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The article is a response to a previous article on the perspective of dietitians in fostering momentum for planetary health change. The authors agree with the importance of integrating planetary health (PH) education into the curriculum of health professional programs. They highlight the recent update to the Australian Medical Council's accreditation standards, which now includes a significant focus on PH. The authors discuss their own approach to incorporating sustainability themes into the curriculum at the University of Sydney and mention other international medical schools' efforts in this area. They emphasize the need for collaboration and further development in integrating PH content into health professional programs. [Extracted from the article]

The environmental impact of large language models (LLMs) in medicine spans carbon emission, water consumption and rare mineral usage. Prior-generation LLMs, such as GPT-3, already have concerning environmental impacts. Next-generation LLMs, such as GPT-4, are more energy intensive and used frequently, posing potentially significant environmental harms. We propose a five-step pathway for clinical researchers to minimise the environmental impact of the natural language algorithms they create., (© 2024 Royal Australasian College of Physicians.)

Background and Aims: Endothelial dysfunction (ED) is considered to be a major driver of the increased incidence of cardiovascular disease in primary aldosteronism (PA). The functionality of the epoxyeicosatrienoic acid (EET) pathway, involving the release of beneficial endothelium-derived lipid mediators, in PA is unknown. Evidence suggests this pathway to be disturbed in various models of experimental hypertension. We therefore assessed EET production in primary human coronary artery endothelial cells exposed to aldosterone excess and measured circulating EET in patients with PA., Methods: We used qPCR to investigate changes in the expression levels of essential genes for the synthesis and degradation of EET, calcium imaging to address the functional impact on overall endothelial function, as well as mass spectrometry to determine endothelial synthetic capacity to release EET upon stimulation. RNA-seq was performed to gain further mechanistic insights. Eicosanoid concentrations in patient's plasma were also determined by mass spectrometry., Results: Aldosterone, while eliciting proinflammatory VCAM1 expression and disturbed calcium response to acetylcholine, did not negatively affect stimulated release of endothelial EET. Likewise, no differences were observed in eicosanoid concentrations in plasma from patients with PA when compared to essential hypertensive controls. However, an inhibitor of soluble epoxide hydrolase abrogated aldosterone-mediated VCAM1 induction and led to a normalized endothelial calcium response probably by restoring expression of CHRNE., Conclusion: EET release appears intact despite aldosterone excess. Epoxide hydrolase inhibition may revert aldosterone-induced functional changes in endothelial cells. These findings indicate a potential new therapeutic principle to address ED, which should be explored in future preclinical and clinical trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Hypothesis: Early steroid withdrawal (ESW) is often preferred over conventional steroid maintenance (CSM) therapy for kidney transplant recipients with low immunological risks because it may minimize immunosuppression-related adverse events while achieving similar transplant outcomes. However, the risk-benefit balance of ESW could be less favorable in retransplant recipients given their unique immunological risk profile. We hypothesized that the association of ESW with transplant outcomes would differ between first-transplant and retransplant recipients., Methods: To assess whether the impact of ESW differs between first and retransplant recipients, we studied 210 086 adult deceased-donor kidney transplant recipients using the Scientific Registry of Transplant Recipients. Recipients who discontinued maintenance steroids before discharge from transplant admission were classified with ESW; all others were classified with CSM. We quantified the association of ESW (vs. CSM) with acute rejection, death-censored graft failure, and death, addressing retransplant as an effect modifier, using logistic/Cox regression with inverse probability weights to control for confounders., Results: In our cohort, 26 248 (12%) were retransplant recipients. ESW was used in 30% of first-transplant and 20% of retransplant recipients. Among first-transplant recipients, ESW was associated with no significant difference in acute rejection (aOR = 1.04 [95% CI = 1.00-1.09]), slightly higher hazard of graft failure (HR = 1.09 [95% CI = 1.05-1.12]), and slightly lower mortality (HR = 0.93 [95% CI = 0.91-0.95]) compared to CSM. Nonetheless, among retransplant recipients, ESW was associated with notably higher risk of acute rejection (OR = 1.42 [95% CI = 1.29-1.57]; interaction p < 0.001) and graft failure (HR = 1.24 [95% CI = 1.14-1.34]; interaction p = 0.003), and similar mortality (HR = 1.01 [95% CI = 0.94-1.08]; interaction p = 0.04)., Conclusions: In retransplant recipients, the negative impacts of ESW on transplant outcomes appear to be non-negligible. A more conservatively tailored approach to ESW might be necessary for retransplant recipients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

The non-selective transient receptor potential canonical 6 (TRPC6) cation channels have several physiological and pathophysiological effects. They are activated by the lipid second messenger diacylglycerol (DAG) and by non-lipidic compounds such as GSK 1702934A (GSK). Advances in photopharmacology led to the development of photoswitchable activators such as PhoDAG, OptoDArG, and OptoBI-1 that can be switched ON and OFF with the spatiotemporal precision of light. We aimed to elucidate whether these photopharmaceuticals allow for a reliable determination of the ion channel current kinetics. We performed electrophysiological whole-cell measurements in the overexpression system and analyzed TRPC6 currents induced by photoswitching. We observed distinct activation, deactivation and inactivation current kinetics suggesting that each photoswitchable activator elicits a distinct active channel state. Notably, the current kinetics strongly depended on the intensity of the light source. Altogether, photopharmaceuticals are advantageous for an extended biophysical characterization of whole-cell currents and provide insight into their gating mechanism., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Introduction: Obstetric anal sphincter injury (OASI) is associated with serious morbidity and reduced quality of life. The role of anorectal manometry (ARM) to guide treatment is unclear. We aimed to define the role of ARM and symptom assessment after OASI in predicting anal incontinence at long-term follow-up., Methods: Prospective evaluation of 205 consecutive post-OASI women who underwent baseline ARM and symptom assessment in a tertiary setting was undertaken. Ninety-nine women were available for long-term follow-up (median 6.6 years). Associations between post-OASI ARM testing and short-term and long-term anal incontinence were examined in addition to clinical and obstetric factors., Results: Fourth degree tears and lower anal resting and squeeze pressures were associated with short-term anal incontinence. Women with anal incontinence at baseline and women with lower anal resting pressure were more likely to suffer from long-term fecal incontinence (FI). A best-fit cutoff value of 59 mm Hg for baseline anal resting pressure predicted long-term FI, and none of the short-term asymptomatic women with an anal resting pressure of >59 mm Hg reported FI at long-term follow-up., Discussion: Symptoms of anal incontinence and ARM in patients after OASI are both useful to predict subsequent long-term FI with a best-fit cutoff of 59 mm Hg for anal resting pressure. This provides rationale for routine ARM and accurate symptom assessment in all patients after OASI, to identify high-risk groups to follow and treat, and it may assist decision making regarding mode of subsequent obstetric deliveries., (Copyright © 2024 by The American College of Gastroenterology.)

The ultimate preferred treatment for hepatocellular carcinoma (HCC) complicated with cirrhosis and portal hypertension is an orthotopic liver transplant (OLT). Loco regional therapy (LRT) has emerged to prevent tumor growth and progression of disease beyond the Milan criteria to achieve transplant. There is a paucity of data regarding safety, posttransplant survival benefits, and tumor recurrence rate achieved by these LRT modalities. We aim to assess and compare the five-year survival rate and tumor recurrence rate with or without LRT in patients after OLT with diagnosed HCC utilizing the nation's largest dataset. This is a retrospective observational study approved by Saint Louis University institutional review board. We utilized the largest dataset from the years 2003-2013 where pertaining data were gathered from Organ Procurement Transplant Network (OPTN) standard analysis and research files (STAR) through novel linkages with Medicare bills. Descriptive and comparative statistics were performed. 2412 (51.6%) patients received any form of locoregional therapy (single or combination) out of 4669 total study sample size. The overall five-year survival in the study sample was 76.1%. There was statistically no significant improvement seen in five-year posttransplant survival in the group that received one mode of LRT (adjusted hazard ratio (aHR) 0.97, P<0.64) or a combination of LRT (aHR 0.94, P<0.58) in comparison to those that received none after adjusting donor and recipient clinical characteristics. However, five-year survival trended higher among those treated with combination therapy over those treated with single LRT or none. Overall HCC recurrence was 4.8%, while no significant difference was noted when comparing above-mentioned groups. Five-year posttransplant survival and HCC recurrence rate were also found to have no difference when compared between above-mentioned groups after adjusting explant pathology. This is the largest retrospective study comparing liver transplant patients with HCC who received LRT to none. Although it did not show any statistically significant benefit of single or combination of LRT on survival or tumor recurrence after liver transplant for HCC patients, the outcomes encourage the safe and feasible use of LRT as a bridging therapy. Our study also suggests an observed pattern of improved posttransplant survival and tumor recurrence rate with combination loco-regional therapy. Larger multicenter prospective studies will be required to achieve the effect size to determine the best therapies for maximizing patient survival cost-effectively., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Desai et al.)

Background: With the introduction of direct-acting antiviral therapies (DAAs), the non-use rate of hepatitis C virus (HCV)-positive donor organs (D+) has decreased significantly. We present the donor, recipient, and transplant allograft characteristics, along with recipient outcomes, in one of the largest cohorts of HCV-D+ transplants into HCV-naïve recipients (R-)., Methods: Charts of HCV D+/R- kidney (KT), liver (LT), and simultaneous liver-kidney (SLKT) transplant recipients between January 2019 and July 2022 were reviewed. Primary outcomes of interest included waitlist times and 1-year graft failure. Secondary outcomes included hospital and intensive care unit length of stay, post-transplant complications, effectiveness of DAA therapy, and characteristics of patients who relapsed from initial DAA therapy., Results: Fifty-five HCV D+/R- transplants at our center [42 KT (26 nucleic acid testing positive [NAT+], 16 NAT-), 12 LT (eight NAT+, four NAT-), and one SLKT (NAT+)] had a median waitlist time of 69 days for KT, 87 days for LT, and 15 days for SLKT. There were no graft failures at 1 year. All viremic recipients were treated with a 12-week course of DAAs, of which 100% achieved end of treatment response (EOTR)-85.7% (n = 30) achieved sustained virologic response (SVR) and 14.3% relapsed (n = 5; four KT, one LT). All relapsed recipients were retreated and achieved SVR. The most common post-transplantation complications include BK virus infection (n = 9) for KT and non-allograft infections (n = 4) for LT., Conclusions: Our study has demonstrated no graft failures or recipient deaths at 1 year, and despite a 14.3% relapse rate, we achieved 100% SVR. Complications rates of D+/R- appeared comparable to national D-/R- complication rates. Further studies comparing D+/R- to D-/R- outcomes are needed., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Although over 90% of the population of the United States supports organ donation, only 60% of the population is registered as donors. Currently, there is a need for a nonmonetary incentive that will improve willingness to donate. We assessed the young adult population's perspective on their willingness to donate organs when merit points are granted to their family members to prioritize their potential transplant if needed., Methods: We administered a Qualtrics survey from March 2022 to September 2022 to the undergraduate students volunteering to participate at Saint Louis University, which comprised 10 questions that addressed the attitudes of participants regarding the effects of various factors, including the type of donation and the presence of merit points (vouchers granted to self or a family member to facilitate a potential transplant if needed), on participant's willingness to donate an organ while alive or after death. The responses were analyzed by using SAS software (SAS Institute)., Results: A total of 572 participants completed the survey. Overall, only 6.5% of surveyed students were unwilling to donate after death. The willingness to donate while alive to a family member was significantly higher than donating to a stranger (95.8% vs 71.2%, P < .0001). When merit points were added, the unwillingness to donate significantly decreased from 6.5% to 3.8%. However, this change was observed only when the merit points were given to a family member and not to self. When merit points were granted, unwillingness to provide a living donation to a stranger decreased from 28.8% to 16.4% (P < .0001)., Conclusions: Merit points to first-degree family members improve students' expressed willingness to donate organs after death; however, self-merit points did not decrease the rate of "unwillingness to donate after death." When living donation is assessed, offering merit points appears to decrease the "unwillingness to donate to strangers." The adoption of a merit point system in the United States may increase the rates of organ donation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The objective was to assess, improve and re-assess Emotional Intelligence (EI) in a group of junior and senior surgeons in a real-world setting., Design: This was a mixed methods study. An EI education program was delivered through a series of webinars. The program drew from the central concepts of emotional intelligence: Motivation, empathy, social skills, self-knowledge, and self-control. There was also a component of professional development. EI assessment was performed pre- and post-intervention using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) and a series of targeted questions. Qualitative assessment was performed by means of structured interviews examining uptake in techniques, understanding of EI, and its effect on personal and professional life., Setting: The Australia and New Zealand Training Board in Colorectal Surgery administers a 2-year bi-national training program in teaching hospitals in Australia and New Zealand and runs a series of educational webinars throughout the training program. The "EI series" was part of this educational program., Participants: Webinars were attended by 35 junior surgeons and 8 senior surgeons RESULTS: Self-perceived knowledge and use of EI increased from a mean of 3.6 to 6.5 (p<0.0001). There was a significant difference between experiential (94) and strategic (101) scores (p=0.005). There was a nonsignificant improvement (98.04-100.6, p=0.16), in the pre-post MSCEIT among the junior surgeons and no change for senior surgeons. Seventy-eight percent (25/32) of surgeons interviewed reported using any new EI strategies. Seventy-five percent actively stopped and considered what other people in a clinical scenario may be thinking; 78% commenced metacognition; 81% practiced the process of self-regulation; 66% had begun to recognise and use emotions as data; and, 47% had actively practiced the process of self-distancing CONCLUSION: This study demonstrated the feasibility and utility of delivering EI training in an online format to a group of time-poor surgeons in a real-world setting., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: Patients with obstructed defecatory symptoms (ODS) are commonly referred to either gastroenterologists (GE) or colorectal surgeons (CS). Further management of these patients may be impacted by this choice of referral., Methods: An online survey of specialist practice was disseminated to GE and CS in Australia and New Zealand. A case vignette of a patient presenting with ODS was described, with multiple subsequent scenarios designed to delineate the responder's preferred approach to management of this patient., Key Results: A total of 107 responders participated in the study, 62 CS and 45 GE. For a female patient with ODS not responding to pharmacological treatment, GE were more likely than CS to refer patients for anorectal manometry, while CS were more likely to refer for dynamic imaging. A quarter of CS and GE referred patients directly to pelvic floor physiotherapy, without any pre-treatment testing. Knowing the result of dynamic imaging, especially if a rectocele was demonstrated, substantially influenced management for both of the specialties: GE became more likely to refer the patients for CS consultation and less likely to refer directly for biofeedback or physiotherapy and CS were more likely to opt for an operative pathway over conservative management than they were prior to knowledge of the imaging findings. The majority (>75%) of GE and CS did not find it necessary to obtain a gynecological consultation, even in the presence of a rectocele., Conclusions & Inferences: Practice variation across medical specialties affects diagnostic and management recommendations for patients with ODS, impacting treatment pathways. Our findings provide an incentive toward establishing interdisciplinary, uniform, management guidelines., (© 2023 John Wiley & Sons Ltd.)

Introduction: The use of a footstool has been advocated to optimize posture when sitting on the toilet and thus facilitate bowel evacuation. We aimed to assess the alterations in defecatory posture, and the changes in simulated defecation with use of a footstool in patients with constipation., Methods: Forty-one patients (female 93%, mean 52 year, SD 14 year) with constipation referred to a tertiary neurogastroenterology unit were enrolled. A bowel questionnaire, Hospital Anxiety and Depression Scale, and Rome questionnaire were administered prior to anorectal manometry. Each patient underwent three rectal balloon expulsion tests in randomized order with no footstool, a 7-inch, and a 9-inch footstool. Additional assessments included angle between spine and femur, and visual analogue scales assessing ease of evacuation, urge to defecate, and discomfort with expulsion., Key Results: Defecatory posture was significantly altered by footstool use, with progressive narrowing of the angle between the spine and femur as footstool height increased (p < 0.001 for all comparisons). Compared with no footstool, the use of a footstool was not associated with a change in balloon expulsion time and there was no difference between the two footstool heights. Subjectively, no significant change was identified in any of the three perceptions of balloon expulsion between no footstool and footstool use., Conclusions and Inferences: Although the use of a footstool led to changes in defecatory posture, it did not improve subjective or objective measures of simulated defecation in patients with undifferentiated constipation. Therefore, the recommendation for its use during evacuation cannot be applied to all patients with constipation., (© 2023 John Wiley & Sons Ltd.)

Background: Incontinence to gas can be a troublesome symptom impacting quality of life for patients even in the absence of fecal incontinence. Whether isolated flatus incontinence represents part of the spectrum of true fecal incontinence or a separate condition with a different pathophysiology remains unclear., Objective: This study aimed to evaluate the clinical features and anorectal physiology in women presenting with severe isolated flatus incontinence compared to women with fecal incontinence and healthy asymptomatic women., Design: This was a retrospective case-control study of prospectively collected data., Settings: Data from participants were obtained from a single tertiary Neurogastroenterology Unit in Sydney, Australia., Patients: Data from 34 patients with severe isolated flatus incontinence, 127 women with fecal incontinence' and 44 healthy women were analyzed., Main Outcome Measures: The primary outcomes were clinical (including demographic, obstetric, and symptom variables) and physiological differences across the 3 groups., Results: Patients with flatus incontinence were significantly younger (mean 39 versus 63 years; p = 0.0001), had a shorter history of experiencing their symptoms ( p = 0.0001), and had harder stool form than patients with fecal incontinence ( p = 0.02). Those with flatus incontinence had an adverse obstetric history and impaired anorectal physiology (motor and sensory, specifically rectal hypersensitivity) but to a lesser extent than patients with fecal incontinence., Limitations: This study was limited by its retrospective design and modest sample size., Conclusions: Anorectal physiology was impaired in patients with flatus incontinence compared to healthy controls, but to a lesser extent than in those with fecal incontinence, raising the possibility that flatus incontinence could be a precursor to fecal incontinence. As clinical and physiological findings are different from healthy controls (including the presence of visceral hypersensitivity), isolated flatus incontinence should be considered a distinct clinical entity (like other functional GI disorders), or possibly part of an incontinence spectrum rather than purely a normal phenomenon. See Video Abstract at http://links.lww.com/DCR/B946 ., Incontinencia De Flatos E Incontinencia Fecal Un Estudio De Casos Y Controles: ANTECEDENTES:La incontinencia de gases puede ser un síntoma molesto que afecta la calidad de vida de los pacientes incluso en ausencia de incontinencia fecal. Aún no está claro si la incontinencia de flatos aislada representa parte del espectro de la incontinencia fecal verdadera o una condición separada con una fisiopatología poco clara.OBJETIVO:Evaluar las características clínicas y la fisiología anorrectal en mujeres que presentan incontinencia grave aislada de flatos, en comparación con la incontinencia fecal y mujeres sanas asintomáticas.DISEÑO:Este fue un estudio retrospectivo de casos y controles de datos recolectados prospectivamente.AJUSTE:Los datos de los participantes se obtuvieron de una sola Unidad de Neurogastroenterología terciaria en Sydney, Australia.PACIENTES:Se analizaron los datos de 34 pacientes con incontinencia grave aislada de flatos, junto con 127 mujeres con incontinencia fecal y 44 mujeres sanas.PRINCIPALES MEDIDAS DE RESULTADO:Los resultados primarios fueron clínicos (incluidas las variables demográficas, obstétricas y de síntomas), así como las diferencias fisiológicas entre los tres grupos.RESULTADOS:Los pacientes con incontinencia de flatos eran significativamente más jóvenes (media de 39 años frente a 63 años, p = 0,0001), tenían un historial más corto de experimentar sus síntomas (p = 0,0001) y tenían heces más duras que los pacientes con incontinencia fecal (p = 0,02). Aquellos con incontinencia de flatos tenían antecedentes obstétricos adversos y fisiología anorrectal alterada (motora y sensorial, específicamente hipersensibilidad rectal); aunque en menor medida que las pacientes con incontinencia fecal.LIMITACIONES:Este estudio estuvo limitado por su diseño retrospectivo y tamaño de muestra modesto.CONCLUSIONES:La fisiología anorrectal se vio afectada en las pacientes con incontinencia de flatos en comparación con las controles sanos, pero en menor medida que en aquellas con incontinencia fecal, lo que plantea la posibilidad de que la incontinencia de flatos pueda ser un precursor de la incontinencia fecal. Dado que los hallazgos clínicos y fisiológicos son diferentes a los de los controles sanos (incluida la presencia de hipersensibilidad visceral), la incontinencia de flatos aislada debe considerarse como una entidad clínica distinta (al igual que otros trastornos gastrointestinales funcionales), o posiblemente como parte de un espectro de incontinencia en lugar de un trastorno puramente a un fenómeno normal. Consulte Video Resumen en http://links.lww.com/DCR/B946 . (Traducción-Dr Yolanda Colorado )., (Copyright © The ASCRS 2022.)

To benefit allergy patients and the medical practitioners, pollen information should be available in both a reliable and timely manner; the latter is only recently possible due to automatic monitoring. To evaluate the performance of all currently available automatic instruments, an international intercomparison campaign was jointly organised by the EUMETNET AutoPollen Programme and the ADOPT COST Action in Munich, Germany (March-July 2021). The automatic systems (hardware plus identification algorithms) were compared with manual Hirst-type traps. Measurements were aggregated into 3-hourly or daily values to allow comparison across all devices. We report results for total pollen as well as for Betula, Fraxinus, Poaceae, and Quercus, for all instruments that provided these data. The results for daily averages compared better with Hirst observations than the 3-hourly values. For total pollen, there was a considerable spread among systems, with some reaching R 2 > 0.6 (3 h) and R 2 > 0.75 (daily) compared with Hirst-type traps, whilst other systems were not suitable to sample total pollen efficiently (R 2 < 0.3). For individual pollen types, results similar to the Hirst were frequently shown by a small group of systems. For Betula, almost all systems performed well (R 2 > 0.75 for 9 systems for 3-hourly data). Results for Fraxinus and Quercus were not as good for most systems, while for Poaceae (with some exceptions), the performance was weakest. For all pollen types and for most measurement systems, false positive classifications were observed outside of the main pollen season. Different algorithms applied to the same device also showed different results, highlighting the importance of this aspect of the measurement system. Overall, given the 30 % error on daily concentrations that is currently accepted for Hirst-type traps, several automatic systems are currently capable of being used operationally to provide real-time observations at high temporal resolutions. They provide distinct advantages compared to the manual Hirst-type measurements., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeroen Buters, Jose M. Maya Manzano, Carsten B. Schmidt-Weber and Marina Triviño report financial support, administrative support, equipment, drugs, or supplies, and travel were provided by Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit (LGL) and EUMETNET. Carsten Skjoth reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by COST Action CA18226 ADOPT – New approaches in detection of pathogens and aeroallergens. Bernard Clot and Fiona Tummon report financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by European Meteorological Society and the EUMETNET AutoPollen Programme. Branko Sikoparija and Predrag Matavulj report financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by BREATHE project from the Science Fund of the Republic of Serbia PROMIS program, under grant agreement no. 6039613 and by the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant agreement number 451–03-68/2022–14/200358). Evgeny Kadantsev and Julia Palamarchuk report financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by Academy of Finland PS4A (grant 318,194). Mikhail Sofiev reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by Academy of Finland project ALL-Impress (grant 329,215). Mikhail Sofiev reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by European Social Fund (project no. 09.3.3-LMT-K-712-01-0066) and Research Council of Lithuania (LMTLT). Nathan Allan, Landon Bunderson, Richard W. Lucas (Pollen science TM), Jorg Haus, Stefan Schaefer, Martin Schnitzler and Tom Stemmler (Helmut Hund Wetzlar), Reto Abt, Elias Graf, Erny Niederberger and Yanick Zeder (Swisens AG) report a relationship with Pollen science TM, Helmut Hund Wetzlar and Swisens AG respectively, that includes: board membership, employment, and travel reimbursement. The investigations were carried out in compliance with good scientific practices and the support provided by these companies in terms of instrumentation had no effect on the results presented., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Gabapentinoids, commonly used for treating neuropathic pain, may be misused and coprescribed with opioid and benzodiazepine, increasing the risk of mortality and dependency among kidney transplant recipients., Methods: We identified adult kidney transplant recipients who enrolled in Medicare Part D in 2006-2017 using the United States Renal Data System/Medicare claims database. We characterized recipients' post-transplant concomitant prescription of gabapentinoids, opioids, and benzodiazepine stratified by transplant year and recipient factors (age, sex, race, and diabetes). We investigated whether concomitant prescriptions were associated with postkidney transplant mortality using Cox regression. Models incorporated inverse probability weighting to adjust for confounders., Results: Among 63,359 eligible recipients, 13% of recipients filled at least one gabapentinoid prescription within 1 year after kidney transplant. The prevalence of gabapentinoid prescriptions increased by 70% over the study period (16% in 2017 versus 10% in 2006). Compared with nonusers, gabapentinoids users were more likely to have diabetes (55% versus 37%) and obesity (46% versus 34%). Of the 8509 recipients with gabapentinoid prescriptions, 45% were coprescribed opioids, 7% were coprescribed benzodiazepines, and 3% were coprescribed both opioids and benzodiazepines. Compared with no study prescriptions, gabapentinoid monotherapy (adjusted hazard ratio [aHR]=1.25; 95% confidence interval [CI], 1.16 to 1.32) and combination therapy (gabapentinoids and opioids [aHR=1.49; 95% CI, 1.39 to 1.60], gabapentinoids and benzodiazepines [aHR=1.46; 95% CI, 1.03 to 2.08], and coprescribing all three [aHR=1.88; 95% CI, 1.18 to 2.98]) were all associated with a higher risk of postkidney transplant mortality., Conclusions: Gabapentinoid coprescription with both benzodiazepines and opioids among kidney transplant recipients increased over time. Kidney transplant recipients prescribed gabapentinoids had a higher risk of post-transplant mortality, and the risk was higher with opioids or benzodiazepine coprescription., (Copyright © 2023 by the American Society of Nephrology.)

Background: The coronavirus disease 2019 (COVID-19) pandemic created unprecedented challenges for solid organ transplant centers worldwide. We sought to assess an international perspective on COVID-19 vaccine mandates and rationales for or against mandate policies., Methods: We administered an electronic survey to staff at transplant centers outside the United States (October 14, 2021-January 28, 2022) assessing the reasons cited by transplant centers for or against implementing a COVID-19 vaccine mandate. Each responding center was represented once in the analysis., Results: Respondents ( N =90) represented 27 countries on five continents. Half (51%) of responding transplant center representatives reported implementing a COVID-19 vaccine mandate, 38% did not, and 12% were unsure. Staff at centers implementing a vaccine mandate cited efficacy of pretransplant vaccination versus post-transplant vaccination, importance for public health, and minimizing exposure of other patients as rationale for the mandate. Of centers with a mandate, the majority (81%) of the centers mandate vaccination regardless of prior SARS-CoV-2 infection status and regardless of prevaccination spike-protein antibody titer or other markers of prior infection. Only 27% of centers with a vaccine mandate for transplant candidates also extended a vaccine requirement to living donor candidates. Centers not implementing a vaccine mandate cited concerns for undue pressure on transplant candidates, insufficient evidence to support vaccine mandates, equity, and legal considerations., Conclusions: The approach to pretransplant COVID-19 vaccination mandate policies at international transplant centers is heterogeneous. International transplant centers with a vaccine mandate were more willing to extend vaccine requirements to candidates' support persons, cohabitants, and living donors. Broader stakeholder engagement to overcome vaccine hesitancy across the world is needed to increase the acceptance of pretransplant COVID-19 vaccination to protect the health of transplant patients., Competing Interests: T. Alhamad reports consultancy for CareDx, Mallinckrodt, and Veloxis; research funding from Angion, CareDx, Europhines, and Natera; honoraria from CareDx, Sanofi, and Veloxis; an advisory or leadership role for CareDx, Europhines, and QSANT; and participation in a speakers’ bureau for CareDx, Sanofi, and Veloxis. S. Anwar reports research funding from Echonous Kosmos (funding research on POCUS-enabled assessment of hemodynamic circuit using handheld ultrasounds and loaning research group 10 devices). D. Axelrod reports consultancy for CareDx and Talaris; ownership interest in CareDx; honoraria from CareDx, Specialist Direct, and Talaris; and serving on the NKF policy committee. B.E. Hippen reports employment as the Senior Vice President for Transplant Medicine and Emerging Capabilities, Global Medical Office, Fresenius Medical Care; ownership interest in Interwell Health; and being a scientific advisory board member of eGenesis Bio (uncompensated). K.L. Lentine reports consultancy for CareDx; participation in a speakers’ bureau for Sanofi; volunteer service on the ASN COVID-19 Response Team; and volunteer service on the NKF Transplant Advisory Committee. M.A. Schnitzler reports consultancy for CareDx and honoraria from OPTUM. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

An electronic survey canvassing current policies of transplant centers regarding a COVID-19 vaccine mandate for transplant candidates and living donors was distributed to clinicians at US solid organ transplant centers performing transplants from October 14, 2021-November 15, 2021. Responses were received from staff at 141 unique transplant centers. These respondents represented 56.4% of US transplant centers, and responding centers performed 78.5% of kidney transplants and 82.4% of liver transplants in the year prior to survey administration. Only 35.7% of centers reported implementing a vaccine mandate, while 60.7% reported that vaccination was not required. A minority (42%) of responding centers with a vaccine mandate for transplant candidates also mandated vaccination for living organ donors. Centers with a vaccine mandate most frequently cited clinical evidence supporting the efficacy of pre-transplant vaccination (82%) and stewardship obligations to ensure organs were transplanted into the lowest risk patients (64%). Centers without a vaccine mandate cited a variety of reasons including administrative, equity, and legal considerations for their decision. Transplant centers in the United States exhibit significant heterogeneity in COVID-19 vaccination mandate policies for transplant candidates. While all centers encourage vaccination, most centers have not mandated COVID-19 vaccination for candidates and living donors, citing administrative opposition, legal prohibitions, and concern about equity in access to transplants., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Relationships between renal function and medical costs for deceased donor kidney transplant recipients are not fully quantified post-transplant. We describe these relationships with renal function measured by estimated glomerular filtration rate (eGFR) and graft failure. The United States Renal Data System identified adults receiving single-organ deceased donor kidneys 2012-2015. Inpatient, outpatient, other facility costs and eGFRs at discharge, 6 and 12 months were included. A time-history of costs was constructed for graft failures and monthly costs in the first year post-transplant were compared to those without failure. The cohort of 24,021 deceased donor recipients had a 2.4% graft failure rate in the first year. Total medical costs exhibit strong trends with eGFR. Recipients with 6-month eGFRs of 30-59 ml/min/1.73m 2 have total costs 48% lower than those <30 ml/min/1.73m 2 . For recipients with graft failure monthly costs begin to rise 3-4 months prior to failure, with incremental costs of over $38,000 during the month of failure. Mean annual total incremental costs of graft failure are over $150,000. Total costs post-transplant are strongly correlated with eGFR. Graft failure in the first year is an expensive, months-long process. Further reductions in early graft failures could yield significant human and economic benefits., Competing Interests: Authors ZW and WW are employed by company Genesis Research LLC; RJN is employed by Beta6 Consulting Group, LLC. MC received research funding and/or consultancy fees unrelated to this study from Angion Biomedica. RJN was an employee of Angion Biomedica at the time of writing. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that Angion Biomedica provided funding for the analysis supporting this research. Genesis Research performed the data analysis under contract to Angion Biomedica. Funding for open access fees has not been provided., (Copyright © 2022 Cooper, Schnitzler, Nilubol, Wang, Wu and Nordyke.)

The patch-clamp method, which was awarded the Nobel Prize in 1991, is a well-established and indispensable method to study ion channels in living cells and to biophysically characterize non-voltage-gated ion channels, which comprise about 70% of all ion channels in the human genome. To investigate the biophysical properties of non-voltage-gated ion channels, whole-cell measurements with application of continuous voltage ramps are routinely conducted to obtain current-voltage (IV) relationships. However, adequate tools for detailed and quantitative analysis of IV curves are still missing. We use the example of the transient receptor potential classical (TRPC) channel family to elucidate whether the normalized slope conductance (NSC) is an appropriate tool for reliable discrimination of the IV curves of diverse TRPC channels that differ in their individual curve progression. We provide a robust calculation method for the NSC, and, by applying this method, we find that TRPC channel activators and modulators can evoke different NSC progressions independent from their expression levels, which points to distinguishable active channel states. TRPC6 mutations in patients with focal segmental glomerulosclerosis resulted in distinct NSC progressions, suggesting that the NSC is suitable for investigating structure-function relations and might help unravel the unknown pathomechanisms leading to focal segmental glomerulosclerosis. The NSC is an effective algorithm for extended biophysical characterization of non-voltage-gated ion channels., (Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Background: Posttransplant diabetes (PTD), a major complication after kidney transplantation (KT), is often attributable to immunosuppression. The risk of PTD may increase with more potent steroid maintenance and older recipient age., Methods: Using United States Renal Data System data, we studied 12 488 adult first-time KT recipients (2010-2015) with no known pre-KT diabetes. We compared the risk of PTD among recipients who underwent early steroid withdrawal (ESW) versus continued steroid maintenance (CSM) using Cox regression with inverse probability weighting to adjust for confounding. We tested whether the risk of PTD resulting from ESW differed by recipient age (18-29, 30-54, and ≥55 y)., Results: Of 12 488, 28.3% recipients received ESW. The incidence rate for PTD was 13 per 100 person-y and lower among recipients who received ESW (11 per 100 person-y in ESW; 14 per 100 person-y in CSM). Overall, ESW was associated with lower risk of PTD compared with CSM (adjusted hazard ratio [aHR] = 0.72 0.79 0.86 ), but the risk differed by recipient age ( P interaction = 0.09 for comparison between recipients aged 18-29 and those aged 30-54; P interaction = 0.01 for comparison between recipients aged 18-29 and those aged ≥55). ESW was associated with lower risk of PTD among recipients aged ≥55 (aHR = 0.62 0.71 0.81 ) and those aged 30-54 (aHR = 0.73 0.83 0.95 ), but not among recipients aged 18-29 (aHR = 0.81 1.18 1.72 ). Although recipients who received ESW had a higher risk of acute rejection across the age groups (adjusted odds ratio = 1.01 1.17 1.34 ), recipients with no PTD had a lower risk of mortality (aHR = 0.58 0.66 0.74 )., Conclusions: The beneficial association of ESW with decreased PTD was more pronounced among recipients aged ≥55, supporting an age-specific assessment of the risk-benefit balance regarding ESW., Competing Interests: D.L.S. receives speaking honoraria from Sanofi and Novartis. The other authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)