Racial and ethnic minority groups have higher rates of SARS-CoV-2 infection, severe illness, and death; however, they receive monoclonal antibody (mAb) treatment at lower rates than non-Hispanic White patients. We report data from a systematic approach to improve equitable provision of COVID-19 neutralizing monoclonal antibody treatment.Treatment was administered at a community health urgent care clinic affiliated with a safety-net urban hospital. The approach included a stable treatment supply, a same-day test and treat model, a referral process, patient outreach, and financial support. We analyzed the race/ethnicity data descriptively and compared proportions using a chi-square test.p < 0.001), a lower proportion were White Non-Hispanic , equal proportion were Black , and equal proportion occurred for other race patients.Over 17 months, 2524 patients received treatment. Compared to the demographics of county COVID-19-positive cases, a greater proportion of patients who received mAb treatment were Hispanic (44.7% treatment vs. 36.5% positive cases, Implementation of multiple systematic strategies to administer COVID-19 monoclonal antibodies resulted in an equitable race/ethnic distribution of treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in the United States in early 2020 and rapidly spread throughout the country –3. CoronIn November 2020, the US Food and Drug Administration issued Emergency Use Authorizations (EUA) for two monoclonal antibody (mAb) treatments for high-risk patients with COVID-19 ,13. SincUnfortunately, despite their higher disease burden and higher rates of having conditions that would qualify them for mAb therapy, Hispanic (any race), Black, Asian, and other non-white patients have received monoclonal antibody treatments at substantially lower rates than White Non-Hispanic patients –22. SpecTo address the disproportionate incidence of COVID-19 infection, hospitalizations, and death in racial/ethnic minority groups in Denver, CO, we designed a multimodal mAb delivery strategy to minimize racial/ethnic disparities in access to this outpatient treatment . This stThis is a retrospective case review of an urgent care clinic-based model for delivery of mAb treatment for COVID-19. We used administrative data to evaluate racial and ethnic characteristics of patients accessing care relative to county demographics of those diagnosed with COVID-19.The outcome of this study is the rate of mAb treatment administration for SARS-CoV-2 infection by patient race and ethnicity following a multi-component systematic approach designed to improve treatment uptake.Denver Health and Hospital Authority (DHHA) is an urban safety-net health system, serving one-third of the population of Denver County, comprising a safety-net hospital, ten federally qualified community health centers, and 18 school-based clinics. The DHHA Federico F. Peña Southwest Urgent Care Clinic (PUCC) is a Federally Qualified Health Center (FQHC) located at the intersection of four Denver neighborhoods that have high concentrations of medically underserved populations including 20% non-English-speaking adults, 70% identifying as Hispanic, 51% low-income households, and 20% living below the poverty level . In partOur urgent care clinic-based mAb delivery model is characterized by a) sustainable use of personnel, space, and materials, including a stable supply of mAb; b) efficient and safe systems and workflows; and c) flexible and equitable policies for treatment access that prioritized those at highest social and medical risk .PUCC, as an urgent care clinic, had many of the necessary resources in place to administer mAb, specifically, registered nurses, refrigerated medication storage space, intravenous access ability and supplies, and medication pumps. DHHA worked in collaboration with the state public health department to establish and secure a supply of mAb. Due to a purchase by the federal government, the mAb medication itself was free. The specific mAb delivered varied depending on which agent was authorized and effective based on SARS-CoV-2 variant prevalence. When patient volumes were very high, a conference room was converted to an infusion site and additional nurses from within the organization and supporting organizations were utilized to facilitate the administration of mAb.A clinic flow process was created to ensure efficiency and safety when caring for these COVID-19-positive patients  or a primary care provider (a barrier to access for patients without a regular source of care). This process was approved through the Colorado Multiple Institutional Review Board. Our electronic health record  was used to generate a daily report of all DHHA patients who tested positive for COVID-19 across the system in the previous 24 hours and met treatment criteria per the EUA. Trained staff reviewed these medical records to confirm eligibility by determining date of symptom onset and confirming a high-risk condition. Direct patient outreach was performed on these patients. Funding for this patient outreach staff member was provided by a grant.In July 2021, we continued to expand access by partnering with the county public health department in Denver, CO. We provided education to public health outreach staff who were contacting COVID-19-positive patients in the community. These outreach workers were taught about the COVID-19 mAb treatment options and who met treatment criteria. When the outreach workers spoke with patients, they gave a brief introduction to the treatment and asked the patient if they would be interested in being contacted by the clinic to learn more about this treatment. If the patient was interested, this generated another daily list of potential patients for treatment.Utilizing both the DHHA electronic health record list and the public health list, staff contacted patients via telephone, utilizing a certified medical interpreter if needed. The patient was offered mAb treatment and provided education on the treatment itself, the administration process, the risks, and the benefits. Additionally, financial support was offered directly to patients to decrease cost as a barrier. If the patient accepted, they were immediately scheduled and received mAb treatment within two days. DHHA was able to bill commercial insurance, Medicaid, and Medicare patients for the administration costs associated with this treatment. For uninsured patients or those on a fee-based sliding scale program, reimbursement was sought through the federal government’s COVID-19 Uninsured Fund.Statistical analysis: We analyzed the race and ethnicity data descriptively and compared proportions using a chi-square test. We specifically compared the self-reported race/ethnicity of the PUCC treatment group to those who tested positive for COVID-19 in Denver County (self-report) and to the racial/ethnic composition of the Denver County population (census data). Due to the structure of the data, for this analysis race/ethnic groups are mutually exclusive. Hispanic persons could be of any race, and all other races were non-Hispanic. The other/unknown category included persons who identified as more than one race, who did not identify as any of selected race/ethnic group options, or who declined to answer.p = 0.0807).From December 1, 2020, through April 30, 2022, 2524 unique patients received COVID-19 mAb treatment in the PUCC for a total of 2540 doses administered. Prior to June 2021, only 162 patients received treatment and 2365 patients received treatment after June 2021. Three patients received treatment during both timepoints. Of these unique patients, 1129 (44.7%) were Hispanic (any race), 1028 (40.7%) White, 207 (8.2%) Black, 62 (2.5%) Asian, 14 (0.6%) American Indian/Alaska Native, and 6 (0.1%) Native Hawaiian/Pacific Islander (Table p < 0.001) patients received mAb treatment, an equal proportion of Black , Asian , American Indian/Alaska Native , and Native Hawaiian/Pacific Islander  patients received mAb treatment and a lower proportion of White  patients received mAb treatment (Table p < 0.001) patients received mAb treatment, an equal proportion of Black , American Indian/Alaska Native , and Native Hawaiian/Pacific Islander  patients received mAb treatment and a lower proportion of White  and Asian  patients received mAb treatment (Table Compared to the Denver County COVID-19-positive case population, a greater proportion of Hispanic (44.7% vs. 36.5%, Implementation of a comprehensive multimodal urgent care clinic-based model for outpatient treatment with monoclonal antibodies against SARS-CoV-2 across a safety-net healthcare system resulted in a more equitable race/ethnic group population-based demographic distribution of treatment recipients. In addition, and potentially more impactful, this model resulted in comparable rates of treatment for racial/ethnic minority groups who were infected with COVID-19 in Denver County. This resulted in a substantial increase in the proportion of Hispanic, Black, Asian, and Other race patients receiving treatment compared to less comprehensive approaches –20. ThisHispanic, Black, Asian, and other non-White patients experience higher rates of infection, severe illness, and death from COVID-19, likely due to lower socioeconomic status and higher prevalence of chronic medical conditions –11, and This multimodal systematic approach addressed many of the identified and perceived barriers to mAb treatment for racial/ethnic minority groups. First, to address the access to healthcare barrier, we ensured a stable mAb supply with our collaboration with the state public health department. We administered this treatment at a set location in a trusted community-based FQHC urgent care clinic and opened access with same-day and referral-based administration. Second, to address the financial/insurance status barrier, we offered financial support programs to the patients and submitted costs to the COVID-19 Uninsured Relief Fund to minimize the financial impact on the patient. Third, to address the language barrier, all communication was performed in the patient’s native language via a bilingual provider/staff member or with the use of certified interpreter. Fourth, to address the health literacy barrier, we partnered with our safety-net organization and local public health departments to identify potential treatment candidates. Each of these individuals was contacted via direct patient outreach and provided education on the mAb treatment. Patient volume increased significantly after June 2021 when direct patient outreach began. We suspect this contributed to more qualifying patients of all races/ethnicities receiving mAb treatment. This timepoint also coincided with increased availability of mAb, increased provider education and awareness, and increased patient awareness of this treatment due to multiple external factors. Lastly, we utilized a team-based approach, and all staff were familiar with COVID-19 patients, mAb treatments, and caring for underserved populations.This study is limited to one clinic within a single health system, using some resources that might not be available in other clinical settings. Additionally, there are limitations in the analytic approach which focused only on patient race and ethnicity, unadjusted for other factors that can affect access but for which our data were incomplete, including insurance status, primary language, and neighborhood. We were also unable to assess different patient populations’ reasons for eligibility, as individual-level medical status and high-risk conditions were unavailable.In conclusion, using a coordinated set of strategies to simultaneously target multiple known barriers to access can dramatically improve receipt of key ambulatory COVID-19 therapeutics for racial and ethnic minority patients. Our experience provides proof of concept that a comprehensive multimodal approach can increase equitable receipt of and decrease racial and ethnic disparities to mAb treatment for COVID-19.


We found novel evidence for elevated wet-weight cerebral sodium levels in VaD brain tissue in six out of the seven regions analyzed. Decreased cerebral-potassium levels as well as increased Na/K ratios (consistent with high tissue sodium and low potassium levels) were also observed in several brain regions. These data suggest that reduced Na+/K+-exchanging ATPase (EC 7.2.2.13) activity could contribute to the contrasting changes in sodium and potassium measured here.Vascular dementia (VaD) is the second most common cause of cognitive impairment amongst the elderly. However, there are no known disease-modifying therapies for VaD, probably due to incomplete understanding of the molecular basis of the disease. Despite the complex etiology of neurodegenerative conditions, a growing body of research now suggests the potential involvement of metal dyshomeostasis in the pathogenesis of several of the age-related dementias. However, by comparison, there remains little research investigating brain metal levels in VaD. In order to shed light on the possible involvement of metal dyshomeostasis in VaD, we employed inductively coupled plasma-mass spectrometry to quantify the levels of essential metals in  Vascular dementia (VaD) comprises a spectrum of conditions characterized by cerebrovascular disease that leads to or causes cognitive impairment, behavioral abnormalities, and motor dysfunction . So defiin vivo, which limits the scope of such investigations. There is evidence that impaired homeostatic regulation of zinc and copper may play substantive roles in the pathogenesis of VaD  production  probably in response to cerebral energy deficiency, which could exacerbate the neuropathology of VaD.In the present study, we used inductively coupled plasma-mass spectrometry (ICP-MS) to measure the concentrations of eight essential metals  and the metalloid, Se, in human l tissue , our respost-mortem VaD/control tissue received Local Research Ethics Committee approval supplied by the Southwest Dementia Brain Bank (SWDBB). Informed consent for the collection of tissue was obtained by the SWDBB. Consent for collection of AD cases was as previously stated , basal ganglia (BG), cingulate gyrus (CG), frontal gyrus (FG), middle temporal gyrus (MTG), occipital cortex (OC), and hippocampus (HP) were acquired. These regions were selected because they are commonly affected in VaD; additionally, they allow for direct comparisons with our previous metallomic studies in AD , and Parkinson’s disease dementia (PDD).Brain tissues from the 10 VaD cases, all of whom had a confirmed neuropathological diagnosis of small vessel disease at es in AD . Althougl levels . The sampost-mortem examination; AD Braak stage of 3 or less ; non-amyloid small vessel disease; mild to moderate cerebral amyloid angiopathy (CAA); histopathological evidence of microinfarction; and no histopathological evidence of other neurological diseases likely to cause dementia. However, due to the limited sample metadata, complete fulfillment of these criteria could not be confirmed for all cases . Despite this, all cases manifested evidence of ischemic cerebral damage, a confirmed diagnosis of VaD at post-mortem examination (as specified by the SWDBB), and no histopathological evidence of other neurological diseases likely to cause dementia. Although mild to moderate CAA was requested, case 1105 was found to have severe CAA potentially consistent with mixed dementia. However, this case did not present any outlying metal values and received a clinical and post-mortem diagnosis of VaD which provided adequate justification for its inclusion in this study. Controls had no clinical history of dementia or other brain disease, and no other neurological abnormalities.The inclusion criteria for VaD cases included: confirmed neuropathological diagnosis of VaD at The Montreal Cognitive Assessment (MoCA), which is considered to be the preferred neuropsychometric test for the assessment of VaD , was recpost-mortem tissue  as further described below.g  to ensure that the tissue sat at the bottom of the tubes. Concentrated nitric acid  and 5% Agilent Internal Standard mixture  were used to make the tissue digestion mixture. Calibration standards were prepared to the appropriate dilutions  values for wet-weight ICP-MS analysis were moderately lower than corresponding dry-weight values , we haveue in AD . Metal c–1 He), except for Se which was analyzed in high-energy helium mode  to reduce interference by polyatomic ion formation. Germanium and indium internal standards were analyzed in both modes. Integration times for relevant trace metals were 3 s for Se; 0.01 s for Fe; 0.03 s for Mn, Cu, and Zn; and 0.1 s for Na, Mg, K, and Ca. A multi-element method using serial dilutions of environmental calibration standards , where indium was used. To remove spectral interferences, two collision-cell gas modes were employed. All elements were analyzed in helium mode  or medians  were calculated and the significance of inter-group differences were determined by either Welch’s p-values < 0.05 were considered significant. Post hoc statistical power and sample-size estimates for both dry- and wet-weight brain tissue were calculated using G*Power v3.1.9.4 . v3.1.9.4 .Receiver operator characteristic (ROC) curves were generated using in GraphPad Prism v8.1.1  using Na data from all regions that displayed statistically significant case-control differences.To identify potential metallomic cluster separation between VaD and our previous AD metallomic datasets , princippost-mortem delay (PMD), brain weight, or dry-weight/wet-weight tissue ratios  in the hippocampal cohort was diagnosed with T2D, which is suggested to independently influence the progression of dementia/cognitive impairment . HoweverInductively coupled plasma-mass spectrometry analysis was used to measure the concentrations of eight essential metals: Na, Mg, K, Ca, Mn, Fe, Cu, Zn, and the metalloid, Se. Our previous hippocampal metal dataset , generatn = 70; Con, n = 70). Wet-weight global elemental analysis revealed increased Na (p < 0.0001) and decreased K levels (p = 0.0145) in VaD cases compared to controls (p = 0.0016) and Se (p = 0.0149), as well increased Cu levels (p = 0.0008) in VaD cases ; however, the wet-weight regression model identified a negative relationship between global Na and Cu, whereas a positive relationship was observed for the dry-weight data , CG (p = 0.0003), FG (p = 0.0009), MTG (p = 0.0280), OC (p = 0.0038), and HP (p = 0.0038) . The ROC curve displayed an area under the curve (AUC) of 0.796 , consistent with fair discriminatory power for cerebral-Na levels in classifying between VaD and controls . In the dry-weight MTG PCA dataset, one sample from the AD group and two from the AD controls were removed as a result of missing values to enable dimension reduction. No other samples from either the HP or CG PCA dry-weight datasets were excluded. However, several samples in the wet-weight investigation of AD were unable to be analyzed due to the limited availability of tissue.To further understand the combined metallomic differences identified in our VaD and AD datasets, PCA was conducted to assess the overall metallomic pattern of these disease states. As previously explained, only the HP, MTG, and CG datasets were used for PCA due to the overlap of metallomic data between AD and VaD datasets. Where applicable, if control groups from both VaD and AD cohorts displayed substantial overlap, then they were grouped and used as a single control cohort against all cases thereafter (as planned p < 0.0001), which provides strong evidence for significant correlation between variables to support data reduction. PCA revealed no separation between all cases and controls used for both dry-  measure for sampling accuracy was 0.598 for MTG, 0.690 for CG, and 0.580 for HP dry-weight datasets. For wet-weight analysis, the KMO was 0.512 for MTG, 0.669 for CG, and 0.695 for HP datasets. As there is some debate regarding whether a KMO of 0.5 or 0.6 should be used as the minimum threshold for dimension reduction, all three regions from both dry- and wet-weight datasets were used for PCA. However, these KMO scores are described as being mediocre, which should be taken into account when interpreting these data . Bartletoth dry-  and wet-oth dry- , which ip = < 0.0001) and dry-weight analysis (p = 0.0001) (p = 0.0039); dry weight (p = 0.0106)], CG , FG , and HP  (p = 0.0011) and HP (p = 0.0006), but not CG, showed similar Na/K ratio increases  . When se0.0314)] . When th0.0314)] , the MTGncreases . Howeverpost-mortem brains with small vessel disease related dementia.Numerous studies have provided evidence for brain-metal dyshomeostasis in several neurodegenerative conditions . In contpost-mortem delay (PMD), brain weight, or wet-weight/dry-weight ratio between VaD cases and controls in the present study. This indicates that such variables are unlikely to have affected the brain-metal differences seen in this study. It is also worth noting that while the PMDs for the cohorts used in this study were not unusually high for United Kingdom-based brain banks, it has been suggested that extended PMDs can alter analyte expression. However, based on our group’s previous findings, it is unlikely that the PMDs presented in this study significantly altered brain-metal levels  has been documented in both AD and VaD cases, which is crucial to the initial stages of cellular respiration and the subsequent generation of ATP  subunits  uses ∼20% of the body’s resting ATP production via Natrations . Previoutrations , we propn of ATP . This gisubunits  and upresubunits  in VaD mll death  potentiall death , which c+/Ca+ exchanger  were calculated. Several reports have also highlighted the utility of high Na/K ratios as a risk factor in cardiovascular disease and stroke   , 17. TheThe finding of increased global brain-Cu levels in VaD is consistent with previous reports of elevated serum-Cu levels in VaD , as wellAlthough multiregional cerebral-Na elevations in VaD remains the focal point of this investigation, concomitant global cerebral-Cu levels are of particular interest given that both metals are tightly associated with bioenergetics. Therefore, to further understand the relevance of these perturbations in relation to one another, linear regression analysis was employed to determine whether Na levels predicted Cu levels in VaD brain tissue. Interestingly, the regression models identified both negative and positive relationships between Na and Cu in wet- and dry-weight tissue, respectively. Although the levels of VaD Na and Cu in the present dataset are of critical importance, further analysis will be needed to fully determine why these differences between wet- and dry-weight regressions exist, given that these data were generated from the same samples.Perturbations in single regions were also observed for Ca, Mn, and Fe in wet-weight analysis, and Zn in dry-weight analysis. Although both Ca and Mn satisfied our criteria for statistical power, these differences were not present in both dry- and wet-weight analysis. Therefore, further investigation will be required to fully understand the relevance of these findings.As both VaD and AD present clinical and pathological similarities , the mulIn the present study, CV values were generally lower in the wet-weight compared to the dry-weight analysis. One possible explanation for the higher CV observed in the dry-weight group may be due to the greater number of analytical steps required. As all dry-weight samples used for ICP-MS analysis underwent an extra day of drying and weighing before measurement, this might have inadvertently increased the variability amongst these samples. Therefore, wet-weight metal measurement may be the preferred method in the present study and for future ICP-MS analyses.post-mortem brain tissue. In addition, patient medical records for example, blood pressure and previous medication were not available for many of the controls and VaD cases used in this study. This information would be of critical importance to the understanding of Na homeostasis in the brain, however, such data is not routinely collected by United Kingdom brain banks which represents an innate flaw in the use of post-mortem tissue. Lastly, diagnostic data including cause of death, Braak stage, and CAA were also not specified for several cases. This was due to the limited availability of metadata in the brain bank database using the specified sample inclusion criteria. While post-mortem examination confirmed the absence of concomitant neurodegenerative diseases capable of causing dementia  in all samples, such diagnostic data would have been valuable for further understanding the mechanism(s) responsible for elevated brain-Na levels. Follow-up analysis may be necessary using Braak stage and CAA at different stages to assess their impact on brain-metal levels in VaD.In addition to low statistical power, other limitations in this study also include potential oncological impact, lack of patient medical records, and lack of diagnostic detail. Several controls, but none of the VaD cases, had cancer (as well as other causes not related to cancer) listed in their cause of death. Some chemotherapies can cause decreased systemic Na levels  and chempost-mortem tissue using ICP-MS. In conclusion, these results present novel evidence for severe widespread Na elevation in VaD brains. Importantly, this pattern of Na elevation was not apparent in our group’s previous investigation of AD brains, measured using the same methodology. This highlights the potential application of Na as a diagnostic biomarker in VaD patients via clinical 23Na magnetic resonance imaging, which may also assist in the ante-mortem discrimination of VaD from AD. Furthermore, decreased brain-K levels as well as increased Na/K ratios were also observed in several regions in the VaD group. This implies that the Na+/K+-ATPase may be functioning at a sub-optimal level, probably due to defective energy utilization, thus contributing to the contrasting Na and K levels seen here. However, it is likely that additional mechanisms such as alterations in voltage-gated Na channels and the Na+/H+ exchanger are also contributing to the Na and K perturbations seen here. Further studies will be required to confirm the diagnostic utility of clinical brain-Na levels and the precise involvement of the Na+/K+-ATPase in VaD.To the Authors’ knowledge, this is the first study to provide a multiregional assessment of cerebral-metal levels in VaD The original contributions presented in this study are included in the article/SP designed and performed the experiments, analyzed and interpreted the data, and wrote the manuscript. JX performed the experiments and revised the manuscript. SC performed the experiments and analyzed the data. RU designed the experiments, interpreted the data, and revised the manuscript. FR advised on the sampling of brain regions and revised the manuscript. GC designed the experiments, interpreted the data, revised the manuscript, and bears overall responsibility for the integrity of this manuscript and of the study. 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.


Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease characterized by the deposition of amyloid-beta (Aβ) peptide and neurofibrillary tangles in the brain. The approved drug for AD has certain limitations such as a short period of cognitive improvement effect; moreover, the development of drug for AD therapeutic single target for Aβ clearance in brain ended in failure. Therefore, diagnosis and treatment of AD using a multi-target strategy according to the modulation of the peripheral system, which is not only limited to the brain, is needed. Traditional herbal medicines can be beneficial for AD based on a holistic theory and personalized treatment according to the time-order progression of AD. This literature review aimed to investigate the effectiveness of herbal medicine therapy based on syndrome differentiation, a unique theory of traditional diagnosis based on the holistic system, for multi-target and multi-time treatment of mild cognitive impairment or AD stage. Possible interdisciplinary biomarkers including transcriptomic and neuroimaging studies by herbal medicine therapy for AD were investigated. In addition, the mechanism by which herbal medicines affect the central nervous system in connection with the peripheral system in an animal model of cognitive impairment was reviewed. Herbal medicine may be a promising therapy for the prevention and treatment of AD through a multi-target and multi-time strategy. This review would contribute to the development of interdisciplinary biomarkers and understanding of the mechanisms of action of herbal medicine in AD. Alzheimer’s disease (AD), a chronic progressive neurodegenerative disease marked by cognitive impairment and behavioral disorder, is characterized by the deposition of extracellular amyloid-beta (Aβ) peptide and intracellular neurofibrillary tangles, cerebral amyloid angiopathy, and neuronal loss . The app42 and elevated levels of phosphorylated tau , AD Assessment Scale-Cognitive Subscale (ADAS-cog), and Montreal Cognitive Assessment (MoCA) compared with conventional medicine alone in AD . HM has A previous study on SD in elder patients with MCI suggested the distribution of six syndromes including three deficiencies  and three excesses  in MCI and suggested that the distribution ratio of deficiency and excess in complexity was higher . AnotherThe literature review included randomized controlled trials (RCTs) published until August 2021 in English, Korean, or Chinese. We searched for studies that classified SD and evaluated the efficacy of herbal medicine based on SD, presented the time-order progression of mild cognitive impairment and AD, and included HM interventions using traditional East Asian medicine. Observational studies, single case reports, literature reviews, re-published research papers, re-cited literature, non-SD studies, and animal studies were excluded. The search strategy is shown in The expression profile in the peripheral blood of patients with AD reflects complex neuropathological conditions, including extensive systemic disruption, demonstrating strong blood-brain correlation . Some stHowever, other studies have revealed that MCI and early stage AD showed unique characteristics compared to the later stages. Compared to severe AD, increased genes were mainly related to neurological processes and inflammation, and decreased genes were related to ionic regulation, cytoskeleton, gas transport, cell signaling and olfactory transduction in mild AD . The resStudies have also been conducted to classify the stages of patients and predict the possibility of exacerbations using machine learning techniques based on transcriptome. A predictive model for AD, which was developed using a combination of clinical, biological, and genetic properties (including EEF2 and RPL7 expression levels), also predicted a risk of MCI with high probability . AnalysiUtilizing gene signatures that are characteristic of each stage of AD enables the establishment of appropriate drug treatment strategies for each stage. The transcriptome analysis of drug-induced changes in cells and tissues can holistically elucidate the multiple mechanisms of drugs. Therefore, it is an excellent tool for analyzing the mechanisms of HM with multi-component and multi-target properties . StudiesSalvia miltiorrhiza bunge) and Yanhusuo  were the HMs that acted on most targets, and the core target genes were ADRB2, ADRA1B, DPP4, ACHE, and ADRA1D. On the other hand, a network pharmacological study on AD suggests different target genes and HMs , is known to play a key role in dementia. Cirsium japonicum var. maackii (ECJM) inhibited lipid peroxidation and nitric oxide production in Aβ25-35-induced mice , oxidative  damage, and inflammatory (interleukins and tumor necrosis factor-α) pathways  capsules ameliorated cognitive impairment by up-regulating low toxic amyloid plaques and down-regulating highly toxic soluble oligomers, such as Aβ42 and Aβ40 in the brain cortex . Xuefu ZHuanglian Jiedu decoction-treated APP/PS1 transgenic mice reversed cognitive deficits with the suppression of Aβ accumulation . Thus, wThe relationship between systemic inflammatory disease and AD incidence is being studied in various fields. Treatment using You-Gui-Yin (YGY) extract significantly mitigated cognitive deficits in mice with chronic renal failure (CRF) by up-regulating the CaMKIIα/CREB/BDNF and EPO/EPOR pathways in the hippocampus . PatientHM treatment for cognitive impairment is based on the theory of a holistic perspective that is not limited to the brain . In thisvia cholinergic signaling (via the peripheral system approach for cognitive impairment is needed. Research on the therapeutic effect and mechanism of HM in cognitive impairment animal models showed ameliorated cognitive deficits by anti-oxidation and anti-inflammation (Neuromodulation therapy and vagus nerve stimulation influence the CNS by accelerating motor refinement in the primary motor cortex ignaling . In otheignaling . In prevignaling . Moreoveignaling . Therefoammation . Additioammation . The kidammation . Similarammation . TherefoNeuroimaging-based and transcriptomic peripheral blood biomarkers were explored as HM markers by therapeutic response or disease stage progression for patients with cognitive impairment. These markers can be detected before clinical symptoms and provide an objective, accurate measurement. In particular, compared to the accumulated research on network pharmacology analysis based on the target information of phytochemicals contained in HMs , transcrIn this review, under the assumption that HM treatment is based on SD diagnosis, biomarkers of the peripheral system approach through HM treatment was presented through neuroimaging and transcriptomic changes . In the J-HJ and KJ: conceptualization. S-MP and SL: formal analysis. JJ, YC, SJ, and SS: methodology. J-HJ: supervision. S-MP, SL, HZ, JK, KJ, and J-HJ: writing – original draft preparation. S-MP, SL, KJ, and J-HJ: writing – review and editing. All authors have read and agreed to the published version of the manuscript.


Participants rated their patient-centered care experience Kunshan Huaqiao People's Hospital in Jiangsu, China.A total of 230 participants .p = 0.823, CFI = 1.000, TLI = 1.019, RMSEA = 0.000, SRMR = 0.032] had a superior model fit over the original first-order with four correlated factors and the second-order structures. The overall reliability was excellent . In terms of patient satisfaction, process, treatment quality, and communication significantly predicted patient satisfaction, while environment, staff attitude, and medical ethics did not . Most importantly, the total score of PPIQ-C predicted patient satisfaction above and beyond the above-mentioned medical service perspectives . Finally, the constructive effect of PCC on patient satisfaction was stronger for departments of Pediatrics than Surgery.PPIQ-C exhibited acceptable psychometric properties. Data revealed a single factor model of the 16 PPIQ-C items [The Chinese version of the PPIQ scale (PPIQ-C) exhibited acceptable psychometric properties. Yet the distinction among the four factors was not supported, suggesting potential difference(s) across cultures. Patient-centered care (PCC), reflected by the overall PPIQ-C score, predicted overall patient satisfaction above and beyond other medical service perspectives. Adopting PCC approach in appropriate situations will probably advance the development of performance evaluation systems in China, thus improving the overall health care and patient satisfaction. Over the last two decades there has been an increasing focus on supporting people to be more involved in their care and in tailoring services around the needs of individuals . EngaginPatient satisfaction is a critical indicator in the evaluation of healthcare service, which is commonly used in performance appraisal of medical institutions , 10. TheHowever, PCC receives relatively less attention in developing countries, for example, China , 20. DueIn light of the insufficient attention to PCC in patient satisfaction evaluation in China , 22, it via introducing the translated, Chinese version of PPIQ . A conventional procedure was conducted to translate the PPIQ into Chinese, and the psychometric properties of the PPIQ-C were examined according to its theoretical structure. It was expected that PPIQ-C could serve as suitable assessment of PCC in Chinese medical settings, and it could predict Chinese patients' satisfaction of their medical experiences among other factors.To briefly summarize, this study provides a clear and comprehensive survey of the influence of PCC on patient satisfaction in China via convenient sampling from the a local second-grade, comprehensive hospital in the Jiangsu, China. The inclusion criteria were outpatients or inpatients of the hospital. Patients who were unable to make an objective and rational assessment because of illness or psychological disorder were excluded. Five respondents were excluded from the analyses regarding patient satisfaction because of incomplete answers in medical perspectives. All eligible participants who consented to participate were informed about the study's purpose and procedures and were asked to respond to the e-survey on tablets during the interview.A cross-sectional survey was conducted through face-to-face interviews from June to September in 2019. A total of 230 participants  were recruited via the 16-item PPIQ-C (1 = quite disagree to 5 = quite agree). The original PPIQ , including hospital environment, treatment process, treatment quality, staff attitude, doctor-patient communication, and medical ethics derived from national patient-perspective of care research (1 = quite disagree to 5 = quite agree) .Participants rated their experience of the received medical service e agree) , 27. Eacfemale and 1 = male), age , marital status (0 = unmarried and 1 = married), education , as well as annual income .Finally, participants reported the medical departments they visited , and provided their sociodemographic information, including gender ; ratio of S-B χ2 to its degree of freedom (cutoff ≤5)  in the R lavaan package with Diagonally Weighted Least Square (DWLS) estimator , 29. Multoff ≤5) ; Root Metoff ≤5) ; Comparatoff ≤5) –34. Averhttps://osf.io/n46ze/. A total of 230 participants were enrolled in this study. Data (identity information masked) and exemplar syntax can be found here: Confirmatory factor analysis was adopted to examine the validity of the PPIQ-C scale. A first-order and a second-order four-factor  models were compared in terms of the model fit. Fit indices were reported in PPIQ-C score was then applied to predict patient satisfaction. Three multiple linear regression models were examined. Model 1 included only medical service perspectives evaluated by patients as the predictors of patient satisfaction. Model 2 further included the PPIQ-C scores to examine the prediction of patient-centered care on patient satisfaction above and over the included medical service perspectives. Bi-variate correlation among all the six medical perspectives and the overall PPIQ-C scores has been shown in R2 = 0.427, F (6) = 24.887, p < 0.001). Specifically, patient satisfaction increased as the evaluation of process, treatment quality, and communication perspectives increased. When PPIQ-C score was further included in the model, it significantly predicted patient satisfaction above and beyond other medical service perspectives  = 11.834, p < 0.001). Notably, treatment quality was no longer significant . Including PPIQ-C score further explained 3.3% of the total variance of patient satisfaction (f2 = 0.033). Finally, three dummy variables for departments  and their product terms with PPIQ-C scores were included . Results suggested that the association of PPIQ-C score and patient satisfaction was only different between Surgery and Pediatrics departments ; no statistical difference was found amongst other departments , such that 1 unit increase in PCC scores additionally brought 0.768 units increase in patient satisfaction in Pediatrics than in Surgery.Results were summarized in This study translated and examined the psychometric properties of the Chinese version of the PPIQ scale (PPIQ-C), and then applied patient-centered care reflected by the PPIQ-C score to predict patient satisfaction. To summarize, the PPIQ-C exhibited excellent internal consistency as well as theorized dimensionality. In addition, patient-centered care, reflected by the PPIQ-C scores, predicted overall patient satisfaction above and beyond other medical service perspectives.Although the first-order and the second-order model structures, as proposed by the original study , both fiImplication of factor scores was still discussed here as it could offer practical advice for local medical institutions to improve their patient centered care deliveries. As for individual scores, EC factor scored the highest across the current sample, which reflects the perceived extent to which professionals could allow patients to detail symptoms and maintain respect during visiting. This corroborates well with the extensive attention to communication skills in the standardized medical training programs in China. It also corroborates well with the growing emphasis of doctor-patient communication in job performance evaluation of professionals in China over the past decades. In contrast, PIC was rated as the lowest by patients. On the base of Chinese large population, it is not practical for medical professionals, especially those employed at large-scale, public hospitals, to involve patients to a large extent in medical decision-making. Therefore, it was reasonable that PIC received lower recognition compared to the other factors.Results suggested that treatment process, treatment quality and communication positively predicted patients' overall satisfaction. It is noteworthy that among the three factors communication exhibited the greatest prediction. This result aligns well with previous investigations in China . Howevervia shared decision making, supporting self-management, and especially proactive communication (r = 0.753) between the two concepts.More importantly, when PCC was further included, it significantly and positively predicted overall satisfaction above and beyond other medical factors that were widely explored in patient satisfaction research , 26. It nication . ResultsWhen comparing the association of PCC and patient satisfaction across different medical departments, the prediction of PCC scores onto overall satisfaction was stronger in Pediatrics than Surgery department. This is reasonable as pediatrics serve a particularly special and vulnerable population, namely children who may be uncapable to clearly communicate symptoms and needs, even for those accompanied by their caregivers . A PCC aNo doubt that PCC makes considerable contributions to the improvement of overall satisfaction, yet this does not deny the critical practitioner-controlling role in life-threatening medical situations . In otheThe generalizability of our findings was somewhat limited as we only recruited patients from one comprehensive hospital, despite that our selection was based on its representative city and population size in southern China. Granted which, this study introduced the concept of PCC in China to evaluate patient satisfaction which furthered the scope of different healthcare perspectives. Additionally, this study provided the Chinese version of the PPIQ scale as a feasible assessment tool for further studies despite the lack of discriminant validity of its factors. Finally, this study shed light on the unique contribution of patient-centered care in addition to other medical perspectives and discussed how healthcare professionals and institutions might make the best use of it in real settings.The Chinese version of the PPIQ scale (PPIQ-C) exhibited excellent internal consistency and acceptable content validity. Patient-centered care (PCC), reflected by the PPIQ-C scores, predicted overall patient satisfaction above and beyond other medical service perspectives. Adopting PCC approach in appropriate situations will probably advance the development of performance evaluation systems in China, thus improving the overall healthcare and patient satisfaction.The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the committee on research involving human subjects of School of Public Health, Shanghai Jiao Tong University School of Medicine. The patients/participants provided their written informed consent to participate in this study.ZZ, XuL, YF, KQ, and XiL: study design and implementation. SL: methodology. TH, SL, and XuL: data curation. TH and SL: analysis, validation, and writing-original draft preparation. CY, JL, TJ, and MB: discussion. HL and ZZ: supervision. All authors have read and agreed to the published version of the manuscript.This study was supported by a grant from Nanjing Jialiang Information Technology Co., LTD to ZZ.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 interestAll 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.


Sustainment refers to continued intervention delivery over time, while continuing to produce intended outcomes, often with ongoing adaptations, which are purposeful changes to the design or delivery of an intervention to improve its fit or effectiveness. The Hispanic Kidney Transplant Program (HKTP), a complex, culturally competent intervention, was implemented in two transplant programs to reduce disparities in Hispanic/Latinx living donor kidney transplant rates. This study longitudinally examined the influence of adaptations on HKTP sustainment.Qualitative interviews, learning collaborative calls, and telephone meetings with physicians, administrators, and staff (n = 55) were conducted over three years of implementation to identify HKTP adaptations. The Framework for Reporting Adaptations and Modifications-Expanded was used to classify adaptation types and frequency, which were compared across sites over time.Across sites, more adaptations were made in the first year (n = 47), then fell and plateaued in the two remaining years (n = 35). Adaptations at Site-A were consistent across years , while Site-B made considerably fewer adaptations after the first year . Both sites proportionally made mostly skipping (32%), adding (20%), tweaking (20%), and substituting (16%) adaptation types. Skipping- and substituting-type adaptations were made due to institutional structural characteristics and lack of available resources, respectively. However, Site-A’s greater proportion of skipping-type adaptations was attributed to greater system complexity, and Site-B’s greater proportion of adding-type adaptation was attributed to the egalitarian team-based culture.Our findings can help prepare implementers to expect certain context-specific adaptations and preemptively avoid those that hinder sustainment. Organizations are commonly unable to maintain implementation of evidence-based interventions (EBIs) over time –3. SustaExamining sustainment can help predict and increase the likelihood of long-term EBI delivery ,10,11. FWhile there are a variety of study designs for sustainment research, scholars recommend assessment over multiple time points throughout a multi-year study to identify potential changes to the intervention that may affect sustainment ,5,19. SuThe Northwestern Medicine™ Hispanic Kidney Transplant Program (HKTP) was established in December 2006 to provide culturally competent and linguistically congruent care to Hispanic/Latinx patients initiating evaluation for kidney transplantation, with the intent of increasing living kidney donation rates . Living HKTP was implemented at two transplant programs and evaluated for effectiveness and implementation fidelity. While most complex interventions occur for one or two years , our intThe Framework for Reporting Adaptations and Modifications-Expanded (FRAME)  guided tWe conducted a type II hybrid effectiveness-implementation study design  to assesHKTP was implemented at two kidney transplant programs: Site-A, located in the southern region of the USA, and Site-B, located in the southwest region. Both sites were selected because they served large Hispanic populations, perform more than 50 LDKTs per year, and have a Hispanic bilingual transplant physician. Two matched control sites were used for comparison.Eligible participants were stakeholders directly involved in HKTP implementation and included transplant physicians , administrators , and clinical and research staff . Site PIs notified and requested stakeholders to participate in data collection activities via email, phone, and/or in-person. Stakeholders did not have a relationship with the co-PIs  prior to study commencement. Co-PIs presented reasons for performing the research with site PIs prior to grant submission and to all stakeholders at the initial site visit.As a multi-level intervention, HKTP is comprised of multiple components and strategies, as shown elsewhere . HKTP prWe used several implementation strategies including learning collaboratives, in-service presentations within each site, marketing events, and data monitoring. The research team held quarterly “Learning Collaboratives” involving stakeholders from both sites to design solutions (including intervention adaptations) to barriers to implementing HKTP . OrganizWe also monitored sites’ progress in establishing HKTP during the pre-implementation period by providing a monthly timeline that compared progress made at each site. Using green, yellow, and red colored indicators of site progress on each implementation step, the timeline was intended to be informative and foster motivation through competition. This approach was discontinued several months after sites began implementing because it was designed to foster program launch and not sustainment.In the primary outcomes paper for this study , we founTo assess HKTP implementation fidelity, research staff documented the a) number of in-service and marketing materials and events used to promote HKTP, b) number of dialysis centers visited and number of hours spent performing outreach, c) bilingual and bicultural status of outreach staff, d) audio-recorded quarterly phone calls with patients scheduling their transplant evaluation visit, e) audio-recorded quarterly HKTP education sessions to document the core content areas covered, f) number of education sessions held and the type of clinician delivering the sessions, g) number of potential recipients and family members attending education sessions, h) whether each potential recipient received a call from a physician 6–8 weeks after the education session to complete transplant evaluation, and i) number of patients who were sent 90-day reminder letters to complete transplant evaluation.Qualitative data were collected during annual site visits in 2017, 2018, and 2019. Study co-PIs  conducted the visits, which involved one-on-one interviews and group discussions with transplant stakeholders to identify barriers and facilitators to HKTP implementation, assess intervention delivery, and troubleshoot ways to facilitate HKTP implementation.www.cfirguide.org). Interview questions included the following: “What kinds of changes have you had to make to your outreach plan to fit with your institutional setting/city/demographics?”, “What kind of changes do you think that you will (still) need to make to the implementation so it will work more effectively in your setting?”, “What kind of data is your organization collecting on the HKTP in how well it’s doing or working?”, and “How hard is it going to be to sustain the HKTP?”. The co-PIs led in-person group discussions to clarify the study protocol, assess progress on intervention implementation, and brainstorm ways to accommodate the intervention.Co-PI EJG conducted in-depth, semi-structured interviews with stakeholders to assess perceptions of organizational culture, attitudes about the implementation complexity, and perceived barriers and facilitators to implementing HKTP components using the CFIR Interview Guide , all transcripts were recoded. Discrepancies between coders were resolved through group discussions. Second, two research staff members independently coded the same transcript for adaptations using the FRAME, identifying the type, instigator, and reason for the adaptation [Descriptive statistics were used to calculate frequencies of adaptations by study site, demographics, adaptation type, instigator, and reason. Analyses were conducted with the Statistical Packages for Social Sciences (SPSS) version 26.Fifty-five stakeholders  participated in one or more of the following research activities across all three years: site visit interview (n = 48), group discussion (n = 18), and/or learning collaborative discussion (n = 22)  and Site-B n = 152)  than Site-B . Site-A closely adhered to the protocol each year of the intervention period . Site-B adhered to the protocol the first two years of the HKTP intervention, but adherence decreased in 2019 .The HKTP protocol requested that all education sessions be delivered by a bilingual, bicultural physician. Site-A reported a greater number and proportion of HKTP education sessions delivered by a bilingual, bicultural physician  than Site-B . Over time, all HKTP education sessions were delivered by a bilingual, bicultural physician at Site-A , while Site-B had a lower proportion .For HKTP to be sustainable, sites must continue to recruit new potential recipients through outreach efforts at dialysis centers, schedule potential HKTP recipients, and conduct culturally competent education sessions. They must also maintain a bicultural/bilingual team and the availability of interpreters or interpreter services. The implementation strategies used in this study also suggest that ongoing training, in-service presentations to local transplant stakeholders, marketing campaigns, ongoing data monitoring for quality assurance, and learning collaboratives might be necessary, but the pre-post non-randomized study design did not allow formal testing .During the pre-implementation period, one 4-hour learning collaborative was held by telephone, and one 1½ day in-person retreat, which entailed discussion to: clarify the intervention protocol, brainstorm approaches to align the intervention with institutional context, train providers through role-playing sessions, and review progress made. During the implementation period, twelve 1-hour telephone meetings were held from 2017–2019 (range: 3–5 per year).Across all years, Site-A hosted more in-service presentations than Site-B (n = 6 versus n = 3). Both sites reported a drop in in-service presentations in 2018 and an increase in 2019 .Across all years, Site-A hosted more marketing events targeting healthcare providers at other institutions than Site-B (n = 23 versus n = 1). Both sites hosted the most events in 2017, which dropped and remained constant in subsequent years .Across all years, Site-A hosted more marketing events targeting patients and family members than Site-B (n = 36 versus n = 3). Both sites hosted most events in 2017, which dropped in subsequent years .Sites aimed to complete 832 h of outreach at dialysis centers per year for a total of 2,496 h during the study period, as per the protocol. Overall, Site-A dedicated more hours and completed a greater proportion of the target goal  than Site-B  . Over time, both sites increased adherence after the first year . At Site-A, the increase coincided with an increased number of potential recipients attending HKTP education sessions. By contrast, despite the increase in adherence over time, Site-B experienced an 8% decrease in attendance in 2018, which may be a result of its decreased outreach efforts. In 2019, Site-B reported its highest adherence to scheduler scripts which coincided with its highest number of potential HKTP recipients. Overall, sites’ adherence to the scheduler scripts resulted in comparable HKTP attendance numbers.Although stakeholders (site PIs) were encouraged to monitor their site data at the study onset, they indicated during site visit interviews that they did not collect or monitor the study-specific data. Stakeholders reported that they lacked awareness of processes for tracking participants involved in the study at Site-A and that tracking participants would have required additional time to manually prepare the list of known participants at Site-B.Across sites, more adaptations were made in the first year 2017: n = 47) and then declined and plateaued over the two remaining years   Fig. b. Both sTM . At Site-A, stakeholders added information to education slides and included town hall meetings to introduce HKTP to potential patients and increase outreach efforts. Site-B included Spanish-speaking transplant professionals  at education sessions to answer questions from Spanish-speaking patients. Further, Site-B created flyers to inform potential HKTP patients at dialysis centers of upcoming outreach sessions and provided telephone assistance to potential living donors when completing the English Breeze. In 2018, Site-A’s previous additions to improve outreach efforts and education sessions continued. By contrast, in 2018, Site-B discontinued its effort to enhance outreach by announcing upcoming dialysis clinic visits through flyers and stopped assisting Spanish-speaking potential living donors to complete the Breeze but continued to have transplant professionals in attendance at education sessions. In 2019, Site-A continued and increased its efforts to improve outreach by adding a “mini-automatic enrollment” procedure to expedite the scheduling of potential HKTP patients.Overall, Site-A made fewer adding-type adaptations than Site-B (Site-A: n = 10 Site-B: n = 13) Fig. c. AddingSite-B made more adding-type adaptations than Site-A, likely because it made more efforts to improve patient engagement  and to assist Spanish speakers in the first year. However, Site-B discontinued 2017 additions to improve outreach  and to assist Spanish-speaking potential living donors, which resulted in a decrease of adding-type adaptations in 2018. By contrast, Site-A continued 2017 additions made to improve outreach efforts, which increased over time. Both sites made adding-type adaptations to address patient needs. Site-A made additions to its outreach efforts to provide accessible information to its Spanish-Speaking patients, while Site-B made additions to increase patient engagement during education sessions and to provide patient support.Over time, both sites made a comparable number of tweaking-type adaptations   Fig. e. Site-AWhile a bilingual/bicultural outreach staff was hired in 2018 at Site-A, the English-speaking outreach staff continued to do outreach. While the English-speaking outreach staff was involved in outreach at dialysis facilities (directed toward facility staff) in all 3 years, the Spanish-speaking outreach staff led patient-directed outreach efforts. Further, the English-speaking staff was accompanied by a Spanish-speaking research staff to help interpret. To improve communication with Spanish-speaking patients, Site-A relied on bilingual research and outreach staff to act as interpreters because there were not enough available interpreters from 2017 to 2018. While Site-B also relied on Spanish-speaking staff members to serve as interpreters, Site-B also relied on Spanish-speaking staff to conduct education and wrap-up sessions because there were not enough available Spanish-speaking physicians throughout the three years of implementation. Site-B made more substituting-type adaptations in 2019 than previous years because there were less Spanish-speaking staff available to assist with scheduling and clinical staff follow-ups and thus relied on a Spanish-speaking research staff.Both sites made substituting-type adaptations because of lack of available resources . Site-B made more substituting-type adaptations than Site-A because it had fewer available Spanish-speaking staff. While Site-B made a relatively consistent number in 2017 and 2018, it increased the number of substitutions made in 2019 because it needed more Spanish-speaking staff to conduct patient scheduling and clinical staff follow-ups which resulted in a Spanish-speaking research staff fulfilling those roles.While the conceptualization of sustainment continues to evolve, most frameworks and models include multiple dimensions thought to be related to, or necessary for, ongoing intervention delivery over multiple years ,10,15. OTM, and this study represented the first attempt to scale up the intervention to other systems.Both study sites made a number of adaptations of different types to HKTP over time. Adaptations of the adding type tended to increase over time in attempts to increase the effectiveness of the intervention. Substituting and delay/skipping-type adaptations decreased over time suggesting a potential need earlier in implementation to prune or de-implement HKTP components that were ineffective or misaligned with the context of the delivery sites. Relatively speaking, Site-B made fewer adaptations early in the implementation, which might have led to poorer fidelity and the need for more adaptations in the third year to increase effectiveness. This degree of adaptations might be expected given that HKTP was developed at Northwestern MedicineNotable intervention adaptation differences emerged between the sites. Site-A, which had higher implementation fidelity than Site-B, made fewer adaptations across all years of implementation. Further, tweaking or substituting types of adaptations were more likely to increase over time, as occurred at Site-B. While adaptation is expected when new interventions are implemented in a particular setting , this fiThe use of the learning collaborative strategy was hypothesized to help ensure adaptations were both fidelity-consistent and would increase the implementation and effectiveness of HKTP through cross-site learning between Sites A and B and Northwestern University, where the HKTP was developed and first implemented. While this seems to have worked well for Site-A, it was not sufficient to overcome contextual barriers in Site-B. Evidence of the effectiveness of learning collaboratives for implementation has been mixed, in large part due to the high degree of protocol variability –41. ThisDespite encouragement to use data monitor strategies, both sites indicated not doing so. Similarly, a review of healthcare organizations implementation of culturally competent interventions found that relatively few studies implemented audit or quality improvement approaches of the intervention . Had sitAlthough sustainment has become recognized as an essential implementation outcome , there mA strength of this study is a longitudinal and ongoing analysis of adaptations to a complex, culturally competent intervention using the FRAME over a three-year period across diverse healthcare organizations. Limitations include reliance on participant self-reports, which may not reflect actual behaviors. Social desirability bias may have affected descriptions of adaptations. However, data triangulation through stakeholder interviews and weekly phone calls with research staff served to clarify and confirm adaptations. Future research could conduct observational evaluations of adaptations, but this is often infeasible due to cost and the nature of the intervention. The two-site design limits our ability to draw conclusions regarding the effects of specific strategies on intervention adaptations and sustainment more broadly. Future research should examine the extent to which adaptations beget other adaptations. Doing so would likely necessitate a more frequent evaluation that could capture the dynamics of adaptation, as well as the use of other implementation strategies, using tools such as the Longitudinal Implementation Strategy Tracking System ,45. LastOur findings illuminate factors that challenge the sustainment of complex interventions and underscore the importance of ongoing assessment of adaptations concerning their impact on target outcomes. Further, certain contextual determinants challenge the sustainment of complex interventions that cannot be overcome solely through adapting the intervention. Chasing fit with context by adapting the intervention led to low-fidelity implementation in one site, and certain adaptations had a clear adverse effect on intervention delivery. For example, lack of time and available Spanish-speaking staff led to adaptations, which resulted in outreach not being performed at target levels.Systematic reviews show that culturally competent care interventions are effective in improving patient, provider, access, and organizational outcomes ,46,47. FPractically, our findings can help prepare implementers to expect certain context-dependent adaptations to preemptively avoid those that reduce fidelity and effectiveness and to focus on those that support sustainment. The manner through which such decisions for adaptations are made remains a question for future research but our findings suggest the potential for learning collaboratives to play a role in these processes.


Robotic-assisted colon surgery may contain advantages over the laparoscopic approach, but clear evidence is sparse. This study aimed to analyze postoperative inflammation status, short-term outcome and cost-effectiveness of robotic-assisted versus laparoscopic left hemicolectomy. All consecutive patients who received minimal-invasive left hemicolectomy at the Department of Surgery I at the University Hospital of Wuerzburg in 2021 were prospectively included. Importantly, no patient selection for either procedure was carried out. The robotic-assisted versus laparoscopic approaches were compared head to head for postoperative short-term outcomes as well as cost-effectiveness. A total of 61 patients were included, with 26 patients having received a robotic-assisted approach. Baseline characteristics did not differ among the groups. Patients receiving a robotic-assisted approach had a significantly decreased length of hospital stay as well as lower rates of complications in comparison to patients who received laparoscopic surgery (n = 35). In addition, C-reactive protein as a marker of systemic stress response was significantly reduced postoperatively in patients who were operated on in a robotic-assisted manner. Consequently, robotic-assisted surgery could be performed in a cost-effective manner. Thus, robotic-assisted left hemicolectomy represents a safe and cost-effective procedure and might improve patient outcomes in comparison to laparoscopic surgery. Robotic surgery has gained momentum worldwide with fast-growing expansions in various disciplines during the last decade . While aIn the field of visceral surgery, robotic-assisted surgery may contain some benefits in complex oncological procedures, such as esophageal and rectal surgery . For theTo assess and evaluate the current role and future potential of robotic-assisted surgery in an established minimal-invasive operation, we analyzed postoperative inflammation, short-term outcomes and costs for all consecutive patients who received left-sided hemicolectomy due to benign and malign diseases before and after re-introduction of robotic-assisted resection at our hospital.All consecutive patients who received minimal-invasive left hemicolectomy due to chronic relapsing diverticulitis, left-sided colon cancer UICC I–III and endometriosis at the Department of Visceral Surgery of the University Hospital of Wuerzburg in 2021 were prospectively included in this study. All surgeries were performed by a senior surgeon (n = 3 surgeons) in line with international standards, and reconstruction was done as end-to-end stapler-anastomosis. Two of these three colorectal surgeons performing the laparoscopic resections also did the robotic operations. Robotic colorectal surgery at the Department of Visceral Surgery was re-launched in May 2021. The robotic surgical experience of the 2 robotic surgeons was limited to being 1st assistant.All patients were divided into two groups depending on the type of surgery (laparoscopic versus robotic-assisted). While in the beginning, all patients were operated laparoscopically, robotic-assisted left hemicolectomy was introduced in May 2021, with most of the patients receiving robotic-assisted surgery for the rest of the observational period. Patients were not specifically selected for laparoscopic or robotic-assisted surgery. Sociodemographic and clinicopathological data, including diagnosis, history of disease and co-morbidities, were collected for each patient from patient records. In addition, surgical data, including the rate of conversion, operating time as well as complications, were also analyzed. Furthermore, postoperative inflammation was evaluated by leukocyte count and C-reactive protein levels.The primary endpoint was defined as the length of hospital stay. Secondary endpoints were postoperative complications within 30 days, including MTL30 . FurtherTo analyze the cost effectiveness between laparoscopic and robotic-assisted left hemicolectomy in our cohort, calculations were performed as published previously . Brieflyp-value < 0.05.Statistical analysis was performed using IBM SPSS Statistics for Windows, version 28.0 . Descriptive data are presented as median with range or total numbers with percentage. Differences in patient characteristics were assessed by the Chi-squared test, Fisher’s exact test, or ANOVA test according to data scale and distribution. Multivariate analyses of variance were performed by using MANOVA. Statistical relevance was considered for a Ethical approval for this study was obtained from the Ethics Committee of the University of Wuerzburg, Germany.In this single-center study, 61 patients received minimal-invasive left hemicolectomy in 2021 at the Department of Surgery at the University Hospital of Wuerzburg. Of those, 35 patients underwent laparoscopic surgery, whereas 26 patients were operated on in a robotic-assisted manner. As presented in p = 0.001). However, rates of conversion were comparable between both groups . Length of hospital stay, the primary endpoint of patients receiving robotic-assisted surgery, was significantly reduced compared to patients who underwent laparoscopic resection  (p = 0.126)  . In a mu= 0.025) . Similar= 0.126) .Serum levels of leukocytes and C-reactive protein (CRP) were analyzed during the postoperative course to evaluate differences in inflammatory responses of patients receiving minimally invasive surgery. While on postoperative day 3, serum levels of CRP trended to be lower following robotic-assisted surgery in comparison to laparoscopic resection, CRP levels were significantly decreased on postoperative day 5 in patients who received robotic-assisted colon resection . No diffCosts for both groups were calculated, and differences are presented in Robotic-assisted surgery represents a rapidly evolving field in visceral surgery. While the advantages of minimal-invasive procedures over open surgery are well established, robust evidence about the benefits of the robotic-assisted approach in comparison to laparoscopic surgery is still underrepresented . In addip = 0.001) (p = 0.989). Operative time and conversion rates in our study were comparable to another comparable study including only left hemicolectomies [After the re-implementation of robotic-assisted left hemicolectomy at our department, robotic-assisted surgery led to a significantly decreased length of hospital stay  . Similar= 0.001) . Thus, tectomies . ImportaIn general, the advantages of robotic surgery have been extensively described elsewhere, including improved visualization and filtration of physiological tremors. While a Danish cohort study analyzed both approaches for right colectomy and found similar morbidity between both techniques , TschannTo further assess potential mechanisms of the beneficial effect of robotic-assisted surgery on short-term patient recovery, we analyzed serum levels of inflammation such as leukocytes and CRP to evaluate the systemic inflammatory response. Indeed, levels of CRP were significantly lower during the postoperative course for patients who were operated on in a robotic-assisted manner in comparison to patients who received laparoscopic resection . ImportaHigh costs remain to be one of the major criticisms about the implementation of robotic systems in surgery. Therefore, and in addition to previous studies, we also performed a cost analysis in our cohort. Interestingly, cost-effectiveness was comparable between both groups, but a relevant cost reduction of EUR 236.48/case was seen for robotic-assisted resections . This efThe major limitations of our study are its retrospective character as well as the single-center design. In addition, the calculated costs for operating time and length of hospital stay are based on average costs and can vary from hospital to hospital depending on various parameters. However, our calculations represent a high validity and are based on previously published and established models. Furthermore, no patient selection was performed, with almost all patients being operated on in a robotic-assisted manner following the implementation of the technique in our department. Finally, the learning curve for the robotic approach must be considered; thus, the extended operating time and the conversion rate might decrease over time, resulting in a further cost reduction. Thus, the cases of conversion occurred at the beginning of the learning curve, supporting previous studies that show that the rate of conversion is even lower in more complex colorectal operations compared to the laparoscopic approach .In conclusion, we demonstrated in a single-center study that robotic-assisted left hemicolectomy resulted in decreased length of hospital stay and trended to lower rates of complications, leading to improved cost-effectiveness. Based on that, our study supports the ongoing implementation of robotic-assisted colon surgery, but further prospective studies are necessary to confirm the results and to evaluate the mechanistic background of a potentially decreased inflammatory stress response.


During the school-to-work transition (STWT), young people enter different states as vocational training, university or unemployment that may have immediate or long-term effects on health. Since research has not paid much attention to this, we investigate the development of self-rated health (SRH) and subjective well-being (SWB) during the STWT.We used data from Starting Cohort 4 of the German National Educational Panel Study (NEPS), a nationally representative cohort of 11,098 ninth graders (50.5% girls) followed over nine years. Linear panel regression analysis with fixed-effects (FE) was used to explore intra-individual changes in SRH and SWB when moving between different STWT states . FE impact functions were used to compare trajectories of SRH and SWB by states reached after school-leave. Time-varying control variables were age, household composition, and residential area.School-leave was linked to increases in SRH and SWB, whereas no impact was found for job entry after vocational training or university. Upward transitions  increased SRH or SWB, while downward transitions  were related to decreases. Over the years after school-leave, we found a decline in SRH and SWB, which was faster in case of transitions to unemployment or prevocational programs directly after school.Findings suggest that a smooth STWT is key for good health in youth and adulthood. Health and labour market intervention programs should focus on the time after school-leave, especially on those who are not able to find an academic or vocational training position.


There are no published data on the effect of patient and technologist gender and ethnicity attributes on off-centering in CT. Therefore, we assessed the impact of patient and technologist variations on off-centering patients undergoing body CT. With institutional review board approval, our retrospective study included 1000 consecutive adult patients  who underwent chest or abdomen CT examinations. We recorded patient , technologist gender, and scan-related  information. Lateral and anteroposterior (AP) diameters were recorded to calculate effective diameter and size-specific dose estimate (SSDE). Off-centering represented the distance between the anterior-posterior centers of the scan field of view and the patient at the level of carina (for chest CT) and iliac crest (for abdomen CT). About 76% of the patients (760/1000) were off-centered with greater off-centering for chest (22 mm) than for abdomen (15 mm). Although ethnicity or patient gender was not a significant determinant of off-centering, technologist-patient gender mismatch was associated with a significantly greater frequency of off-centering (p<0.001). Off-centering below the gantry isocenter was twice as common as off-centering above the gantry isocenter (p<0.001). The latter occurred more frequently in larger patients and was associated with higher radiation doses than those centered below the isocenter (p<0.001). Technologists’ years of experience and patient factors profoundly affect the presence and extent of off-centering for both chest and abdomen CTs. Larger patients are more often off-centered than smaller patients. Most modern CT scanners are equipped with automatic tube current modulation techniques, which modulate tube current based on the patient’s attenuation profile and the specified image quality metric , 2. In aBeyond the automatic tube current modulation and tube potential selection techniques, multidetector-row CT scanners have beam shaping or bow tie filters which help homogenize image quality across the image cross-section and reduce surface radiation dose . In patiSeveral prior studies have reported the frequency and effect of patient off-centering in the CT gantry isocenter –9. HowevThis study was exempted under Ministry of Public Health (MOPH) guidelines, research involving the collection or study of existing: data, documents, records and the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects. Under the exempt status, the need for obtaining informed consent is waived. Our observational study received institutional review board (IRB) approval from the human research committee of the HMC Medical Research Centre (MRC) (Protocol ID: MRC-01-21-477). A study coauthor (MKK) received research grants from Siemens Healthineers, Riverain Tech, and Coreline Inc. for unrelated projects. None of the authors have any pertinent financial disclosures related to the submitted work.The study included 1000 consecutive adult patients  who underwent standard of care chest or abdomen CT examinations at Al-Wakra Hospital, a tertiary care hospital-based in Al-Wakra, Qatar from 1st January 2021 to 1st May 2021. All CT examinations represented the standard of care imaging as part of patients’ clinical care, regardless of clinical indications. Most common indications for chest and abdomen CT examinations were cancer staging, treatment response, and surveillance.For each patient, we recorded the following information at the time of scanning: date of CT examination, body part imaged, patient age, gender, body weight, and height. Body mass index was estimated as a surrogate for patient size. In addition, the nationality of each patient was recorded and classified into one of the geographic regions for analysis: the Middle East, Asia (not including the Middle East), Africa, Europe, and Americas . There were no patients from Australia.In addition to the patient information, we recorded CT technologists’ gender and years in service as CT technologists.All patients underwent chest or abdominal CT on one of the two multidetector-row, single-source CT scanners: 128-detector-row  or 320-detector-row  scanners. All patients were scanned in a supine position and with a single-breath-hold. Per standard of care, scan parameters for all CT examinations included: 100–120 kV, vendor-specific automatic tube current modulation techniques, scanner-selected pitch or 0.9:1 beam pitch, and 0.5 (chest) or 0.8 (abdomen) second gantry rotation times.Apart from the standard of care skin-in-skin reconstructed images for routine chest or abdomen CT, technologists reconstructed a single transverse CT image with full 50 cm field of view (FOV) at the level of tracheal bifurcation (carina) for each chest CT exam within 1 cm of the iliac crest for each abdomen CT. These full FOV images were transferred to PACS for estimating patient centering.To estimate off-centering, one of the two CT technologists first drew a line connecting the anterior and posterior margin of the full FOV and determined the gantry isocenter at the midpoint of this line. Patient’s center corresponded to the midpoint of a straight line connecting the anterior and posterior surface of the patient. The distance between the gantry isocenter and patient center conveyed information on patient centering in the scanner. Distance less than or equal to 0.5 cm was deemed optimal (patient adequately centered), while distance greater than 0.5 cm suggested off-centering. The off-centering direction was classified as gantry table too high (patient was centered above the gantry isocenter) or too low (patient was below the gantry isocenter). In addition to centering, scan start and end locations were recorded to estimate scan length for each CT. body part imaged, patient age, gender, body weight, and height. Body mass index was estimated as a surrogate for patient size. In addition, the nationality of each patient was recorded and classified into one of the geographic regions for analysis: the Middle East, Asia (not including the Middle East), Africa, Europe, and North America. There were no patients from South America and Australia.In addition to the patient information, we recorded CT technologists’ gender and years in service as CT technologists.We recorded volume CT dose index (CTDIvol in milli-Gray or mGy) and dose length product (DLP in in milli-Gray.cm or mGy.cm) from the dose information page for each CT examination. The dose data were collected to determine how off-centering affects CTDLvol and DLP in patients with similar size and scan protocol. From the full FOV image, each patient’s anterior-posterior and lateral diameters were measured to estimate effective diameter . From the look-up table, we obtained the constant which was multiplied with CTDIvol to obtain size-specific dose estimate (SSDE) for each CT .Statistical analysis of the data was performed in Microsoft Excel  and SPSS Statistical Software . Since the data were not normally distributed, we estimated the median and interquartile range (IQR) of patient weights, body mass index, effective diameters, off-centering distance, CTDIvol, and DLP. We assessed the differences in off-centering and radiation doses for patients of different gender, age group, geographic origin, as well as the body region and scanner. Chi-squared and Kruskal-Wallis omnibus tests (which include the post-hoc tests for pairwise testing of variables within the SPSS software) were used for statistical analysis. P-values < 0.05 was considered as the significance level.Of the 1000 patients included in our study, more than three-fourths of the patients  were off-centered, and 24% were centered correctly (240/1000). The median off-centering distance for chest CT exams  was more significant than for abdominal CT  (p = 0.003). In addition, off-centering below the gantry isocenter  was more frequent than above the gantry isocenter . The distance between patient center and the scanner isocenter was significantly greater for all off-centered chest and abdomen CT examinations  than for optimally centered CT  (p<0.001). For all CT examinations performed with and without optimal centering, there were no significant differences in patients’ age , gender (p = 0.923), geographic regions (p = 0.876), body mass index , CTDIvol , and DLP . Off-centering was common on both vendors’ scanners included in our study .Patients centered above the gantry isocenter had greater body weight, BMI, and effective diameter than those centered below the isocenter ; Fig 2. The proportion of CT examinations with and without off-centering varied significantly across different CT technologists (14–37% versus 63–86%) (p< 0.001). There was also a difference in the extent of off-centering based on technologists’ gender however skewed distribution of technologists’ gender  limited Like several prior studies, our results document the high frequency of patient off-centering for both chest and abdomen CT examinations . HoweverInterestingly, patients centered above the gantry isocenter tended to be larger than those centered below the isocenter. Although most patients were centered below the gantry isocenter in all BMI groups (obese versus non-obese patients) as reported in prior publications , 11, a lThere was no impact of patients’ geographic region of origin on the frequency of off-centering, possibly related to a high prevalence of off-centering regardless of patients’ geographic origins.There are several clinical implications of our study. Apart from understanding the causes of off-centering from the perspective of a conservative society, our results have led us to initiate a comprehensive mitigation quality improvement program at our site, which we hope to extend across our multi-institutional healthcare enterprise. First, we shared our results with all CT technologists and department leadership to appraise them about the issues with patient centering. Second, we formally educated the CT technologists on the frequency and impact of off-centering in CT. Third, we emphasized the need to center the patient rather than re-center the reconstruction field of view. Fourth, a decision was made to post a note on each CT gantry to remind technologists that their last step before exiting the gantry room for scanning is to turn on the laser markers and check the centering. Fifth, we implemented a form that each technologist must fill to explain the reasons for off-centering. The reasons pertained to complex anatomy (kyphoscoliosis), inability to raise arms over their head, morbid obesity, critical patient with lines/ tubes/life support devices, and "forgot to check patient centering before centering." Sixth, two technologists were assigned to conduct a periodic prospective evaluation of off-centering and reward the best performing technologists. Seventh, need and program to train the support staff of both genders to aid in patient centering in case of patient-technologist gender mismatch. Eighth, we have decided to extend our findings and patient centering strategies to multiple other CT sites affiliated with our healthcare system. Though it is not possible to replace and upgrade to automatic AI-based patient positioning and centering technologies on all scanners, we hope that procurement of such technologies will help address manual errors in off-centering. We believe that our future studies will establish the value of continuous monitoring in mitigating issues related to patient off-centering.Our study has limitations. Our study was limited to data from a single site and may not generalize across other practices. The data were skewed towards male technologists due to the disproportionately more male than female technologists in our department. There were also more male patients and abdominal CT examinations than female patients and chest CT. With a higher or more symmetric dataset, the study could have yielded different results and conclusions. Still, we did not want to induce non-consecutive or selection bias in our study. Although we withheld information from all technologists about evaluating their centering data, we cannot be sure if some technologists came to know about the audit due to the need to generate an additional CT image in each CT included in our study. Yet, given the similarities across patients’ and technologists’ demographics across many Arabic countries, it is likely that some factors will have similar performance across sites in the region.Another limitation of our study included the lack of CT head, face, or neck since we wanted to investigate body CT examinations in more challenging regions. We also limited our evaluation to off-centering in the y-axis since prior work suggests that x-axis off-centering is less severe (mean off-centering 0.01 cm), and therefore, less impactful , 12. SomDue to unintended skewed distribution of male and female patients and technologists at the study site, the results of our study might not be generalizable at sites with more balanced distribution of patients. However, as stated above, our study included consecutive patients and exams to avoid any selection or temporal biases. Finally, our study did not assess the impact of off-centering on image quality and diagnostic information.In conclusion, off-centering of patients during body CT examination is up to three times more common than optimal centering, regardless of patient gender, size, ethnicity, scanner type, and technologists’ experience. Gender mismatches between technologists and patients are associated with higher off-centering in a conservative society. Targeted mitigating strategies are required to address the issue of off-centering at such sites.