Transcatheter heart valve (THV) selection for transcatheter aortic valve implantation (TAVI) is crucial to achieve procedural success. Borderline aortic annulus size (BAAS), which allows a choice between two consecutive valve sizes, is a common challenge during device selection. In the present study, we evaluated TAVI outcomes in patients with BAAS according to THV size selection.We performed a retrospective study including patients with severe aortic stenosis (AS) and BAAS, measured by multi-detector computed tomography (MDCT), undergoing TAVI with self-expandable (SE) or balloon-expandable (BE) THV from the Israeli multi-center TAVI registry. The aim was to evaluate outcomes of TAVI, mainly paravalvular leak (PVL) and valve hemodynamics, in patients with BAAS (based on MDCT) according to THV sizing selection in between 2 valve sizes. In addition, to investigate the benefit of shifting between different THV types (BE and SE) to avoid valve size selection in BAAS.p = 0.019). Of note, rates of mortality, left bundle branch block, permanent pacemaker implantation, stroke, annular rupture, and/or coronary occlusion did not differ between groups.Out of 2,352 patients with MDCT measurements, 598 patients with BAAS as defined for at least one THV type were included in the study. In BAAS patients treated with SE-THV, larger THV selection was associated with lower rate of PVL, compared to smaller THV . Regarding BE-THV, larger valve selection was associated with lower post-procedural transvalvular gradients compared to smaller THV (mean gradient: 9.9 ± 3.7 vs. 12.5 ± 7.2 mmHg; BAAS is common among patients undergoing TAVI. Selection of a larger THV in these patients is associated with lower rates of PVL and optimized THV hemodynamics with no effect on procedural complications. Additionally, shift from borderline THV to non-borderline THV modified both THV hemodynamics and post-dilatation rates. Aortic valve stenosis (AS) is the most common valvular heart disease among elderly . TranscaMulti-detector computed tomography (MDCT) is the gold standard method for pre-procedural planning and annular sizing of both balloon-expandable (BE) and self-expanding (SE) THV . THVs arThe aim of the present study was to evaluate outcomes of TAVI, mainly PVL and valve hemodynamics, in patients with BAAS (based on MDCT) according to THV sizing selection in between 2 valve sizes. In addition, to investigate the benefit of shifting between different THV types (BE and SE) to avoid valve size selection in BAAS.We performed a retrospective analysis from the Israeli multi-center TAVI registry, including patients with severe symptomatic AS and BAAS, measured by MDCT, undergoing TAVI with SE-THV  or BE-THV  during the years 2015–2019, at 1 of 4 tertiary centers in Israel: Rabin Medical Center, Sheba Medical Center, Tel-Aviv Sourasky Medical Center, and Hadassah Medical Center. The study was approved by the institutional review board of each of the participating centers.Eligibility for TAVI was established after a multi-disciplinary approach as indicated by the current recommendations. The preoperative workout included MDCT scan to plan the most appropriate route of intervention and to establish the aortic size and dimensions. Aortic sizing and valve measurements were performed by the local team in each center. All centers adopted a transfemoral-first approach policy; other vascular accesses  were considered in cases in which the transfemoral access was not feasible. According to the local policy, TAVIs were performed under local or general anesthesia. The selection of prosthesis type and size was at the discretion of the treating physicians at each center. Pre-specified clinical and laboratory data were collected for all patients at baseline before the procedure, immediately after the procedure, during the index hospitalization, and during long-term follow-up. Collected data included medical history, electrocardiogram, echocardiography studies, MDCT measurements, laboratory tests, and clinical outcomes. Outcomes were collected according to the Valve Academic Research Consortium (VARC) 2 consensus document .2 for valve size of 20 vs. 23 mm; 420–440 mm2 for 23 vs. 26 mm; 530–560 mm2 for 26 vs. 29 mm)  and borderline range for BE-THV (330–350 mm. 29 mm)  (8). PatThe Evolut R SE valve is constituted by a nitinol frame mounting three porcine pericardial leaflets. The valve is repositionable, partially recapturable, and it is deliverable using a dedicated delivery system 14/16-Fr compatible depending on valve size. The Evolut PRO device represents an evolution of its predecessor and features a porcine pericardial outer wrap that contributes to reduce the risk of residual PVL. Evolut R covers a wide range of sizes and is available in 23, 26, 29, and 34 mm sizes .The Sapien XT/3 BE valve incorporates a cobalt chromium stent that mounts bovine pericardial leaflets. Sapien 3, has both an inner and an outer polyethylene terephthalate fabric seal to minimize the risk of paravalvular leaks. The delivery system has an active 3-dimensional coaxial positioning catheter and a 16-Fr expandable sheath .p < 0.05 was considered statistically significant.Continuous variables were expressed as mean ± standard deviation and as median and interquartile range (IQR) and compared using Mann-Whitney test. Categorical variables were compared using Chi-square or Fisher's exact tests as needed. All analyses were conducted using Python version 3.5, 2 who were implanted with BE-THV were excluded from the analysis since the smaller valve size of 20 mm was not implanted. Eventually, 598 patients with BAAS as defined for at least one THV type, 309 for SE-THV, 248 for BE-THV and 41 patients for both devices were included in the analysis. Of them, 367 (61.4%) patients were implanted with borderline valves, while all others were implanted with non-borderline valves due to shift from SE-THV to BE-THV, or vice versa. The SE-THV group included 93 patients implanted with smaller valves, and 150 patients implanted with larger valves. In the BE-THV group, 22 patients were implanted with smaller valves, and 102 patients with larger valves  or BE-THV  with pre-procedural MDCT measurements, 124 were excluded due to valve in valve, valve in ring, or mitral valve interventions. Additional 38 patients with BAAS and an annulus area of 330–350 mmr valves .Table 2A). In BAAS patients implanted with BE-THV, differences were noted in left ventricular function (Table 2B). Other measured baseline clinical and imaging characteristics did not differ between smaller and larger valves implantation (2B).In BAAS patients implanted with SE-THV, the baseline clinical characteristics of both groups  did not differ, except for the New York Heart Association (NYHA) functional class . In addiantation , 2B.Baseline clinical and imaging characteristics of patients with borderline annulus for SE devices implanted with borderline large SE-THV or non-borderline BE-THV did not differ, except for aortic valve mean pressure gradient . CompariIn the present cohort, favorable outcomes were observed while using larger valves in BAAS patients. For SE-THV, selection of larger valves compared to smaller valves was accompanied with significantly lower rates of PVL measured by both echocardiography  is common among patients undergoing TAVI, however, the most effective THV selection strategy for these patients remains unclear. The present study of 598 patients with severe symptomatic AS undergoing TAVI based on the ISRAELI-TAVI registry is the largest observational study to date comparing clinical outcomes according to size selection of SE-THV and BE-THV in patients with BAAS. The main findings of our study  are as fIn patients with BAAS, the larger THV device reduced PVL rates and optimized THV hemodynamics.Selection of a larger valve in BAAS patients did not increase adverse clinical outcomes such as new LBBB, rate of new pacemaker implantation, stroke or TIA, annular rupture, coronary occlusion or mortality.Shift from borderline THV to non-borderline THV modified THV hemodynamics and post dilatation rates. Shift from borderline SE-THV to non-borderline BE-THV was associated with lower post dilatation rates, but with higher gradients. Shift from borderline BE-THV to non-borderline SE-THV led to optimized THV hemodynamics, but with increased post-dilatation rates; In addition, in a subgroup of patients in whom post-dilatation was not performed, increased PVL rates were observed.Large size THV implantation was previously shown to be associated with favorable hemodynamics and lower PVL rate, both are important determinants of clinical outcomes in AS patients following TAVI , 12. In In our cohort of BAAS patients, 93% of cases were defined as BAAS for one device only . In these patients, it is thus conceivable to apply a strategy of selecting the non-borderline device whenever possible. In fact, non-borderline devices were selected over borderline devices in 38.6% of patients in our cohort. We found that selection of non-borderline SE-THV over borderline BE-THV led to lower gradients. On the other hand, selection of non-borderline BE-THV over borderline SE-THV was associated with lower rates of post-dilatation, but at the cost of increased gradients. This trade-off between PVL and higher gradients was repeatedly described in comparative studies between BE and SE devices both in tricuspid and bicuspid AS patients , 19. The2 from the analysis. BE-TVH over or under-sizing by over or under-inflation of the valve balloon in order to fine tune the valve dimensions was not registered and might have affected in-situ valve size. Nevertheless, the practice of over/under-inflation in the four centers was according to a known algorithm proposed by the company.We acknowledge several limitations of our study. The main limitation is the observational nature of the study. Therefore, undocumented factors, such as sinus of valsalva diameter or calcium score, may have affected device selection. In addition, potential impact of unknown or unmeasured confounding factors on study outcomes cannot be excluded. The low number of patients implanted with smaller BE-valve may affect the significance of the results and even necessitated the exclusion of patients with annulus measurements of 330–350 mmThe results of the present study support, for both devices (BE and SE), the selection of larger valves for TAVI candidates with BAAS. Shifting from borderline devices to non-borderline devices resulted in significant changes in post-dilatation, PVL, and gradients across the THV. Therefore, our findings point out that the same consideration taken while selecting THV type for non-BAAS patients, should be applied in BAAS patients, and whenever a borderline device is selected the larger valve device should be recommended.The results of the present study support, for both devices (BE and SE), the selection of larger valves for TAVI candidates with BAAS. Shifting from borderline devices to non-borderline devices resulted in significant changes in PVL and THV hemodynamics. Therefore, our findings point out that the same consideration taken while selecting THV type for non-BAAS patients, should be applied in BAAS patients, and whenever a borderline device is selected the larger valve device is recommended.The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author.YT-B, RK, JB-S, and PC conceived the project, designed and interpreted the results, and wrote the manuscript. NB conducted all analyses and interpreted the results. HV-A, AH, BK, HD, GP, MK, AF, ASt, IM, ASe, and AB coordinated and designed data collection and interpreted the results. 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.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.


Acute intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders and non-acute IT-IEM such as phenylketonuria (PKU) and their treatment have a major impact on the life of affected children and families. Yet patients’ and parents’ perspectives on the burdens of IT-IEM and its effects on everyday functioning and well-being have rarely been addressed. Patient- and observer-reported outcomes (PROs/ObsROs) are critically important to evaluate and target health care and treatment efficacy. Therefore, it is mandatory to define PROs/ObsROs relevant to patients with IT-IEM, their families, and health care professionals and to provide valid, standardised and reliable measuring instruments. To achieve consensus we performed a two-round, electronic-based modification of a Delphi survey including 27 parents of affected children, nine teenage patients and 35 health professionals . The final set of PROs/ObsROs was discussed and defined in an online consensus meeting with a subsample of three health professionals, three parents and two patients. For this final set, appropriate measures (PROMs/ObsROMs) were assembled.Seventeen PROs/ObsROs constitute the final core set for paediatric IT-IEM. They cover social , emotional (e.g. positive affect), and disease-related aspects (e.g. attitude towards treatment) of patients’ lives as well as the experience of parents .To promote a holistic treatment approach, this consensus-driven set of relevant PROs/ObsROs should be incorporated into daily IT-IEM care and considered as the key psychological outcomes in clinical trials. We have identified existing—psychometrically and contextual—appropriate PROMs/ObsROMs with open access to facilitate this process.The online version contains supplementary material available at 10.1186/s13023-022-02183-2. Intoxication-type inborn errors of metabolism (IT-IEM) are a group of rare, chronic diseases. Some take an acute course with metabolic crises (e.g. urea cycle disorders or organic acidurias); others, like phenylketonuria (PKU) are non-acute IT-IEM. In some disorders, even lifelong adherence to treatment such as protein-restricted diet, supplementation of amino acids, and medication may not prevent patients from neurocognitive impairment. Many patients experience variable somatic symptoms such as nausea or fatigue. Especially in children and adolescents the considerable burden of both disease and treatment may impair health-related quality of life (HrQoL) and result in emotional constraints , 2.A patient-reported outcome (PRO) is a report about the subjective perception in relation to a health condition directly from the affected patient, without interpretation by physicians or others . In paedImplementation of meaningful PROs into research trials and clinical practice improve provider-patient communication, informed decision-making and successful medical monitoring , 6–8. ItUp to date, a core set of relevant PROs completed by a list of corresponding PROMs has not been elaborated for paediatric IT-IEM patients. Such a core set, however, would allow for the comparison of self- and observer-reported data across metabolic centres and research studies as well as for a focused, targeted, economic assessment of patients’ and families’ needs.Which PROs are relevant for paediatric IT-IEM patients, their families and specialised health care providers?Which PROMs are adequate (based on predefined criteria) to measure the relevant PROs?To overcome this unmet medical need we investigated the following research questions:An extensive list of potentially relevant PROs in IT-IEM was assembled based on a systematic literature review  and qualhttps://metab.ern-net.eu/) and the local network of the metabolic centre of the University Children’s Hospital Zürich.IT-IEM patients between 12 and 18 years and parents of IT-IEM patients between 0 and 18 years treated at the University-Children’s Hospitals Zürich and Basel or at the Bregenz State Hospital were eligible. Patients and parents meeting the criteria were recruited by telephone. Health care providers  actively engaged in treating IT-IEM patients were recruited via the European Reference Network for Rare Hereditary Metabolic Disorders . They were encouraged to suggest PROs not yet represented in the survey. In addition, patients and parents were asked to provide sociodemographic and disease-related data; HP were asked for information about their background such as profession and years of experience. Furthermore, every participant was asked about his or her interest to take part in the final consensus meeting.Survey two was sent electronically to all respondents of survey one. All PROs from survey one were forwarded and additional PROs suggested by participants were added following revision and categorisation. For each PRO, the results of survey one were included: median score per stakeholder group, a bar chart of score-distribution by stakeholder group, and the score the participant him-/herself had given in survey one. Participants were asked to review their answers from survey one under consideration of the input by all stakeholder groups . The scoIn addition to the standard Delphi approach a subsequent consensus meeting was held based on the data derived from survey two. A subsample of three HP , three parents  and two patients , opposite opinions were explored and the voting process was repeated until a consensus was reached. All PROs rated as “important” were then included in the final list. Additionally, participants were asked for their input on corresponding PROM-questionnaires in a semi-structured way.Subsequently, appropriate PROMs to measure the final set of PROs were identified based on a literature research, the expertise of the authors and the PROMIS® (Patient-Reported Outcomes Measurement Information System) database. A list of criteria for inclusion was predefined  participated in survey one. Fourteen of their children met the age criteria and 9 (69%) agreed to participate in the study. E-mail invitations were sent to 42 health professionals of whom 35 (83%) returned survey one. Survey two was completed by 24 parents (89%), 9 patients 100%) and 30 HP (86%). 2 parents  and 1 HP  stated lack of time as the reason for their drop out. One parent of a non-acute IT-IEM patient (3.7%) and 4 HP  could not be reached until the completion of survey two. Table 00% and 3Twenty-nine PROs were identified and respective items tested in a pilot sample, adapted accordingly, and consecutively presented in survey one. Three additional PROs were suggested by stakeholders . As described above, all 32 PROs were forwarded to survey two. Figure According to the ratings in survey two 17 PROs were forwarded to the final consensus meeting. During the consensus meeting all 17 PROs were rated as very important and eventually included in the final core set. Table According to the predefined and prioritized list of criteria, appropriate PROMs were selected to measure the final core set of PROs. Additional file In this modified Delphi-study we aimed at defining a core outcome set of 17 PROs considered relevant by patients, parents and HP for paediatric IT-IEM and provided information on their standardised, valid assessment (PROMs). Beyond the well-established but rather broad construct of quality of life, more specific PROs like stress, physical activity, peer relationships, social participation, cognitive functioning, disease-specific self-efficacy, disease- and treatment knowledge, attitude towards, adherence to and burden of dietary treatment, family time resources, parental general health, and social support for the family were considered important. The set was developed based on the existing literature, focus groups with acute IT-IEM patients and parents and a subsequent quantitative consensus process including 64 stakeholders. The international board of specialised and experienced HP from the fields of medicine, nutrition science, and psychology represents the multidisciplinary state-of-the-art treatment approach. In the stakeholder group of patients and parents a variety of IT-IEM diagnoses is represented.Ratings in the Delphi survey two were predominantly similar across the two stakeholder groups. This may indicate an already well-established HP-patient/parent communication. Often, a metabolic team sees patients with IT-IEM and their families for many years. This may allow for a patient-centred treatment approach with better understanding of patients’ and parents’ needs and sorrows .Ratings of parents and patients with acute compared to non-acute IT-IEM, too, were similar. Both patient groups share the burden of an intoxication-type disorder and lifelong dietary treatment, and despite the absence of metabolic decompensations in e.g. PKU patients, there is previous evidence that they share most psychosocial impairments with acute-type patients .Although IT-IEM are associated with heterogeneous, often burdensome physical symptoms, psychosocial PROs accounted for the majority of the final core set, suggesting that IT-IEM have an enormous impact on patients’ and families’ everyday life. A holistic treatment approach which considers not only physical symptoms but also mental and social challenges relevant to patients , 20 is mPsychological data are sometimes looked at sceptically by the medical system that often considers them weak and unreliable. To overcome this prejudice, we provide a list of PROMs which have been selected according to their psychometric quality following state-of-the-art scientific standards of validity, reliability, and standardisation. While the PRO set advises clinicians and researchers which parameters should be assessed, the PROM list shows how and by what means this can be achieved. The consistent application of PROMs promotes patient satisfaction and provider-patient communication and ensures comparability of research data . EspeciaThis study provides a first multidimensional, consensus-based core set of relevant PROs for usage in paediatric IT-IEM. A list of corresponding open access PROMs ought to facilitate the implementation in daily care and research. The underrepresentation of fathers in the consensus process is a limitation of this study, which is unfortunately rather typical for paediatric IT-IEM research . FurtherFinally, there is no agreement on the optimal methodology for the development of a PRO core set. Any alternative consensus approach, such as structural interviews in vivo, may have produced a different core set. However, based on consensus finding in other rare diseases such as paediatric rheumatology , the onlThis study provides a core set of PROs relevant to paediatric IT-IEM patients, their parents and HP likewise. Corresponding PROMs are listed to ensure measurement consistency. The implementation of this core set in IT-IEM care has the potential to further advance provider-patient communication and a patient-centred treatment approach. This core set further ensures consistency in PRO assessment, both in daily care and in research. Especially in rare diseases like IT-IEM, data-comparability is of crucial importance to allow cross-national research and the inclusion of PRO-data in patient registries.Additional file 1. List of criteria for inclusion of PROMs to measure the PRO core set.Additional file 2. Stakeholder ratings of all PRO across the two Delphi surveys.Additional file 3. Core selection of PROMs to measure the final PRO core set.Additional file 4. Additional PROMs to measure the PROs included in the core set (predefined requirements not fulfilled).


Pediatric myocarditis is a commonly missed diagnosis in the pediatric emergency department (ED) with high morbidity and mortality. The presentation of cardiogenic shock secondary to myocarditis and septic shock can be difficult to differentiate during initial resuscitation, and incorrect treatment can lead to poor prognosis. Early diagnosis may provide a better prognosis for this life-threatening condition.We report a case of a five-year-old female who presented to the ED with non-specific symptoms of myocarditis. Rapid point-of-care ultrasound led to early diagnosis, correct management, and great prognosis for the patient.Providers must maintain a high index of suspicion for cardiogenic shock in patients with nonspecific symptoms and fluid unresponsiveness. Point-of-care ultrasound can help in the identification of cardiac disorders and guide practitioners in their management plans. Point-of-care ultrasonography (POCUS) is a safe, effective imaging modality with a rapidly expanding array of life-saving, time-saving, and cost-saving applications in pediatric emergency medicine. The American Academy of Pediatrics recently published the first policy statement endorsing the use of POCUS by pediatric emergency physicians (EP). An accompanying technical report concluded: “It is our responsibility to our patients to stay abreast of the most current advances in medicine and provide the safest, most efficient, state-of-art care. Point-of-care [ultrasound] will help us meet that goal.” Rapid ultrasound for shock and hypotension (RUSH) exam includes standardized views of the heart, inferior vena cava (IVC), lungs, and abdomen to further categorize the type of shock .3Myocarditis is rare in children, with an estimated annual incidence of 1–2 per 100,000 children.5In the pediatric ED several tests aid in the diagnosis of this life-threatening condition. Electrocardiogram (ECG) and troponin levels are performed when the suspicion is high. The RUSH exam conducted to evaluate shock may be of determinant help in assessing cardiac contractility and enlargement. We report a case of a five-year-old female who presented to the pediatric ED with non-specific symptoms of myocarditis. Rapid POCUS led to early diagnosis, correct management, and great outcome for this patient.A five-year-old female presented to the pediatric ED with a chief complaint of vomiting. According to her parents, the patient had been having three days of fever and vomiting up to 10 times a day, which was non-bilious and non-bloody. She was also noted to have a sore throat, poor appetite, decreased sleep, and mild cough. The patient had seen her primary care physician the day before the pediatric ED visit; rapid streptococcal antigen test was negative, and she was sent home. The patient had no other past medical or surgical problems, no allergies, and was not taking any medications.Her vitals on presentation was a temperature of 96.6°F orally, heart rate of 159 beats per minute, respiratory rate of 66 breaths per minute, blood pressure of 93/42 millimeters mercury (mm Hg), and oxygen saturation of 98% on room air. The patient was lethargic on examination, had dry mucous membranes, weak peripheral pulses, and capillary refill of 3–4 seconds. She had no abnormal lung sounds or heart murmur, and no hepatosplenomegaly.In the pediatric ED, she was immediately connected to a monitor, and point-of-care blood glucose was obtained . The differential diagnosis was broad and included dehydration, viral gastroenteritis, sepsis, appendicitis, obstruction, and pneumonia. Due to poor perfusion, no blood tests could be obtained but a peripheral intravenous access was established through which a 20 milliliters per kilogram (kg) normal saline bolus was given rapidly. Her initial capillary blood gas showed a pH of 7.30 (7.35–7.45), partial pressure of carbon dioxide of 26 mm Hg (35–45 mm Hg), and bicarbonate of 12 milliequivalents per liter (mEq/L) (22–28 mEq/L).A POCUS was conducted , 2, 3 usWhat do we already know about this clinical entity?Cardiogenic shock is not uncommon in pediatric population but the diagnosis is often missed or delayed due to lack of specific clinic features.What makes this presentation of disease reportable?This child presented with non-specific symptoms of myocarditis but the early diagnosis was critical to prevent poor outcome.What is the major learning point?Point-of-care ultrasound (POCUS) can be useful in diagnosing cardiogenic shock in children.How might this improve emergency medicine practice?By using POCUS, providers can make early diagnosis and improve outcome of children in the emergency department.A chest radiograph  and ECG The same day in the PCICU, the patient became bradycardic and lost pulses. Cardiopulmonary resuscitation was initiated, and the patient was placed on extracorporeal membrane oxygenation. She stayed in the hospital for 10 days and recovered almost completely. She was discharged with some left-sided weakness, and mild speech and swallowing difficulty for which she is undergoing rehabilitation. The final diagnosis was fulminant viral myocarditis (due to enterovirus) with cardiogenic shock.Pediatric myocarditis is a commonly missed diagnosis in the pediatric ED. In up to 50% of cases, an etiology is never identified; therefore, most cases are deemed idiopathic. The most common identified source in the developed world is viral. However, it can be caused by systemic disorders, bacteria, fungi, parasites, and toxins. Chagas disease is the most prevalent cause worldwide.Electrocardiogram is abnormal in most cases, but not specific. Changes can include sinus tachycardia, widening of QRS complex, and possible ST-segment changes. Pericarditis can be concomitant. Troponin is frequently elevated, and elevated inflammatory markers can aid in diagnosis. The gold standard for diagnosis is cardiac biopsy, which is rarely preformed before the death of the patient.9Pediatric POCUS is an emerging modality that physicians are becoming more comfortable with implementing in their practice. Visualization with ultrasound is a fast and easy tool that can be used upon arrival before any laboratory tests have been released. The advantages of POCUS also entail immediate diagnosis, increased accuracy, and minimal radiation dose.13In this case, the patient was presumed to have septic shock and received rapid fluid bolus until POCUS altered our management. The echocardiogram also allowed effective management of laboratory studies, as it was extremely difficult to obtain blood secondary to poor perfusion. It was elected to send troponin as the only initial serum test until central venous access could be obtained. Implementing POCUS in critically ill-appearing patients with non-specific symptoms can increase the sensitivity and efficiency of detecting myocarditis early in the ED as well as guiding the resuscitation team accordingly.Providers must maintain a high index of suspicion for cardiogenic shock in patients with nonspecific symptoms and unresponsive to fluids. Myocarditis is the leading cause of cardiogenic shock in the pediatric population. Point-of-care ultrasound can help in the identification of cardiac disorders and guide management in such patients.Video 1Parasternal long-axis view. Point-of-care ultrasound in parasternal long-axis view demonstrating global hypokinesis. Left ventricular ejection fraction less than 30%. Right ventricle mildly dilated.LV, left ventricle; RV, right ventricle; LA, left atrium.Video 2Apical 4-chamber view. Point-of-care ultrasound in apical 4-chamber view demonstrating slight pericardial effusion and decreased left ventricular ejection fraction.Video 3Sub-xyphoid inferior vena cava (IVC) view. Point-of-care ultrasound in sub-xiphoid IVC view demonstrating a plethoric IVC and a small pericardial effusion. Also noted is a small pericardial effusion posteriorly with B-lines.


Full STEM Ahead in Lancaster, Pennsylvania. Thirty-five Penn State and community partners engaged participants in discovery-focused learning through activity stations. Topic areas included: 3D printing in medicine, herd immunity, HPV cancer prevention, lung health, and germ prevention. Evaluation data from participants and organizational partners was collected to assess process outcomes and qualitative feedback. This event was part of a randomized controlled trial to improve attitudes toward adolescent vaccination. RESULTS/ANTICIPATED RESULTS: Seventy-four parents and students participated in the two-hour event. Evaluation data indicated that 100% of participants who completed the evaluation rated the event as “good” or “excellent” and agreed that they “learned something new.” Specific qualitative feedback indicated that participants enjoyed the STEM information and various learning activities offered. School district leadership hopes to continue the partnership to host the event in future years and expand to other schools, offering an opportunity for academic-community collaboration. DISCUSSION/SIGNIFICANCE OF IMPACT: This event was an innovative approach to connect low-income communities with science and potentially effective in engaging participants in learning. Similar opportunities should be explored to bridge the gap between research and community engagement, especially to increase research awareness.OBJECTIVES/GOALS: To provide a translation of health sciences and research to a low-income population and elevate the role of science in personal health and career pathways through the implementation of a STEM-focused, researcher-led, school-community event. METHODS/STUDY POPULATION: Through a strong school district partnership, families from two urban, low-income, high-minority middle schools were invited to attend an academic-community event entitled,


Bone marrow (BM) is a reliable source of multipotent mesenchymal stromal cells (MSCs), which have been successfully used for treating osteonecrosis. Considering the functional advantages of BM-MSCs as bone and cartilage reparatory cells and supporting angiogenesis, several donor-related factors are also essential to consider when autologous BM-MSCs are used for such regenerative therapies. Aging is one of several factors contributing to the donor-related variability and found to be associated with a reduction of BM-MSC numbers. However, even within the same age group, other factors affecting MSC quantity and function remain incompletely understood. For patients with osteonecrosis, several underlying factors have been linked to the decrease of the proliferation of BM-MSCs as well as the impairment of their differentiation, migration, angiogenesis-support and immunoregulatory functions. This review discusses the quality and quantity of BM-MSCs in relation to the etiological conditions of osteonecrosis such as sickle cell disease, Gaucher disease, alcohol, corticosteroids, Systemic Lupus Erythematosus, diabetes, chronic renal disease and chemotherapy. A clear understanding of the regenerative potential of BM-MSCs is essential to optimize the cellular therapy of osteonecrosis and other bone damage conditions. Bone marrow-multipotent mesenchymal stromal cells (BM-MSCs), the key bone regenerating cells, were first identified as attached to plastic culture surfaces and characterized by a self-renewal capacity to form a colony and the ability to differentiate into bone, cartilage and fat cells . With acOsteonecrosis (ON), also named avascular necrosis, is a multifactorial and painful bone disease characterized by vascular insufficiency, progressive collapse of subchondral bone and cartilage damage. This disease often develops in the femoral head, but it could also affect other joints, mostly in young or middle-aged individuals. One main mechanism of ON pathogenesis is vascular damage due to clotting, embolism, increased intraosseous pressure and direct blood vessel injury . ON can Extensive experimental research (in vitro and in vivo studies) has confirmed the unique and multifaceted regenerative capacities of MSCs. Because of their unique biological properties, MSCs represent a promising therapeutic tool for ON . ImportaAn important factor in the therapy of ON is the use of 3D scaffolds that are used as bone fillers and additionally support the repair functions of MSCs . These s® collagen membrane [In a composite approach, bioactive cells and growth factors are included to ‘functionalize’ the scaffolds and enhance the osteoinductivity. A combination of scaffolds and MSCs is a popular method to repair necrotic areas, as the scaffolds help direct MSCs to the necrotic areas and deliver mechanical support for these cells. Ceramic scaffolds loaded with BM-MSCs promoted the healing of bone defect in a canine model of femoral head ON . Porous membrane . This hymembrane . The seemembrane . In addimembrane . Another successful approach for ON therapy is the use of scaffolds functionalized by growth factors to ensure the sustained release of these factors, which would enhance MSC regenerative functions and blood vessel formation. This combination also solves the problems of local application of growth factors, such as their short half-life in vivo or heterogenous ossification related to the applications of BMPs . EncapsuInitial studies on using autologous MSCs for the treatment of ON were based on cultured MSCs from bone marrow (BM) aspirates and have demonstrated excellent patient safety and efficacy profiles as proved by pain relief and radiological signs of healing ,33. A phUsing uncultured autologous MSCs are particularly preferred for ease of extraction, safety and minimal need for handling, processing, and ethics . PioneerCore decompression is a classical surgical treatment for ON but usually effective for small necrotic lesions. The combination of core decompression with autologous BM was associated with improved clinical scores and radiological signs . Some clThe BM is a common source for MSCs used for ON, and the clinical delivery of BM MSCs as mononuclear cells was found to be better than using whole BM, likely because of concentrated cells . AdiposeIn summary, the great potential of autologous MSCs alone or in combination with scaffolds and growth factors for tissue repair in ON is evident ,48. HoweON is common in the young/middle age group ,49. WhilPrevious in vitro studies have used the long-term passaged MSCs in vitro as an indication of ageing. These studies showed that several changes are associated with in vitro ageing of MSCs . These cThe CFU-F assay has been the oldest method for enumerating BM-MSCs by counting the numbers of single cell-derived colonies based on first the MSC ability of plastic-adherence and second their ability to proliferate forming a colony. Over the years, several groups have performed CFU-F experiments to examine the age-related changes in the number of aspirated iliac crest BM-MSCs . The varIrrespective of these compounding factors, a general trend for a decline in BM MSC numbers has been confirmed in several recent studies. Most recent data from our laboratory  indicated a significant age-related decline in the number of colonies in relation to donor age in both males and females . IntereslowCD271+ phenotype [Enumeration of uncultured BM-MSCs has also been attempted by flow cytometry using several surface markers ,76,77. Chenotype ,73, and henotype ,73. HoweUsing uncultured MSCs, our group has recently shown no significant age-related increase in adipogenic or osteogenic differentiation transcripts or ROS levels in uncultured MSCs from old donors compared to young donors ,80. ThisThe age-related changes of the extra cellular matrix (ECM) could affect the functions of MSCs and their use for ON therapy . The ECMSummarizing the current literature in relation to age-related changes in BM-MSCs, it becomes apparent that young individuals are likely to have several-fold more MSCs in aspirated BM compared to donors over 40 years old. This can have implications on the dose of MSCs delivered into the damaged femoral head in ON patients. However, middle-aged and older donors show significant variability in relation to their MSC numbers, possibly because their skeletal biological ages are not the same as their chronological ages and may have been affected by environmental causes listed at the beginning of this section. With regards to MSC functions, such as differentiation, anti-oxidative and bone-remodeling capacities, age-related declines reported using cultured MSCs may represent an artefact of culture-expanded in vitro, and different types of assays need to be developed for the assessment of these functions in uncultured MSCs. In relation to ON treatment with autologous MSCs, these findings indicate that MSC dose-determination based on rapid laboratory tests , rather Physiological Glucocorticoids (GC) hormones are produced by the adrenal cortex, bind to their cell receptors and, consequently, transport to DNA, modifying cell biology. Although GC therapies are commonly used for anti-inflammatory effect, their significant immunomodulation could trigger undesirable effects that impair bone biology, causing osteoporosis . AdditioThe effect of GC on MSC biology was investigated in the cells of several experimental models as well as human cells ex vivo. BM-MSCs of age-matched rats were treated in vitro with various concentrations of 17 β-estradiol and dexamethasone. Interestingly, the data showed that these steroids changed MSC proliferation and differentiation in a dose-dependent manner. A low dose of these steroids helped to enhance MSC proliferation and osteogenic differentiation as noted by an upregulation of alkaline phosphatase (ALP), osteocalcin (OCN) and calcium levels as well as TGF-β1 and BMP-7 transcripts. However, a high dose of these steroids inhibited MSC differentiation and proliferation . TherefoGC was also found to upregulate the Dickkopf1 (DKK-1) levels that inhibit the osteogenic Wnt/β-catenin signaling pathway in BM-MSCs, leading to bone resorption . SimilarHuman BM samples from individuals with GC-induced ON had lower CFU-F numbers compared to two groups of those with ON related to sickle cell disease and healthy controls , furtherIn patients receiving systemic GC, a significant drop of serum sclerostin, OPG and OCN levels were observed. However, an increase of type 1 collagen cross-linked C-telopeptide, which were positively correlated with DKK-1 levels, were noted . TogetheOverall, a systematic effect of GC treatments on BM-MSCs is highly probable, potentially causing a reduction of their numbers in vivo. Nevertheless, more studies are needed to confirm this GC effect, particularly considering additive aging-related reduction of MSC numbers. In addition, impairment of repair function may be expected; therefore, boosting MSC osteogenic pathways are highly desirable in these cases. For example, targeting DKK-1 in MSCs before being used for regenerative purposes could be the solution. It is also of value to include other tools of therapeutic regeneration, such as tissue growth factors. For example, using bFGF releasing scaffolds in the dexamethasone-induced ON rat model allowed increased cartilage regeneration without cytotoxic effects on MSCs .Chronic and heavy alcohol intake is a high-risk factor for secondary osteoporosis, bone mineral density loss, and bone remodeling impairment. Consolidate evidence showed that bone turnover and healing is negatively affected by alcohol ,118. ForSIRT1) gene, which also controls the osteogenic commitment of MSCs and an increase of proliferation controlling gene, P38 [Studies on in vitro expanded human BM-MSCs indicated the damaging effects of alcohol on various MSC biological functions, particularly proliferative capacity that can translate into low in vivo counts. Alcohol induces senescence in BM-MSCs, which gradually lose self-renewal potential and are known to exhibit impaired multi-lineage differentiation potentials that will reduce the rate of bone formation and raise the osteoporosis risks ,121. Cheene, P38 . Additioene, P38 . Consistene, P38 . In contene, P38 .In terms of differentiation, chronic alcohol consumption decreases the bone-forming capacity and conversely increases the adipogenic differentiation of BM-MSCs . AdditioIn an experimental study, alcoholic rats showed decreased serum levels of certain inflammatory markers, interleukin (IL)-6, IL-2, IL-10, and C-reactive protein after induction of femoral mid-diaphyseal closed fracture as well as reduction of white blood cell numbers compared to saline-injected rats . AdditioOne recent study has compared the numbers of MSCs in BM concentrates from three ON patient groups: alcohol, GC and trauma. Similar numbers of MSCS measured by CFU-F assay were reported for the three groups . AlthougIn summary, chronic alcoholism has a detrimental effect on several MSC regenerative functions. Therefore, growing research aims to improve these functions. Anti-oxidant therapies, e.g., N-acetylcysteine and Vitamin D, have been proposed as therapeutic tools to prevent or minimize the negative effect of alcohol intake on bone healing, as reported in animal studies ,145. WhiSickle cell disease (SCD) is a red cell disorder associated with various vascular pathologies, capillary damages and a high prevalence of bone involvement . AdesinaThe experimental mice model for SCD is usually used to understand the pathogenesis and test the gene therapy for this disease . No animIn one study, the proliferation of MSCs from SCD patients was similar to that of healthy MSCs as tested by the in vitro doubling time and the surface marker phenotype. Isolated MSCs from BM aspirate concentrates of these patients maintained their proliferative potential and chondrogenic, adipogenic and osteogenic differentiation potential . Further6 nucleated BM cells, with a satisfactory outcome when used for ON therapy [In addition to repair functions, SCD MSCs have also been shown to preserve immunoregulatory capacity, with IDO found to be the major immunoregulatory mediator . Interes therapy . In viewConsidering their preserved functionality and proliferative potential, autologous MSCs were used in phase I/II, non-controlled studies of 89 SCD patients with ON via local implantation of BM aspirate concentrate ,155. TheGaucher disease (GD) is commonly associated with bone abnormalities such as osteoporosis, ON or pathological bone fractures . The mecAn experimental study using a mouse model of GD demonstrated that the skeletal manifestations of this disease are connected to an impairment of MSC proliferation. Additionally, a decrease in the osteogenic potential of GD MSCs in this model was shown by low ALP and RUNX2 gene expression levels .MSCs from one adult patient with GD was tested for the phenotype and functions of MSCs. These MSCs displayed standard MSC surface markers as well as normal osteogenic and adipocytic differentiation and growth. However, these MSCs showed an altered inflammatory secretome with a marked increase in COX-2, PGE2, interleukin-8 and CCL2 production relative to the normal controls . These pTogether, these data suggest defective proliferation and differentiation. More pre-clinical and clinical studies on the potential use of autologous MSCs in the treatment of GD-related ON are highly needed.A high prevalence of ON in Systemic Lupus Erythematosus (SLE) has been reported, with nearly 37% of lupus arthritis patients eventually developing ON . The maiBM-MSCs from a lupus mouse model have shown proinflammatory rather than inhibitory phenotype when stimulated by IL-1 and TNF-α. In these MSCs, there was an increase in the expression levels of CCL19, VCAM1, ICAM1, TNF-α and IL-1β, together with induction of CD4T cells proliferation . FurtherSeveral mechanisms have been proposed for SLE-related senescence and apoptosis of MSCs. The abnormalities of SLE BM-MSCs have been linked to abnormal JAK-STAT, Wnt/β-catenin, P53/P21 and PTEN/Akt signaling pathways in both human and mouse studies ,166,167.Cultured BM-MSCs from SLE patients displayed early senescence by increased β-gal activity, cell cycle arrest, disordered F-actin distribution and/or downregulated telomerase activity ,166,168.MSCs from SLE also express standard surface markers CD44 and CD105 and lack CD14, CD34, CD45 and HLA-DR. However, these MSCs had downregulation of IL-6, macrophage colony-stimulating factor (M-CSF) and IL-7 transcripts , indicatShi et al. found that MSCs from SLE patients demonstrated a defective migration capacity using the trans-well assay. Additionally, fluorescence microscopy images showed an abnormal over-polymerization of the F-actin cytoskeleton, accompanied by a high level of intracellular ROS. When these MSCs were treated with anti-oxidant N-acetylcysteine, F-actin restored conformation and enhancement of the migration was noted . AnotherIn summary, BM-MSCs in SLE patients have low proliferation, and this could affect their quantities in vivo. The use of these BM-MSCs as autologous therapy for ON should also consider the other biological defects of these cells, including reduced differentiation and migration abilities. In a recent study, culture-expanded autologous MSCs were applied to treat ON patient with comorbidity of SLE . The cliAlthough diabetes has not been linked to ON as an underlying factor, the simultaneous existence of both conditions is common, particularly in elderly patients or diabetic individuals who are treated with long-term GC . FurtherSeveral functional properties were tested for diabetic BM-MSCs and found to be defective. High serum concentrations of TNF-α in diabetic mice was directly linked to low expression of Indian hedgehog (Ihh) in MSCs and, consequently, suppression of MSC expansion and bone regenerative potential . InteresKim et al. showed that the gene expression of angiogenic factors, VEGFs and angiotensin were reduced in diabetic MSCs, which, when cocultured with endothelial cells, showed significantly lower endothelial tube formation . The groThe osteogenic differentiation of MSCs in a diabetic rat was reported to be impaired compared to control MSCs, as measured by calcium deposition . FurtherWith regards to immunoregulation, a recent study using a diabetic mice model has suggested a link of diabetes to the altered MSC-mediated immunoregulation. Bone MSCs showed an aberrant nuclear factor-kB (NF-kB) activation, reducing TGF-β1 expression in association with defective macrophage (M2) polarization and substantially enhanced inflammation in diabetic . FurtherCompared to pre-clinical studies, less research was conducted on the characterization of human MSCs from diabetic patients. In a recent study directly comparing MSCs from type 2 diabetes to age-matched MSCs from a healthy donor, it was concluded that diabetes seems to affect the numbers but no functional capacities of MSCs . CFU-F aAdditionally, MSCs from adipose tissue samples of type 2 diabetic patients induced lower suppression of PBMCs proliferation, declined expression of anti-inflammatory TGF-β1 and increased expression of proinflammatory mediators, TNF-α and IL-6 . These dCollectively, diabetic-MSCs showed impairment of proliferation, angiogenesis-support, osteogenesis, enhancing adipogenesis and immunoregulatory potential. These defects should be considered to improve the outcomes for ON lesions in diabetic patients. The biological stimulation of MSCs in diabetic patients has been proposed as a potential therapeutic strategy to improve the outcomes of using these MSCs for bone healing . The expChronic kidney diseases have been linked to ON, particularly of the jaw, with aging and low renal function  in additBM-MSCs derived from chronic kidney disease rats demonstrated premature senescence as indicated by the upregulation of β-gal activity, spontaneous adipogenesis, reduced growth rate and accumulation of actin . AdditioEven though several clinical studies have assessed the safety and outcomes of using autologous MSCs for the treatment of mixed cause ON ,202,203,Chemotherapy is one of the reasons that can increase the risk of ON, most commonly in male patients receiving chemotherapy for testicular cancer and those treated by chemotherapy for breast, ovarian, small-cell lung cancers and osteosarcoma . The mecThe effect of anti-cancer chemotherapy on MSC biology has been studied in different reports. An in vitro study tested the functions of BM-MSCs that were treated with chemotherapeutic agents used to treat leukemia such as cytarabine, daunorubicin and vincristine. These MSCs showed reduced viability, osteogenic, chondrogenic and adipogenic differentiation. Interestingly, these MSCs also showed decreased expression of cell surface receptors CD90 and CD73 but increased expression of inflammatory cytokines, IL-6 and TNF-α . AnotherOther studies investigated the biology of in vivo MSCs in host treated with chemotherapy. In an experimental study, mice were treated with busulfan, cyclophosphamide, cytarabine, methotrexate and bortezomib, as used clinically. The data showed that CFU-F numbers were reduced significantly and were not recovered after 6 weeks. However, differentiation capacities of MSCs were not affected by these chemotherapeutic medications . FurtherWith regards to human studies, the numbers of BM-MSCs from patients who received chemotherapy for BM transplantation were suppressed as indicated by significant lower CFU-F numbers than controls. The reduction of MSC quantity was verified to be host, not donor-related, and these patients also had a reduced bone mineral density . SimilarAltogether, these data suggest potential disadvantages of using autologous MSCs in chemotherapy-treated patients for further use for ON, mainly due to reduced proliferative potential.Treatment of ON is generally challenging due to late symptoms, complicated pathogenesis, different severity stages and multiple causes. Using MSCs in the therapy of ON is promising, with agreement on their benefits for the early-stage ON and the value of having adequate numbers, but there are still issues to be resolved . The MSCWhile the numbers of BM-MSCs decline with advancing age, their potential and functionalities undergo subtle changes in vivo that might be influenced by environmental factors such as diet, exercise and other lifestyle factors. Furthermore, individuals with comorbidities, for example, diabetes, SLE and GD or those who chronically use GC or alcohol, potentially have significant defective functions of MSCs. Different functional abnormalities of MSCs were detected in secondary ON due to the etiological factors, with some reports showing no differences between the various causes. However, it is important to stress that future studies comparing the ON causes should consider the age and probably gender matching as well as other technical details, e.g., fold-enrichment in BM concentrates if these samples are analyzed for MSC quantities.Considering the defective quality or quantity in aged or ON-related conditions, using MSCs for ON therapy is likely to require larger or concentrated volumes of autologous BM aspirate or biological stimulation prior to the application of autologous MSCs to achieve successful ON treatment. In this context, new centrifugation techniques such as vertical centrifugation could show enhanced potential to harvest more MSCs from these individuals . CombineAutologous BM-MSCs can be delivered for regenerative therapies in their native form within BM aspirate concentrates or after culture expansion, aiming to achieve reparative effects with minor complications ,202,203.


Introduction: Tuberculosis (TB) is a major infectious disease that seriously endangers human health and female reproduction. In our previous study, 10.4% of infertile patients preparing for In vitro fertilization and embryo transfer (IVF-ET) had prior pulmonary TB (PTB) as detected on chest X-ray (CXR) screening. Among them, 81.8% did not receive anti-TB treatment. It remains unclear whether infertile women with untreated prior PTB have latent TB infection (LTBI) and whether LTBI affects IVF-ET outcomes. In this study, we aim to analyze the relationship between LTBI and pregnancy outcomes following IVF-ET in patients with untreated prior PTB.Methods and Analysis: We designed a prospective cohort study of 1,200 infertile women with CXR findings suggestive of old-healed untreated TB, who are preparing for IVF-ET. Patients with a history of active TB and anti-TB treatment will be excluded. Interferon-gamma release assay (IGRA) will be used in patients with CXR findings suggestive of old-healed untreated TB to construct a cohort of IGRA-positive and IGRA-negative patients. Participants will undergo IVF-ET. General information, including age, body mass index, infertility causes, and controlled ovarian hyperstimulation protocol, will be recorded. Participants will be followed up during pregnancy. The primary outcome is live birth. Secondary outcomes include the numbers of retrieved oocytes, high-quality embryo rate, clinical pregnancy, number of active TB cases during pregnancy, and miscarriage.Ethics and Dissemination: The study was approved by the Ethics Committee of Peking University Third Hospital . The research results will be disseminated through scientific/medical conferences and published in academic journals.Trial Registration:ClinicalTrials.gov; identifier: NCT04443283. Mycobacterium tuberculosis, seriously affects human health (In vitro fertilization and embryo transfer (IVF-ET) remains the most effective method of treating associated infertility (Tuberculosis (TB), an infectious disease caused by n health , 2. Accon health . TB may n health , 4. Earlertility .M. tuberculosis infection  is an essential examination before IVF-ET, and active TB should be identified and treated accordingly. Seven cases of miliary TB during pregnancy after IVF-ET have been reported in our previous article . Active nfection , 12. Mornfection . The resnfection . We specLatent TB infection (LTBI) is defined by a positive test for infection and no active TB , 15. ForCurrent guidelines recommend screening for LTBI with a TST, IGRA, or both; many also recommend chest radiography. Uzorka et al. reviewed 25 different studies on LTBI and CXR and reported that ~15% of individuals with LTBI had specific lesions on CXR that possibly reflect prior PTB . In contHere, we hypothesized that adverse IVF-ET pregnancy outcomes in infertile patients might be related to untreated IGRA-positive prior PTB. If confirmed, further scientific evidence is essential to help understand the effect of LTBI on IVF-ET outcomes to optimize the management of LTBI in infertile patients with untreated PTB and update the guidelines.We designed a prospective cohort study of infertile women who will undergo IVF-ET. IGRA will be performed in patients with CXR findings suggestive of old-healed untreated TB. A cohort of IGRA-positive and IGRA-negative patients will be constructed. Pregnancy outcomes will be followed prospectively, and the relationship between LTBI and pregnancy outcomes will be analyzed.This is a prospective cohort study of infertile patients who will undergo IVF-ET from January 1, 2022, to December 30, 2024, at Peking University Third Hospital. According to the sample size calculation, ~1,200 participants will be enrolled. The inclusion criterion is untreated PTB on CXR. The exclusion criteria are (1) active TB, (2) a previous diagnosis of TB, (3) TB other than PTB , (4) the presence of central nervous system diseases, cancer, or AIDS, (5) long-term oral corticosteroids, immunosuppressants, and inhaled corticosteroid therapy, which may increase the risk of TB, and (6) patients who lack decisional capacity or who cannot guarantee their participation until the end of the study . ParticiInfertile patients who will undergo IVF-ET at the Center for Reproductive Medicine of Peking University Third Hospital will be screened. According to the Code of Practice for Assisted Reproductive Technology developed by the Ministry of Health of the People's Republic of China, all patients will undergo routine CXR examination before IVF-ET . PatientParticipants' baseline characteristics  will be obtained from the case registration research database, including age, body mass index (BMI), infertility years, causes of infertility, and the controlled ovarian hyperstimulation (COH) protocol. Baseline levels of hormones will also be recorded, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone (P), prolactin, testosterone (T), androstenedione (A), and anti-Müllerian hormone (AMH), and antral follicle count. Follicles after oocyte promotion, hormone levels  on human chorionic gonadotropin (HCG) day, and B-ultrasound findings, such as a gestational sac and endometrial thickness, will also be recorded .IVF-ET patients will be followed in early pregnancy ( ≤ 12 weeks), middle pregnancy (13–27 weeks), late pregnancy (≥28 weeks), and at 3 months after delivery. All pregnant women will be followed to fill out the case report form (CRF), and pregnancy outcomes will be assessed by telephone interviews .Whether there are symptoms, such as fever, cough, night sweat, or blood in sputum during the pregnancy;Whether blood routine test, chest X-ray examination, lung computed tomography examination, and sputum test have been performed and the results;Whether the patient has been diagnosed with active TB;Whether the TB has been diagnosed by clinical diagnosis, microbiology, or both;Whether the pregnancy outcome is live birth, premature birth, abortion, or stillbirth; andWhat are the birth weight and health statuses of the newborn?LTBI testing will be conducted for the participants with untreated PTB using IGRA. The QFT assay  will be performed according to the manufacturer's instructions. Individuals will be categorized into two groups based on the IGRA results: (1) Group 1: those with negative IGRA results and (2) Group 2: those with positive IGRA results. A special team will be assigned to perform follow-up on the pregnancy outcomes.Prior PTB is defined as the presence of radiologic evidence suggestive of old/inactive PTB , 21, 22,via ultrasonography at 30 days after ET.All the eligible participants will undergo a standardized COH protocol, oocyte retrieval, fertilization, and embryo transfer, as described previously , 23. COHThe primary outcome is live birth . Live biThe secondary outcomes include the numbers of retrieved oocytes, high-quality embryo rate, clinical pregnancy, number of active TB cases during pregnancy, and miscarriage . ClinicaWe explored the effect of positive IGRA on pregnancy outcomes after adjustment for age, BMI, infertility causes, COH protocol, endometrial thickness, and number of good-quality embryos. There were 19 variables (including the dummy variables) in the logistic regression model. Considering the sample size requirement of multivariate logistic regression, 190 live birth events are required based on the 10 events per variable (including dummy variables) rule . Assumint-tests or the Mann-Whitney U test for between-group differences. Categorical variables such as causes of infertility and COH protocol will be represented as frequency and percentage and analyzed using the Chi-square test.Statistical analysis will be performed using SPSS version 25 . Continuous data will be expressed as means (± standard deviation), with independent sample p-values will be reported. A two-tailed p-value < 0.05 will be considered statistically significant.The pregnancy outcomes of the IGRA-positive and IGRA-negative groups will be compared using the Chi-square test. We will use multivariate logistic regression to adjust for the effect of baseline characteristics. Adjusted odds ratios, 95% confidence intervals, and This is an observational study. The patient will be informed of all the procedures and will be asked to sign the informed consent voluntarily.To the best of our knowledge, this is the first prospective study on the impact of positive IGRA on IVF-ET pregnancy outcomes in infertile patients with untreated prior pulmonary TB. We will enroll 1,200 participants and analyze whether positive IGRA will affect the pregnancy outcome of IVF-ET. The primary outcome is live birth rate. Secondary outcomes include the numbers of retrieved oocytes, high-quality embryo rate, clinical pregnancy, number of active TB cases during pregnancy, and miscarriage.Identifying and treating individuals with a high risk of progression from LTBI to active TB disease is critical. Studies have indicated that untreated participants with a positive IGRA result have a 10.8-fold higher rate of progression to active TB . MoreoveOur hypothesis is that LTBI will affect pregnancy outcomes in infertile women receiving IVF-ET. Knowledge of the relationship between LTBI and pregnancy outcomes could provide evidence for clinical decision-making regarding anti-LTBI treatment in this population. If this hypothesis is verified, further studies will be carried out to evaluate anti-TB therapy for patients with LTBI. The standardized protocol of isoniazid with rifampicin for 3 months may be administered for these infertile patients with LTBI, and improvements in pregnancy outcomes will be explored in the future.The current study has several key strengths. First, our prospective study design, in which LTBI and pregnancy outcomes are reliably followed, will allow us to analyze the relationship between LTBI and pregnancy outcomes and provide stronger evidence for causality. The results of our study can offer insights into LTBI and IVF-ET outcomes within a country with an intermediate TB burden, such as China. The outcomes of our study will serve as strong evidence for preventive anti-TB treatment of LTBI in infertile women within a country with an intermediate TB burden and provide data for updating guidelines. Second, this is a prospective study designed by a multidisciplinary team of respiratory physicians, obstetricians, obstetrician-gynecologists, epidemiologists, statisticians, and other related experts, a collaborative effort to ensure the quality of the study.The limitation of the study is that this is a single-center study in China, without multi-center participation. However, as one of the largest and most authoritative reproductive centers in China, we perform nearly 20,000 IVF-ET cycles annually. Moreover, the population in this study is from all over the country and is representative of the Chinese population. In addition, accepted standards are available for IGRA quality control and the IVF-ET process in the same single center.The studies involving human participants were reviewed and approved by Ethics Committee of Peking University Third Hospital. The patients/participants provided their written informed consent to participate in this study.RL and YS jointly conceived and directed this work, and RL is the leading corresponding author. XG and HC were responsible for protocol editing and recruitment of participants. LZ was responsible for sample size estimation and statistical analysis. YS and RL were involved in manuscript editing. All authors participated in the project and the acquisition, analysis, or interpretation of the data, and the final version has been reviewed and approved.This work was supported by the National Natural Science Foundation [No. 81400041 and 81871212], the National Natural Science Foundation of China Youth Fund Project [No. 81400038], and the Cohort study project of the Peking University Third Hospital (Y70545-04). The funding bodies had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the protocol; or in the decision to submit the article for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


A moderation analysis with Andrew Hayes’ PROCESS macro showed a significant moderating effect of lower-extremity muscle strength  on the relationship between nutritional health risk and depression; the weaker was the muscle strength, the steeper was the slope of the GDS score for nutritional health risk. Conclusions: The current findings suggest the need for an intervention targeting both high nutritional risk and weak muscle strength as a therapeutic strategy against depression in Korean older adults.Background: Little is known about the relationships between muscle strength and nutritional health risk with late-in-life depression. This study aimed to investigate the moderating effect of lower-extremity muscle strength on the relationship between nutritional health risk and depression in Korean older adults. Methods: Data obtained from 5949 women and 3971 men aged ≥ 65 years in the 2020 Korea Longitudinal Study on Aging were used in this study. Exposures included lower-extremity muscle strength and nutritional health risk. Lower-extremity muscle strength was measured with a modified sit-to-stand test. The nutritional health risk was assessed using a screening tool. Depression was defined as a score ≥ 8 points on the Geriatric Depression Scale (GDS). Results: Logistic regression analyses showed that depression was positively associated with nutritional health risk ( In Korea, depression has been a major public health concern because of its devastating consequences, such as increased risks of chronic diseases [Depression is a serious mental disorder, affecting 3.8% of the global population, and is a leading cause of disability worldwide, representing an important contributor to the global burden of diseases . The remaining 9920 samples (including 3971 men and 5949 women) were used for the final data analyses. The Institutional Review Board of the Korea Institute for Health and Social Affairs reviewed and approved the 2020 KLoSA  in accordance with the Declaration of Helsinki. Signed informed consent was obtained from all participants. KLoSA data collection was carried out during face-to-face interviews via a computer-assisted personal interviewing protocol using a tablet. A detailed KLoSA information is accessible via the national public database (https://survey.keis.or.kr/eng/myinfo/login.jsp/ accessed 10 June 2021).Data were obtained from the 2020 Korea Longitudinal Study on Aging (KLoSA), a nationwide-population-based survey of 6062 women and 4035 men aged ≥ 65 years conducted in Korea. As shown in Depression was assessed using a Korean version of a 15-item Geriatric Depression Scale (SGDS-K) . DepressThe nutritional health risk was assessed using the DETERMINE Your Nutritional Health Checklist developed by the Nutrition Screening Initiative . The cheThe sit-to-stand test developed by Buatois et al.  was modi2), educational background , smoking (current/past smoker or nonsmoker), alcohol consumption , regular exercise (yes or no), and comorbidities. Patients’ comorbidity status was determined using diagnoses reported by a doctor of at least one of 17 selected chronic conditions . The number of chronic conditions (comorbidities) was summed and categorized as no health condition (none), one health condition (single), and two or more health conditions (multiple).Covariates included age (year), gender , body mass index (BMI)  and 95% confidence intervals (CIs) of nutritional health and lower-extremity muscle strength for depression. Finally, as illustrated in n = 5000) and 95% CIs. The statistical significance of a relationship was tested with a nonzero value of a 95% bootstrapped CI. All other statistical significances were tested at p = 0.05 using SPSS version 27.0 for Windows .Quantile–quantile plotting and a variance inflation factor were used to verify data distribution normality and the absence of multicollinearity, respectively. Student’s p < 0.001) and more likely to be female (p = 0.013), with lower mean BMI (p < 0.001), lower educational background (p < 0.001), weaker lower-extremity muscle strength (p < 0.001), and more infrequent regular exercise, greater heavy alcohol consumption (p = 0004), more comorbidities (p < 0.001), and higher nutritional health risk (p < 0.001), compared with nondepressed individuals.p < 0.001), BMI (p < 0.001), and lower-extremity muscle strength (p < 0.001) but positively with education (p < 0.001), multiple comorbidities (p < 0.001), and nutritional health risk (p < 0.001).In this population-based cross-sectional study, we examined the impacts of lower-extremity muscle strength and nutritional health risk on depression in 9920 Korean older adults aged ≥ 65 years and found that nutritional health risk and weak lower-extremity muscle strength were associated with greater odds for late-in-life depression. The novel finding of the current study is that the weaker was the muscle strength, the greater was the impact of nutritional health risk on depression.The current findings are in accordance with those of previous studies reporting an association between nutritional status and depression in older adults. For example, malnutrition was found to be an independent risk factor for depression in older outpatients in Turkey  and commThe findings of the current study are also in line with those of previous studies reporting an association between weak muscle strength and depression in older adults. For example, several previous studies using data obtained from the Korea National Health and Nutrition Examination Survey showed that handgrip strength was inversely associated with depression risk and suicidal ideation in Korean middle-aged and older adults ,41. In aIn particular, the findings of this study extend those of previous studies by showing that muscle strength is an important moderator in determining the relationship between nutritional health risk and late-in-life depression. The moderating effect of lower-extremity muscle strength on the relationship implies the clinical importance of both good nutrition and muscle fitness as a therapeutic strategy against late-in-life depression. In support of the current findings, Pinheiro et al.  conducteSome explanations are possible regarding the modulating effect of lower-extremity muscle strength on the relationship between nutritional health risks and late-in-life depression. First, chronic exposure to nutritional health risks might lead to or exacerbate geriatric conditions that contribute to depression, such as functional limitations , physicaSecond, maintaining muscle mass and strength itself may minimize or counteract the risk of late-in-life depression . For exaThird, other health conditions, such as chronic diseases, increased oxidative stress, immobility, and dysregulated hormonal cycles, which are attributed to nutritional health risk and/or weak muscle strength, might be involved in the moderating effect of lower-extremity muscle strength on the relationship between nutritional health risk and depression ,54.Lastly, poor socio-economic status  and poor health behaviors  may be entangled in the moderating effect of lower extremity muscle strength on the relationship between nutritional health status and late-life depression . The invThis study is not without limitations. First, the cross-sectional nature of this study does not allow us to offer any cause-and-effect interpretation regarding the moderating effect of lower-extremity muscle strength on the relationship between nutritional health risk and depression. Second, the relationships of nutritional health risk and lower-extremity muscle strength with depression can be bidirectional. In other words, either nutritional health risk or lower-extremity muscle strength or both can increase the risk for depression, or vice versa, and this remains to be addressed in a well-designed intervention study. Third, the relationships of nutritional health risk and lower-extremity muscle strength with late-in-life depression may imply adverse effects of other health conditions that are not included in the current study. Consequently, caution is necessary when interpreting the moderating effect of muscle strength on the relationship between nutritional health risk and depression.Despite these limitations, this study also has strengths. First, it is a population-based study with large sample size. Second, to the best of our knowledge, we are the first to report the potential of lower-extremity muscle strength as an important moderator in determining the relationship between nutritional health risk and depression in older adults.In this population-based study, we examined the relationships of nutritional health risk and lower-extremity muscle strength with depression in Korean older adults and found that late-in-life depression was positively associated with nutritional health risk and inversely with lower-extremity muscle strength. Particularly, we found that high lower-extremity muscle strength attenuates the negative impact of nutritional health risk on depression, implying an urgency of an intervention targeting both nutritional health risks and weak muscle strength as a therapeutic strategy against depression in Korean older adults.


Based on upper echelons, paradox, and social capital theory, this study extends the association of CEO vision articulation and feedback-seeking behavior with firm sustainability by identifying the mediating role of eco-innovation and top management team (TMT) boundary-spanning behavior as a moderator. By analyzing the data of mid-sized to large Chinese firms using hierarchical regression and bootstrapping-based moderated path analysis, we found that product and process eco-innovation mediates the link between CEO vision articulation and firm sustainability while CEO feedback-seeking behavior enhances firm’s sustainability through product eco-innovation only. Finally, conditional indirect effects show the vital role of TMT boundary-spanning behavior in facilitating CEOs to improve the firm’s long-term sustainability through eco-innovation. Around the globe, firms are continuously making efforts to mitigate the environmental impact of their economic activities to deal with public awareness for green products and climate-friendly technology . HoweverBased on the review of prior literature, we identified certain gaps to complement current studies in eco-innovation. First, there is a general dearth of evidence related to the association of eco-innovation and firm sustainability as most of the studies are inclined toward firm performance with mixed views . Even thAlthough a few studies addressed the importance of CEO vision articulation and feedback-seeking on firm sustainability , 2018, oHumble CEOs more effectively share information and collaborate with their top management team (TMT) by adopting an ambidextrous strategic orientation . NonetheBesides the paradox perspective, the co-existence of opposite elements can be explained by “cultural additivity.” The term was initially coined by Third, we argue that TMT boundary-spanning behavior strengthens the mediating effect of eco-innovation between underlying CEO characteristics and firm sustainability. The seminal work on team boundary-spanning behavior has considered three dimensions, i.e., ambassador activities, task coordinator activities, and scout activities . ThroughIn summary, our study contributes to the upper echelon, sustainability, and eco-innovation literature by addressing and statistically investigating a moderated mediation model in which eco-innovation intervenes in the effect of the CEO leadership qualities (vision articulation and feedback-seeking) and TMT boundary-spanning behavior on firm sustainability. The research model of the study is shown in Eco-innovation may include several activities such as clean energy utilization, green patents, environmentally responsive management systems, green technology, recycling, and so on . Eco-innTaking a step forward, based on the upper echelons theory (UET), organizational performance and behaviors are not merely dependent upon firm value or external environment but also the result of top management’s traits and cognitive capabilities . Over thAlong with 1:HProduct eco-innovation mediates the relationship between CEO vision articulation and firm sustainability.2:HProcess eco-innovation mediates the relationship between CEO vision articulation and firm sustainability.Recently, considerable research is devoted to the leader’s humility and its influence on firm innovation, firm performance, and team effectiveness . NonetheFeedback is considered as a dynamic process that consists of a feedback receiver’s perception, feedback information quality, and feedback source credibility . All the3:HProduct eco-innovation mediates the relationship between CEO feedback-seeking behavior and firm sustainability.4:HProcess eco-innovation mediates the relationship between CEO feedback-seeking behavior and firm sustainability.The framework of upper echelons theory incorporates the role of top management teams who are responsible for strategic change, adaption, and organizational growth. The efficient top management team favors creativity, an idea generation environment, effective communication, and a cooperative climate which improves product and process innovation performance . CorrespTMT boundary-spanning functions through the ambassador, task coordinator, and scout activities. Top management teams coordinate with the CEO, board, and other higher departments to gain trust and appreciation through ambassador activities. TMTs solve institutional, operational, and strategic issues by creating an alliance with their external human resources through task coordinator activities. Furthermore, top management teams attain technical information, reconnoiter market prospects, and oversee similar projects of their competitors through scout activities. By gaining resource support from internal and external stakeholders, TMT boundary-spanning behavior may support CEO’s vision to improve product and process eco-innovation to meet sustainability needs of the firm as TMT members tend to have a more sensitive market perception, vigorous sense of vision, and broader vision .TMT members build effective lateral communication networks with external stakeholders by holding outside directorships  that pro5:HTMT boundary spanning behavior moderates the positive indirect relationship between CEO feedback-seeking behavior and firm sustainability through product eco-innovation such that the link is stronger when the TMT boundary spanning behavior is high.6:HTMT boundary spanning behavior moderates the positive indirect relationship between CEO feedback-seeking behavior and firm sustainability through process eco-innovation such that the link is stronger when the TMT boundary spanning behavior is high.7:HTMT boundary spanning behavior moderates the indirect positive relationship between CEO vision articulation and firm sustainability through product eco-innovation such that the link is stronger when the TMT boundary spanning behavior is high.8:HTMT boundary spanning behavior moderates the indirect positive relationship between CEO vision articulation and firm sustainability through product process eco-innovation such that the link is stronger when the TMT boundary spanning behavior is high.SD = 22.80) with moderate tenure of CEO .Survey data were collected from TMT members (identified by their CEO) of 91 mid-sized to large enterprises comprised of 8 different industries located in China. Primarily, we contacted 284 TMT members for their participation in the survey (94 from large enterprises and 190 medium enterprises). Some of the TMT members did not respond, while others denied sharing information due to their organizational policy. After discarding missing data, a final sample of 234 TMT members was considered. Major industries were related to fertilizer, transportation, automobile, energy supply, sugar, cement, retail, and paperboard. The average age of sample firms was 28.7 years .1We used the scale developed by CEO feedback-seeking behavior was measured using the scale developed by The measurement of process and product eco-innovation was adapted from the studies of We measured TMT boundary-spanning behavior through the modified scale of The incorporation of control variables in the hierarchical regression model does not assure the elimination of biases that emerge between predictor and explanatory variables regardless of their extensive use in business and organizational research . Thus, tSimilarly, CEO gender is also one of the important factors that influence a firm’s major decisions. Studies revealed that female CEOs are risk-averse and less likely to enhance the firm’s innovative activities . To meas2/df = 2.78, Confirmatory Fit Index (CFI) = 0.92, Goodness-of-fit Index (GFI) = 0.95, Tucker–Lewis Index (TLI) = 0.90, Root Mean Square Error of Approximation (RMSEA) = 0.05. Furthermore, the validity indices of moderated mediation model also show good fit: χ2/df = 2.91, Confirmatory Fit Index (CFI) = 0.94, Goodness-of-fit Index (GFI) = 0.93, Tucker–Lewis Index (TLI) = 0.91, Root Mean Square Error of Approximation (RMSEA) = 0.06.We used abbreviated scales because CEOs or top managers may not respond adequately to lengthy or repetitive questions . Althougwg(j)] are evaluated for each construct while the F-tests are utilized from a series of one-way ANOVAs to evaluate if the average rating of TMT members is significantly different across firms. After excluding two firms with only one TMT member, the results of analyses show that there is considerable consistency among survey responses from members of the same firm as the F-test indicates significant results and the values ICC1, ICC2, and rwg(j) exceeds the suggested threshold level , process eco-innovation , and TMT boundary-spanning behavior  were positively correlated with firm sustainability. CEO vision articulation was significantly associated with product eco-innovation  while CEO feedback-seeking behavior was positively associated with both product  and process eco-innovation .1 and H2, after controlling the effect of CEO age, gender, tenure, TMT size, and firm age, we entered CEO vision articulation (independent variable) in Model 2 and eco-innovation (mediating variable) in Model 3 and 4 (see p < 0.05) in Model 2 but insignificant when product eco-innovation  and process eco-innovation  were introduced in the Model 3 and 4 which provided support for our first and second hypothesis as the effect of CEO vision articulation was also positively significant on product and process eco-innovation (see To test the Hnd 4 see . The dirtion see .p < 0.01) and product eco-innovation  were positively associated with firm sustainability in Model 6 and the effect of CEO feedback-seeking behavior is also positively significant on product eco-innovation  in p > 0.05) when it was incorporated with CEO feedback-seeking behavior in Model 6. Thus, H4 was not supported.On the other hand, CEO feedback-seeking behavior . However, the direct effect of the interaction on product eco-innovation was not significant, which suggested that the interaction of TMT boundary spanning behavior and feedback-seeking was fully mediated through product eco-innovation on firm sustainability that supported the H5. Nevertheless, we did not find full empirical support for the sixth hypothesis as the interaction of TMT boundary spanning behavior and feedback-seeking behavior was significant with both processes eco-innovation and firm sustainability. Additionally, the conditional indirect effects of CEO feedback-seeking behavior on firm sustainability through process eco-innovation was not significant with low TMT boundary spanning behavior .To test HP = 0.13, p < 0.01), while the mediating link of CEO feedback-seeking behavior on firm sustainability through process eco-innovation can be moderated with TMT boundary-spanning behavior . Owing to the insignificant estimates for the sixth and seventh hypotheses, the null of these hypotheses cannot be rejected.Results also show that TMT boundary-spanning behavior moderates the mediating link of CEO vision articulation on firm sustainability through product eco-innovation (Owing to exorbitant economic activities, Asian economies are on the verge of an atmospheric catastrophe. Thus, business sectors should transcend from greenwashing campaigns and veridically transform their core cultural values to environmental healing. To achieve higher sustainable performance, organizations need to transform their eco-deficit culture to eco-surplus culture . Thus, rFirst, we find that eco-innovation is an important mechanism that builds the link between CEO vision articulation and firms’ sustainability. Consistent with the upper echelons perspective, it is argued that visionary leaders dynamically thrive for achieving competitive advantage and sustainability by stimulating eco-friendly technological innovation . AlthougOn the other hand, CEO feedback-seeking behavior can improve firm sustainability through product eco-innovation only. Humble leaders who consistently seek feedback on their performance may consider environmental concerns before executing their profit-oriented strategies . HumilitResults are also partially consistent with a paradox perspective that vision articulation and feedback-seeking behavior can coexist in a CEO . When CEOur findings make several theoretical and practical implications. We enrich the literature on the linkage between top management behavior and the firm’s green practices for sustainable long-term development. We suggest that environmental innovation is an adequate mechanism to link the goals of visionary and humble CEOs with the firm’s sustainable growth. Although the role of a CEO’s vision to fortify organizational innovation is important, humility may overcome the fragile sense of vision to foster eco-innovation and sustainability. Nonetheless, excessive humility may threaten the leader’s prestige, due to which visionary leadership should be combined for enhancing innovative culture, TMT integration, and organizational sustainability.Unlike prior studies, we integrate the upper echelons perspective with the social capital perspective by incorporating TMT boundary-spanning behavior in the framework. Organizations should focus on improving the boundary-spanning functions of their top management teams to gain flexible and low-cost external resources to improve firm sustainability through green product and process innovation. Additionally, TMT boundary-spanning behavior extracts resources for visionary CEOs for product eco-innovation and feedback-seeking CEOs for process eco-innovation. Thus, boundary-spanning behavior is a powerful tool to manage both process and product innovation for sustainable organizational development.Concerning the practical implications of our findings, it is suggested that organizations should focus on the behaviors of CEOs to engage the enterprises in the green innovation of products and processes. The selection of CEOs should be based on their ability to articulate a clear vision and be humble with their followers as these behaviors complement each other to foster sustainable competitiveness. Additionally, corporations should establish effective procedural mechanisms to recognize the integration of TMT boundary-spanning behavior by encouraging them to create valuable resource networks and communicate actively through trial-and-error learning systems. Unfortunately, Asian countries are hard hit by climate change but still, their understanding of corporate sustainability issues is inadequate . These fThis study is subject to certain limitations that can provide additional opportunities for future studies. First, this study has utilized multisource cross-sectional data, which did not account for the variation in organizational behavior, processes, and the possibility of reverse causality over time. Thus, the longitudinal time-lagged study may provide more robust estimates. Secondly, our sample size is smaller at an organizational level despite surveying a large number of TMT members. Future studies may consider a large sample size to mitigate the statistical biases associated with a smaller sample size. Thirdly, studies should include national factors or conduct a cross-country study as the cultural background of China may vary from other Asian or Western countries.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 Ethics Committee at Jiangsu University. The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.