Persistent SARS-CoV-2-specific immune defects in kidney transplant recipients following third mRNA vaccine dose.

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBDNEG; n = 42 anti-RBDLO), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8+%, and SARS-CoV-2-reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBDNEG remained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P < .001). Day 30 spike-specific CD8+% was negative in 91% KTRs (vs 20% HCs; P = .07), without correlation to anti-RBD (rs = 0.17). Day 30 SARS-CoV-2-reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P = .11). Spike-specific CD4+ TCR expansion was similar between KTRs and HCs, yet KTR CD8+ TCR depth was 7.6-fold lower (P = .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P = .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8+ responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4+ expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263).

From the United Kingdom to Australia-Adapting a Web-Based Self-management Education Program to Support the Management of Type 2 Diabetes: Tutorial.

Diabetes self-management education and support can improve outcomes in people with diabetes. Providing health interventions via digital modes of delivery can extend the reach of programs delivered through traditional means. The web-based version of the Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (MyDESMOND) is a digital diabetes education and support program for people with type 2 diabetes. The program was originally developed in the United Kingdom and is evidence-based, grounded in behavioral theory, and designed through a rigorous process of intervention mapping. As such, MyDESMOND was considered an ideal candidate for adaptation to the Australian setting. Program content and the digital platform were modified to suit the local context to increase the likelihood that the revised version of MyDESMOND will deliver similar outcomes to the original program. The aim of this paper is to describe the systematic processes undertaken to adapt the digital MyDESMOND diabetes education and support program for people with type 2 diabetes to the Australian setting. The adaptation involved a multidisciplinary group with a diverse range of skills and expertise-a governance structure was established, a skilled project team was appointed, and stakeholder engagement was strategically planned. The adaptation of the program content included modifications to the clinical recommendations, the inclusion of local resources, practical changes, and revisions to optimize readability. A 2-stage independent review of the modified content was enacted. Digital adaptations were informed by relevant standards, local legislative requirements, and considerations of data sovereignty. The digital platform was extensively tested before deployment to the production setting. MyDESMOND is the first evidence-based digital diabetes education and support program for Australians with type 2 diabetes. This paper provides a road map for the adaptation of digital health interventions to new contexts.

Providing evidence from practice: Evaluating 4.5 years of implementing diabetes education support program in carbohydrate management.

OBJECTIVE: To evaluate personal and economical outcomes of CarbSmart, a 3-hour person-centered, theory-based program implemented throughout Australia, targeting optimal dietary carbohydrate management. METHODS: More than 500 CarbSmart programs were implemented over 4.5 years. Pre-, post-, (N = 4656) and 3-month follow-up assessments (N = 188) of knowledge, empowerment, confidence, and patient activation were collected from people with diabetes. Participant satisfaction and potential annual cost-savings were calculated. FINDINGS: Repeated measures ANCOVAs showed large improvements pre- to post-program in all outcome variables (d = 0.80-1.68), which were maintained at 3-month follow-up in a sub-sample. Participant satisfaction was high (Net Promoter Score = 72.3). Potential annual cost-savings nation-wide were estimated at US$512million. CONCLUSION: This paper provides evidence that CarbSmart is effective in improving behavioral indicators of self-management outcomes in Australians living with diabetes. PRACTICE IMPLICATIONS: CarbSmart has the potential to prevent diabetes-related complications. However, not engaging people living with diabetes with lower levels of patient activation at baseline was recognized as a future opportunity to improve the impact of our service. Strategies are needed to engage people with lower activation levels to improve outcomes in vulnerable and at-risk populations. FUNDING: The development of CarbSmart was funded by Diabetes WA, the national implementation of CarbSmart by the National Diabetes Services Scheme, an initiative of the Australian Government.

The design of an evaluation framework for diabetes self-management education and support programs delivered nationally.

BACKGROUND: The aim of this work was to develop a National Evaluation Framework to facilitate the standardization of delivery, quality, reporting, and evaluation of diabetes education and support programs delivered throughout Australia through the National Diabetes Services Scheme (NDSS). The NDSS is funded by the Australian Government, and provides access to diabetes information, education, support, and subsidized product across diverse settings in each state and territory of Australia through seven independent service-providers. This article reports the approach undertaken to develop the Framework. METHODS: A participatory approach was undertaken, focused on adopting nationally consistent outcomes and indicators, nominating objectives and measurement tools, specifying evaluation processes, and developing quality standards. Existing programs were classified based on related, overarching indicators enabling the adoption of a tiered system of evaluation. RESULTS: Two outcomes (i.e., improved clinical, reduced cost) and four indicators (i.e., improved knowledge and understanding, self-management, self-determination, psychosocial adjustment) were adopted from the Eigenmann and Colagiuri national consensus position statement for diabetes education. This allowed for the identification of objectives (i.e., improved empowerment, reduced distress, autonomy supportive program delivery, consumer satisfaction) and related measurement instruments. Programs were categorized as comprehensive, topic-specific, or basic education, with comprehensive programs allocated to receive the highest-level of evaluation. Eight quality standards were developed, with existing programs tested against those standards. Based on the results of testing, two comprehensive (OzDAFNE for people with type 1 diabetes, DESMOND for people with type 2 diabetes), and eight topic-specific (CarbSmart, ShopSmart, MonitorSmart, FootSmart, MedSmart, Living with Insulin, Insulin Pump Workshop, Ready Set Go - Let's Move) structured diabetes self-management education and support programs were nominated for national delivery. CONCLUSIONS: The National Evaluation Framework has facilitated consistency of program quality, delivery, and evaluation of programs delivered by multiple service providers across diverse contexts. The Framework could be applied by other service providers who facilitate multiple diabetes education and support programs and could be adapted for use in other chronic disease populations where education and support are indicated.

Avoidance of CNI and steroids using belatacept-Results of the Clinical Trials in Organ Transplantation 16 trial.

Immunosuppression devoid of corticosteroids has been investigated to avoid long-term comorbidities. Likewise, alternatives to calcineurin inhibitors have been investigated as a strategy to improve long-term kidney function following transplanion. Costimulatory blockade strategies that include corticosteroids have recently shown promise, despite their higher rates of early acute rejection. We designed a randomized clinical trial utilizing depletional induction therapy to mitigate early rejection risk while limiting calcineurin inhibitors and corticosteroids. This trial, Clinical Trials in Organ Transplantation 16 (CTOT-16), sought to evaluate novel belatacept-based strategies employing tacrolimus and corticosteroid avoidance. Sixty-nine kidney transplant recipients were randomized from 4 US transplant centers comparing a control group of with rabbit antithymocyte globulin (rATG) induction, rapid steroid taper, and maintenance mycophenolate and tacrolimus, to 2 arms using maintenance belatacept. There were no graft losses but there were 2 deaths in the control group. However, the trial was halted early because of rejection in the belatacept treatment groups. Serious adverse events were similar across groups. Although rejection was not uniform in the belatacept maintenance therapy groups, the frequency of rejection limits the practical implementation of this strategy to avoid both calcineurin inhibitors and corticosteroids at this time.

Challenges of calcineurin inhibitor withdrawal following combined pancreas and kidney transplantation: Results of a prospective, randomized clinical trial.

In a phase 2 multicenter open-label randomized trial sponsored by the National Institutes of Health, simultaneous pancreas-kidney (SPK) recipients were randomized to a calcineurin inhibitor (CNI)-based immunosuppressive regimen (tacrolimus) (n = 21), or an investigational arm using low-dose CNI plus costimulation blockade (belatacept) with intended CNI withdrawal (n = 22). Both arms included induction therapy with rabbit ATG, mycophenolate sodium, or mycophenolate mofetil and rapid withdrawal of steroids. Enrollment and CNI withdrawal were stopped after 43/60 planned subjects had been enrolled. At that time, the rate of biopsy-proven acute rejection (BPAR) of the pancreas was low in both groups until CNI was withdrawn, with four of the five pancreas rejections occurring during or after CNI withdrawal. The rate of BPAR of kidney allografts was low in both control (9.5%) and investigational (9.1%) arms. Pancreas graft survival at 52 weeks, defined by insulin independence, was 21 (100%) in the control group and 19 (86%) in the investigational arm. One subject in the investigational arm died with functioning pancreas and kidney grafts. Renal function at week 52 was similar in both arms. Costimulation blockade with belatacept did not provide sufficient immunosuppression to reliably prevent pancreas rejection in SPK transplants undergoing CNI withdrawal.

Increasing patient activation through diabetes self-management education: Outcomes of DESMOND in regional Western Australia.

OBJECTIVE: To evaluate the effects of the Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND) program on patient activation in adults living with type 2 diabetes (T2D). METHODS: 233 individuals attended a DESMOND program in 26 locations across regional Western Australia. Individuals completed the Patient Activation Measure (PAM) prior to and immediately after DESMOND participation. RESULTS: Patient Activation significantly increased by 9.7 points from pre to post DESMOND intervention (p < 0.001, z = -7.94). Of all participants who exhibited an increase in patient activation, 87% (n = 142) experienced a clinically significant (>5 point) increase. Post-DESMOND participation, an 86% reduction (from 6% -0.9%) in the proportion of participants scoring in the lowest PAM level (Level 1) was observed (p < 0.01). CONCLUSION: DESMOND, a structured diabetes self-management education (DSME) program aimed at strengthening the role of people living with type 2 diabetes in self-managing their healthcare, significantly increased patient activation in a real-world setting. PRACTICE IMPLICATIONS: In line with international diabetes guidelines it is recommended that people living with T2D, particularly those with lower levels of activation, attend an evidence based DSME such as DESMOND to increase their capacity to effectively self-manage their condition.

e-ageing: development and evaluation of a flexible online geriatric medicine educational resource for diverse learners.

AIMS: To determine preferred content and format for online education modules in aged care among inter-professional learners; to develop resources that meet user preferences. METHODS: Stakeholders were interviewed. A survey was administered to all health/medical students and teachers at The University of Western Australia. An iterative process was used to develop modules, and user feedback was collated. RESULTS: The educational needs of each discipline related primarily to foundation level knowledge in major aged care topics. Stakeholders sought modules incorporating communication skills, cultural and social issues and the importance of a multidisciplinary approach to aged care. Students from all disciplines sought online materials that are interactive, engaging, case-based and locally relevant. Online modules were developed. Evaluation of the modules by users has been strongly positive. CONCLUSION: There was consensus regarding the major curricular areas that online resources should encompass. The e-ageing modules developed in this project have been evaluated positively by users.

Factors regulating viable cell density in the intervertebral disc: blood supply in relation to disc height.

The intervertebral disc is an avascular tissue, maintained by a small population of cells that obtain nutrients mainly by diffusion from capillaries at the disc-vertebral body interface. Loss of this nutrient supply is thought to lead to disc degeneration, but how nutrient supply influences viable cell density is unclear. We investigated two factors that influence nutrient delivery to disc cells and hence cell viability: disc height and blood supply. We used bovine caudal discs as our model as these show a gradation in disc height. We found that although disc height varied twofold from the largest to the smallest disc studied, it had no significant effect on cell density, unlike the situation found in articular cartilage. The density of blood vessels supplying the discs was markedly greater for the largest disc than the smallest disc, as was the density of pores allowing capillary penetration through the bony endplate. Results indicate that changes in blood vessels in the vertebral bodies supplying the disc, as well as changes in endplate architecture appear to influence density of cells in intervertebral discs.

Students and teachers' preferences for undergraduate dementia education in Western Australia.

Medical graduates require positive attitudes toward older people with cognitive impairment, in addition to knowledge and skills in the diagnosis and management of dementia. The Student Training Project in Dementia (STriDE) project was conducted to ensure that these needs are met through curricula in Western Australian medical schools. Two medical schools in Perth, Western Australia, participated. Mixed methods were utilized comprising a) focus groups and interviews and b) a survey of teachers and students. Participants recommended clearer structure and standardization in the curriculum to ensure that all students receive similar educational experiences regardless of hospital placement. Both teachers, and to a lesser extent students, held positive attitudes toward older people. Teachers tended to be more dissatisfied with current curricula than students. Teachers and learners endorsed a broad range of teaching and learning methods, assessments, and skills/competencies. The results of this study present major challenges for professional entry dementia education given the breadth, flexibility, and depth of dementia education recommended by teachers and learners.

Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test.

Approximately 1-2% of colorectal cancers (CRC) arise because of germline mutations in DNA mismatch repair genes, referred to as Lynch syndrome. These tumours show microsatellite instability (MSI) and loss of expression of mismatch repair proteins. Pre-symptomatic identification of mutation carriers has been demonstrated to improve survival; however, there is concern that many are not being identified using current practices. We evaluated population-based MSI screening of CRC in young patients as a means of ascertaining mutation carriers. CRC diagnosed in patients aged <60 years were identified from pathology records. No prior information was available on family history of cancer. PCR techniques were used to determine MSI in the BAT-26 mononucleotide repeat and mutation in the BRAF oncogene. Loss of MLH1, MSH2, MSH6 and PMS2 protein expression was evaluated in MSI+ tumours by immunohistochemistry. MSI+ tumours were found in 105/1,344 (7.8%) patients, of which 7 were excluded as possible Lynch syndrome because of BRAF mutation. Of the 98 "red flag" cases that were followed up, 25 were already known as mutation carriers or members of mutation carrier families. Germline test results were obtained for 35 patients and revealed that 22 showed no apparent mutation, 11 showed likely pathogenic mutations and 2 had unclassified variants. The proportion of MSI+ cases in different age groups that were estimated to be mutation carriers was 89% (<30 years), 83% (30-39), 68% (40-49) and 17% (50-59). We recommend MSI as the initial test for population-based screening of Lynch syndrome in younger CRC patients, regardless of family history.

Heterogeneous staining for mismatch repair proteins during population-based prescreening for hereditary nonpolyposis colorectal cancer.

The aim of this study was to determine the frequency of microsatellite instability (MSI(+)) in tumors from a population-based series of young colorectal cancer patients and its correlation with the loss of expression of mismatch repair (MMR) proteins. The BAT-26 mononucleotide repeat was used to screen for MSI(+) in all colorectal cancers diagnosed in Western Australia throughout a 5-year period in patients <60 years of age. MSI(+) was found in 75 of 1003 (7.5%) cases, of which six contained a concomitant mutation in BRAF and were therefore excluded from further investigations as possible hereditary nonpolyposis colorectal cancer. Immunohistochemistry was used to evaluate expression of the four major MMR proteins (MLH1, MSH2, MSH6, and PMS2) in the remaining 69 MSI(+) tumors. Complete loss of MLH1 and PMS2 expression or of MSH2 and MSH6 expression was found in 35 (51%) and 17 (25%) cases, respectively, whereas other patterns of complete loss were observed in eight cases (12%). Eight tumors (12%) were initially recorded as showing normal expression, but on review seven were reclassified as having abnormal staining because of heterogeneous patterns of MMR loss. Three of these seven cases had previously been found to have germline mutations. Because of possible misinterpretation of heterogeneous immunohistochemistry staining for MMR protein loss, MSI testing is recommended as the initial screen for population-based detection of hereditary nonpolyposis colorectal cancer.