Alkenylbenzenes are potentially toxic (genotoxic and carcinogenic) compounds present in plants such as basil, tarragon, anise star and lemongrass. These plants are found in various edible consumer products, e.g., popularly used to flavour food. Thus, there are concerns about the possible health consequences upon increased exposure to alkenylbenzenes especially due to food intake. It is therefore important to constantly monitor the amounts of alkenylbenzenes in our food chain. A major challenge in the determination of alkenylbenzenes in foods is the complexity of the sample matrices and the typically low amounts of alkenylbenzenes present. This review will therefore discuss the background and importance of analytical separation methods from papers reported from 2010 to 2020 for the determination of alkenylbenzenes in foods and related products. The separation techniques commonly used were gas and liquid chromatography (LC). The sample preparation techniques used in conjunction with the separation techniques were various variants of extraction  and distillation (steam and hydro-). Detection was by flame ionisation and mass spectrometry (MS) in gas chromatography (GC) while in liquid chromatography was mainly by spectrophotometry. Throughout human history, plants and their constituents have been used as a source of medicine . The avaAlkenylbenzenes are present in many edible consumer products including spices, plant food supplements and herbal medicines. The most common spices containing alkenylbenzenes are anise star, basil, black pepper, cinnamon, coriander, dill, nutmeg, parsley and tarragon. In particular, estragole is present in significant amounts in fennel  while meThe alkenylbenzenes apiol, elemicin, estragole, methyleugenol, myristicin, and safrole have been considered toxic ,10,11,12All phytochemicals are possibly toxic and large doses can lead to poisoning effects . ChemicaTo conduct a comprehensive research on alkenylbenzenes studies, Scopus database was used. The search parameter involved different sets of keywords “alkenylbenzenes”, “methyleugenol”, “myristicin”, “estragole”, “safrole” and “analytical separation technique”, and the year of publication was limited between 2010 to 2020. Liquid chromatography (LC), gas chromatography (GC) or capillary electrophoresis (CE) are the analytical separation techniques. There were >20 research papers, and most papers were on GC and LC. The latest study conducted using CE was in 2008, which was also included in this review. Sample preparation is an important step in the analysis, thus the extraction and clean-up methods reported in the considered papers were categorised and discussed. For GC, these were liquid- liquid extraction (LLE), liquid-phase microextraction (LPME), Quick Easy Cheap Effective Rugged Safe (QuEChERS), distillation (steam and hydro-), and solid phase extraction (SPE). Interestingly, only solvent extraction (primarily with methanol) was reported in combination with HPLC.Gas chromatography was invented in 1952 by A. T. James and A. J. P. Martin. GC is a simple and fast analytical separation technique that is applicable to many volatile compounds (with high vapour pressure at temperature below 350 °C to 400 °C) such as alkenylbenzenes . It utilFor high-sensitivity analysis with confident identification of alkenylbenzenes, a few studies combined FID with MS ,18,19. MIn terms of GC conditions see , majoritIn GC, the sample is vaporised and injected into a port at the head of GC column. Food samples are not amenable to directly injection into GC columns; therefore, sample preparation is essential prior to analysis. The aim of sample preparation is to alter the sample to a form that is suitable for final chemical analysis. The number of steps in the sample preparation method depends on the concentration of the analyte in the sample, complexity of the sample, and the limit of quantitation (LOQ) and linear range of the analytical separation method . Some of the earliest sample preparation methods is simple dilution and extraction ). In the case of extraction, this method allows the analyte of interest to be extracted from a sample matrix with optimum yield and selectivity . A multin-tetradecane) were added and mixed thoroughly prior to measurement [Addition of an appropriate solvent to the sample is the simplest way for sample preparation prior to GC analysis. For example, hexane was used as dilution solvent in the determination of methyleugenol in tea tree oils. To 5 µL of oil in 2 mL GC vials, 1 mL of n-hexane and 50 mg/L internal standard (IS)  in pepper and its varieties using GC, a solvent extraction aided by ultrasound was developed. Ethyl acetate (AcOEt) was chosen as extraction solvent because it was suitable for the extraction of non-polar alkenylbenzenes. The procedure was very straightforward, a weighed sample (1 g), AcOEt 20 mL) and dicyclohexylmethanol  was sonicated at 37 kHz for 45 min at room temperature in an ultrasonic bath. After centrifugation at 3700 rpm (5 min), an aliquot of the AcOEt supernatant was subjected to GC analysis. The mean recovery reported was acceptable in the range of 70% to 120% [ mL and dn-butyl chloride, hexane and toluene [n-hexane and MTBE. MTBE and 1,1,2-trichloro-1,2,2-trifluoroethane showed a similar extraction behaviour (about 90% at first extraction), whereas n-hexane had a lower yield (about 65% at first extraction). 1,1,2-trichloro-1,2,2-trifluoroethane was an ozone-depleting chemical; therefore, MTBE was used for further experiments in the study. Cyclodecaneone was used as internal standard (IS) in the experiment to improve the accuracy of quantification. For solid samples, ethanolic homogenate was made by mixing with 100 mL of 60% ethanol. Beverage solution or 1 mL of the ethanolic homogenate was spiked with 200 µL of 40 mg/L cyclodecanone (IS), 5 mL of water and 1 mL of extraction solvent. After shaking and centrifugation, the organic phase was subjected to GC analysis. The recovery for this sample preparation was notable in the range from 95% to 105%.LLE is widely used to transfer an analyte from an aqueous matrix into an extraction solvent. The aqueous matrix and extraction solvent should be immiscible or partially miscible with each other so that the two solvents can be separated easily. Moreover, the analytes from the aqueous matrix should be soluble in the extraction solvent and ideally exhibit high partition coefficients in the solvent. The common extraction solvents used are dichloromethane, chloroform,  toluene . An exam toluene . In thisLPME which is a miniaturized version of LLE was introduced by Jeannot can Cantwell in the early 1990s . It is dn-hexane) into the sample oil phase. The organic phase was then subjected to the second (backward) DLLME in order to remove the surfactant which was detrimental during GC-MS analysis. In the backward DLLME, water and ethyl acetate (dispersant) were added to the hexane extract, and the surfactants were removed into the water phase. The efficiency of the dual DLLME method was determined by calculating the enrichment factor which were 4.5, 9.1, 9.8, 16.7 and 37.1× for estragole, eugenol, methyleugenol, safrole and myristicin, respectively [An innovative dual DLLME  was usedectively .QuEChERS was initially established to detect pesticide residues in fruits and vegetables but had now rapidly gained attention in the extraction of analytes from different matrices. It is a very popular technique with thousands of papers published according to PubMed . QuEChER3 (100 µL) and AcOEt (10 mL) was added, and the mixture was vortexed (1 min). Anhydrous magnesium sulphate (2 g) and sodium chloride (0.5 g) was added and the resulting mixture was sonicated for 10 min. After centrifugation, 1 mL of supernatant was collected for clean-up. This was by adding anhydrous magnesium sulphate (500 mg) and primary/secondary amine PSA (100 mg). PSA is a solid phase extraction adsorbent used for sample clean-up, which is available commercially. After the vortex and centrifugation steps, the sample was filtered through a 0.22 µm polytetrafluoroethylene (PTFE) syringe filter and analysed by GC. Satisfactory recoveries were obtained in the range of 94.3–100.3% by this method [QuEChERS was recently used in the determination of methyleugenol in food samples . For bots method . In anots method , which wSPE uses a liquid phase and a solid phase to separate analytes from a solution. It is often used to clean-up the sample before final chemical analysis. In general, the procedure starts by loading a sample solution into a SPE column, and undesired components are removed by flushing with a non-eluting solvent. An appropriate (eluting) solvent is loaded into the column to wash off the desired analytes that were retained in SPE material during the initial steps.A phenyl-containing group SPE material was used to clean-up the hexane extract of fish fillets that potentially contained methyleugenol, eugenol and isoeugenol  see Sec. The SPEAccording to the type of interaction between the water and/or steam, there are two main variants for extraction using distillation: steam distillation and hydro-distillation. Steam distillation has been used for a long time in the analysis of volatiles from high-water-content foods, beverages and essential oils ,44. It eHydro-distillation is a common extraction method used in GC analysis. In hydro-distillation, there are three main physicochemical processes involved: hydro-diffusion, hydrolysis and decomposition by heat . ClevengCymbopogon khasianus Hack., Gogoi, et al. [Pimenta pseudocaryophyllus essential oil which contained chavibetol and methyleugenol. Semi-preparative HPLC was then used to purify chavibetol and methyleugenol from the crude essential oil. GC with FID was used to determine the purity, with chavibetol (98.7%) having a higher purity compared to methyleugenol (85.3%). The purification method of hydrodistillation method coupled with semi-preparative HPLC can provide chavibetol with high purity and recovery. HPLC will be discussed in the next section, but for analysis.Since 2010, eight articles described hydro-distillation for the extraction of alkenylbenzenes in various types of food related samples. In the analysis of methyleugenol present in , et al.  collecte, et al. , most li, et al. ,23,24,29, et al.  showed t, et al.  used theThe development of modern HPLC has been commonly linked to the research achievements of Prof. C. Horvath of Yale University. HPLC is one of the most important analytical separation techniques nowadays. A HPLC system consists of five main components: pump, injector, column, detector, data acquisition and control system. The pump provides constant and continuous flow of liquid mobile phase throughout the system. The sample is injected at the injector port and enters the column. The column contains a stationary phase, and it is where the separation of the components in the mixture happens. Once the components exit the column, it enters the detector and produces signals. Data acquisition and control system is a computer-based system that monitors all HPLC parameters .Cinnamomum zeylanicum Blume), foods and commercial herbal formulations as shown in Pimenta pseudocaryophyllus [HPLC was used to determine different types of alkenylbenzenes in various plants /diode array detector (DAD). UV-VIS/DAD is highly applicable to alkenylbenzenes because these compounds contain a UV active chromophore see  did not Cinnamomum zeylanicum Blume. Recovery of methyleugenol was 99% after solvent extraction with sonication followed by simple filtration. The recovery value was considered acceptable because the recovery value was within 80% to 110%  [Many studies evaluated the use of different solvents such as hexane, methanol and ethanol for the solvent extraction of secondary metabolites in various plant parts  . They haMethods) . This stMethods)  used metMethods)  determinIn the determination of myristicin in pesto sauce, Al-Malahmeh and co-workers  used theMeanwhile, the study by Lung et al.  was inteCapillary electrophoresis (CE) is an electric field driven analytical technique used for the separation of compounds in a mixture ,63. In C2 allowed to fine-tune the electroosmotic flow without influencing the effective electrophoretic mobility. A sample electrochromatogram of the separation of the sassafras essential oil components, including the targeted alkenylbenzenes is shown in Indeed in 2008, Huhn, et al.  utilizedThis review highlighted the different analytical separation methods  for alkenylbenzenes analysis from mainly between 2010 and 2020, with GC and LC as the main players. The most popular sample preparation method for GC was hydrodistillation whereas solvent extraction with methanol was typical in LC. Hydrodistillation was applicable for extraction of essential oils but not for food samples. Due to the complexity of food matrices, extraction techniques such as LLE, SPE and QuEChERS have been developed. Methanol extraction is simple with high recoveries but may suffer from matrix interferences during the analytical separation. We expect new developments for extraction that reduces matrix interferences while increasing detection sensitivity. During the review period, various alkenylbenzenes were found in many food and food related products. Analysis of alkenylbenzenes will remain to be an important research topic for guarding our public health, since these compounds are  carcinogenic and genotoxic. The availability of alkenylbenzenes in food is huge, due to the many sources of these compounds from various plants used mainly as spice or flavouring.Most of the methods were able to perform analysis of the targeted samples. For example in GC, the analysis were satisfactory using one dimension only, while two dimensional GC separation are applied for more complicated samples . For LC,


Pulmonary hypertension (PH) is common in patients with heart failure (HF). The role of PH in patients with HF with reduced (HFrEF) and preserved (HFpEF) left ventricular ejection fraction (LVEF) has been extensively characterized during the last years. In contrast, the pathophysiology of HF with mid-range LVEF (HFmrEF), and in particular the role of PH in this context, are largely unknown. There is a paucity of data in this field, and the prevalence of PH, the underlying mechanisms, and the optimal therapy are not well-defined. Although often studied together there is increasing evidence that despite similarities with both HFrEF and HFpEF, HFmrEF also differs from both entities. The present review provides a summary of the current concepts of the mechanisms and clinical impact of PH in patients with HFmrEF, a proposal for the non-invasive and invasive diagnostic approach required to define the pathophysiology of PH and its management, and a discussion of future directions based on insights from mechanistic studies and randomized trials. We also provide an outlook regarding gaps in evidence, future clinical challenges, and research opportunities. Pulmonary hypertension (PH) in patients with left heart diseases is the most common form of PH . The preThe relatively new entity of HFmrEF has been introduced by the 2016 European Society of Cardiology (ESC) guidelines on the diagnosis and management of HF . In thesNotably, in both the new ESC HFA-PEFF score  and the In patients with left heart disease, PH is most often a reflection of elevated LA pressure and pulmonary artery wedge pressure, respectively, i.e., post-capillary PH group 2 PH) , 2. Acco PH , 2. The 2018 PH World Symposium has proposed a new PH definition, which aims to overcome the above-mentioned limitations of the 2015 definition and to consider new data on the normal range of pulmonary pressures. This new definition is under intense discussion, however, and there are no new PH guidelines yet. According to this approach, pre-capillary PH is defined as mPAP >20 mmHg (new cut-off), mPAWP ≤ 15 mmHg, and PVR ≥3 WU (new compulsory criterion) . Post-can = 10,023), 46% of all patients undergoing right heart catheterization had post-capillary PH  (In the largest study from a catheterization laboratory database (with PH) , and 39%with PH) . Althougwith PH) , it is lwith PH) –20. Mortwith PH) . The pron = 1,079), the median LVEF according to secondary core lab analysis was 59%, and LVEF was ≥50% in 79%, 40–50% in 18%, and <40% in 3% of patients. The prevalence of PH (defined as peak TRV >2.9 m/s) in this PARAGON-HF subgroup was 31% (n = 289), HFmrEF (n = 82), and HFpEF (n = 85) were ≈2.9, ≈2.9, and ≈3.0 m/s, respectively (no difference) (In one study using a non-invasive PH definition , a high PH prevalence of 83% was found among 244 HFpEF (LVEF ≥50%) patients from a community based study . Many of was 31% . The mea was 31% . This wa was 31%  and Treaference) . Thus, aference)  [cf. PARference) ]. Given  31% n = 9, HFmrEFThe primary driver of PH in any type of left heart disease is an elevation in LA pressure, which in turn depends on the properties of the left ventricle, the function of the mitral valve, and the compliance of the left atrium. Data examining this pathopathopysiology specifically in HFmrEF are sparse. To understand the mechanism of PH in HFrEF, we first discuss available studies looking at the clinical characteristics and echocardiographic features in HFmrEF, and then look at the mechanistic studies on PH in HFrEF and HFpEF as a basis to speculate about the situation in HFmrEF.In terms of clinical characteristics, HFmrEF patients more closely resemble the HFrEF rather than the HFpEF group  . The avaIn the well-characterized TIME-CHF population, the ischemic HF etiology was similarly common in HFmrEF as in HFrEF, and the atrial fibrillation (AF) prevalence was similar in HFmrEF and HFpEF . Left veThe biomarker profile in HFmrEF is also characterized by intermediate plasma concentrations of natriuretic peptides and a pattern of biomarkers that includes features of both HFpEF and HFrEF, i.e., markers of both inflammation and cardiac stretch, whereas in HFpEF, biomarkers were related to inflammation, and in HFrEF, biomarkers were related to cardiac stretch .There is evidence for substantial differences in the pathophysiology of PH between patients with HFpEF and HFrEF . In HFpEThere are two factors with an important interaction with LA function and thereby promoting PH: MR and AF. In HFrEF, various degrees of functional MR are common and predict prognosis . In thesn = 55) and HFpEF (n = 53) with PH  has revealed global  pulmonary vascular remodeling  and subsequent remodeling under the influence of several mediators seems to be of paramount importance , and assessment of LVEF in clinical practice is associated with substantial variability . There iPatients with a mildly reduced LVEF, i.e., between 41 and 49%, and evidence of possible PH represent a diagnostic challenge because a broad spectrum of disease mechanisms and hemodynamic patterns can be hidden behind this constellation , Table 2There are algorithms composed of clinical parameters and non-invasive findings for the discrimination between pre- and post-capillary PH –61. TablIn a patient with LVEF 41–49% and intermediate or high likelihood of PH, PH can be the consequence of LV dysfunction with LA pressure elevation, i.e., HFmrEF with group 2 PH, or this maybe a non-group 2 PH that co-exists with mild left ventricular dysfunction , 2. MeasThe classical class I indication for right heart catheterization in patients with group 2 PH is in the context of transplant evaluation . GuideliNotably, most patients with an LVEF between 41 and 49%  seen in daily practice are not symptomatic from HF, and therefore mechanisms for dyspnea other than the mildly reduced LVEF have to be carefully looked for . Patientpost-hoc analyses of three large “HFpEF studies” using variable LVEF cut-offs for inclusion and evaluating the effect of candesartan vs. placebo (LVEF >40%)  , spironoEF >40%) , and sacEF >40%)  have revEF >40%) . Thus, wEF >40%) , and carEF >40%)   . The rolEF >40%) . A recenEF >40%) . It is spost-hoc analysis of hemodynamics in 79 patients treated with the intraatrial shunt device  revealed that the 27% increase in pulmonary flow at rest was accompanied by a 17% reduction in PVR and a 24% increase in pulmonary artery compliance , cardiac resynchronization, and transcatheter mitral valve repair. In transplant candidates with advanced HFrEF (mean LVEF 18%) and CpcPH without acute reversibility, left ventricular unloading by implantation of an assist device has been shown to result in a reduction in PVR from 5.1 to 2.0 WU within 6 weeks . It is umpliance . Similarmpliance .Patients with HFmrEF and PH  may benefit from a particularly aggressive use and combination of the available treatments including diuretics. There are, however, no established drugs specifically targeting PH in HF in general and also in HFmrEF. Only a few studies have studied the effect of specific pulmonary arterial hypertension-targeted therapeutics in patients with HFpEF or HFmrEF and PH  78–87).–87.78–87Intense research will be required to define the key mechanism underlying the pathophysiology of (a) HFmrEF and (b) PH in HFmrEF. This will lead to a refinement of the definition, the diagnostic criteria and the therapeutic approach. Very recently, a universal definition and classification of HF has been proposed . In thisApart from the treatment of the underlying left heart pathology  there is currently intense research investigating novel treatments targeting the pulmonary vasculature directly , 94. AppHeart failure with mid-range LVEF in general, and PH in HFmrEF in particular, are entities that have been incompletely characterized. Cross-sectional studies suggest that HFmrEF patients are overall characterized by a left heart phenotype which is intermediate between HFrEF and HFpEF. With regards to the pathophysiology of PH the available data suggest that there are many similarities with HFpEF. In clinical practice, patients with shortness of breath, an LVEF in the mid-range of 41–49% and evidence of PH represent a diagnostic challenge. First, a careful differentiation between post- and pre-capillary PH is required. Second, in patients with post-capillary PH the predominant mechanism of LA pressure elevation has to be identified as this will represent the primary target for therapy. In terms of medical therapy, there is some evidence for a benefit of classical HFrEF therapeutics, i.e., angiotensin receptor blockers, spironolactone, sacubitril/valsartan, and betablockers for HFmrEF and presumably also for HFmrEF with PH. However, at the moment, this is still speculative, and substantial additional research will be required to define the optimal management of these patients.MM: conception, collection of data, writing of first draft, and finalization of paper. LW, MB, RB, LJ, and HR: critical revision and final approval. All authors contributed to the article 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.


The triple benefit health education intervention package employed in this study can serve as an intervention tool to combat malnutrition among adolescent girls in Nigeria at large.Knowledge and attitude are essential components of food security as malnutrition remains a critical public health concern among adolescents. The study evaluates the effectiveness of a Triple Benefit Health Education Intervention on knowledge, attitude and food security towards malnutrition among adolescent girls. This was a cluster randomized controlled trial among 417 randomly selected adolescent girls aged 10 to 19 years old in Maiduguri, Borno state, Nigeria from October 2019 to March 2020. About 208 respondents were assigned to experimental while 209 to control group, respectively, using an opaque sealed envelope. A structured questionnaire using KoBo Collect Toolbox was used for the collection of data at baseline, three and six-months post intervention while the data collected were analyzed using generalized estimating equation (GEE). The outcome of the baseline shows no statistically significant difference in sociodemographic characteristics, knowledge, attitude and food security between experimental and control groups. The study reveals a statistically significant difference between experimental and control groups for knowledge ( Adolescents are the nation’s future, so there is a need for them to have an adequate knowledge of, and attitude towards, the importance of balanced diet and the importance of food security in terms of its availability, accessibility, affordability and utilization, as it forms the basis for a healthy life, mental development, intellectual abilities, physical growth and strength to cope with daily activities ,2. The eGlobally, it has been reported that many children and adolescents (young people) are not able to develop and grow to reach their full potential and become productive in life due to an inadequate diet to meet their daily nutritional needs. In order for children and adolescents to have good nutritional intake, it is important for them, especially adolescent girls, to have a nutritious, affordable, safe, and sustainable diet to meet their everyday needs. The triple burden of malnutrition  has become a threat to the growth, development and survival of children and adolescents, further endangering the productivity of nations, as a result of the poor quality and quantity of diet consumed . KnowledHealth education intervention for adolescents in a school setting provides them with the required skills, knowledge and attitudes for healthy selection and utilization of food. Unhealthy selection of food, inadequate information on the importance of food and food groups, malnutrition and its consequences and lack of a kitchen garden among adolescents can increase the burden of malnutrition, which can be mitigated through health education intervention. Previous studies have revealed that health education intervention lays a foundation for the improvement of nutritional knowledge and attitudes relevant to healthy living ,15,16,17Since there are high burdens of malnutrition among children and adolescents that may heighten health related problems, there is need for nutrition sensitive intervention, especially in low and middle-income countries, which must be addressed as a priority. The sustainable development goals have pointed out ways of reducing the determinant of malnutrition, including no poverty, no hunger, quality education, and gender equality, but for the adolescent age group social determinants and nutrition sensitive intervention must be addressed to improve their health and wellbeing. Healthy adolescents who are protected from morbidity and early pregnancy are less likely to develop all forms of malnutrition during adolescence and adulthood, and more likely to reduce the occurrence of non-communicable diseases, have optimal maternal and birth outcomes, and enjoy increased productivity and work capacity . There are no existing data on the overall current prevalence of malnutrition, knowledge, attitudes and food security related issues among adolescents in Nigeria. The trend of malnutrition among women aged 15–49 years, with adolescents included, has been stable for the past 10 years, reporting 12% from 2008 to 2018 . FurtherThere are several policies and programs put in place by the Nigerian government to address the problem of malnutrition among children including the national policy on food and nutrition in Nigeria ,26, the Usually, researchers incorporate a theory-based approach for their research to be successful. The information, motivation, behavioral skills model (IMB) has been used in promoting nutrition-related practices and the development of preventive intervention . AlthougA school-based single blinded cluster randomized controlled trial designed was used to evaluate the effectiveness of the triple benefit health education intervention among adolescent girls in four randomly selected secondary schools in Maiduguri, Borno state, Nigeria. A two population proportion formula was used to calculate the population size , based oInclusion criteria were government secondary schools, schools with full secondary school, schools with boys and girls or girls school only, schools within Maiduguri only and adolescent girls between 10 and 19 years old. Schools not owned by the government, primary schools and schools with women and not girls were excluded. This study was conducted between October 2019 and March 2020. A two-stage sampling method was adopted to randomly select four schools using a software number generator, and a total of 424 were randomly selected from six arms of the schools (JSS1 to SS3) to partake in the study. About 212 participants were recruited into the experimental group and 212 into the control group; each group was allocated using the simple random method, the allocation was performed as a cluster into the experimental and control groups using opaque sealed envelopes. However, 417 were eligible for participation in the study. Seven participants were excluded from the study, of which three were more than 19 years old, while parents of the four students did not give their consent. About 417 respondents brought back the signed consent form. Participants were interviewed using KoBo Toolbox at baseline with 208 in the intervention group and 209 in the control group, respectively.The triple benefit health education intervention module was guided by the information, motivation, behavioral skill (IMB) theory to educate adolescent girls on knowledge, attitudes and food security. The experimental group in this study received the triple benefit health education intervention twice in a month for three months. The module was developed with the clear intention of reducing the burden of malnutrition and ultimately improving the health, well-being and the health of the future offspring of adolescent girls. The Triple Benefit Health Education Intervention module was subdivided into six modules and was conducted for three months with the experimental group by the facilitator. Each session lasted for 1 h:30 min, and the topics covered in the sessions are presented in A questionnaire was used for the collection of data, using KoBo Toolbox, on sociodemographic characteristics, knowledge, attitude and food security. The questionnaire was developed by the researcher in English.This segment comprises 15 questions on sociodemographic characteristics including age, ethnicity, class in school, religion, household size, place of residence, household income, head of household, age of father, father’s education, father’s occupation, age of mother, mother’s education, mother’s occupation, and family type. This section has both nominal and continuous scale variables.The knowledge questionnaire was adapted from the Food and Agricultural Organization of the United Nations  and consIn this study the attitude questionnaire was adapted from the Food and Agricultural Organization of the United Nations . AttitudFood security questions were adapted from those for older children  and const-test was used. A generalized estimating equation was used to evaluate the changes between experimental and control group at three and six-months post intervention. Statistical significance was determined using p-value < 0.05 for all the comparisons in this study. Data were collected at baseline, three and six-month post intervention using KoBo Toolbox and were analyzed using SPSS version 25. Variables that are continuous were presented as mean and standard deviation before being categorized, while categorical variables were presented in the form of frequency and percentage. The differences between experimental and control group for each demographic feature were determined using Chi-square at baseline, whereas for differences in overall scores between experimental and control group for knowledge, attitude and food security at baseline, independent Approval for ethics was obtained from Universiti Putra Malaysia Ethical Committee UPM/TNCPI/RMC/JKEUPM/1.4.18.2 (JKEUPM). Permission was obtained from the Ministry of Education. Written consent from parent/guardian and respondents was obtained before the intervention. The study was also registered with Pan African Clinical Trials Registry (PACTR201905528313816). This study evaluates the effectiveness of a triple benefit health education intervention in improving knowledge, attitude and food security among adolescent girls. Out of a total of 424 participants, 417 gave their consent to partake in the study. A total of 208 were assigned to the experimental group, while 209 to the control group. There was a response rate of 100% at baseline, 98.1% at three-months and 96.6% at six-months post-intervention in both groups, respectively. Intention to treat analysis was employed and all randomized participants were included in the analysis by the imputation of the mean of the responses at three and six-months post-intervention . The prop = 0.589). The mean ± SD for attitude score between experimental and control group at baseline was 53.36 ± 5.0. The scores range from 41 to 70. There was no statistically significant difference between experimental and control group for attitude at baseline for attitude (p = 0.744). The mean ± SD for food security score between experimental and control group at baseline was 5.49 ± 3.5. The scores range from 0 to 9. There was no statistically significant difference between experimental and control groups for food security at baseline (p = 904).The participants in the experimental and control groups were compared on knowledge, attitude and food security towards malnutrition at three and six-month post intervention using generalized estimating equation (GEE). The following are the results of the changes in knowledge, attitude and food security at 3 and 6-month post-intervention.p < 0.001). Participants at 3 and 6-month post-intervention have higher odds of having good knowledge compared to participants at baseline respectively . p < 0.25 at a univariate level were tested as the covariates in the final model. p = 0.837). Participants at three and six-months post-intervention have higher odds of having good knowledge compared to participants at baseline respectively . GEE was used to assess the effectiveness of the Triple Benefit Health Education Intervention on knowledge from baseline to three and six-months post-intervention adjusted with covariates. Factors with p < 0.001; AOR = 9.397, 95% CI: 3.915–22.471, p < 0.001). There was a significant interaction at three and six-month post-intervention; participants at three and six-month post-intervention have higher odds of having good knowledge compared to control group at baseline, respectively . Participants from Chibok ethnic group have higher odds of having good knowledge compared to those from Bura ethnic group . Participants in food secured level have higher odds of having good knowledge compared to those in very low food secured level . Participants with good information have higher odds of having good knowledge compared to those with poor information . Participants with good motivation have higher odds of having good knowledge compared to those with poor motivation . Participants with good behavioral skills have higher odds of having good knowledge compared to those with poor behavioral skills . Participants in SS1 and SS2 have higher odds of having good knowledge compared to those JSS 1 . Participants at three and six-months post-intervention have higher odds of having good attitude compared to those at baseline respectively . p < 0.25 at a univariate level were tested as the covariates in the final model. p = 0.998). Participants at three-months post-intervention have higher odds of having good attitude towards malnutrition compared to those at baseline . GEE was used to assess the effectiveness of the Triple Benefit Health Education Intervention on the attitude of participants from baseline to three and six-months post-intervention adjusted with covariates. Factors with p = 0.017; AOR = 3.076, 95% CI: 1.636–5.785, p < 0.001), respectively. There was a significant interaction at three and six-months post-intervention; participants at three and six-months post-intervention have higher odds of having good attitude compared to control group at baseline . Participants with normal BMI have higher odds of having good attitude compared to underweight . Participants in low food secured level have higher odds of having good attitude compared to very low food secured level . Participants with good information on malnutrition have higher odds of having good attitude compared to those with poor information on malnutrition .Islamic participants have higher odds of having good attitude compared to those from the Christian religion . Participants at three and six-months post-intervention have higher odds of being in food secured level compared to those at baseline respectively . p < 0.25 at a univariate level were tested as the covariates in the final model. p = 0.539). There were no significant differences at three and six-months post-intervention for food security level compared to those at baseline , respectively. GEE was used to assess the effectiveness of the Triple Benefit Health Education Intervention on the food security level of respondents from baseline to three and six-months post-intervention adjusted with covariates. Factors with p = 0.010; AOR = 2.552, 95% CI: 1.467–4.440, p = 0.001), respectively. There was a significant interaction at three and six-months post-intervention; participants at three and six-months post-intervention have higher odds of being in food secured level compared to control group at baseline . Participants whose monthly income was between ₦31,000–₦50,000 and ₦51,000 and above have higher odds of being in food secured level compared to those with monthly income less than ₦18,000 . Participants whose mothers’ education were primary and tertiary education have higher odds of being in food secured level compared to those whose mothers had no education . Participants whose sources of information were from health worker/clinic and schoolteachers have lower odds of being in food secured level compared to those whose sources of information were from social media . For every increase in protein, participants have higher odds of being in food secured level compared to very low food secured level .Participants in urban areas have higher odds of being in food secured level compared to those in rural areas . There was a statistically significant improvement after the Triple Benefit Health Education Intervention on knowledge of participants towards malnutrition at three (p < 0.001) and six-months (p < 0.001) post-intervention compared to the baseline result. This significant improvement might be attributed to the information obtained from the Triple Benefit Health Education Intervention module. Therefore, the outcome of this study supports the effectiveness of Triple Benefit Health Education Intervention in improving the knowledge of adolescent girls. The findings of the current study regarding the effectiveness of the Triple Benefit Health Education Intervention was significantly supported by educational interventions in India (p < 0.05), Palestine (p < 0.001), Bangladesh (p < 0.001), Iran (p < 0.05), Baltimore (p < 0.001) and Urbana city (p < 0.05) [p = 0.45), which may be due to the absence of a theory of behavioral change, the methodological nature of the intervention program and the narrow focus of the intervention program [p < 0.001). Similarly, the educational intervention by Shesha et al. (2018) [p < 0.05) after the educational intervention, as it has proven to bridge the gap in knowledge among adolescent girls. Knowledge is the corner stone of attitude, and limited access to knowledge has been assumed to be among the causes of malnutrition [p = 0.010) were significantly associated with good knowledge, which suggests that the triple benefit health education intervention was more effective among respondents in the higher class SS1 and SS2 compared to those in lower class JSS1, indicating that the higher the social class, the better the understanding [p < 0.025) was significantly associated with good knowledge, and socio-demographic characteristics and cultural norms and differences prevalent in the various communities could be the contributing factors to good knowledge. This study also reveals that food security  was significantly associated with good knowledge. Food secured adolescents are more likely to have good dietary intake, contributing to healthy and good nutritional status, supporting these girls during their first pregnancy and, in turn, a positive impact on the future generation. Food insecurity or hunger reduces learning capacity, school attendance, and earning capacity, thereby increasing the risk of hunger and poverty in the future [p < 0.001), motivation , and behavioral skills  further reveal the significant association between knowledge of malnutrition and the IMB model, indicating that the incorporation of the IMB model in the intervention study would improve knowledge [The findings from this study reveal a statistically significant difference between the experimental and control groups for knowledge ( < 0.05) ,53,54,55 program . The stu program  further . (2018)  consisteutrition . Adolescutrition ,60. Imprutrition . Adolescutrition . The nututrition . Other fstanding . Ethnicie future . Informanowledge . p < 0.001). There was also a statistically significant difference at three (p < 0.001) and six-months (p < 0.001) post-intervention after the Triple Benefit Health Education Intervention. The findings showed that the content of the Triple Benefit Health Education Intervention module and the methodological concept had positively influenced the attitude of adolescent girls. Similarly, education intervention studies in Canada (p < 0.001), Palestine (p < 0.001), Shahr-e-kord city, Iran (p < 0.001), Bangladesh (p < 0.05), and China (p < 0.023) reported significant changes in post-intervention and follow up [p > 0.05) and Bangalore (p > 0.05) showed no significant result in post-intervention. This may be due to a small sample size of less than 100 with less than 50 respondents in each group, inadequate training on some specific aspect of the study, presentation skills, and, more importantly, a large number of dropouts in the control group during post-intervention could be a contributing factor to its non-significance [p < 0.001) [p = 0.007) from baseline to post-intervention and follow up. It appears that education interventions that concentrates on developing health-related skills and imparting health-related attitudes are more likely to benefit adolescent girls in health-enhancing practices [p = 0.001) was significantly associated with attitude. Religion has its unique way of disseminating information to its adherents and this information is transmitted through generations to meet the basic needs of its groups and for survival, shaping the attitude of individuals in the form of norms and values [p = 0.008), respondents with normal nutritional status significantly improved from baseline, and there was also a significant decrease in underweight from baseline as a result of the triple benefit health education intervention, giving the adolescent child hope for future survival. Food security  was significantly associated with attitude towards malnutrition. Food security can have impact on attitude and nutritional status thereby influencing the growth and development of adolescents as it becomes woven in an intergenerational cycle of malnutrition [p < 0.001), good information is likely to improve attitude, as acquired information on malnutrition  tends to change beliefs and personal values associated with various health behaviors capable of changing attitudes towards malnutrition and knowing fully the future consequences.The results reveal a statistically significant difference in attitude between the experimental and control groups  . Furtherractices . School ractices . Attitudractices . Religiod values . In termutrition . As for p < 0.001). There was a statistically significant difference at three (p = 0.026) and six-month (p = 0.001) post-intervention for food security after the Triple Benefit Health Education Intervention compared to the control group at baseline. This indicated that Triple Benefit Health Education Intervention improved the food security situation of participants. The effects of malnutrition in women are borne throughout their lifecycle and through generations. Nutritional inadequacy through food insecurity during the period of adolescence can affect present and future health and well-being, as it is intrinsically linked to the health and well-being of offspring [p = 0.007). This study reveals that urban residence has higher odds of being food secure compared to rural dwellers, perhaps due to non-availability of sufficient farm produce and the financial resources caused by displacement as a result of the lingering humanitarian crises that have limited farm production and food availability in the rural areas and the outskirts of the urban areas. As regards education [p = 0.012, ₦51,000 and above; p < 0.001), this study reveals that households with better income have higher odds of being food secured compared to lower income households. Income is an important determinant of food insecurity. Higher household income reduces the severity of food insecurity, as lack of financial security can lead to food insecurity. High household income means earning more, making more food choices and better management of the household [p = 0.015, tertiary education; p = 0.027), mothers who are educated might have less tendency to become food insecure, as since they are educated there is tendency for them to be working or in menial business, earning income that will help in cushioning the family needs in term of food choice, availability and utilization. Mothers with higher level of education are more likely to earn income, adopt technology and be engaged in livelihood activities that can contribute to better food production, thereby reducing the risk of household food insecurity [Findings from this study reveal a statistically significant difference for food security between the experimental and control group . The study was conducted in only one out of the 27 districts in the state. Another limitation of the intervention includes non-inclusion of schools with married women, schools with boys only, private schools, primary schools with early adolescents, school dropouts, and adolescents not attending any school at all. Other limitations of our intervention include limited time, lack of funding, and inability to strategize for a parent teacher’s association (PTA) meeting before the onset of the intervention to enable full participation of all eligible participants.Globally, humanitarian and developmental agencies have acknowledged the importance of recognizing that adolescents belong to a separate age group, from children to young adults. Adolescents, especially girls, poorly transit into adulthood at the risk of being pushed into the vicious cycle of the intergenerational cycle of malnutrition, deficiency and poverty. In this study the Triple Benefit Health Education Intervention was found to be effective in improving knowledge, attitudes and food security towards malnutrition among adolescent girls in Maiduguri Metropolitan Council, Borno State, Nigeria. Participants in the intervention group had higher odds of having good knowledge and attitude and also had higher odds of being in the food secured level at three and six-months post intervention compared to those at baseline due to the impact of the Triple Benefit Health Education Intervention. This health education intervention towards malnutrition among adolescents will go a long way in giving them a better future life. There is need for more awareness among adolescent girls for both school based and community based intervention in the future to ensure all adolescents across the community benefit from health education intervention for the betterment of their future family.


Research-oriented hospitals are responsible for medical services tasks, medical education, and scientific research, playing an important role in medical research and application. The research efficiency of a clinical specialty is influenced by factors such as the characteristics of the specialty, the organizational atmosphere, and the clinical director’s leadership. The present study aimed to describe the research efficiency of clinical specialties, explore the factors influencing it, and clarify the argument of co-evolution theory regarding the collaborative development of medical services, education, and research. Logistic regression and multiple linear regression were adopted to estimate the correlation between influencing factors and scientific research efficiency. Hospital H, which is representative of research hospitals in China, was taken as an example. Taking three efficiency values—comprehensive technical efficiency (CTE), pure technical efficiency (PTE), and scale efficiency (SE)—as dependent variables, the independent variables affecting research productivity were statistically analyzed. This study also examined the scientific research efficiency of 41 specialties between 2013 and 2017, and found that the independent variables affected CTE, PTE, and SE to various degrees. Collaborative innovation in medical education and research must be based on clinical research; how to balance medical and teaching quality, and research efficiency requires further discussion. While young people play a major role on the research team because of their creativity and initiatives, which improve CTE and PTE, high-level researchers with better research and leadership abilities lead to the rational allocation and effective utilization of resources, thus improving SE. In 2013–2017, discipline construction focused on scale expansion, resulting in the decline of SE in China. Therefore, this study suggests further improvements for the efficiency of clinical specialties in research hospitals. Many countries have placed scientific and technological innovations at the core of health and wellness. Increasing investment in medical research has improved health care. The United States has invested more than one-third of total funding in nondefense fields for National Institutes of Health (NIH) research. In the past 10 years, the average annual funding for NIH reached 30 billion dollars and has shown an increasing yearly trend . Johns HIn China, research hospitals began to be built in 2003 .Gu et al. identified the major factors that impact doctoral graduates’ research efficiency (DRP) in China, such as academic status, academic experience, and energy distribution [Scientific research is a unique creative activity , and itsribution . Edgar eribution . Sung etribution . Hospitaribution ; howeverAt present, research on the influencing factors of scientific research efficiency is mainly conducted through questionnaire surveys , 12. In Different influencing factors affect different objects’ research efficiency; scientific research is a long-term continuous process that is affected by multiple factors. According to Bland, and Center et al., three factors affect scientific research productivity: individual, organizational, and leadership factors . IndividThis study used China’s research-oriented Hospital H as an example. The study first aims to describe the research efficiency of clinical specialties; second, it aims to investigate the characteristics of these factors, and third, it aims to explore the factors influencing research efficiency in hospitals.Hospital H is representative of research hospitals in China and has been ranked first among Chinese hospitals in terms of science and technology influence for seven consecutive years. Hospital H comprises 41 clinical specialties, including nonsurgical specialties , surgical specialties , and medical technology specialties .The data were obtained from Hospital H’s scientific research data management system, and the extraction time was from 2013 to 2017. We analyzed the value of each specialty’s scientific research input and output, and built a Super-Epsilon-Based Measure (EBM) model based on the decision-making method to evaluate Hospital H’s scientific research efficiency . The ChaBased on the three-dimensional factors affecting productivity, and considering the availability and representativeness of the data, we selected eight possible influencing factors: (1) medical quality: comprehensive scores of the annual assessment of specialties’ medical effectiveness , medical efficiency , medical safety and infection , and nursing quality  , 23; (2)We used multiple linear regression models to explore the impact of relevant factors on scientific research efficiency. Given that the maximum estimated value of the EBM is 1, it does not meet the condition which states that the value of the dependent variable in the classical linear regression needs to obey the normal distribution. Too many 1s lead to an unstable parameter estimation and a low-test efficiency. In this study, there were 41 decision making units (DMUs) from 2013 to 2017, with a total of 205 observation efficiency values. The observation values of CTE, PTE, and SE that were equal to 1 were 34, 68, and 34, respectively, and the cut-off value was more than 15%. To improve the model’s efficiency, the efficiency value estimated by the Super-EBM model with a window width of 3 was used as the dependent variable. The value of PTE represents the scientific research level and management ability, while the SE value represents resource allocation and utilization . The speOwing to the large number of independent variables and a certain degree of multicollinearity, parameter estimation is bound to be unstable. This study adopted a two-way stepwise regression, and the variables were selected according to the Akaike information criterion (AIC) minimum principle. The variables included in the model are shown in Table 5. The statistical software used was R-4.0.2, and the inspection level was 0.05.IBM1 SPSS1 Statistics software  was used to analyze the data, and the participants’ general characteristics were determined by descriptive statistics. Correlations between variables were examined using bivariate correlation. Multiple linear regression analysis was performed to study the variables that can significantly influence specialties’ research efficiency.The mean CTE, PTE, and SE values of all specialties in 2013–2017 were less than 1, and little difference was detected in the annual mean. According to the specialties’ CTE values, CTE > 1 was effective, indicating that the scientific research input had produced a good output—about 19.51%, 12.20%, 17.07%, 14.63%, and 19.51% in 2013, 2014, 2015, 2016, and 2017, respectively .Next, we conducted a hierarchical analysis of the average annual CTE values of the 41 specialties, positioning CTE > 1 as the first level, indicating that the efficiency was effective. Efficiency values in the range of 0.8–1 were positioned as the second level, suggesting that the efficiency was close to effective; those in the range of 0.6–0.8 were positioned as the third level, meaning that the efficiency was lower. Finally, efficiency values below 0.6 were positioned as the fourth level, indicating that the efficiency was particularly low. We collected a total of eight factors that may affect the efficiency of scientific research. We found that the distribution of age ratios in various specialties was relatively balanced, the average proportion of MDs or PhDs in each specialty was 0.45, with the minimum and maximum being 0.03 and 0.90, respectively. Polarization was more obvious. The average proportion of senior professional titles in each department was 0.34. The quantitative scores of the other five indicators are listed in r = 0.369, p < 0.05). Teaching quality showed a positive correlation with discipline construction , specialty operations , and director leadership . The proportion of MDs or PhDs and proportion of senior professional titles, and age ratio and proportion of senior professional titles had a statistically obvious linear correlation, and the correlation coefficients were all greater than 0.3 (p < 0.05).The linear correlations between the variables are shown in In this study, a two-way stepwise regression was conducted to select variables based on the AIC minimum principle. For different dependent variables, the independent variables included in the model are listed in We used the least squares method to estimate the parameters of the three models separately; the standardized parameter estimation results are listed in R2 values were 0.27, 0.21, and 0.35, revealing that the 27%, 21%, and 35% variance in efficiency, respectively, could be explained by the seven aforementioned variables. Compared with the zero model, the p values were all less than 0.001. The three models’ residual graphs had no obvious change rules. Except for individual extreme values, they were close to white noise, indicating that the establishment of this model and the results are reasonable.In this regression model, the three models’ adjusted The present study found that the mean CTE values  were 0.74 (19.51%), 0.71 (12.20%), 0.76 (17.07%), 0.72 (14.63%), and 0.69 (19.51%) for 2013, 2014, 2015, 2016, and 2017, respectively. A five-year comparison could imply that each year, the proportion of research effective specialties was in a stable fluctuation of around 15%. In total, 19 specialties were effective, and the proportion of research effective specialties was 46.34% in 2013–2017. Scientific research is a continuous, long-term process. The annual proportion of research effective specialties was relatively small, but after five years of accumulation, the output of research results increased significantly, and the overall efficiency saw a substantial increase. The proportion of research effective specialties increased to 46.34%. Regarding research specialty efficiency at Peking University People’s Hospital, Ling found that effectiveness had reached 38.90% in 2010–2015 , which eThe results of the multiple linear regression model demonstrated that research efficiency and teaching quality are positively correlated. For instance, graduate students, as the main driving force on a research team, received training from and conducted research with the team, and their research productivity was apparently influenced by teaching quality.The synergy theory on medical service and research collaboration assumes that research results will improve the quality of medical services . HoweverTaking the 40 years as the limit , an age A limitation of our study is the incompleteness of the factors. Research is a long-term, complex, productive activity and is affected by many factors. Based on the theory of scientific research productivity, we screened eight indicators that might affect specialties’ research efficiency in hospitals and also considered the feasibility of indicator data acquisition.R2 , the selected variables in the three models had a certain degree of explanatory strength for the changes in efficiency; the strength was relatively small, however, suggesting that the specialties’ efficiency values maybe were also determined by other factors such as physician–nurse ratio, number of beds, medical research time ratio, teaching, and research motivation. We will continue to explore other influencing factors and improve the influencing factor system to better reveal the influencing mechanism and effectiveness.According to the models’ adjusted The five-year effectiveness ratio of research hospitals’ specialties is approximately 50% in China. In terms of research efficiency, more than half of the specialties were ineffective, indicating input redundancy. The annual scientific research efficiency in developed countries is significantly higher than that of China, owing to the advantages of technology and other mechanisms. Regarding the abovementioned factors, the results demonstrated the co-evolution of teaching and research. Collaborative innovation in medical quality and research must be based on clinical research. Methods for balancing medical and teaching quality, and research efficiency require further discussion. While young people are creative with strong initiatives, high-level researchers have better scientific research abilities; better leadership abilities lead to rational allocation and effective utilization of resources, which would result in improvements in efficiency. Discipline construction should not focus on the construction of scale in the next few years. The study’s findings provide ideas for further improving the research efficiency of clinical specialties in research-oriented hospitals.S1 Data(XLSX)Click here for additional data file.


The results indicate that chiropractic spinal adjustment increases the corticomotor excitability of ankle dorsiflexor muscles in people with chronic stroke. Further research is required to investigate whether chiropractic spinal adjustment increases dorsiflexor muscle strength and walking function in people with stroke.This study aimed to investigate the effects of a single session of chiropractic spinal adjustment on the cortical drive to the lower limb in chronic stroke patients. In a single-blinded, randomized controlled parallel design study, 29 individuals with chronic stroke and motor weakness in a lower limb were randomly divided to receive either chiropractic spinal adjustment or a passive movement control intervention. Before and immediately after the intervention, transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) were recorded from the tibialis anterior (TA) muscle of the lower limb with the greatest degree of motor weakness. Differences in the averaged peak-peak MEP amplitude following interventions were calculated using a linear regression model. Chiropractic spinal adjustment elicited significantly larger MEP amplitude (pre = 0.24 ± 0.17 mV, post = 0.39 ± 0.23 mV, absolute difference = +0.15 mV, relative difference = +92%,  Stroke is the second-most common cause of death worldwide  and the Multiple rehabilitation techniques, such as physical therapy, brain-computer interface-based approaches, and motor relearning techniques have been shown to enhance motor recovery after a stroke –10. ReceIn the past two decades, research has demonstrated that chiropractic spinal adjustment has a neural plastic effect on the central nervous system (CNS). Multiple studies have found that (a single session of) chiropractic spinal adjustment modifies central processing, including somatosensory processing, sensorimotor integration, motor control, and pain, suggesting that the chiropractic intervention can rapidly affect neural and neuromuscular function in multiple ways , 18–32. Multiple studies have explored the mechanism responsible for such changes in strength following HVLA chiropractic adjustments. The recruitment patterns of lower motor neurons has been evaluated using the transcranial magnetic stimulation (TMS) induced stimulus-response (SR) curves for both upper limb and lower limb muscles . The HVLThe changes in motor control at the cortical level and neural plasticity can be assessed by TMS. It has been used in studies exploring the effects of chiropractic spinal adjustment , 30, 36.The improvement in muscle control and strength may be necessary for a variety of clinical populations but essential for persons who had a stroke since motor functionality is often affected by stroke, and its improvement has been identified as one of the top 10 research priorities by stroke survivors, caregivers, and clinicians . TherefoSince it has been shown that chiropractic spinal adjustment affects motor control and its associated cortical processing, we hypothesized that chiropractic adjustment would affect the TMS response in stroke patients. To date, the effect of chiropractic adjustment on MEP has been investigated in people with sub-clinical spinal pain . HoweverWe used a double-blinded, randomized controlled, parallel design in the study. The experiments were conducted at the Railway General Hospital in Rawalpindi, Pakistan. The study was approved by the Riphah International University Research Ethics Committee, Pakistan (ref # Riphah/RCRS/REC/000118). The New Zealand College Chiropractic Research Committee also approved the study. The study was conducted in accordance with the Declaration of Helsinki.Twenty-nine stroke patients  participated in this study. The participants were recruited from the outpatient facility of the rehabilitation department at Railway General Hospital, where they were present for conventional physical therapy. All participants gave their written informed consent to participate in the study. The participant details are shown in Participants were introduced to the lab environment before enrolling in the study. Participants were eligible to participate in the study if it had been at least 12 weeks since they had suffered from a stroke and they had some level of lower limb motor impairment. Motor performance was assessed by Fugl-Meyer (FM) motor assessment scale . Particin = 13, age = 54.1 ± 13.1 years, FM score = 65.9 ± 22.2) and control , using minimization tool  based on age and Fugl-Meyer Score after the eligibility assessment  electrodes . Two electrodes were placed ~2 cm apart on the belly of the TA muscle, and a ground electrode was placed on the distal end of the tibia. The EMG signals from these electrodes were amplified by OT EMG USB  at 4,000 Hz with a gain of 1,000.MEPs were elicited using a single-pulse TMS generated using a Magstim 200 . A figure-of-eight double cone-coil, placed in a posterior-anterior current direction over the cortical motor area, was used to deliver the magnetic stimulus. Initially, the optimal stimulation site and resting threshold (RTh) were determined. The optimal stimulation site was the location where the largest MEPs were evoked compared to adjacent areas. The optimal stimulation site was marked on the tightly-fitted neoprene cap with 1 × 1 cm grid secured to the participant's head to ensure placement of the coil at the same location throughout the experimental session. The RTh was defined as the lowest stimulator output, which elicited 5 out of 10 MEPs with a minimum amplitude of 50 μV. Twelve stimuli, separated by 5–7 s, were delivered at 120% of the RTh before and after the interventions.Using Signal Software version 4 , the peak-peak amplitudes were extracted from each MEP and saved in an Excel  file. The average of the 12 MEPs was computed for each participant at each time point  and exported to R version 4.0.2  for further analysis. Differences across the two intervention sessions were evaluated on the absolute and relative scales. Mean MEP amplitude values for individual participants were transformed to relative changes in MEP sizes using the following formula:Separate statistical models evaluated MEP amplitudes in absolute and relative units. A linear regression model was set up for the absolute units, which included intervention  as a dichotomous variable and baseline MEP amplitude as a continuous variable. The inclusion of baseline scores as a linear covariate enabled the model to account for any baseline differences. As the data were not normally distributed for the relative units, a robust linear regression model was set up, which included intervention  as a dichotomous variable. This model also included MEP amplitudes in absolute units at baseline as a linear covariate to adjust baseline differences.abs and MEP%) estimated with the models have been reported, along with standard errors, 95% confidence intervals, and relevant hypothesis tests with a significance level set at 0.05. No adjustments were applied for multiple comparisons as this reduces type-I errors at the cost of increased type-II errors  in the spinal adjustment group. In the control group, 14 out of 16 considered that the intervention they received was active, i.e., they perceived that they received chiropractic adjustments, but in reality, they received control intervention.p < 0.001) compared to the control intervention.The differences between the two groups at the post-intervention time-point after removing the pre-intervention differences are given in MEP sizes estimated from the statistical models in both absolute and relative units at the post-intervention time-point are given in The primary outcome of this study was that chiropractic spinal adjustment increased the average MEP amplitude in both absolute (by 0.15 mV) and relative (by 126%) units. No differences in the MEP amplitude were seen after the control intervention. To the best of our knowledge, this study is the first to investigate and report changes in MEP following chiropractic spinal adjustment in people with stroke.The increased MEP amplitude following chiropractic spinal adjustment in this study implies increased excitability of motor pathways to the TA muscle. An increase in MEP size following chiropractic adjustment has been found in a recent crossover-designed study in people with SCSP . It was Changes in corticomotor excitability following chiropractic adjustment have also been reported by studies utilizing other TMS-induced outcome measures, such as the cortical silent period (CSP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF). Two crossover studies in people with SCSP found a significant shortening of the CSP recorded from the APB muscle following a single session of chiropractic spinal adjustment , 31. TheThe evidence that chiropractic adjustment increases cortical drive is also supported by studies that have reported an increase in V-wave/Mmax ratio and V-wave amplitude for lower limb muscles following a single session of chiropractic spinal adjustment , 18, 28.Furthermore, chiropractic spinal adjustment-induced changes in all the above measures occurred with minimal or no change in the H-reflex , 18, 28 The increased MEP amplitudes found in this study can also indicate improved sensorimotor integration and functional connectivity in stroke survivors following spinal adjustment. The early peaks of somatosensory evoked potentials (SEPs) are severely decreased or even absent in stroke populations –59. HoweMotor recovery following a stroke depends on adaptive and maladaptive neural plasticity changes. As vertebral subluxations are central segmental motor control problems that cause ongoing maladaptive neural plastic changes in the CNS, correction of vertebral subluxation by chiropractic spinal adjustments results in central neural plastic changes , 67, 68.The control intervention acted as a physiological control for possible changes occurring due to the cutaneous, muscular, or vestibular input that would have occurred with the passive and active movements involved in preparing a patient for chiropractic spinal adjustment. This was chosen to determine if the difference in outcome measure was due to the application of HVLA thrust or other cutaneous, muscular, or vestibular input caused by passive and active movements occurring during a chiropractic session. As is done before spinal adjustment, loading a joint has been shown to alter paraspinal proprioceptive firing in anaesthetized cats . TherefoThere was no restriction on the type of stroke and the affected brain regions in the inclusion criteria. Therefore, there are possible differences in the brain morphology of the stroke patients and non-uniformity of the kind of stroke and affected brain regions. Thus, it is possible that we could have found even larger changes in MEPs if more homogenous patients with respect to stroke type and location were recruited. This would, of course, make the recruitment of individuals more difficult and limit the generalizability of the study. Furthermore, the onset of stroke was quite variable in the participants of the current study. Following a stroke, neuroplasticity is more pronounced in the first 3 months . TherefoThis was an exploratory study with a sample size of 29. However, previous studies based on stroke survivors have used sample sizes smaller than this study (10–21 participants) , 71–75. This is a basic science study; therefore, the results from this study should not be extrapolated to clinical implications for the chronic stroke population. For clinical implication, Holt et al.  has founThe study results suggest that a single session of chiropractic spinal adjustment increases the corticomotor excitability in chronic stroke survivors by increasing the TA MEPs. Along with the previous findings, it can be postulated that such changes in corticospinal excitability improve muscle strength efficiency and function. Future studies should investigate the long-term effects of the adjustment in different stages and types of stroke for a better understanding of the impact of chiropractic care on stroke rehabilitation.The numerical data supporting the conclusions of this article will be made available by the authors without, undue reservation. The Local Ethics Committee adhering to local data protection laws does not allow the sharing of patient's raw data.The studies involving human participants were reviewed and approved by Riphah International University Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.MN, IN, DL, MS, AD, KH, and HH: conceptualization. MN, IN, IA, and MS: data curation. MN, UR, and IN: formal analysis and software. HH, DL, AD, and MS: funding acquisition. MN, IN, DL, MS, IA, and KH: investigation. MN, IN, DL, NK, MS, and AD: methodology. IN, DL, MS, AD, and HH: project administration. IN, MS, AD, and HH: resources. IN, DL, KH, AD, and HH: supervision. MN, IN, NK, UR, KH, and AD: validation. MN, UR, and NK: visualization. MN and NK: writing—original draft preparation. MN, IN, DL, NK, MS, KH, IA, UR, AD, and HH: writing—review and editing. All authors contributed to the article and approved the submitted version.This study was funded by the Centre for Chiropractic Research Supporters Program at the New Zealand College of Chiropractic.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.


Western medicine has played an essential role in treating poststroke insomnia (PSI) in China, and traditional Chinese medicine therapy based on Chinese characteristics is also effective. Combined with China's national conditions, we plan to conduct this systematic review and meta-analysis to compare the efficacy of integrated traditional Chinese medicine and Western medicine (INTEGRATED TCM and WM) therapy and Western medicine alone for PSI.We will search the following 5 electronic databases: PubMed, Wanfang, Chinese biomedical literature database, the Chongqing VIP Chinese Science and Technology Periodical, and China national knowledge infrastructure. Randomized controlled trials that compared the efficacy of INTEGRATED TCM and WM with Western medicine alone in the treatment of PSI will be considered. Primary outcomes have Treatment effectiveness rate, and Pittsburgh sleep quality index. Secondary outcomes include traditional Chinese medicine syndrome score, Athens insomnia scale, the incidence of adverse reactions, and outcome follow-up. Based on the eligibility criteria, we will conduct literature screening and data extraction. The quality of the included literature will be evaluated using the Cochrane risk of bias tools. We will use Review Manager software (Version 5.3) for data synthesis and statistical analyses. If sources of heterogeneity exist, we will perform a subgroup analysis or sensitivity analysis. A funnel plot will be used to analyze publication bias.This study will provide evidence-based medicine evidence for treatment of PSI with INTEGRATED TCM and WM in terms of its efficacy.This systematic review aims to provide new options for INTEGRATED TCM and WM treatment of PSI in terms of its efficacy. It is an important public health problem in poststroke illness associated with a high prevalence rate, accounting for about 38.2%, which increases the risk of death and recurrence of stroke, and seriously affects the recovery and prognosis of patients,–9 but it does not draw enough attention by both patients and doctors. Sleep occupies 1/4 to 1/3 of a lifetime in most humans and is an essential physiological process to maintain human health. Good sleep is the basis of high quality of life and the completion of various social activities. Improving patients’ and doctors’ awareness of the impact of sleep disorders on stroke and active treatment are beneficial to patients’ functional recovery and mental health, and reduce the recurrence rate and mortality rate of stroke.Poststroke insomnia (PSI) is a common type of stroke-related sleep disorders. It is a disease that first appears after stroke and reaches the diagnostic criteria of insomnia.,11 It is of great significance to choose the appropriate treatment for stroke patients in China. At present, PSI pathogenesis remains incompletely understood. Western medicine mainly uses sedative-hypnotics, antianxiety, and antidepressants to improve the sleep status of patients with PSI, but it is easy to produce drug resistance and addiction. The clinical effect of traditional Chinese medicine (TCM) is positive, but the onset of efficacy occurs slowly. Integrated traditional Chinese medicine and Western medicine therapy can improve clinical effectiveness and reduce side effects. However, there is currently no meta-analysis on the effectiveness of Integrated traditional Chinese medicine and Western medicine in the therapy of patients with PSI. This study will use meta-analysis methods to evaluate the efficacy of the combined therapy in the treatment of PSI, aiming to provide evidence-based medicine for clinical practice.China is a large population, with a heavy burden of stroke and a high incidence rate of stroke. The age of onset, the major lesion, and the type of the disease are different from those of other countries.22.1We will report the protocol based on the 2015 preferred reporting items for systematic reviews and meta-analysis protocols (PRISMA-P) guidelines.https://inplasy.com/). The registration number is INPLASY202140028.The protocol has been registered on the INPLASY website . Therefore, ethical approval is not required. We will disseminate the results in a peer-reviewed journal.2.3Two review authors (Wenwen Li and Guomin Si) will independently assess every retrieved article. Eligibility criteria are as follows:2.3.1All the studies are RCTs of PSI treated by a combination of Chinese and Western medicine. Studies involving animal experiments, case reports, basic research, reviews, non-RCTs will be excluded.2.3.2The study participants are PSI patients with clear and standardized diagnostic criteria, regardless of case source, age, gender, and race. Patients with other types of sleep-related diseases such as excessive daytime sleepiness, restless leg syndrome, and sleep-disordered breathing will be excluded.2.3.3The control group only received conventional Western medicine treatment, and the experimental group was treated with TCM on the basis of the control group. The conventional Western medicine treatment may be different for each study, but whether or not they received TCM treatment was the only difference between the experimental group and the control group. TCM included single herb (including extract from single herb), Chinese patent medicine or Chinese medicine compound prescription, regardless of drug preparation , route of administration , dosage, and regimen of herbs.2.3.4Primary outcomes: Treatment effective rate, Pittsburgh sleep quality index.Secondary outcomes: TCM syndrome score, Athens insomnia scale, the incidence of adverse reactions, outcome follow-up.2.4Electronic databases will be systematically searched for relevant reports from their inception to August 24, 2021: PubMed, Wanfang, Chinese biomedical literature database (CBM), the Chongqing VIP Chinese Science and Technology Periodical (VIP), and China national knowledge infrastructure (CNKI). We will use the following combined free text terms and Medical Subject Headings (Mesh) terms as follows: “PSI” or “Insomnia after stroke”, “Sleep Initiation and Maintenance Disorders” or “Disorders of Initiating and Maintaining Sleep”, “stroke” or “Strokes”. Using PubMed as an example, the initial search strategy is shown in Table 2.52.5.1The databases are searched according to the search strategy, and all the retrieved studies are imported into Endnote X9 software  for screening. After eliminating duplicates, 2 independent researchers (Wenwen Li and Guomin Si) further read the titles and abstracts to exclude noncompliant literature. The literature included after the initial screening is carefully read in full and then screened again to decide on the final inclusion. Any objections during the screening process are referred to a third party (Min Peng) for decision. The screening process is shown in Figure 2.5.2We will perform data collection and management according to Cochrane Review procedures. The extracted information will include: the first author, year of publication, funding source, sex, age, duration of disease, sample size , interventions, course of treatment, and outcome indicators. Based on the characteristics of the information extracted, an excel sheet is prepared for data collection. The same 2 review authors (Wenwen Li and Guomin Si) will independently extract data. In case of disagreement, they will be discussed or decided by an independent third review author (Min Peng). If data in the literature is incomplete, we will try to contact the authors of the original study to complete the information. If the author cannot be contacted, we will exclude the study due to a lack of essential data.2.5.3Two researchers (Cuncheng Liu and Ruiqi Wang) will independently assess the methodological quality of each paper by using the Cochrane risk of bias tools. The main items include random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other bias. Each item is divided into “low risk”, “unclear risk”, and “high risk”. Where differences exist, we will reach a consensus through discussions with third parties (Ruxue Liu). The risk of bias assessment map will be created through Revman software .2.5.4P < .05 is a statistically significant difference for all analyses. The level of statistically significant heterogeneity will be set at P < .1. In addition, the I2 value will be used to analyze the heterogeneity quantitatively. If P > .1 and I2 ≤ 50%, meta-analysis will adopt fixed-effect; If P ≤ .1 or I2 > 50%, meta-analysis will adopt random-effect. If the random-effect is used, we will perform subgroup analysis or sensitivity to clarify the source of heterogeneity. If quantitative synthesis is not possible, we will perform a descriptive analysis.Review Manager software version 5.3  will be used for meta-analysis. Relative risk (RR) with 95% confidence interval (CI) will be calculated for dichotomous data, and mean difference (MD) with 95% CI will be calculated for continuous data. 2.5.5We will explore the sources of heterogeneity through subgroup analysis based on age, gender, duration of disease, different interventions, duration of treatment, etc.2.5.6To determine whether the decisions at each step are robust and impact the combined results, a sensitivity analysis will be conducted. Each time a study is excluded, a new meta-analysis is conducted separately to see if the effect size changes. We will also use this method to explore the sources of heterogeneity if there is significant heterogeneity in the studies.2.5.7If more than 10 studies are eventually included, we will use a funnel plot to analyze publication bias and interpret the results with caution.2.5.8In this study, we will use the internationally accepted Grades of Recommendations Assessment, Development and Evaluation (GRADE) system to assess the quality of the evidence. The quality of evidence is classified into 4 levels: high quality, medium quality, low quality, and very low quality.3 As China enters an aging society, there will be more people suffering from cerebrovascular disease. PSI usually occurs during the acute phase of stroke and is a common type of sleep disorders after stroke. A systematic review and meta-analysis shows that the probability of insomnia after a stroke has reached about one-third, and PSI often causes more severe consequences. Therefore, effective treatment methods are extremely essential to improve the survival rate and quality of life of patients. One study has shown that the use of Gamma-aminobutyric acid (GABA) receptor agonists in the acute phase of a stroke may be harmful, and other studies have shown that the use of benzodiazepines can increase the risk of cognitive impairment and stroke.,16 To compensate for the lack of Western medicine alone and reduce the possible risks, we believe that a combination of Western and Chinese medicine can be used. With more and more research linking Chinese medicinal herbs and their extracts to various modern diseases, TCM is gaining more and more recognition in the international medical field. TCM believes that the cause of insomnia is mainly related to the imbalance of yin-yang. As PSI is secondary to the stroke, the disease also reflects the characteristics of the recovery and the sequelae of the stroke period, that is, a mixture of xu and shi. Therefore, the treatment should be directed at yin-yang and xu-shi. Good results have been achieved in terms of both specific medication and prescription. Herbs often used include Yuan Zhi, Ziziphus jujuba Mill, Albiziae Cortex, Fu Shen, Shou Wu Vine, and platycladi seed. In terms of prescription, the commonly used Chinese medicine prescriptions include Sour Jujube decotion, Tian-wang-bu-xin-dan, Huanglian Ejiao decoction, and Jiaotai Pill. Modern pharmacological studies confirmed the sedative and hypnotic effects of Chinese medicine and its active ingredients. They expounded the action ways of Chinese medicine in regulating central neurotransmitter affecting sleep-related cytokines, and improving the structure of the central nervous system.,19The incidence of stroke increases with age.However, due to the complex mechanism of TCM therapy, its main application area are still in China, which limits the development of TCM. It is this uniqueness of TCM that makes our research meaningful.Wenwen Li, Cuncheng Liu, and Guomin Si proposed this research and wrote the first draft of the manuscript. Guomin Si and Peng Min provided research funds and supervised the whole process. Wenwen Li, Cuncheng Liu, Ruxue Liu, and Ruiqi Wang collected resources and conducted data analysis. All authors participated in the finalization of the manuscript and approved the manuscript.Conceptualization: Wenwen Li, Cuncheng Liu, Guomin Si.Data curation: Wenwen Li, Min Peng, Guomin Si.Formal analysis: Ruiqi Wang, Guomin Si.Funding acquisition: Min Peng, Guomin Si.Investigation: Wenwen Li, Cuncheng Liu, Ruxue Liu.Methodology: Ruiqi Wang, Ruxue Liu.Project administration: Wenwen Li, Cuncheng Liu, Guomin Si.Resources: Wenwen Li, Cuncheng Liu.Software: Wenwen Li, Cuncheng Liu, Ruiqi Wang.Supervision: Min Peng, Guomin Si.Validation: Ruiqi Wang, Ruxue Liu.Visualization: Wenwen Li, Cuncheng Liu.Writing – original draft: Wenwen Li, Guomin Si.Writing – review & editing: Cuncheng Liu, Guomin Si.