When There is No Guidance From the Guidelines: Renal Transplantation in Recipients With Class III Obesity.

Whilst renal transplantation is the optimal treatment for many patients with end-stage kidney disease, the latest international guidelines are unable to make recommendations for the management of patients with end-stage kidney stage kidney disease and Class III Obesity (BMI ≥40 kg/m2). Data on all adult patients receiving a kidney-only-transplant in the UK between 2015-2021 were analysed from a prospectively collected database and interrogated across a range of parameters. We then analysed in detail the outcomes of patients transplanted at the highest-volume unit. There were 22,845 renal transplants in the study time-period; just 44 (0.2%) were performed in recipients with a BMI ≥40 kg/m2. Most transplant centres did not transplant any patients in this category. In the centre with the highest volume, there were 21 transplants (9 living donor) performed in 20 individuals (13 male, median age 46 years). One-year patient and death-censored graft survival was 95% and 85%. Successful transplantation is possible in patients with BMI ≥40 kg/m2 but carries additional risk. Obesity should not be the sole factor considered when deciding on transplant suitability. Restricting transplantation to a small number of high-volume centres in each country should be considered to optimize outcomes.

The UK kidney donor risk index poorly predicts long-term transplant survival in paediatric kidney transplant recipients.

Background: The UK kidney offering scheme introduced a kidney donor risk index (UK-KDRI) to improve the utility of deceased-donor kidney allocations. The UK-KDRI was derived using adult donor and recipient data. We assessed this in a paediatric cohort from the UK transplant registry. Methods: We performed Cox survival analysis on first kidney-only deceased brain-dead transplants in paediatric (<18 years) recipients from 2000-2014. The primary outcome was death-censored allograft survival >30 days post-transplant. The main study variable was UK-KDRI derived from seven donor risk-factors, categorised into four groups (D1-low risk, D2, D3 and D4-highest risk). Follow-up ended on 31-December-2021. Results: 319/908 patients experienced transplant loss with rejection as the main cause (55%). The majority of paediatric patients received donors from D1 donors (64%). There was an increase in D2-4 donors during the study period, whilst the level of HLA mismatching improved. The KDRI was not associated with allograft failure. In multi-variate analysis, increasing recipient age [adjusted HR and 95%CI: 1.05(1.03-1.08) per-year, p<0.001], recipient minority ethnic group [1.28(1.01-1.63), p<0.05), dialysis before transplant [1.38(1.04-1.81), p<0.005], donor height [0.99 (0.98-1.00) per centimetre, p<0.05] and level of HLA mismatch [Level 3: 1.92(1.19-3.11); Level 4: 2.40(1.26-4.58) versus Level 1, p<0.01] were associated with worse outcomes. Patients with Level 1 and 2 HLA mismatches (0 DR +0/1 B mismatch) had median graft survival >17 years regardless of UK-KDRI groups. Increasing donor age was marginally associated with worse allograft survival [1.01 (1.00-1.01) per year, p=0.05]. Summary: Adult donor risk scores were not associated with long-term allograft survival in paediatric patients. The level of HLA mismatch had the most profound effect on survival. Risk models based on adult data alone may not have the same validity for paediatric patients and therefore all age-groups should be included in future risk prediction models.

Vaccine Effectiveness Against the SARS-CoV-2 B.1.1.529 Omicron Variant in Solid Organ and Islet Transplant Recipients in England: A National Retrospective Cohort Study.

BACKGROUND: The effectiveness of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 Omicron variant in immunosuppressed solid organ and islet transplant (SOT) recipients is unclear. METHODS: National registries in England were linked to identify SARS-CoV-2 positive tests, noninjury hospitalization within 14 d, and deaths within 28 d between December 7, 2020, and March 31, 2022 in adult SOT recipients. Incidence rate ratios (IRRs) for infection, and hospitalization or death, were adjusted for recipient demographics and calendar month for the Omicron-dominant period (December 20, 2021, to March 31, 2022). Mortality risk following SARS-CoV-2 infection was adjusted for recipient demographics and dominant variant using a Cox proportional-hazards model for the entire time period. RESULTS: During the Omicron-dominant period, infection IRRs (95% confidence intervals) were higher in those receiving 2, 3, and 4 vaccine doses than in unvaccinated patients (1.25 [1.08-1.45], 1.46 [1.28-1.67], and 1.79 [1.54-2.06], respectively). However, hospitalization or death IRRs during this period were lower in those receiving 3 or 4 vaccine doses than in unvaccinated patients (0.62 [0.45-0.86] and 0.39 [0.26-0.58], respectively). Risk-adjusted analyses for deaths after SARS-CoV-2 infection between December 7, 2020, and March 31, 2022, found hazard ratios (95% confidence intervals) of 0.67 (0.46-0.98), 0.46 (0.30-0.69), and 0.18 (0.09-0.35) for those with 2, 3, and 4 vaccine doses, respectively, when compared with the unvaccinated group. CONCLUSIONS: In immunosuppressed SOT recipients, vaccination is associated with incremental, dose-dependent protection against hospitalization or death after SARS-CoV-2 infection, including against the Omicron variant.

Real-world Effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S Vaccines Against SARS-CoV-2 in Solid Organ and Islet Transplant Recipients.

BACKGROUND: The clinical effectiveness of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunosuppressed solid organ and islet transplant (SOT) recipients is unclear. METHODS: We linked 4 national registries to retrospectively identify laboratory-confirmed SARS-CoV-2 infections and deaths within 28 d in England between September 1, 2020, and August 31, 2021, comparing unvaccinated adult SOT recipients and those who had received 2 doses of ChAdOx1-S or BNT162b2 vaccine. Infection incidence rate ratios were adjusted for recipient demographics and calendar month using a negative binomial regression model, with 95% confidence intervals. Case fatality rate ratios were adjusted using a Cox proportional hazards model to generate hazard ratio (95% confidence interval). RESULTS: On August 31, 2021, it was found that 3080 (7.1%) were unvaccinated, 1141 (2.6%) had 1 vaccine dose, and 39 260 (90.3%) had 2 vaccine doses. There were 4147 SARS-CoV-2 infections and 407 deaths (unadjusted case fatality rate 9.8%). The risk-adjusted infection incidence rate ratio was 1.29 (1.03-1.61), implying that vaccination was not associated with reduction in risk of testing positive for SARS-CoV-2 RNA. Overall, the hazard ratio for death within 28 d of SARS-CoV-2 infection was 0.80 (0.63-1.00), a 20% reduction in risk of death in vaccinated patients (P = 0.05). Two doses of ChAdOx1-S were associated with a significantly reduced risk of death (hazard ratio, 0.69; 0.52-0.92), whereas vaccination with BNT162b2 was not (0.97; 0.71-1.31). CONCLUSIONS: Vaccination of SOT recipients confers some protection against SARS-CoV-2-related mortality, but this protection is inferior to that achieved in the general population. SOT recipients require additional protective measures, including further vaccine doses, antiviral drugs, and nonpharmaceutical interventions.

HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation.

BACKGROUND: HLA incompatible renal transplantation still remains one of best therapeutic options for a subgroup of patients who are highly sensitized and difficult to match but not much is known about its long-term graft and patient survival. METHODS: One hundred thirty-four HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 y were analyzed retrospectively to estimate patient and graft survivals. Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes. RESULTS: The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively, compared with other groups (Bead/CDC, P = 0.007; CDC/Flow, P = 0.001; and microbead assay/flow cytometry crossmatch, P = 0.837), although those with a low CDC titer (<1 in 2) have comparable outcomes to the CDC negative group. Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance. Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection (P < 0.001). Rejection that occurred or continued to occur after the first 2 wk of transplantation caused a significant reduction in graft survivals (P < 0.001), whereas good outcomes were seen in those with a single early rejection episode. CONCLUSIONS: One-, 5-, and 10-y HLA incompatible graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high-CDC titer cases. Antibody-positive female patients show worse long-term survival. Resolution of early rejection is associated with good long-term graft survival.

Designing a co-productive study to overcome known methodological challenges in organ donation research with bereaved family members.

BACKGROUND: Co-production of research into public health services has yet to demonstrate tangible benefits. Few studies have reported the impact of co-production on research outcomes. The previous studies of organ donation have identified challenges in engaging with public organizations responsible, gaining ethical approval for sensitive studies with the recently bereaved and difficulty in recruiting bereaved family members who were approached about organ donation. OBJECTIVE: To address these challenges, we designed the first large co-productive observational study to evaluate implementation of a new system of organ donation in Wales. This paper outlines the co-productive strategies that were designed to overcome known methodological challenges and reports what impact they had on resolving these challenges. DESIGN: Two-year co-produced study with multiple stakeholders with the specific intention of maximizing engagement with the National Health Service arm in Wales responsible for organ donation, and recruitment of bereaved family members whose perspectives are essential but commonly absent from studies. SETTING AND PARTICIPANTS: NHS Blood and Transplant, Welsh Government and multiple patient and public representatives who served as co-productive partners with the research team. RESULTS: Co-productive strategies enabled a smooth passage through four different ethics processes within the 10-week time frame, family member recruitment targets to be surpassed, sharing of routinely collected data on 100% of potential organ donor cases and development of further research capacity and capability in a critically under researched area. DISCUSSION AND CONCLUSION: Although expensive and time consuming, co-production was effective and added value to research processes and study outcomes.

Short-term impact of introducing a soft opt-out organ donation system in Wales: before and after study.

OBJECTIVES: To determine the short-term impact of a soft opt-out organ donation system on consent rates and donor numbers. DESIGN: Before and after observational study using bespoke routinely collected data. SETTING: National Health Service Blood and Transplant. PARTICIPANTS: 205 potential organ donor cases in Wales. INTERVENTIONS: The Act and implementation strategy. PRIMARY AND SECONDARY OUTCOMES: Consent rates at 18 months post implementation compared with 3 previous years, and organ donor numbers 21 months before and after implementation. Changes in organ donor register activity post implementation for 18 months. RESULTS: The consent rate for all modes of consent was 61.0% (125/205), showing a recovery from the dip to 45.8% in 2014/2015. 22.4% (46/205) were deemed consented donors: consent rate 60.8% (28/46). Compared with the 3 years before the switch there was a significant difference in Welsh consent rates (χ2 p value=0.009). Over the same time period, rest of the UK consent rates also significantly increased from 58.6% (5256/8969) to 63.1% (2913/4614) (χ2 p value<0.0001), therefore the Wales increase cannot be attributed to the Welsh legislation change. Deceased donors did not increase: 101 compared with 104. Organ donation registration increased from 34% to 38% with 6% registering to opt-out. CONCLUSION: This is the first rigorous initial evaluation with bespoke data collected on all cases. The longer-term impact on consent rates and donor numbers is unclear. Concerns about a potential backlash and mass opting out were not realised. The move to a soft opt-out system has not resulted in a step change in organ donation behaviour, but can be seen as the first step of a longer journey. Policymakers should not assume that soft opt-out systems by themselves simply need more time to have a meaningful effect. Ongoing interventions to further enhance implementation and the public's understanding of organ donation are needed to reach the 2020 target of 80% consent rates. Further longitudinal monitoring is required.

Vedolizumab in Combination With Corticosteroids for Induction Therapy in Crohn's Disease: A Post Hoc Analysis of GEMINI 2 and 3.

BACKGROUND: Combined therapy with vedolizumab and corticosteroids may improve clinical response or remission in Crohn's disease. The aim of this study is to assess efficacy and safety/tolerability of vedolizumab plus stable doses of corticosteroids at baseline during induction therapy in moderately to severely active Crohn's disease. METHODS: A post hoc exploratory analysis was performed on data from GEMINI 2 (NCT00783692) and GEMINI 3 (NCT01224171), which assessed outcomes following induction therapy over 6- and 10-week periods, respectively. Patients receiving vedolizumab or placebo were stratified by corticosteroid use at baseline. Efficacy endpoints were clinical remission (CR; Crohn's Disease Activity Index [CDAI] score ≤150 points) and enhanced clinical response (ECR; decrease of ≥100 points in CDAI score from baseline), assessed at week 6 (GEMINI 2 and GEMINI 3) and week 10 (GEMINI 3). Safety endpoints included the incidence of adverse events. RESULTS: Vedolizumab plus corticosteroids resulted in higher CR rates than placebo plus corticosteroids at week 6 in GEMINI 2 and at week 6 and week 10 in GEMINI 3. More patients receiving vedolizumab plus corticosteroids achieved CR at week 6 in GEMINI 2 and at week 10 in GEMINI 3 than patients receiving vedolizumab alone. Vedolizumab plus corticosteroids also resulted in significantly higher ECR rates than placebo plus corticosteroids at all timepoints in both studies. More patients receiving vedolizumab plus corticosteroids achieved higher ECR rates at week 6 in GEMINI 2 and at week 10 in GEMINI 3 than patients receiving vedolizumab alone. Adverse event incidence was similar across groups. CONCLUSIONS: Vedolizumab in combination with stable doses of corticosteroids at baseline may improve induction of clinical response or remission in moderately to severely active Crohn's disease. TRIAL REGISTRATION NUMBERS: NCT00783692, NCT01224171.

Sustained Clinical Remission With Vedolizumab in Patients With Moderate-to-Severe Ulcerative Colitis.

BACKGROUND: Sustaining clinical remission is an important treatment goal in moderate-to-severe UC. This post hoc exploratory analysis assessed the long-term efficacy of vedolizumab in the subset of patients with UC in the GEMINI 1 study who were in clinical remission by week 14 after 3 induction doses, administered at weeks 0, 2, and 6. METHODS: Sustained clinical remission (primary endpoint) was evaluated using 2 definitions: (1) a partial Mayo Score (pMS) of ≤2 with no subscore >1 and (2) a rectal bleeding subscore (RBS) of 0 throughout weeks 14, 26, 38, and 52. RESULTS: The proportion of patients in clinical remission at week 14 was significantly higher in patients receiving vedolizumab (n = 620) compared with placebo (n = 149) (pMS: 32.7% vs 20.1% [percentage-point difference (∆) 12.6%; 95% confidence interval [CI], 5.2-20.0]; RBS: 47.3% vs 28.9% [∆18.4%; 95% CI, 10.1-26.7]). Of patients in clinical remission at week 14, a significantly higher proportion of vedolizumab-treated patients achieved sustained clinical remission compared with placebo (pMS: 66.5% vs 26.7%; ∆39.8%; 95% CI, 22.7-56.9; RBS: 56.7% vs 20.9%; ∆35.7%; 95% CI, 22.3-49.1). Findings were consistent in tumor necrosis factor (TNF) antagonist-naive and antagonist-failure patients. CONCLUSION: Compared with placebo, 35%-40% more patients receiving a full induction course of vedolizumab had sustained clinical remission after 52 weeks of therapy. This result was observed irrespective of TNF antagonist treatment history. Clinical remission at week 14 may therefore be a predictor for sustained clinical remission with vedolizumab.

Fecal Calprotectin Responses Following Induction Therapy With Vedolizumab in Moderate to Severe Ulcerative Colitis: A Post Hoc Analysis of GEMINI 1.

BACKGROUND: In patients with ulcerative colitis (UC), fecal calprotectin (FC) concentrations correlate with endoscopic inflammation evidence. This study investigated the effect of vedolizumab induction on FC concentrations and whether FC concentrations could be a reliable surrogate measure of disease status. METHODS: Data from the placebo-controlled, phase 3 trial GEMINI 1 were used to evaluate week-6 relationships between outcomes (including clinical remission, mucosal healing [MH], and endoscopic remission) and both absolute FC concentration values and relative FC concentration changes from baseline (%FC0-6). Sensitivity and specificity were calculated by cross-tabulation; the value of week-6 FC concentration as surrogate biomarker was measured with Youden J statistic computed for various cut points. RESULTS: GEMINI 1 induction phase enrolled 895 patients. Fecal calprotectin concentration decreases were deeper in patients with clinical remission, MH, and/or endoscopic remission than in patients without. The best week-6 indicator of clinical or endoscopic remission in this data set was absolute FC concentration ≤150 µg/g. The surrogate biomarker values (based on areas under the curve) for the best-performing cut points (FC0-6 reduction >90%, FC ≤150 µg/g) were fair (range, 0.70-0.77, total population). More patients met the ≤150 µg/g cut point with vedolizumab than with placebo. Baseline FC concentrations were not correlated with clinical outcomes. CONCLUSIONS: Fecal calprotectin concentration reductions were greater with vedolizumab induction than with placebo. Week-6 FC concentrations had only fair surrogate biomarker value for endoscopic status. Our data suggest that, while FC may reflect inflammatory burden, FC concentration after vedolizumab induction may not be a robust biomarker of mucosal inflammation.

Systematic review with meta-analysis: real-world effectiveness and safety of vedolizumab in patients with inflammatory bowel disease.

BACKGROUND: Selective patient recruitment can produce discrepancies between clinical trial results and real-world effectiveness. METHODS: A systematic literature review and meta-analysis were conducted to assess vedolizumab real-world effectiveness and safety in patients with ulcerative colitis (UC) or Crohn's disease (CD). MEDLINE, MEDLINE In-Process, EMBASE, and Cochrane databases were searched for real-world studies of vedolizumab in adult patients with UC/CD reporting clinical response, remission, corticosteroid-free remission, UC/CD-related surgery or hospitalization, mucosal healing, or safety published from May 1, 2014-June 22, 2017. Response and remission rates were combined in random-effects meta-analyses. RESULTS: At treatment week 14, 32% of UC patients [95% confidence interval (CI) 27-39%] and 30% of CD patients (95% CI 25-34%) were in remission; and at month 12, 46% for UC (95% CI 37-56%) and 30% for CD (95% CI 20-42%). For UC, the rates of corticosteroid-free remission were 26% at week 14 (95% CI 20-34%) and 42% at month 12 (95% CI 31-53%); for CD they were 25% at week 14 (95%, CI 20-31%) and 31% at month 12 (95%, CI 20-45%). At month 12, 33-77% of UC and 6-63% of CD patients had mucosal healing. Nine percent of patients reported serious adverse events. CONCLUSIONS: Vedolizumab demonstrated real-world effectiveness in patients with moderate-to-severely active UC or CD, with approximately one-half and one-third of patients, respectively, in remission at treatment month 12. These findings are consistent with clinical trial data and support the long-term benefit-risk profile of vedolizumab.

Increasing intracellular magnesium levels with the 31-amino acid MgtS protein.

Synthesis of the 31-amino acid, inner membrane protein MgtS (formerly denoted YneM) is induced by very low Mg2+ in a PhoPQ-dependent manner in Escherichia coli Here we report that MgtS acts to increase intracellular Mg2+ levels and maintain cell integrity upon Mg2+ depletion. Upon development of a functional tagged derivative of MgtS, we found that MgtS interacts with MgtA to increase the levels of this P-type ATPase Mg2+ transporter under Mg2+-limiting conditions. Correspondingly, the effects of MgtS upon Mg2+ limitation are lost in a ∆mgtA mutant, and MgtA overexpression can suppress the ∆mgtS phenotype. MgtS stabilization of MgtA provides an additional layer of regulation of this tightly controlled Mg2+ transporter and adds to the list of small proteins that regulate inner membrane transporters.

Group health coaching: strengths, challenges, and next steps.

There is great need for cost effective approaches to increase patient engagement and improve health and well-being. Health and wellness coaching has recently demonstrated great promise, but the majority of studies to date have focused on individual coaching (ie, one coach with one client). Newer initiatives are bringing a group coaching model from corporate leadership development and educational settings into the healthcare arena. A group approach potentially increases cost-effective access to a larger number of clients and brings the possible additional benefit of group support. This article highlights some of the group coaching approaches currently being conducted across the United States. The group coaching interventions included in this overview are offered by a variety of academic and private sector institutions, use both telephonic and in-person coaching, and are facilitated by professionally trained health and wellness coaches as well as trained peer coaches. Strengths and challenges experienced in these efforts are summarized, as are recommendations to address those challenges. A working definition of "Group Health and Wellness Coaching" is proposed, and important next steps for research and for the training of group coaches are presented.

Existe una gran necesidad de planteamientos económicamente rentables que incrementen el compromiso de los pacientes, y mejoren su salud y su bienestar. La formación de salud y bienestar ha demostrado recientemente ser muy prometedora, pero la mayoría de los estudios realizados hasta la fecha se han centrado en la formación individual (es decir, de un entrenador con un cliente). Existen iniciativas más recientes, procedentes del área de desarrollo del liderazgo empresarial y de entornos académicos, para trasladar modelos de formación en grupo al ámbito de la atención sanitaria. El abordaje en grupo podría proporcionar un acceso rentable a un mayor número de clientes, además de contar con la posible ventaja adicional del apoyo del grupo. En este artículo destacamos algunos de los planteamientos de formación en grupo que se están llevando a cabo en Estados Unidos. Las intervenciones de formación en grupo que incluimos en este resumen provienen de diversas instituciones académicas y privadas, utilizan la formación telefónica y presencial, y cuentan con el apoyo de monitores de salud y bienestar con formación profesional, así como de colegas entrenadores cualificados. Resumiremos los puntos fuertes y los retos a los que se enfrentan estas iniciativas, y se ofrecerán recomendaciones para abordar dichos desafíos. Se propondrá una definición operativa de "formación de grupos de salud y bienestar" y se mostrarán los próximos pasos importantes que deben seguir la investigación y la formación de monitores de grupos.

Speaking freely: my experiences in individual psychotherapies, group therapies, and growth groups.

This article traces the author's experiences in sensitivity, Tavistock, and psychotherapy groups, an experience in individual psychotherapy, and two experiences in psychoanalysis. Group work was very helpful in learning how the author came across to others in general and in improving the author's ways of being helpful to others. Although the experience was valuable, difficulties emerged in the first psychoanalysis, largely because of the psychoanalyst's belief that psychoanalysis was the best form of treatment for everyone. Desiring a variety of approaches, the author undertook a second analysis with more of an integrative and intuitive therapist, which worked better for her. Lasting lessons are shared from this series of personal therapy experiences.