This paper described the use of photovoice within design thinking to empathise with patients’ challenges and co-create ideas on asthma management in Singapore. A one-day workshop was organised and conducted in Singapore by SingHealth Polyclinics to discuss the challenges and enablers of good asthma care and ideate innovations to address the issues discussed. The workshop was conceptualised based on the Stanford’s d: school Design Thinking Process: 1. empathise, 2. define, 3. ideate, 4. prototype, and 5. test, focussing on the first three stages. Empathise stage was executed by having two patients share their challenges and enablers of good asthma care using photovoice. Define and ideate stage were accomplished through the multidisciplinary team discussion, with the patient going to every group to allow them to seek clarifications and opinions on ideas. The study findings were summarised based on the Empathise, Define and Ideate stages. Thirty-seven healthcare providers attended—9 doctors, 14 nurses, 4 pharmacists, 3 clinical service, 3 medical students and 4 research staff. Participants’ feedback was collected via an online feedback form to evaluate the effectiveness of an innovation workshop. More than 90% of participants strongly agreed or agreed that they could generate ideas to improving asthma care, the workshop helped drive innovation, and the use of photovoice helped them empathise with patients challenges. A design thinking framework can be used for innovation workshops. Photovoice is a useful method for understanding the problems faced by patients. A multidisciplinary team format with patient involvement was highly favoured. According to the Centres for Disease Control and Prevention, 61.9% of adults have poorly controlled asthma, defined as having at least one symptom more than twice a week2. In Singapore, the asthma prevalence is 11.9%3, and 87% have poorly controlled asthma4. Uncontrolled asthma can result in poorer quality of life5, higher healthcare utilisation and cost compared to well-controlled asthma6.Asthma is a chronic respiratory disease characterised by reversible airway obstruction. Asthma affects around 262 million people worldwide, with a prevalence of 6.6% in adults7. Innovation workshops can be used to co-create new and creative ideas, solve problems, and improve existing processes8. The design thinking framework can be used to guide the development of innovations9. The framework was initially conceptualised by the design school to teach students to design products that meet the needs of users10, but has been extrapolated to the healthcare sector as it results in more successful, sustainable, and user-centred innovations while ensuring technical feasibility and economic viability12.Improving asthma care in the primary care settings is important as it is where most of the care is providedThis paper will outline the development and execution of an asthma innovative workshop called the InnovFamLab. Design thinking framework was used to identify the problems faced by patients with asthma and to ideate creative and actionable interventions involving both healthcare providers (HCPs) and patients to improve asthma care in the primary care setting.8.A one-day workshop was organised to discuss the challenges and enablers of asthma care, and ideate innovations to address the issues discussed. HCPs from SingHealth Polyclinics were purposively selected for their involvement in asthma care in the institution and their interest in innovations. The HCPs included doctors, nurses, pharmacists, clinic executives, and medical students. Invites were sent to members of the institution’s asthma workgroup, asthma champions of the clinics, and those involved in asthma-related quality improvement projects, to ensure that the HCPs were directly or indirectly involved in improving asthma care and in a position to execute changes to asthma care. Research coordinators who were interested in innovation acted as laypeople in the group. The HPCs were split into five groups, seven to eight members each, with a facilitator and a scribe. All groups comprised members of multidisciplinary HCPs to ensure that group discussions included diverse insights and perspectivesTwo patients with asthma attended this workshop alongside the HCPs. The patients selected had chronic severe asthma with a history of exacerbation and were on regular follow-ups with a family physician for the last 5 years in a polyclinic. One patient had well-controlled asthma, while the other had poorly controlled asthma. This was to understand the needs of patients with varying degrees of asthma control.This is a description of an innovation workshop using design thinking framework. These individuals are not research participants or subjects hence formal ethical approval is not required. However, we uphold the principles of informed consent, and written consent was obtained from the patients for the use of photographs in non-commercial purposes such as journal publication, training, and report writing for funders.10. It focused on the first three stages of empathise, define and ideate. Fig. The study team conceptualised the workshop based on the Stanford’s d: school Design Thinking Process: 1. empathise, 2. define, 3. ideate, 4. Prototype, and 5. TestThe workshop flow is illustrated in Fig. 13. Two patients volunteered and underwent pre-workshop photovoice training 4 weeks before the workshop by two team members. During the initial online meeting, patients were introduced to using photovoice, the ethics of photography and the tasks they needed to complete. The patients were informed to share their challenges and enablers with good asthma care using photovoice. After the initial meeting, patients were given 2 weeks to take the photographs, and the photographs were discussed during the second meeting. The third meeting was a final run-through with the patients on the photographs they were presenting at the workshop.Photovoice is an arts-based qualitative method where people use photographs to document and share their health and realityThe workshop began with an introduction to photovoice. A 20-min-each presentation by the two patients using photovoice followed this, who also provided the rationale and explanation for the photographs. Only two patients were included to allow time for in-depth sharing by each participant. Afterward, the participants had a question-and-answer session to clarify the photographs.The workshop included a 10-min briefing by facilitators before each group discussion. The first briefing session guided the participants to identify the key challenges and enablers in the asthma care journey based on patients’ photovoice sharing. Participants were also advised to refrain from judging or criticising other participants’ ideas in speech or body language and encouraged to generate ‘out of the box’ ideas. The participants were introduced to the Stanford d: school Design Thinking Process during the second briefing session.Identifying the challenges and enablers of self-care in patients with asthma andBrainstorming for innovative ideas to address the challenges identified.The workshop comprised two 90-min small group discussions:A small group discussion format allowed all participants to express their thoughts and views. A facilitator was assigned to each group to guide the discussion session. One group member was allocated as a scribe to document the discussions and evaluate the group dynamics. During these group discussions, the patients went to every group to allow them to seek the patients’ opinions on their ideas.The group presentations followed the discussions. During this session, individual groups presented the outcomes of their respective small group discussion. These presentations allowed participants to share their small group discussions with the other groups and generate further discussions on the ideas. The first presentation was 10 min, and the second was 15 min.14.The minutes and outcomes of the small group discussions were obtained from the scribe. The findings were categorised into themes and synthesised into a report at the end of the workshop. The scribes, who were not part of the clinical team, were instructed to provide feedback on the team dynamics during discussion. This was to account for potential power distance and fear of more senior staff in the team during the team discussionsParticipants’ feedback was collected via an online feedback form to evaluate the effectiveness of this innovation workshop. Four questions were rated on a 5-point Likert scale to evaluate if they felt they had a better understanding of the challenges of patients with asthma, gained new insights to the enablers, generated ideas to improving asthma care and if the workshop helped drive innovation. Three open-ended questions obtained information on their preferences and suggestions for the workshop.n = 1), having personal matters (n = 1), and being rostered for work (n = 1). The demographics of the HCPs were as follows: doctors , nurses , pharmacists , clinical service , medical students , and research staff . Of the two patients invited, one could not present in person at the workshop as she was unwell due to asthma. Her presentation was conducted using a virtual platform, Zoom.Forty HCPs were invited, and 37 attended. Three were unable to attend due to being on sick leave , 94.4% of participants strongly agreed or agreed that they had a greater understanding of the patients’ challenges in asthma care. A total of 91.6% of participants strongly agreed or agreed that they had gained new insights into the enablers of asthma patients.From the photovoice presentation, eight challenges to good asthma care were identified. The key challenges were: 1. Executing AAP; 2. Managing triggers; 3. Participating in outdoor activities and exercise; 4. Inconveniences when travelling; and 5. Lack of public awareness of asthma triggers from social activities . The enablers were: 1. Knowing triggers; and 2. Patient’s motivations. The challenges and enablers are described in Table An example of using photovoice to define the problem is Fig. Six ideas to improve asthma self-care were highlighted: 1. Improve delivery of the asthma action plan (AAP); 2. Develop a symptom monitoring calendar; 3. Provide accessible travel information; 4. Develop an exercise programme for patients with asthma; 5. Promoting patient self-efficacy; and 6. Public awareness about asthma triggers and prevention.94.4% of participants strongly agreed or agreed that they could generate ideas to improve asthma care, and the workshop helped drive innovation. Participants enjoyed listening to patients’ sharing, interactions and input, the multidisciplinary approach to facilitate group discussion, and the brainstorming session. To improve the workshop, HCPs suggested inviting more patients to share their experiences, incorporating discussions on translating the innovations to clinical setting and updating the HCP on the outcomes of the workshop discussions.All scribes reported that their team members actively contributed and were involved in the group discussions. The facilitators also helped by actively seeking the input of all team members.15.This study demonstrated that incorporating the photovoice technique into the design framework of an innovation workshop helped to generate innovative ideas for improving patient care by helping workshop participants better understand the problems faced by patients. From the participants’ feedback, more than 90% of HCPs strongly agreed or agreed that they could generate ideas to improving asthma care, and the workshop helped drive innovation. In another design thinking workshop, more than 70% of participants agreed that they could apply design thinking to a problem in the clinical setting to generate potential ideas17, leading to discussion of topics that mattered to the participants18. From the participants’ feedback, more than 90% strongly agreed or agreed that photovoice helped them understand the challenges and enablers of good asthma care. This supported the use of photovoice in the empathise step of design thinking.To the best of the author’s knowledge, this is the first innovation workshop that used photovoice in the empathise step of design thinking. As ‘A picture speaks a thousand words’, photographs give context to a narrative by providing information on the environment , relationships and norms. HCPs could visualise patients’ lives19. The stakeholders’ feedback that they favoured the multidisciplinary team approach to group allocation. Being in different professions, they often did not know the work processes of the other departments. As the operation and logistical challenges could pose a barrier to the interventions, it enabled them to understand the challenges faced by the different departments in executing the intervention. Such team grouping opened discussions on tackling these challenges from a clinical and logistics perspective.Stakeholder engagement allows interventions to cater to the preferences of both patients and care providers, which are then more likely to improve patient care and outcomes20. This study is novel as involvement of patients was less common in developing technological innovations21. It is also vital that stakeholder engagement remains a continuous activity to seek feedback on the interventions developed and to keep them informed on the discussion outcomes. A limitation with inviting patients to the discussion could be related to confidentiality issues if the patient did not want to be identified and the inability to anonymise if sensitive topics were raised.The HCPs appreciated having patients present and share their perspectives during the workshop and suggested inviting more patients to such events in the future. Increasing involvement of laypeople in healthcare research can provide information on users’ expectations and experiences23. This framework emphasises the importance of a phased approach, including the development, feasibility, and evaluation stages. By incorporating the prototype and test stages into our future work, we aim to gather more comprehensive data on the effectiveness and practicality of the proposed solutions. This iterative process will allow us to refine and optimise the interventions based on real-world feedback and ensure their relevance and applicability in practice.The strength of this workshop was the participation of multidisciplinary teams and patient advocates to co-create innovative ideas that have meaningful outcomes for patients. As this was a 1-day workshop, the prototype and test stage of the design thinking framework was not achieved. We plan to adopt the Medical Research Council framework for evaluating complex interventionsWhile the design thinking framework is widely used, the integration of the Photovoice method brings a novel and valuable dimension to intervention development. Its participatory nature, generation of rich qualitative data, user-centred approach, and collaborative decision-making contribute to the depth, relevance, and authenticity of the interventions. We believe that the inclusion of Photovoice enhances the workshop’s uniqueness and strengthens the overall quality of the intervention development process.We acknowledge the limitations of having only two patients involved in the workshop, which limited the breadth of patients’ experiences shared. Despite this, the photographs allowed for a deep exploration of the topic, with rich and detailed insights obtained from patients’ perspectives and experiences expressed through photographs. In addition, the workshop team spent a significant time with each patient to foster trust and rapport. This facilitated the collection of detailed and nuanced findings, uncovering the complexities and intricacies of the patients’ perspectives.One of the challenges of a face-to-face workshop is the patient not being able to turn up last minute. Thus, it is essential to have contingency plans. An alternative would be to record the patient’s presentation before the workshop as a backup.A design thinking framework can be used for innovation workshops. Photovoice is a useful method for understanding the problems faced by patients. A multidisciplinary team format with patient involvement was highly favoured. This framework could be considered in the design of future innovation workshops for other health conditions and settings.Further information on research design is available in the reporting summary checklist


Early-on post kidney transplantation, there is a high risk of graft rejection and opportunistic viral infections. A low tacrolimus concentration/dose (C/D) ratio as a surrogate marker of fast tacrolimus metabolism has been established for risk stratification 3 months post-transplantation (M3). However, many adverse events occurring earlier might be missed, and stratification at 1 month post-transplantation (M1) has not been investigated. We retrospectively analyzed case data from 589 patients who had undergone kidney transplantation between 2011 and 2021 at three German transplant centers. Tacrolimus metabolism was estimated by use of the C/D ratio at M1, M3, M6, and M12. C/D ratios increased substantially during the year, particularly between M1 and M3. Many viral infections and most graft rejections occurred before M3. Neither at M1 nor at M3 was a low C/D ratio associated with susceptibility to BKV viremia or BKV nephritis. A low C/D ratio at M1 could not predict acute graft rejections or impaired kidney function, whereas at M3 it was significantly associated with subsequent rejections and impairment of kidney function. In summary, most rejections occur before M3, but a low C/D ratio at M1 does not identify patients at risk, limiting the predictive utility of this stratification approach.  Kidney transplantation is the best long-term renal replacement therapy for quality of life and survival . Althougi) How stable is the C/D ratio throughout the first year after kidney transplantation?ii) Can early determination of the C/D ratio at M1 predict viral infections?iii) Can early determination of the C/D ratio at M1 predict acute graft rejections?The tacrolimus metabolism rate varies extensively between kidney graft recipients. A simple way of estimating the metabolism rate was proposed by Thölking et al., who suggested using the concentration/dose (C/D) ratio as a surrogate marker . The autWe screened 824 patients who had received kidney transplants from deceased or living donors at the three participating centers in Kiel, Essen, and Cologne-Merheim between February 2011 and July 2021. The standard immunosuppressive protocol at these centers included a twice-daily immediate-release formulation of tacrolimus , mycophenolate mofetil or mycophenolic acid, and prednisone (tapered to and continued at 5 mg/d by M6). Patients lost-to-follow-up, patients with combined-organ transplantations such as pancreas-kidney transplantation, and patients who had been switched to tacrolimus-free immunosuppression during the first year post-transplantation were not included in the study. We included 589 adult patients for analysis of tacrolimus metabolism who had at least one calculable C/D ratio available at M1, M3, M6, or M12. The subsequent analyses of 1-year outcomes contained only 551 patients because 38 patients did not have a calculable C/D ratio at M1 or M3 .Similar to Thölking et al’s study, C/D ratios were determined by dividing the tacrolimus trough level by the total daily dose. A C/D ratio <1.05 ng/(mg*ml) was considered as suggestive of fast tacrolimus metabolism, a C/D ratio between 1.05 and 1.55 ng/(mg*ml) as suggestive of intermediate metabolism, and a ratio ≥1.55 ng/(mg*ml) as suggestive of slow metabolism .We defined BKV or CMV viremia as any infection with a detectable copy load in the plasma by using polymerase chain reaction (PCR). Severe BKV infection was defined as a copy load exceeding 100,000 U/mL. BKVN was defined as biopsy-proven BKVN. CMV organ infection was defined as a clinical diagnosis of CMV esophagitis, enteritis, encephalitis, hepatitis, pneumonitis, or retinitis. Acute graft rejections were defined as biopsy-proven acute graft rejections of any entity according to the most recent Banff classification at the respective time that required immunosuppressive treatment and/or plasmapheresis, including borderline rejections . The estThis study was approved by the ethics committee of the Christian-Albrecht University of Kiel (D 429/18).post hoc test was used for the comparison of multiple groups. Log-rank (Mantel-Cox) tests were used for analysis of Kaplan-Meier survival curves. All hazard ratios (HR) were calculated at a 95% confidence level. Values of probability (p) <0.05 were considered statistically significant.All statistical analyses were conducted using GraphPad Prism (version 5.0). Two-sided t-test was used for normally distributed linear variables, Mann-Whitney test was used for non-normally distributed linear variables, and chi-square test (95% confidence level) was used for categorical variables, respectively, when two groups were compared. One-way ANOVA with Bonferroni Baseline characteristics of the study group are shown in p = 0.290) nor at M3  was associated with a successively increased occurrence of BKV viremia when compared with the rest of the cohort (p = 0.549) nor at M3 . Additionally, the eGFR of these fast metabolizers neither differed significantly from the rest of the cohort, nor did fast metabolizers show impaired graft development, as the eGFR in both groups improved significantly between M1 and M12  for acute graft rejection between M3 and M12 as compared to patients with a slower tacrolimus metabolism , whereas the eGFR of the more slowly metabolizing patients improved considerably from 45.4 at M3 to 52.4 mL/min/m2 at M12  or died 0.9%; . The kidtabolism . In thes2 at M12 .In this retrospective multicenter cohort study, we evaluated the tacrolimus C/D ratio of kidney graft recipients throughout the first-year post-transplantation and assessed whether earlier estimation of their metabolizer status than previously established could identify patients at risk for viral infection and graft rejection. We found that particularly during the early months after transplantation, the C/D ratio was unstable, and that it was not associated with opportunistic viral infections. Using the C/D ratio as a surrogate of metabolizer status 1 month post-transplantation did not identify patients at risk, but a low C/D ratio after 3 months predicted subsequent acute rejections and impaired kidney function.The clinical purpose of determining the C/D ratio is to predict harmful events such as opportunistic viral infections or graft rejections. This could potentially enable transplant nephrologists to pre-emptively adjust immunosuppressive medication and more tightly monitor patients at risk. However, for such a preventative approach, the C/D ratio needs to be determined at the earliest opportunity, because most infections and rejections occur early after transplantation –7. SinceHowever, our data also show that at M3, a substantial number of viral infections and acute graft rejections had already occurred, which severely limits the utility of the C/D ratio at M3. The evidence from other studies regarding the value of the C/D ratio earlier than at M3 is scarce, and previous large trials have not evaluated whether stratification of patients at a much earlier point would predict outcomes –12, 17. Fast metabolizers at M3 had significantly lower tacrolimus levels than slower metabolizers, which implies that fast metabolizers were consequently exposed to less immunosuppression. This might explain why we could confirm the previously reported association of fast metabolism at M3 with graft rejections and impaired kidney function , 12, 17,Our study has some limitations. It should be kept in mind that we did not directly measure the tacrolimus metabolism, but rather used the C/D ratio as a surrogate marker. While this limits our ability to correlate the actual tacrolimus metabolism with clinical outcomes, it is a pragmatic approach because of its simplicity and clinical transferability. As this is a retrospective study, we were unable to draw causal assumptions from our findings and could only generate hypotheses. The study was underpowered to detect small differences of rarely occurring outcomes such as BKVN or CMV organ infections. However, the cohort size of nearly 600 patients from three transplant centers is one of the largest to evaluate the impact of tacrolimus metabolism on clinical outcomes, and sufficient power was present to detect differences in the primary outcomes. Additionally, as we were primarily interested in short-term complications, the follow-up period of 1 year was relatively short.post hoc analysis of a randomized-controlled phase III trial, Suwelack et al. assessed if fast metabolizers, as determined at M1, had better outcomes when administered prolonged-release tacrolimus (In conclusion, our study confirmed the C/D ratio as a pragmatic tool to identify patients at risk for graft rejections and sub-optimal development of kidney function after transplantation. Unfortunately, the C/D ratio only appears useful from M3 onwards, and many early complications can therefore not be addressed. Investigating whether fast metabolizers could benefit from switching an immediate-release to a prolonged-release formulation of tacrolimus, which allows more steady tacrolimus levels throughout the day, remains reasonable. In this respect, in a recent crolimus . Althougcrolimus –21. Thiscrolimus . However


However, in the authors' recent publication only a minority of patients overprescribed SABA  were eosinophilic , those with multiple mental health comorbidities (P<0.001), and those with SABA on repeat prescription (P<0.001). Latent class analysis identified the following three classes of patients overprescribed SABA: class 1, which represents classical uncontrolled asthma ; class 2, which represents mild asthma ; and class 3, which represents difficult asthma . The mild asthma class was the largest.Eosinophilia was significantly less likely in female patients  and use of SABA for non-asthma breathlessness . Further research is needed into management of SABA overuse in patients without other markers of uncontrolled asthma. Overuse of SABA reliever inhalers and peripheral blood eosinophilia are two risk factors both associated with increased risk of asthma exacerbations. Stepping-up inhaled corticosteroids is effective at reducing future exacerbations in eosinophilic patients; however, this study showed most patients with asthma who were overprescribed SABA inhalers were not eosinophilic.The characteristics of eosinophilic and non-eosinophilic patients overprescribed SABA were found to be different. Lack of eosinophilia in a patient with asthma with high SABA use should alert the clinician to look for other causes of overuse, such as inappropriate SABA use for other causes of breathlessness.Through analysis of routinely collected clinical data, distinct patient subgroups overusing SABA are readily identifiable by clinicians, potentially prompting different management approaches. More research is needed in this area. yet remains highly prevalent. Indeed SABA overuse can paradoxically worsen asthmatic airways pathology and dampen response to SABA taken appropriately when needed. Additionally, as most SABA inhalers are pressurised metred-dose inhalers (pMDIs), their use is associated with a major carbon footprint, which is harmful to the environment. There is therefore a current focus on reducing patient SABA overuse and overprescription.Overuse of SABA inhalers, such as salbutamol relievers, is an acknowledged indicator of uncontrolled asthma with increased risk of exacerbations and hospital admissions, Such approaches encourage a one-size-fits-all model in contrast to increasing conceptual understanding of asthma as a disease of treatable traits, and that not all ‘asthma’ symptoms are due to uncontrolled small airways inflammation. While uncontrolled asthma is associated with increased SABA usage, it is less certain whether most patients who overuse SABA have uncontrolled asthma, in terms of active small airways inflammation.For patients with frequent SABA use, most asthma guidelines recommend that the clinician addresses potential poor adherence to preventer medications and inhaler technique, and then considers a step-up in asthma medications including higher-dose inhaled corticosteroids. The objective of this further evaluation was to examine whether the characteristics of patients overusing SABA differ by presence of an eosinophilia or not, and by potential latent class analysis of patients overprescribed SABA. Blood eosinophil counts, as a surrogate biomarker of airways type 2 (T2) inflammation, are increasingly recognised as a marker of exacerbation risk in asthma and an indicator of patients likely to benefit from increased inhaled corticosteroids. The findings suggest that there are different phenotypes of patients overusing SABA , who may need different approaches to manage their SABA overuse in primary care.Factors associated with SABA overprescription in the North East London population were investigated by the authors in a recent publication, and an association with prescription type was identified. Primary care data, including all prescriptions for inhaled asthma medications and courses of oral corticosteroids in the preceding year, were extracted on secure N3 terminals from EMIS Web during October and November 2021. Data extracted on SABA prescriptions included prescribing modality . All participants had a coded diagnosis of asthma in their primary care electronic medical record. SABA overprescription was defined as the prescription of ≥6 salbutamol 200-dose 100 µg/dose equivalent inhalers in the preceding 12 months, as previously described. Potential selection bias was addressed by including all patients with asthma from all primary care practices in the region. Use of clinical data extracted from regional standard-of-care templates for clinical care addressed potential information bias.Patients overprescribed SABA inhalers in the preceding 12 month period and with a full blood count measured in the past 2 years were selected from the previous evaluation of SABA prescription. Primary care data were used from more than 30 000 patients aged 5–80 years with asthma from North East London.9cells/l (no eosinophilia) and those ≥0.3 x 109 cells/l (eosinophilia).Blood eosinophil counts, undertaken as part of clinically indicated full blood counts, were extracted from primary care medical records. Where patients had had more than one eosinophil count in the preceding 2 years, the count closest to the  data extraction date was used. Characteristics were compared between those whose last eosinophil count was <0.3 × 10Patient demographics  were extracted as most recently recorded in primary care records. Ethnic categories were based on the 18 categories of the UK 2011 census and were combined into four groups reflecting the study population. Asthma medication step was extracted from the patient’s last annual asthma review. Courses of oral corticosteroids in the preceding year were determined from prescribing records. Medication prescription refill for inhaled corticosteroids was calculated from prescription data as previously described. using the earliest recorded diagnostic code before the start of the study, supplemented by SNOMED codes (www.snomed.org) for chronic rhinitis and generalised anxiety.Comorbidities data were extracted on 16 conditions that form part of the UK Quality and Outcomes Framework (QOF),To compare the characteristics of eosinophilic and non-eosinophilic groups, regression models were undertaken, both unadjusted and adjusted for other variables of interest, as described below. Regression models were analysed in R (version 4.0.4).For the latent class analysis, models were developed with blood eosinophil count, courses of oral corticosteroids in the preceding year, asthma medication step, and SABA prescription type as indicator variables and other variables as covariates. Models were developed with 2, 3, and 4 classes and then the best one was selected based on Bayesian information criterion (BIC). Models with smaller values of BIC were preferred, with the use of additional parameters justified by sufficient improvement in the likelihood of the fitted model. This criterion provided a balance between improvement in fit (represented by increased log-likelihood) and model complexity (represented by the number of parameters used). Based on the BIC values , latent class analysis with three classes was selected. These analyses were run using package poLCA in R (version 4.0.4). AUKCAR PPI have reviewed the results of the evaluation of which this publication forms a part, with their views informing the analysis of the ongoing asthma programme.Input from Asthma UK Centre for Applied Research (AUKCAR) patient and public involvement (PPI) representatives has informed this programme of work addressing SABA overuse.This cross-sectional observational research was reported according to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines. The data analysed formed part of a service evaluation intrinsic to a regional quality improvement project, and under this framework the dataset cannot be publicly released.In the recent analysis of SABA prescribing in North East London, 10 081 of 30 694 patients with asthma were overprescribed SABA inhalers . On their last blood eosinophil count, 3507 patients overprescribed SABA were eosinophilic and 4375 not eosinophilic (no full blood count for remaining 2199 patients).P = 0.005). In multivariate analysis, factors significantly associated with being eosinophilic included Asian ethnic group ; being on step two or three asthma medications ; and having received ≥3 courses of oral steroids in the preceding year . Eosinophilia was significantly less likely in female patients ; those with multiple mental health comorbidities ; or those for whom SABA was issued through repeat or repeat dispense prescription types  of 0.85 for being eosinophilic compared with non-eosinophilic for those who had previously smoked referenced to those who had never smoked (P = 0.005), anxiety (P = 0.001), comorbid chronic obstructive pulmonary disease , heart failure (P = 0.047), and gastro-oesophageal reflux disease  were associated with significantly decreased OR of being eosinophilic. Rhinitis was associated with significantly increased OR (P<0.001).Given the association with numbers of comorbidities, the authors further examined whether there might be associations with specific comorbidities . DepressGiven the significant differences in patients overprescribed SABA by eosinophil count, the authors next examined whether there might be latent subclasses of patients overprescribed SABA by latent class analysis. Indicator variables of blood eosinophil count, courses of oral corticosteroids in the preceding year, asthma medication step, and SABA prescription type were chosen  and higher probabilities for patients having a repeat prescription type for their SABA inhalers.Class 2 comprised 6627 patients compared with 799 patients in class 3. Comparing class 2 and class 3, those in class 3 had much higher probabilities for having had courses of oral steroids in the preceding year despite patients in class 3 having a higher probability of being on higher asthma step medications than patients in class 2.There are significant differences in the characteristics of eosinophilic and non-eosinophilic patients with asthma overprescribed SABA inhalers in the North East London population, with the majority not eosinophilic on their last full blood count. Adjusted multivariate regression models found eosinophilia in patients overprescribed SABA to be associated with male sex, Asian ethnic group, multiple courses of oral steroids in the preceding year, SABA not of repeat or repeat dispensing prescription modality, and absence of multiple mental health comorbidities. In terms of specific comorbidities, eosinophilia was positively associated with rhinitis, and negatively associated with anxiety, depression, GORD, cardiac failure, and comorbid COPD. To further explore these differences, a latent class analysis was conducted with indicator variables of blood eosinophil count, courses of oral corticosteroids in the preceding year, asthma medication step, and SABA prescription type. This identified three latent classes that corresponded, as discussed below, to patients with classical eosinophilic uncontrolled asthma (class 1), those with difficult asthma (class 3) and a class of patients with ‘mild’ asthma with high SABA prescription discordant to other measures of asthma control (class 2).The strength of this analysis is the large size of the population studied and use of routine electronic health record data from primary care, reducing potential selection bias. Furthermore, use of routine clinical data, together with the latent class methodology in particular, revealed patient subgroups readily identifiable by clinicians in routine primary care practice, potentially prompting different management approaches.A limitation of this analysis is that not all of the patients overprescribed SABA from the original evaluation could be included, as a minority of patients did not have a blood eosinophil count within the required timeframe. Although the relative sizes of the three latent classes identified may have been affected by that issue, it is unlikely that inclusion of ‘missing’ patients would have changed the characteristics of the identified latent classes. Although the relative proportions of patients within each latent class may vary geographically with differing healthcare systems and prescribing preferences, the three identified latent classes requiring different interventions are likely to be generalisable to other primary care asthma populations. but the finding has been extended to show this association is a particular feature in non-eosinophilic patients. The association between eosinophilia and frequent exacerbations is well-described in poorly controlled asthma. The higher prevalence of eosinophilia in Asian patients with poorly controlled asthma in this evaluation is consistent with reports of differences by ethnic group in characteristics of patients with severe asthma in the UK. Differences by sex have also been described in severe asthma, consistent with the findings in a broader population of patients with asthma in this analysis. For example, Eastwood and colleagues have recently reported poor symptom control with discordantly low biomarker levels is particularly a feature in female patients with severe asthma.The associations identified in the regression studies are consistent with those reported in other populations. For example, the association between mental health comorbidities and SABA overprescription in non-eosinophilic patients is consistent with previous studies showing an association between SABA overuse and mental health conditions,et al did include a minority of primary care-managed patients with asthma in their cluster analysis of predominantly patients with severe asthma, and interestingly reported a symptomatic female-predominant cluster with absent eosinophilic airway inflammation, a cluster with concordant symptoms and eosinophilic airway inflammation, and a cluster with few symptoms and absent eosinophilia. The present research extends the understanding of SABA overprescription in patients with asthma by describing subgroups easily identifiable by routine clinical markers in primary care, including blood eosinophil count, and these have significant implications for clinical practice, as described below.The latent class analysis extends the published literature by identifying that the subgroup of eosinophilic patients with exacerbating asthma is a minority of the larger population of patients with asthma overprescribed SABA. Latent class analysis is a form of cluster analysis that can include categorical variables and is designed to identify latent clusters within a population. Cluster analyses have been conducted in asthma research before, but predominantly in severe asthma. Haldar  However, these patients with classical uncontrolled asthma, who are the focus of most guidelines, were a minority of the entire population of patients overprescribed SABA.The three latent classes identified correspond to distinct patient groups for which different approaches are required in primary care if their SABA overprescription is to be safely addressed. Class 1 in the latent class analysis was enriched for patients with eosinophilia with uncontrolled asthma, who would likely respond to guideline-based review and increase in inhaled corticosteroids in primary care. Therefore, this class has been termed classical uncontrolled asthma. In these patients switching to a combined anti-inflammatory reliever may be a pragmatic approach to ensuring adequate inhaled corticosteroids to prevent future exacerbations. Many patients in class 3 were not eosinophilic and potentially their symptoms and exacerbations might be secondary to other causes than asthma; for example, inducible laryngeal obstruction and breathing pattern disorders. However, the addition of tezepelumab to the biologics armamentarium has extended the range of patients with severe asthma who benefit from biologics to include those without current eosinophilia or other raised T2 biomarker, and the lack of raised inflammatory biomarkers should not dissuade primary care clinicians from referring these patients to regional difficult asthma services.On the other side, many of the patients in class 3 had been prescribed multiple courses of oral steroids despite being on higher-step asthma medications, identifying them as patients who may benefit from referral to specialist severe asthma services, as recommended in most guidelines. Therefore, this class has been termed difficult asthma.Although a single eosinophil count cannot exclude uncontrolled T2 airways inflammation, the high proportion of patients who were not eosinophilic suggests many patients were being overprescribed SABA, despite controlled airway inflammation and low exacerbation risk as exemplified by patients in class 2. This class has been termed mild asthma given the low medication step for most of these patients and low exacerbation frequency (despite discordant high SABA prescription).The majority of patients in class 2 were receiving their SABA inhalers under repeat prescription (or repeat dispensing) and may be receiving unwanted repeat prescriptions of SABA inhalers they are not using. Switching SABA prescription type for these patients to as-requested acute prescriptions may significantly reduce overprescription, and addressing SABA prescription type should be included in future asthma guidelines. How best to manage such patients is not a focus of most asthma guidelines, despite these patients being in the majority in the latent class analysis. Importantly, frequent usage of SABA for complex breathlessness is likely associated with extra-pulmonary side effects of excess ß-adrenergic stimulation in addition to the complications of not actually treating the underlying pathology driving the breathlessness.However, approximately 20% of patients with mild asthma (class 2) were receiving multiple SABA inhalers through acute prescriptions, suggesting actual overuse despite a low proportion of these patients being eosinophilic. SABA inhalers may be being taken inappropriately for other causes of breathlessness, such as breathing pattern disorders and anxiety; this possibility needs further research. Stepping up the strength of their inhaled corticosteroids is unlikely to be beneficial in these non-eosinophilic patients and may be associated with unwarranted inhaled corticosteroid side effects. Alternative strategies for managing symptoms in these patients are needed. Elements of an inpatient SABA withdrawal programme have been described, but given the numbers of patients overusing SABA, consideration needs to be given to how this can be safely done in the community.Research is now needed on how to reduce SABA usage in those patients overusing despite control of underlying asthmatic airways inflammation. SABA reduction and/or withdrawal needs to be done with a safe approach but also in a manner that respects the complex health beliefs of many patients who overuse SABA inhalers.In conclusion, there are significant characteristic differences among patients with asthma overprescribed SABA between those who are and are not eosinophilic. In a latent class analysis, only a minority in the largest class of patients (class 2) were eosinophilic on their last blood eosinophil count. The lack of eosinophilia in many patients overprescribed SABA raises concern that these patients are either collecting but not using the inhalers, or inappropriately using SABA inhalers for other causes of breathlessness. Research and guidelines are now needed on how to manage SABA overuse in patients inappropriately taking excessive doses despite controlled airways inflammation.


Adolescent high blood pressure (HBP) can lead to several end-organ complications if it continues into adulthood. The 2017 AAP Guideline has lower blood pressure cut-off points and consequently leads to the identification of more people with high blood pressure. This study evaluated the impact of the 2017 American Academy of Pediatrics (AAP) Clinical Guideline on the prevalence of high blood pressure among adolescents when compared to the 2004 Fourth Report.A descriptive cross-sectional study was conducted from August 2020 to December 2020. The selection of 1,490 students, 10–19 years old, was by a two-stage sampling technique. Socio-demographic information and relevant clinical data were obtained using a structured questionnaire. Blood pressure was measured according to standard protocol. Categorical and numerical variables were summarized using frequency, percentages, mean, and standard deviation. The McNemar-Bowker test of symmetry was used to compare the blood pressure values in the 2004 Fourth Report and the 2017 AAP Clinical Guideline. The Kappa statistic was used to test for the degree of agreement between the 2004 Fourth Report and the 2017 AAP Clinical Guideline.The prevalence rates of high blood pressure, elevated blood pressure, and hypertension among adolescents were 26.7%, 13.8%, and 12.9%, respectively, using the 2017 AAP Clinical Guideline, and 14.5%, 6.1%, and 8.4%, respectively, using the 2004 Fourth Report. The degree of agreement between the 2004 and 2017 guidelines with respect to the classification of blood pressure was 84.8%. The Kappa statistic was 0.71 (CI: 0.67–0.75). The impact of this was a 12.2%, 7.7%, and 4.5% increase in the prevalence of high blood pressure, elevated blood pressure, and hypertension, respectively, using the 2017 AAP Clinical Guideline.The 2017 AAP Clinical Guideline detects a greater proportion of high blood pressure among adolescents. The adoption of this new guideline in clinical practice and its use in the routine screening of high blood pressure among adolescents is recommended. The global burden of high blood pressure (HPB) in adolescents is rising and constitutes a major public health challenge, affecting approximately one billion people worldwide and accounting for 9.4 million deaths each year . Song etHowever, the evaluation and detection of adolescent HBP can be cumbersome and complex with many challenges and discrepancies  given thThe advent of EBP led to the development of several guidelines which serve to aid physicians in identifying symptoms and signs while making the best clinical decisions based on the most recent available evidence. Amongst these guidelines are the 2004 Fourth Report and the 2017 American Academy of Pediatrics (AAP) Clinical Guideline.The 2004 Fourth Report included normative data and an adaptation of this data to the childhood growth charts from the Centers for Disease Control and Prevention for the year 2000 . FurtherGiven the significant changes in the 2017 AAP Clinical Guideline and its projected impact on the evaluation and management of high blood pressure in adolescents, there was therefore a need for a more systematic evaluation of the impact of its use on the prevalence of HBP in Nigerian children. It is hoped that our findings will provide data for clinicians to implement appropriate changes in their practice to ensure early diagnosis, treatment, and prevention of end-organ damage among adolescents.This was a descriptive cross-sectional study conducted in the Mushin Local Government Area of Lagos State in southwestern Nigeria from August 2020 to December 2020. It is one of the 20 Local Government Areas in Lagos State. Mushin is a densely populated, urban area covering a land area of 14.05 square kilometers with an estimated population of 1,868,743 . It sharThis study was conducted among adolescents aged 10–19 years, in 14 (12 private and 2 public) secondary schools in the Mushin Local Government Area of Lagos State. The total population of students in both public and private secondary schools, as obtained from the Educational District VI Oshodi, was 38,266 with 25,125 of them in public secondary schools and 13,141 students in private secondary schools. The ratio of students in public to private schools was approximately 2:1. Our work was done over a 5-month period, August through December 2020. Ethical approval was obtained from the Health Research Ethics Committee of the Lagos University Teaching Hospital numbered as NHREC/DCST/HERC/2659. Approval was also obtained from the Lagos State Ministry of Education with approval number LG/C530/VI/122.The sample size was determined using the formula for prevalence studies .where:n = minimum sample size when the study population is >10,000z = Standard normal deviate corresponding to 95% confidence interval = 1.96p = prevalence rate of HBP in adolescents from a previous study done inLagos, Nigeria, i.e., 16.5% (0.17) .q = (1 − p), i.e., 0.83d = precision level was set at 2% (0.02)Substituting these figures into the formula:n = 1.962 × 0.17 ×  0.830.022 = 1,355.The minimum sample size was 1,355. An additional 10% (135 pupils) was added to make up for possible non-responses. This brought the total calculated sample size for the study to 1,490. Thus 1,490 adolescents were recruited for the study.A total of 1,355 students aged 10–19 years who attended private or public secondary school in Mushin Local Government Area of Lagos State whose parents/guardians gave consent; and adolescents aged 18 years or more who gave consent were consecutively enrolled. Adolescents who were known or suspected to have renal conditions, such as acute glomerulonephritis, reno-vascular, and renal parenchymal diseases, and those who were on antihypertensive medications were excluded.A two-stage sampling technique was used. Based on the student population, a ratio of one public school to six private schools was selected by simple random sampling. Within selected schools, participants were recruited from each class determined by proportional allocation using the school's register. Students were stratified along gender lines (girls and boys) using the class register. Participants were selected from each stratum by simple random sampling . Before being enrolled in the study, the selected students and their parents gave written and oral consent/assent. Socio-demographic information and relevant clinical data were obtained using a structured questionnaire. Questions were asked to exclude participants based on the presence of symptoms of renal disease and a history of hypertension.Anthropometry and blood pressure measurements were taken according to standard protocol. Body mass index Z scores were determined using the WHO chart for children 5–19 years . Weight Normal blood pressure (NBP) was defined as an SBP and DBP that are <the 90th percentile for gender, age, and height . ElevateSocial class was determined using the socioeconomic indices of the parents as described by Oyedeji .Healthy weight was defined as a Body Mass Index (BMI) for age between the 5th and 85th percentiles, overweight was defined as a BMI for age between the 85th and 95th percentiles, and obesity as a BMI for age above the 95th percentile .Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 23. Descriptive statistics were used to describe the socio-demographic and anthropometric characteristics. The prevalence rates of HBP, elevated BP, and HTN based on the 2017 AAP Clinical Guideline and 2004 Fourth Report were summarized using frequency and percentages, while numerical variables were summarized using mean and standard deviation. The McNemar-Bowker test of symmetry was used to compare the difference in the prevalence of HBP values using the 2017 AAP Clinical Guideline and the 2004 Fourth Report. The Kappa statistic was used to test for the degree of agreement between the 2004 Fourth Report and the 2017 AAP Clinical Guideline.Of the initial 1,500 adolescents invited into the study, 1490 completed responses, giving a response rate of 99.3%. There was approximately equal representation of boys and girls and the mean age of the participants was 14.39 ± 2.79 years. The highest proportion of participants (649: 43.6%) belonged to the upper socio-economic class. The majority of the participants (83.5%) had a healthy weight as assessed by BMI, while 88 (5.9%) were underweight. There were 132 (8.9%) overweight and 25 (1.7%) obese participants .n = 216), while 1,274 (85.5%) had NBP.The overall prevalence of HBP in the study population based on the 2004 Fourth Report was 14.5% . The increase was reflected in the prehypertension and stage 1 HTN groups (p = 0.001 each) but not in the stage 2 HTN group (p = 0.999). This is shown in Overall, the prevalence of HBP was higher based on the 2017 AAP Clinical Guideline than on the 2004 Fourth report (26.7% vs. 14.5%) with an increase of 12.2% (p = 0.001). The higher prevalence affected prehypertension/elevated BP and stage 1 HTN but not stage 2 HTN. This is shown in Within each age group, the prevalence of HBP was significantly higher based on the 2017 AAP Clinical Guideline  and HTN (4.5%) over what they might have been using the 2004 Fourth Report. This is akin to the findings by Bell et al. , Sharma Another striking finding with respect to age in the present study was that the prevalence of HBP increased progressively with the age group when the 2017 AAP Clinical Guideline was applied. This differed markedly from the pattern when using the 2004 Fourth Report in which the prevalence was lowest in the oldest age group and rates did not differ as much across age groups. This finding with the 2004 Fourth Report was unusual because BP is known to progressively increase with age.The degree of agreement between the 2004 and 2017 guidelines with respect to the classification of BP was reasonably high at 84.8%, corroborating an earlier report of 84.8% by Sharma et al.  The coroThe current report is one of the earliest in Nigeria that used the 2017 AAP Clinical Guideline and the first to prospectively compare with the 2004 Fourth Report recommendation, with a fairly large sample of participants covering the full range of adolescent years. Evidence has been provided showing high prevalence rates of elevated BP and HTN among adolescents in secondary schools in Lagos. Due to limited resources, the study was done only in adolescents in secondary students to the exclusion of those who were not in school. It is plausible that social factors that influence BP may differ between the two subgroups of adolescents.That more than a quarter of the adolescents in the present study had high blood pressure is indicative of a high prevalence, underscoring the need for routine blood pressure screening. Application of the 2017 AAP Clinical Guideline instead of the 2004 Fourth Report results in a substantial increase in the prevalence of high blood pressure among adolescents in secondary schools.


Background and Objectives: The aim of our study was to categorize very highly sensitized kidney transplant recipients with pre-transplant panel reactive antibody (PRA) ≥ 98% using an unsupervised machine learning approach as clinical outcomes for this population are inferior, despite receiving increased allocation priority. Identifying subgroups with higher risks for inferior outcomes is essential to guide individualized management strategies for these vulnerable recipients. Materials and Methods: To achieve this, we analyzed the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database from 2010 to 2019 and performed consensus cluster analysis based on the recipient-, donor-, and transplant-related characteristics in 7458 kidney transplant patients with pre-transplant PRA ≥ 98%. The key characteristics of each cluster were identified by calculating the standardized mean difference. The post-transplant outcomes were compared between the assigned clusters. Results: We identified two distinct clusters and compared the post-transplant outcomes among the assigned clusters of very highly sensitized kidney transplant patients. Cluster 1 patients were younger (median age 45 years), male predominant, and more likely to have previously undergone a kidney transplant, but had less diabetic kidney disease. Cluster 2 recipients were older (median 54 years), female predominant, and more likely to be undergoing a first-time transplant. While patient survival was comparable between the two clusters, cluster 1 had lower death-censored graft survival and higher acute rejection compared to cluster 2. Conclusions: The unsupervised machine learning approach categorized very highly sensitized kidney transplant patients into two clinically distinct clusters with differing post-transplant outcomes. A better understanding of these clinically distinct subgroups may assist the transplant community in developing individualized care strategies and improving the outcomes for very highly sensitized kidney transplant patients. Kidney transplantation is recognized as the most effective treatment for enhancing the quality of life and survival in patients with end-stage kidney disease (ESKD) ,2. HowevMachine learning (ML) is an artificial intelligence subfield that can effectively analyze large datasets autonomously, and has been successfully applied in clinical medicine ,10,11. MKidney transplant recipients are a heterogeneous population with distinct underlying illnesses, genetic profiles, and immune responses. This variability can lead to inconsistent outcomes after transplantation, with some patients achieving exceptional graft functionality while others encounter issues such as rejection or allograft failure. Recent research has demonstrated unique subgroups identified by ML consensus clustering among solid organ transplant recipients such as the heart, kidney, and liver ,17,18,19This cohort study aims to categorize very highly sensitized kidney transplant recipients with a PRA ≥ 98% based on comprehensive recipient-, donor-, and transplant-related variables using an unsupervised ML tool, and then assess post-transplant outcomes among the ML identified distinct clusters.Data for this study were sourced from the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database for patients who underwent kidney transplants in the United States between 2010 and 2019. Very highly sensitized kidney transplant patients, defined as having pre-transplant PRA ≥ 98% , were inThe OPTN/UNOS database contains patient-level data of all transplant events in the United States. The recipient-, donor-, and transplant-related variables, listed in In this study, the clinical phenotypes of very highly sensitized kidney transplant patients were categorized using an unsupervised ML technique called consensus clustering . We utilThe research investigated various outcomes in kidney transplant recipients such as patient death, death-censored graft failure at 1 and 5 years, and acute allograft rejection within one year of transplantation. Nevertheless, it is crucial to mention that the OPTN/UNOS registry merely offers information about whether allograft rejection happened within a year following the kidney transplant, without specifying the exact date of occurrence.We utilized the consensus clustering approach to categorize highly sensitized kidney transplant patients and compared their clinical characteristics and post-transplant outcomes among the assigned clusters. Categorical and continuous characteristics were compared using chi-squared tests and analysis of variance, respectively. To identify key characteristics of each cluster, we looked for a standardized mean difference of >0.3 compared to the overall cohort. We then used the Kaplan–Meier method to estimate cumulative risks of patient survival, death-censored graft survival, and overall graft survival following kidney transplant. The log-rank test was employed to compare the assigned clusters, while Cox proportional hazard regression was used to estimate hazard ratios for patient death, death-censored graft failure, and overall graft failure. Conversely, to compare the incidence of 1-year acute allograft rejection, we used the chi-squared test, and logistic regression was used to estimate the odds ratio. Statistical analyses were performed using R, version 4.0.3, with the Consensus-ClusterPlus package (version 1.46.0) utilized for consensus clustering analysis. This allowed us to determine the optimal number of clusters by examining the CM heat map, CDF, cluster-consensus plots with the within-cluster consensus scores, and the PAC. Finally, we used the MICE command in R for multivariable imputation by chained equation .Out of the 158,367 adult patients receiving kidney transplants from 2010 to 2019 in the United States, 7458 (4.7%) were very highly sensitized. Thus, we performed consensus clustering analysis in a total of 7458 very highly sensitized kidney transplant patients. Of these, 1081 (14%), 2129 (29%), and 4248 (57%) had a PRA of 98, 99, and 100%, respectively. In Two distinct clinical clusters were identified by the consensus clustering analysis, as illustrated in Cluster 1 patients were younger (median age 45 (IQR 35–54)), more likely male (59% vs. 9%), and more likely to be undergoing kidney re-transplantation (98% vs. 3%). In comparison, cluster 2 recipients were older (median age 54 (45–62) years), more likely to be female (91% vs. 41%), and more likely to be undergoing a first-time transplant (97% vs. 2%). Additionally, more patients in cluster 1 had a PRA of 100% (65% vs. 48%) and had greater than 3 years of dialysis time prior to undergoing transplant (60% vs. 48%). Recipients in cluster 1 also experienced longer cold ischemia time (median (IQR), 19 (13.9–24.1) vs. 17.8 (12.3–23.2) hours), and were more likely to have received a nationally allocated kidney (52% vs. 41%) in comparison to cluster 2.p = 0.19) (p = 0.006) (p < 0.001). = 0.19) A. The 1-= 0.006) B. ClusteInferior clinical outcomes have been observed in very highly sensitized kidney transplant recipients PRA ≥ 98%). Factors contributing to these inferior outcomes are multifactorial and include variables both directly and indirectly linked to immunologic risk ,8,22,23.%. FactorMechanisms for sensitization are likely to be different between the two clusters as the cluster 1 recipients were more likely to be male and undergoing re-transplantation while the cluster 2 recipients were more likely to be female and undergoing a first-time transplantation. The first cluster, cluster 1, was more likely to be composed of male recipients who were undergoing re-transplantation, and their immune system may have recognized the new transplanted organ as foreign and mounted a response against it, potentially leading to rejection. In contrast, the second cluster, cluster 2, was more likely to be composed of female recipients undergoing their first transplant. These individuals may have been sensitized by prior pregnancies, which can lead to the development of antibodies against the transplanted organ as foreign and lead to rejection. Additionally, more recipients in cluster 1 had a PRA of 100%, suggesting that their immune system had a high level of pre-existing antibodies due to the sensitizing events associated with their prior transplants, which could have led to the development of a more robust immune response. In summary, the two clusters of organ transplant recipients may have had different mechanisms for sensitization based on their gender, previous transplant history, or pregnancies, which could affect their likelihood of developing rejection after transplant.Furthermore, cluster 1 recipients were also more likely to have had exposure to prior immunosuppression, which is associated with an increased risk of infection and malignancy, in addition to the risk of donor-specific antibody reactivation and antibody-mediated graft rejection. These cumulatively may have translated to cluster 1′s lower patient and graft survival ,25,26,27Recipients in cluster 1 had a higher likelihood of receiving dialysis for over three years before transplantation compared to those in cluster 2. This prolonged waiting time and dialysis vintage were likely contributors to cluster 1’s inferior long-term outcomes ,30,31. PThere has been a long-standing debate in the transplant community about the appropriate level of priority that should be given to highly sensitized patients. The current algorithm allocates kidneys based on the level of PRA, which some have argued gives too much weight to sensitization status. In the present study, the majority of kidney transplants in both clusters 1 and 2 were from standard KDPI non-ECD donors, indicating that these patients had access to good quality allografts. However, the transplant outcomes observed in highly sensitized patients were not as good as might be expected. Recent discussions about the development of a new kidney allocation framework have focused on decreasing the emphasis on PRA and providing more equitable access to kidney transplantation for patients on the waiting list. These discussions have been fueled in part by the findings of studies like this one, which highlight the need for a more nuanced approach to kidney allocation. Specifically, the study suggests that while PRA remains an important factor in determining priority for transplantation, other factors such as dialysis vintage and waiting time should also be taken into account . AdditioIn this study, there were several limitations that should be acknowledged. First, due to the national registry’s limitations, details regarding graft rejection, graft failure, and patient death are lacking. Moreover, there might be missing data and loss of follow-up in patients, which could have led to the underestimation of outcomes. However, to minimize bias, we utilized the multivariable imputation by the chained equation strategy for missing data. Additionally, the OPTN/UNOS registry tends to underreport rejection events, so the reported rejection events in this study may not fully represent the immunologic risk events in highly sensitized patients. Finally, our outcomes are not reflective of highly sensitized patients who remain on the waitlist.To our knowledge, this is the first ML clustering approach that has been successfully applied to very highly sensitized kidney transplant recipients (PRA ≥ 98%). The ML clustering algorithms allowed for the identification of two distinct subgroups without human intervention. The patients in cluster 2 had better outcomes regarding death-censored graft survival and acute rejection, indicating that highly sensitized kidney transplant recipients, even with a PRA of ≥98%, are a heterogeneous population. Consequently, this categorization could enable targeted interventions to improve outcomes. Furthermore, the different cluster distributions among the 11 OPTN/UNOS regions may facilitate the identification of future management strategies that incorporate geographical location to enhance outcomes for highly sensitized kidney transplant recipients.While this study’s unsupervised ML clustering approach provides extensive insight into the various phenotypes of very highly sensitized kidney transplant recipients in the United States and their corresponding post-transplant outcomes, it is important to note that ML clustering algorithms have limitations in terms of directly generating risk predictions for individual cases. As such, future research should investigate the efficacy of supervised ML prediction models  utilizing labeled outcomes for the purpose of predicting graft loss and mortality in very highly sensitized kidney transplant recipients. These models should be compared against traditional prediction models and standard risk-adjusted outcomes to ascertain their predictive performances.Our study successfully utilized an unsupervised ML consensus clustering tool to classify highly sensitized kidney transplant recipients in the OPTN/UNOS database into two subtypes with differing clinical outcomes, specifically acute rejection and death-censored graft loss. The results of our study demonstrate that consensus clustering is a viable and effective method for identifying patient subgroups with distinct clinical characteristics in very highly sensitized kidney transplant patients. By tailoring treatment plans based on subgroup membership, this approach may enhance the clinical outcomes and inform clinical decision-making.


After we performed multivariable logistic regression analysis, except age and glucose, serum suPAR  was independently associated with arterial stiffness in chronic HD patients. In the multivariable linear regression analysis, suPAR positively correlated with cfPWV  and could serve as a biomarker for arterial stiffness development in patients undergoing HD.Cardiovascular diseases (CVDs) remain a significant cause of death in hemodialysis (HD) patients. To explore their associations, we examine the role of soluble urokinase-type plasminogen activator receptor (suPAR) in arterial stiffness in chronic HD patients. From June to August 2020, we recruited 135 chronic HD patients. The arterial stiffness group included patients with a carotid–femoral pulse-wave velocity (cfPWV) of >10 m/s. Fifty-five HD patients (40.7%) were in the arterial stiffness group. They had a higher prevalence of diabetes ( Cardiovascular (CV) diseases remain the leading cause of death worldwide . SeveralAlthough both invasive and non-invasive imaging studies are essential to CV diseases diagnosis, several serum markers are under investigation. During inflammation, soluble urokinase plasminogen activator receptor (suPAR) is detached from the endothelia, fibroblasts, and immune cells . It promn = 10), acute infection (n = 3), malignancy (n = 15), liver cirrhosis (n = 5), chronic obstructive lung disease (COPD) (n = 8), and acute heart failure (n = 1) or were bedridden (n = 10) were excluded. Finally, a total about 135 chronic HD patients who signed their informed consent for this study were included. High-flux, polysulfone, disposable artificial kidneys were used . Basic demographic data and medical history were collected from medical records. This study recruited patients undergoing HD between 1 June 2020 and 31 August 2020 in the HD unit of a medical center in Hualien, Taiwan. Patients aged >20 years undergoing HD who receive standard 4 h HD, three times a week, and HD > 6 months, were screened for enrolment. Patients who had a limb amputated . Enrolled patients provided informed consent.g, and blood urea nitrogen, creatinine, albumin, total cholesterol, triglyceride, glucose, calcium, phosphorus, alkaline phosphatase, and C-reactive protein (CRP) levels were measured by an autoanalyzer  [Body mass index was calculated using height in meters and post-HD body weight in kilograms. Before HD, approximately 5 mL of blood was collected. Serum was obtained after 10 min centrifugation at 3000× Germany) ,15. DM wGermany) ,15. RighWe measured their brachial blood pressure three times at five-minute intervals after they had finished HD for thirty minutes. We averaged brachial systolic blood pressure (SBP) and brachial diastolic blood pressure (DBP). Hypertension was defined as brachial SBP ≥ 140 mmHg, brachial DBP ≥ 90 mmHg or having received any antihypertensive medication in the past two weeks. cfPWV needed electrocardiography (ECG) leads to record R wave interval and pressure applanation tonometry  to record carotid and femoral artery pulse waves, as previously described . Data wep-value less than 0.05 was statistically significant.We performed the Kolmogorov–Smirnov test to examine data distribution. HD duration, albumin, triglyceride, glucose, iPTH, alkaline phosphatase, CRP, and suPAR were logarithmically transformed for normality. Normally distributed data are expressed as mean ± standard deviation, and non-normally distributed data are expressed as median and interquartile ranges. To detect between-group differences, we applied the two-tailed Student’s independent t-test to normally distributed data and the Mann–Whitney U test to non-normally distributed data. We express data as percentages and differentiate using the χ2 test for categorical variables. In these variables, significantly associated with arterial stiffness, simple linear regression analysis, multiple logistic regression analysis, and multivariable forward stepwise regression analysis were performed. For log-transformed suPAR and variables, we examined their association using Spearman’s rank-order correlation coefficient. After confirming the effect of suPAR on arterial stiffness, we depicted the receiver operating curve to calculate the power using the area under the curve (AUC). Data were analyzed using IBM SPSS for Windows version 19.0 . A p = 0.001) and hypertension (p = 0.039), as well as higher AIx75 (p = 0.003), higher aortic SBP (p = 0.034), and higher brachial SBP (p = 0.025), and they were older (p = 0.007). They also had more elevated glucose (p = 0.019), higher CRP (p = 0.039), and higher suPAR (p < 0.001) than the control group. There were no significant differences in sex and percentage of taking angiotensin receptor blockers, beta-blockers, calcium channel blockers, fibrate, or statins.p < 0.001), age , and glucose  predicted arterial stiffness in chronic HD patients after multivariable logistic regression analysis , age , aortic SBP , brachial SBP , log-glucose , log-CRP , and serum log-suPAR levels  are positively correlated with cfPWV. After we adjusted the above factors in the multivariable forward stepwise linear regression analysis, age , aortic SBP , and log-suPAR levels  had an independent and positive correlation with cfPWV in HD patients. The ROC curve for predicting arterial stiffness using suPAR demonstrated the AUC was 0.81   . Accordip = 0.047), age (p = 0.010), log-CRP (p < 0.001), AIx75 (p = 0.003), and cfPWV (p < 0.001) were positively associated with log-suPAR.The correlation between log-suPAR and variables was also explored by Spearman’s rank-order correlation coefficient . DM , a glycosylphosphatidylinositol-anchored protein on the cell surface, has been recognized as a potential marker of atherosclerosis . In acutArterial stiffness, an early pathology of atherosclerosis, and suPAR, a serum marker in CV diseases, have been studied in different populations. The SAfrEIC study measured suPAR and arterial stiffness in Africans and Caucasians . AlthougThis study has several limitations. First, this is a single-center cross-sectional study; thus, it may be difficult to generalize the results to all patients on HD, even the general population. To strengthen the relationship, analyzing larger samples and an extended follow-up period may be helpful. Second, although suPAR is less likely affected by acute illness, a mild infection may disrupt actual relationships. Evaluating more acute phase proteins such as IL-6, IL-10, and IL-18 may reduce the discrepancy. Third, emerging results show that home blood pressure has a stronger association with cfPWV than post-dialysis blood pressure. However, we did not collect data on home blood pressure. Finally, we took all these arterial stiffness indexes and blood pressure after HD. The relation between cfPWV, AIx75, aortic blood pressure and suPAR is unclear. A study by Erdan et al. indicates that these indexes decreased after dialysis . HoweverAlong with old age and glucose, our study showed a positive relationship between arterial stiffness and suPAR in patients on chronic HD; however, the mechanism must be further examined.


Critical closing pressure (CrCP) and resistance-area product (RAP) have been conceived as compasses to optimize cerebral perfusion pressure (CPP) and monitor cerebrovascular resistance, respectively. However, for patients with acute brain injury (ABI), the impact of intracranial pressure (ICP) variability on these variables is poorly understood. The present study evaluates the effects of a controlled ICP variation on CrCP and RAP among patients with ABI.Consecutive neurocritical patients with ICP monitoring were included along with transcranial Doppler and invasive arterial blood pressure monitoring. Internal jugular veins compression was performed for 60 s for the elevation of intracranial blood volume and ICP. Patients were separated in groups according to previous intracranial hypertension severity, with either no skull opening (Sk1), neurosurgical mass lesions evacuation, or decompressive craniectomy (DC) (patients with DC [Sk3]).r = 0.643 [p = 0.0007], group with neurosurgical mass lesions evacuation r = 0.732 [p < 0.0001], and group Sk3 r = 0.580 [p = 0.003], respectively). Patients from group Sk3 presented a significantly higher ΔRAP (p = 0.005); however, for this group, a higher response in mean arterial pressure  was observed. Exclusively, group Sk1 disclosed reduction in ICP before internal jugular veins compression withholding.Among 98 included patients, the correlation between change (Δ) in ICP and the corresponding ΔCrCP was strong (group Sk1 This study elucidates that CrCP reliably changes in accordance with ICP, being useful to indicate ideal CPP in neurocritical settings. In the early days after DC, cerebrovascular resistance seems to remain elevated, despite exacerbated arterial blood pressure responses in efforts to maintain CPP stable. Patients with ABI with no need of surgical procedures appear to remain with more effective ICP compensatory mechanisms when compared with those who underwent neurosurgical interventions.The online version contains supplementary material available at 10.1007/s12028-023-01691-8. It is kce (CVR) . In the ce (CVR) , 6.Acute brain damages related to traumatic brain injury, subarachnoid hemorrhage, and both hemorrhagic or ischemic strokes lead to either diffuse or focal injuries that rationally would conduce to a nonhomogeneous compromise of CPP, challenging the veracity of CPP remaining exclusively on the interactions of MAP and ICP . FurtherTherefore, assessment of cerebral hemodynamics is crucial for the neurocritical patient because ignoring it may lead to ventilatory, volemic, and pressure mismanagement . TranscrIt is important to highlight that the brain is located within a rigid skull structure known as a fragile environment for changes in pressures as complications following ABI. Hence, the present study tests the hypothesis that changes in CrCP and RAP are strongly associated with changes in ICP in patients with ABI.This is a single center, prospective, observational study performed at Hospital das Clínicas, São Paulo University, Brazil. The study protocol was approved by the local Ethics Committee, in May/23/2017 (REB register 66721217.0.0000.0068) and registered under number NCT03144219 . All methods were performed in accordance with the relevant guidelines and regulations, and informed consent was obtained from all legally authorized representatives or next of kin instead of the patients because of illness severity.3, midline shift more than 0.5 cm, or imminent risk of herniation in the case of severe brain swelling on admission CT scans. Clinical and laboratory variables were collected at the day of study inclusion.The inclusion criteria were patients with a diagnosis of ABI within 5 days of hospital admission submitted to ICP monitoring according to the guidelines of the Brain Trauma Foundation for patients with traumatic brain injury and tomographic evaluation in the case of nontraumatic patients. Exclusion criteria were absence of TCD acoustic windows, neurological examination indicative of brain death, and absence of informed consent. Computed tomography (CT) scans, performed within 24 h prior or posterior to inclusion, were assessed to separate patients in groups according to injury severity, corresponding to the following: no skull opening group (Sk1), surgical mass evacuation group (Sk2), and primary decompressive craniectomy (DC) group (Sk3). Decision for surgical management was performed according to the local institutional neurosurgical guidelines. Nevertheless, surgical management was based either on the presence of mass lesions greater than 30 cm2 (EtCO2) was measured continuously with an infrared capnograph . Prior to data collection, an ultrasound examination was performed to discard significant intracranial stenosis [CBv was recorded bilaterally in the middle cerebral arteries (MCAs) with TCD  equipped with a 2-MHz probe. Recording was initiated after the best MCA signal quality was acquired and without insonation angle variation during the session. Intraventricular ICP was measured with the Neurovent monitoring system using a solid-state transducer . ABP was recorded invasively with a radial artery catheter. The pressure transducer was leveled and zeroed to the intersection of the anterior axillary line and the fifth intercostal space. End-tidal COstenosis . Monitorstenosis . Continu.Beat-to-beat data were analyzed by using in-house custom software written in Fortran. Continuous recordings were visually inspected and narrow artifacts (< 100 ms) were removed by linear interpolation. Spikes in the CBv channels were removed with a median filter and all signals were low-pass filtered with a zero-phase eighth-order Butterworth filter with a cut-off frequency of 20 Hz. The beginning and end of each cardiac cycle was detected in the ABP signal, visually checked, and used to obtain beat-to-beat values of heart rate, MAP, mean CBv, and ICP. The instantaneous relationship between ABP and CBv was used to estimate CrCP and RAP for each cardiac cycle using the first harmonic method . Beat-toThe resampled time-series of ICP was visually inspected, and the beginning of compression was marked. All recorded variables were then synchronized with the instant of compression placed at time = 60 s within a 3-min data window Fig. , and theW test was applied for normality determination. Student’s t test was used for pairwise comparisons and one-way analysis of variance for the effects of skull condition. In the case of absence of interhemispherical differences, the parameters were averaged. Pearson correlation coefficient and linear regression analysis were used to assess associations between changes in parameters, due to IJVC. Differences between correlation coefficients were tested after log transformation. The General Linear Model was used to test for the effect of skull condition on the slopes of linear regressions. A value of p < 0.05 was adopted to represent statistical significance. Statistical analysis was performed with STATISTICA .Parameter distributions were expressed as mean ± standard deviation. The Shapiro–Wilk p = 0.025), and heart rate was lower (p = 0.045) for the group Sk3, but all other variables did not show any significant differences due to skull status.We report the inclusion of 98 eligible patients admitted between August 2017 and May 2020. ICP recordings were of poor quality for nine patients. Data of other four patients were lost, yielding a final sample of 85 patients for analyses. Sixteen patients (19%) had intracranial hypertension (baseline ICP > 20 mm Hg). Right and left hemisphere values of CBv, CrCP, and RAP were averaged following pairwise testing. Table p = 0.052). On the other hand, following compression, there was a very strong linear relationship between ΔICP and the corresponding ΔCrCP , r = 0.732 (p < 0.0001), and r = 0.580 (p = 0.003) for Sk1, Sk2, and Sk3, respectively. General Linear Model analysis indicated that the three slopes in Fig. p = 0.041). Tukey’s post hoc analysis showed differences in slope between Sk3 and both Sk1 (p = 0.00012) and Sk2 (p = 0.0066). Considering the entire sample (n = 85), a strong relationship between absolute values of CrCP and ICP was observed, either before (p = 0.0007) or after (p = 0.00006) IJVC, as expressed by Pearson’s correlation coefficient.IJVC led to an increase in ICP and CrCP with a drop in CBv and CPP in all groups. RAP did not have significant changes for groups Sk1 and Sk2, but for group Sk3 there was a marked increase of this parameter. Likewise, MAP response was also remarkable in this group . No significant differences were observed for the comparison between injured and noninjured hemispheres for all parameters variations  during IJVC  and RAP . No significant correlations with age were observed for any of the parameters in Table p = 0.028). For the parameters in Table p = 0.028). All other parameters remained significant or nonsignificant as in Table For the parameters in Table The present study has indicated that the cerebral hemodynamic responses following ICP variations can behave differently among patients in the early stages after ABI, according to the severity of these brain injuries. This was markedly observed among patients who presented with refractory raised ICP and underwent DC. To our knowledge, changes in TCD-derived CrCP and RAP using controlled ICP variations have not been previously reported in this population, eliciting a better understanding of the hemodynamic consequences of ABI. Of considerable relevance, the strong linear association between the changes in CrCP and ICP should stimulate further advances in noninvasive methods for assessment of cerebrovascular function Fig. .Fig. 4RIn the literature, there is an index also called RAP, however, it is derived from ICP pulse amplitude and ICP mean values. This index is estimated for the assessment of intracranial compensatory reserve , 22. Difr = 0.91) in 70 patients and by Czosnyka et al. [r = 0.51) in 98 patients with head injury. In our study, we confirmed this strong association between CrCP and ICP when the entire sample was pooled into the same linear regression, as well as for all three distinct groups separately.Several investigators have proposed that CrCP could replace ICP in noninvasive estimates of CPP , 23–26. a et al.    , despiteOur data demonstrated a very close relationship of RAP and MAP in DC group Table , which cAll this reinforces the idea that CA  is not an all-or-nothing phenomenon, and the decomposition of CVR in two variables (CrCP and RAP) would give a more realistic bedside interpretation of the complex changes in cerebral hemodynamics of neurocritical patients. Likewise, these findings also emphasize the importance of not considering CPP strictly determined by the interaction between MAP and ICP in ABI , 51, 52 2 was not registered, although maintained within controlled limits due to mechanical ventilation and did not show significant changes during monitoring sessions; rather, EtCO2 was used as a proxy of changes in arterial CO2 tension.The given observations of the present study were supported by the analysis of data extracted from the early stages of ABI in a single monitoring session. It is acknowledged that a cohort study design would increase the possibility to follow-up physiological changes in this population. Our results are derived from MCA blood transit velocity, instead of actual cerebral blood volume or brain perfusion, and this limitation could have affected our results. IJVC increased ICP and this could have caused a reduction in MCA diameter, thus leading to overestimation of the corresponding drop in CBv, as well as small errors in CrCP and RAP. Despite a large range of ages included, our main findings persisted even with the removal of data from patients under 18 years old. Automated and continuous PaCOTo maintain the focus of the study on the main hypothesis outlined in the Introduction, we have not explored other interparameter relationships, such as the association between ΔCrCP and ΔRAP. Changes in RAP due to IJVC and its association with corresponding changes in MAP can reflect the status of dynamic CA, which are under investigation and will be reported elsewhere. Finally, TCD measurements were performed exclusively on main distal branches of internal carotid arteries, the MCAs more specifically, not considering disturbances on the posterior fossa.Critical closing pressure is correlated with ICP variations and may aid in planning therapeutic interventions based on hemodynamic adjustments. An induced mild ICP elevation in the present study did not impact the CPP of craniectomized patients. These patients demonstrated elevated MAP response to ICP variation, despite the persistence of higher CVR, which may be interpreted as a protection mechanism provided by DC. Patients with ABI not submitted to neurosurgical procedures revealed a higher capacity of handling artificial ICP elevation, which may be attributed to less severe injury, appropriate ICC, and efficient compensatory reserve. These observations altogether reinforce the need for multimodal monitoring of the neurocritical patient.Supplementary file1 (DOCX 34 kb)Supplementary file2 (DOCX 12 kb)Below is the link to the electronic supplementary material.