including all journals produced in the study region, we were able to generate a broad, comprehensive list of the top-cited journals, top-cited countries, top-cited documents, and most relevant countries by corresponding authors. There are also some limitations to the study. First, bibliometric investigation on newly published high-quality articles would be overlooked or ignored. This is a drawback connected to the effect of the number of times cited. Furthermore, the worth or value of an article influences and progress in a field or area cannot be known only by the number of citations. Furthermore, paper publication’s language plays a key role with favouritism or bias towards articles published in English language journals. In addition, low publication/collaboration rate of a country should not suggest that the quality of scientific research is low.This study provides quantitative and qualitative analyses of the top leading journals, most cited published papers, most relevant authors in publications on tuberculosis from 2010–2019. This bibliometric study also provides insights into authors research outputs, countries collaborations, and relevant countries by corresponding authors. This will help create or generate evidence-based reports, evaluations, and visualizations of research outputs on tuberculosis research. Furthermore, we observed little or no collaboration between authors from non-English or less developed African countries with other English-speaking or developed African countries. In this setting, the involvement in collaboration of these countries with other African countries in research activity should be promoted, mostly those initiatives that consider their priorities and interests ,69. Ther