An Environmental Scan of Canadian Kidney Transplant Programs for the Management of Patients With Graft Failure: A Research Letter.

Background: Kidney transplant recipients with graft failure (KTR-GF) and those with a failing graft are an increasingly prevalent group of patients. Their clinical management is complex, and outcomes are worse than transplant naïve patients on dialysis. In 2023, the Kidney Disease: Improving Global Outcomes (KDIGO) organization reported findings from a controversies conference and identified several clinical practice priorities for KTR-GF. Objective: As an exercise in needs assessment, we aimed to collate and summarize current practices in adult Canadian kidney transplant programs around these KDIGO-identified clinical practice priorities. Design: Environmental scan followed by content analysis. Setting: Canadian adult kidney transplant programs. Measurements: We categorized the themes of our content analysis around 7 clinical practice priorities: (1) determining prognosis and kidney failure trajectory; (2) immunosuppression management; (3) management of medical complications; (4) preparing for return to dialysis; (5) evaluation and listing for re-transplantation; (6) management of psychological effects; and (7) transition to supportive care. Methods: We solicited documents that identified each program's current care practices for KTR-GF or patients with a failing graft, including policies, procedures, pathways, and protocols. A content analysis of documents and informal correspondence (email or telephone conversations) was done to extract information surrounding the 7 practice priorities. Results: Of the 18 programs contacted, 12 transplant programs participated in this study and a document from a provincial organization (where 2 non-responding programs are located) was procured and included in this analysis. Overall, practice gaps and discrepancies were noted. Many participants highlighted the lack of evidence or consensus to guide the management of KTR-GF as the key reason. Immunosuppression management was the most frequently addressed priority. Six programs and the provincial document recommended a nuanced approach to immunosuppressant management based on clinical factors and re-transplant candidacy. Two programs used the Kidney Failure Risk Equation and eGFR to determine referral trajectories and prepare patients for return to dialysis. Exact processes outlining medical management during the transition were not found except for nephrectomy indications and in 1 program that has a specific transition clinic for KTR-GF. All programs have a formal or informal policy that KTR-GF should be assessed for re-transplantation. Referrals for psychological support and transition to supportive care were made on a case-by-case basis. Limitations: Our environmental scan was at risk of non-response bias and restricted to transplant programs. Kidney clinics and dialysis units may have relevant policies and procedures that were not examined. Conclusion: The findings from our environmental scan suggest gaps in care and potential areas for quality improvement, including a lack of multidisciplinary care, structured dialysis preparation and psychological support. There is also a need to prioritize research that generates evidence to guide the management of KTR-GF and contributes to the aim of developing clinical practice guidelines.

Contexte: Les receveurs d'une greffe rénale avec perte du greffon (RGR-PG) et ceux dont le greffon est défaillant constituent un groupe de patients de plus en plus répandu. La prise en charge clinique de ces patients est complexe et les résultats sont moins bons que ceux des patients dialysés naïfs de transplantation. En 2023, l'organisme KDIGO (Kidney Disease: Improving Global Outcomes) a présenté les résultats d'une conférence portant sur les controverses et a identifié plusieurs priorités de pratique clinique pour les RGR-PG. Objectif: Dans le cadre d'un exercice d'évaluation des besoins, nous avons voulu rassembler et résumer les pratiques actuelles dans les programs canadiens de transplantation rénale chez les adultes en lien avec les priorités de pratique clinique identifiées par le KDIGO. Conception: Analyze contextuelle suivie d'une analyze du contenu. Cadre: Les programs canadiens de transplantation rénale chez l'adulte. Mesures: Nous avons classé les thèmes de l'analyze de contenu autour de sept priorités de pratique clinique: 1) la détermination du pronostic et de la trajectoire de l'insuffisance rénale; 2) la gestion du traitement immunosuppresseur; 3) la prise en charge des complications médicales; 4) la préparation au retour à la dialyze; 5) l'évaluation et l'inscription pour la retransplantation; 6) la gestion des effets psychologiques; et 7) la transition vers les soins de soutien. Méthodologie: Nous avons sollicité les documents (politiques, procédures, parcours, protocoles) des programs de transplantation qui décrivent les pratiques de soins actuelles pour les RGR-PG ou les patients avec un greffon défaillant. Une analyze du contenu de ces documents et de la correspondance informelle (courriels ou conversations téléphoniques) a été effectuée pour en extraire les données sur les sept priorités de pratique. Résultats: Des 18 programmes de transplantation contactés, 12 ont participé à l'étude et un seul document provenant d'une organisation provinciale (où se trouvent deux programmes n'ayant pas participé) a été obtenu et inclus dans l'analyse. Dans l'ensemble, on a observé plusieurs lacunes et divergences dans la pratique. La principale raison donnée par plusieurs participants étant le manque de données ou de consensus pour guider la prise en charge des RGR-PG. La gestion du traitement immunosuppresseur était la priorité la plus fréquemment abordée. Le document provincial et six programmes recommandaient une approche nuancée, fondée sur les facteurs cliniques et la candidature à la retransplantation, pour la gestion du traitement immunosuppresseur. Deux programmes utilisaient l'équation KFRE (Kidney Failure Risk Equation) et le DFGe pour aiguiller les patients et les préparer à retourner en dialyse. Nous n'avons pas trouvé de processus précis décrivant spécifiquement la prise en charge médicale pendant la transition, mis à part dans les indications de néphrectomie et un programme ayant une clinique de transition spécifique aux RGR-PG. Tous les programmes disposent d'une politique formelle ou informelle indiquant que les RGR-PG doivent être évalués pour la retransplantation. Les aiguillages vers du soutien psychologique et la transition vers les soins de soutien sont traités au cas par cas. Limites: L'analyse contextuelle présentait un risque de biais de non-réponse et elle a été limitée aux programmes de transplantation. Les cliniques de soins rénaux et les unités de dialyse pourraient disposer de politiques et de procédures pertinentes qui n'ont pas été examinées. Conclusion: Les résultats de l'analyse contextuelle suggèrent qu'il existe des lacunes dans les soins et de possibles domaines d'amélioration de la qualité. On a notamment observé un manque de soins multidisciplinaires, de préparation structurée à la dialyse et de soutien psychologique. Il est également nécessaire de prioriser la recherche produisant des données probantes afin de guider la prise en charge des RGR-PG et l'élaboration de lignes directrices de pratique clinique.

Role of scheduled repeat CT scan in traumatic brain injuries: A prospective observational study.

Background: Scheduled CT scan is a routine practice at many centers after traumatic brain injury (TBI), but it has been questioned by few authors. The majority of the studies are reported in mild TBI; however, no specific data exist for the same in moderate and severe TBI. Methods: This was a single-center and 1-year prospective study. All cases with TBI who underwent scheduled repeat scans were included in the study. Patients who underwent emergency surgery after first computed tomography (CT) and those who expired before repeat CT were excluded from the study. Data included demographics, Glasgow coma scale (GCS) score, initial head CT findings, findings of repeat CT, and the need for any intervention (medical/surgical). Results: A total of 231 cases were analyzed. The mean time interval for the repeat CT was 7.8 h. One hundred and seventy-one patients underwent scheduled repeat CT (Group 1), 53 patients with GCS >13 were discharged from emergency before the repeat scan (Group 2), and seven cases underwent repeat CT before the scheduled time in view of clinical deterioration (Group 3). The mean age and gender did not vary significantly between the three groups. Mixed lesions predominated in all; however, the proportion significantly differed between groups. In Group 1, two patients required surgery; in Group 3, all patients required a significant change in treatment, whereas none deteriorated or required a repeat scan in Group 2. Conclusion: In our study, the yield of routine repeat CT scans requiring surgery was 3.5%. Based on the results of our study and the observations from previous studies, we have proposed a few general working statements regarding indications for repeat CT scans in TBI.

The role of gut-derived short-chain fatty acids in Parkinson's disease.

The emerging function of short-chain fatty acids (SCFAs) in Parkinson's disease (PD) has been investigated in this article. SCFAs, which are generated via the fermentation of dietary fiber by gut microbiota, have been associated with dysfunction of the gut-brain axis and, neuroinflammation. These processes are integral to the development of PD. This article examines the potential therapeutic implications of SCFAs in the management of PD, encompassing their capacity to modulate gastrointestinal permeability, neuroinflammation, and neuronal survival, by conducting an extensive literature review. As a whole, this article emphasizes the potential therapeutic utility of SCFAs as targets for the management and treatment of PD.

Unveiling the potential of novel Metschnikowia yeast biosurfactants: triggering oxidative stress for promising antifungal and anticancer activity.

BACKGROUND: Sophorolipids are glycolipid biosurfactants with potential antibacterial, antifungal, and anticancer applications, rendering them promising for research. Therefore, this study hypothesizes that sophorolipids may have a notable impact on disrupting membrane integrity and triggering the production of reactive oxygen species, ultimately resulting in the eradication of pathogenic microbes. RESULTS: The current study resulted in the isolation of two Metschnikowia novel yeast strains. Sophorolipids production from these strains reached maximum yields of 23.24 g/l and 21.75 g/l, respectively, at the bioreactors level. Biosurfactants sophorolipids were characterized using FTIR and LC-MS techniques and found to be a mixture of acidic and lactonic forms with molecular weights of m/z 678 and 700. Our research elucidated sophorolipids' mechanism in disrupting bacterial and fungal membranes through ROS generation, confirmed by transmission electron microscopy and FACS analysis. The results showed that these compounds disrupted the membrane integrity and induced ROS production, leading to cell death in Klebsiella pneumoniae and Fusarium solani. In addition, the anticancer properties of sophorolipids were investigated on the A549 lung cancer cell line and found that sophorolipid-11D (SL-11D) and sophorolipid-11X (SL-11X) disrupted the actin cytoskeleton, as evidenced by immunofluorescence microscopy. The A549 cells were stained with Acridine orange/Ethidium bromide, which showed that they underwent necrosis. This was confirmed by flow cytometric analysis using Annexin/PI staining. The SL-11D and SL-11X molecules exhibited low levels of haemolytic activity and in-vitro cytotoxicity in HEK293, Caco-2, and L929 cell lines. CONCLUSION: In this work, novel yeast species CIG-11DT and CIG-11XT, isolated from the bee's gut, produce significant yields of sophorolipids without needing secondary oil sources, indicating a more economical production method. Our research shows that sophorolipids disrupt bacterial and fungal membranes via ROS production. They suggest they may act as chemo-preventive agents by inducing apoptosis in lung cancer cells, offering the potential for enhancing anticancer therapies.

Disorders of potassium homeostasis after kidney transplantation.

Disturbances of potassium balance are often encountered when managing kidney transplant recipients (KTR). Both hyperkalemia and hypokalemia may present either as medical emergencies or chronic outpatient abnormalities. Despite the high incidence of hyperkalemia and its potential life-threatening implications, consensus on its management in KTR is lacking. Hypokalemia in KTR is also well-described, although it is given less attention by clinicians compared to hyperkalemia. This article discusses the etiology, pathophysiology and management of both types of potassium disorders in KTR. Once any emergent situation has been corrected, treatment approaches include correcting insulin deficiency if present, adjusting non-immunosuppressive and immunosuppressive medications, eliminating or supplementing potassium as needed, and dietary counselling. Although commonly of multifactorial etiology, ascertaining the specific cause in a particular patient will help guide successful management. Monitoring KTR through regular laboratory testing is essential to detect serious disturbances in potassium balance since patients are often asymptomatic.

Mycobacterium tuberculosis virulence lipid PDIM inhibits autophagy in mice.

Mycobacterium tuberculosis (Mtb) infects several lung macrophage populations, which have distinct abilities to restrict Mtb. What enables Mtb survival in certain macrophage populations is not well understood. Here we used transposon sequencing analysis of Mtb in wild-type and autophagy-deficient mouse macrophages lacking ATG5 or ATG7, and found that Mtb genes involved in phthiocerol dimycocerosate (PDIM) virulence lipid synthesis confer resistance to autophagy. Using ppsD mutant Mtb, we found that PDIM inhibits LC3-associated phagocytosis (LAP) by inhibiting phagosome recruitment of NADPH oxidase. In mice, PDIM protected Mtb from LAP and classical autophagy. During acute infection, PDIM was dispensable for Mtb survival in alveolar macrophages but required for survival in non-alveolar macrophages in an autophagy-dependent manner. During chronic infection, autophagy-deficient mice succumbed to infection with PDIM-deficient Mtb, with impairments in B-cell accumulation in lymphoid follicles. These findings demonstrate that PDIM contributes to Mtb virulence and immune evasion, revealing a contributory role for autophagy in B-cell responses.

Shifts in Serum Bile Acid Profiles Associated With Barrett's Esophagus and Stages of Progression to Esophageal Adenocarcinoma.

INTRODUCTION: Reflux bile acids are believed to promote esophageal adenocarcinoma (EAC), but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett's esophagus (BE) progression. METHODS: Subjects with and without BE were enrolled in this multicenter cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression. RESULTS: A total of 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high-grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia ( P = 0.004). Increasing cholic acid was associated with high-grade dysplasia/EAC compared with non-BE, even after adjusting for EAC risk factors (adjusted odds ratio 2.03, 95% confidence interval 1.11-3.71) as was the combination of unconjugated primary bile acids (adjusted odds ratio 1.81, 95% confidence interval 1.04-3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes. DISCUSSION: Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, proneoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.

Tau proteins and senescent Cells: Targeting aging pathways in Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by abnormal accumulation of tau proteins and amyloid-ß, leading to neuronal death and cognitive impairment. Recent studies have implicated aging pathways, including dysregulation of tau and cellular senescence in AD pathogenesis. In AD brains, tau protein, which normally stabilizes microtubules, becomes hyperphosphorylated and forms insoluble neurofibrillary tangles. These tau aggregates impair neuronal function and are propagated across the brain's neurocircuitry. Meanwhile, the number of senescent cells accumulating in the aging brain is rising, releasing a pro-inflammatory SASP responsible for neuroinflammation and neurodegeneration. This review explores potential therapeutic interventions for AD targeting tau protein and senescent cells, and tau -directed compounds, senolytics, eliminating senescent cells, and agents that modulate the SASP-senomodulators. Ultimately, a combined approach that incorporates tau-directed medications and targeted senescent cell-based therapies holds promise for reducing the harmful impact of AD's shared aging pathways.

Functional outcomes in unstable complete subaxial cervical spinal injuries with respiratory paralysis and/or hemodynamic instability.

INTRODUCTION: Subaxial cervical spine injuries (SCSI) can lead to disastrous consequences such as quadriplegia, with/without respiratory paralysis (RP) and hemodynamic instability (HDI). Till date, there is no literature available for reporting outcomes of SCSI patients specifically pertaining to those presenting with RP/HDI and ours is the first study to document the same. METHODS: Retrospective 6-year study from a tertiary trauma centre database including patients >/= 18 years of operated SCSI. Only patients with ASIA A grade with admission RP/HDI and unstable injuries (fractures, subluxations) were included. Patients with ASIA grade B and above, patients with non-osseous injuries (such as disc herniation, central cord syndrome etc.) were excluded. RESULTS: 24 cases were analysed. C5 and C6 levels were the commonest. Vertebral listhesis/subluxation was the predominant radiological finding. The mean age was 47.4 years (22-79 years) and all, except one were males. Fall from height and road traffic accident (RTA) were the most common mechanisms of injury. The most common surgery was anterior discectomy and fusion followed by corpectomy. The overall mortality rate was 22/24 (92)%. Cord edema and hemorrhage had significant association with survival. None of the grade A survivors with HDI/RP showed improvement. The mean FU duration was 18.5 months (range, 16.5-20.5 months). CONCLUSIONS: Subaxial ASIA A cervical spine injuries with pre-operative RP/HDI is an indicator for non-improvement. This is the first study documenting outcome in such patients. The mortality rate in these patients is very high and is an extremely poor prognostic factor for recovery. Hence, surgery in such patients need to be decided judiciously, especially in developing countries that has a significant financial impact on the family members.

Proteostasis disruption and senescence in Alzheimer's disease pathways to neurodegeneration.

Alzheimer's Disease (AD) is a progressive neurological disease associated with behavioral abnormalities, memory loss, and cognitive impairment that cause major causes of dementia in the elderly. The pathogenetic processes cause complex effects on brain function and AD progression. The proper protein homeostasis, or proteostasis, is critical for cell health. AD causes the buildup of misfolded proteins, particularly tau and amyloid-beta, to break down proteostasis, such aggregates are toxic to neurons and play a critical role in AD pathogenesis. The rise of cellular senescence is accompanied by aging, marked by irreversible cell cycle arrest and the release of pro-inflammatory proteins. Senescent cell build-up in the brains of AD patients exacerbates neuroinflammation and neuronal degeneration. These cells senescence-associated secretory phenotype (SASP) also disturbs the brain environment. When proteostasis failure and cellular senescence coalesce, a cycle is generated that compounds each other. While senescent cells contribute to proteostasis breakdown through inflammatory and degradative processes, misfolded proteins induce cellular stress and senescence. The principal aspects of the neurodegenerative processes in AD are the interaction of cellular senescence and proteostasis failure. This review explores the interconnected roles of proteostasis disruption and cellular senescence in the pathways leading to neurodegeneration in AD.

Molecular Analysis of Persistent and Recurrent Barrett's Esophagus in the Setting of Endoscopic Therapy.

INTRODUCTION: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. METHODS: We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre-treatment and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. RESULTS: The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway ( P = 0.01), amplifications of oncogenes ( P = 0.01), and deletions of tumor suppressor genes ( P = 0.02). These associations were no longer significant after adjusting for patient age and BE length. More than half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre-treatment and post-treatment samples that shared at least 50% of their driver mutations. DISCUSSION: Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. Although it was expected to find shared driver mutations in pre-treatment and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.

Rubella immunity among pregnant women and the burden of congenital rubella syndrome (CRS) in India, 2022.

BACKGROUND: India aims to eliminate rubella and congenital rubella syndrome (CRS) by 2023. We conducted serosurveys among pregnant women to monitor the trend of rubella immunity and estimate the CRS burden in India following a nationwide measles and rubella vaccination campaign. METHODS: We surveyed pregnant women at 13 sentinel sites across India from Aug to Oct 2022 to estimate seroprevalence of rubella IgG antibodies. Using age-specific seroprevalence data from serosurveys conducted during 2017/2019 (prior to and during the vaccination campaign) and 2022 surveys (after the vaccination campaign), we developed force of infection (FOI) models and estimated incidence and burden of CRS. RESULTS: In 2022, rubella seroprevalence was 85.2% (95% CI: 84.0, 86.2). Among 10 sites which participated in both rounds of serosurveys, the seroprevalence was not different between the two periods (pooled prevalence during 2017/2019: 83.5%, 95% CI: 82.1, 84.8; prevalence during 2022: 85.1%, 95% CI: 83.8, 86.3). The estimated annual incidence of CRS during 2017/2019 in India was 218.3 (95% CI: 209.7, 226.5) per 100, 000 livebirths, resulting in 47,120 (95% CI: 45,260, 48,875) cases of CRS every year. After measles-rubella (MR) vaccination campaign, the estimated incidence of CRS declined to 5.3 (95% CI: 0, 21.2) per 100,000 livebirths, resulting in 1141 (95% CI: 0, 4,569) cases of CRS during the post MR-vaccination campaign period. CONCLUSION: The incidence of CRS in India has substantially decreased following the nationwide MR vaccination campaign. About 15% of women in childbearing age in India lack immunity to rubella and hence susceptible to rubella infection. Since there are no routine rubella vaccination opportunities for this age group under the national immunization program, it is imperative to maintain high rates of rubella vaccination among children to prevent rubella virus exposure among women of childbearing age susceptible for rubella.

Eosinophilic granuloma of the cervical spine in a young adult: A rare case report.

Background: Spinal eosinophilic granulomas (EG) are rare tumors, mostly reported in the pediatric age group. They constitute <1% of primary bone neoplasms, and cervical spine involvement is uncommon. Case Description: A 20-year-old male presented with neck pain for a 4-month duration. Six years previously, he had received six cycles of vinblastine for biopsy-proven histiocytosis of an axillary lymph node; this resulted in incomplete remission. Present magnetic resonance/computed tomography (CT) imaging revealed a lytic C2 body lesion with atlantoaxial instability. When the CT-guided biopsy was suggestive of EG, he was managed with definitive surgery and adjuvant radiotherapy. Conclusion: Cervical spine EG is rare in adults. CT-guided biopsy should confirm the diagnosis and should be followed by definitive surgery and adjuvant radiotherapy.

Metabolically active neutrophils represent a permissive niche for Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb)-infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils to the lung is linked to increased bacterial burden and aggravated pathology in TB. The basis for the permissiveness of neutrophils for Mtb and the ability to be pathogenic in TB has been elusive. Here, we identified metabolic and functional features of neutrophils that contribute to their permissiveness in Mtb infection. Using single-cell metabolic and transcriptional analyses, we found that neutrophils in the Mtb-infected lung displayed elevated mitochondrial metabolism, which was largely attributed to the induction of activated neutrophils with enhanced metabolic activities. The activated neutrophil subpopulation was also identified in the lung granulomas from Mtb-infected non-human primates. Functionally, activated neutrophils harbored more viable bacteria and displayed enhanced lipid uptake and accumulation. Surprisingly, we found that interferon-γ promoted the activation of lung neutrophils during Mtb infection. Lastly, perturbation of lipid uptake pathways selectively compromised Mtb survival in activated neutrophils. These findings suggest that neutrophil heterogeneity and metabolic diversity are key to their permissiveness for Mtb and that metabolic pathways in neutrophils represent potential host-directed therapeutics in TB.

Improving esophageal cancer screening across the globe: Translating knowledge into action.

Esophageal cancer (EC) is a pressing global health concern, ranking as the eighth most common cancer and the sixth leading cause for cancer-related deaths worldwide. Esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) are the two major histological types of esophageal cancer associated with distinct risk factors and geographical distributions. Unfortunately, the outcomes for both types of EC remain discouraging, with a five-year survival rate of less than 20% when diagnosed at advanced stages. Advanced endoscopic techniques have the potential to vastly enhance patient outcomes and impede the progression of pre-malignant lesions to cancer. However, low screening rates with endoscopy due to its invasive nature and high cost hinder its effectiveness. Despite extensive research on risk predictors, a significant number of cases still go undiagnosed, highlighting the need for improved screening techniques that can be implemented at the population level. To increase uptake, a shift towards minimally invasive, well-tolerated and cost-effective non-endoscopic technologies is crucial. The implementation of such devices in primary care settings, specifically targeting high-risk populations, can be a promising strategy. With early detection and enrollment in surveillance programs, there is hope for substantial improvement in morbidity and mortality rates through modern minimally invasive endoscopic and surgical techniques.

Stratification of Barrett's esophagus surveillance based on p53 immunohistochemistry: a cost-effectiveness analysis by an international collaborative group.

BACKGROUND: Surveillance of nondysplastic Barrett's esophagus (NDBE) is recommended to identify progression to dysplasia; however, the most cost-effective strategy remains unclear. Mutation of TP53 or aberrant expression of p53 have been associated with the development of dysplasia in BE. We sought to determine if surveillance intervals for BE could be stratified based on p53 expression. METHODS: A Markov model was developed for NDBE. Patients with NDBE underwent p53 immunohistochemistry (IHC) and those with abnormal p53 expression underwent surveillance endoscopy at 1 year, while patients with normal p53 expression underwent surveillance in 3 years. Patients with dysplasia underwent endoscopic therapy and surveillance. RESULTS: On base-case analysis, the strategy of stratifying surveillance based on abnormal p53 IHC was cost-effective relative to conventional surveillance and a natural history model, with an incremental cost-effectiveness ratio (ICER) of $8258 for p53 IHC-based surveillance. Both the conventional and p53-stratified surveillance strategies dominated the natural history model. On probabilistic sensitivity analysis, the p53 IHC strategy ($28 652; 16.78 quality-adjusted life years [QALYs]) was more cost-effective than conventional surveillance ($25 679; 16.17 QALYs) with a net monetary benefit of $306 873 compared with conventional surveillance ($297 642), with an ICER <$50 000 in 96% of iterations. The p53-stratification strategy was associated with a 14% reduction in the overall endoscopy burden and a 59% increase in dysplasia detection. CONCLUSION: A surveillance strategy for BE based on abnormal p53 IHC is cost-effective relative to a conventional surveillance strategy and is likely to be associated with higher rates of dysplasia diagnosis.

Hypertension and Kidney Function After Living Kidney Donation.

Importance: Recent guidelines call for better evidence on health outcomes after living kidney donation. Objective: To determine the risk of hypertension in normotensive adults who donated a kidney compared with nondonors of similar baseline health. Their rates of estimated glomerular filtration rate (eGFR) decline and risk of albuminuria were also compared. Design, Setting, and Participants: Prospective cohort study of 924 standard-criteria living kidney donors enrolled before surgery and a concurrent sample of 396 nondonors. Recruitment occurred from 2004 to 2014 from 17 transplant centers (12 in Canada and 5 in Australia); follow-up occurred until November 2021. Donors and nondonors had the same annual schedule of follow-up assessments. Inverse probability of treatment weighting on a propensity score was used to balance donors and nondonors on baseline characteristics. Exposure: Living kidney donation. Main Outcomes and Measures: Hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure [DBP] ≥90 mm Hg, or antihypertensive medication), annualized change in eGFR (starting 12 months after donation/simulated donation date in nondonors), and albuminuria (albumin to creatinine ratio ≥3 mg/mmol [≥30 mg/g]). Results: Among the 924 donors, 66% were female; they had a mean age of 47 years and a mean eGFR of 100 mL/min/1.73 m2. Donors were more likely than nondonors to have a family history of kidney failure (464/922 [50%] vs 89/394 [23%], respectively). After statistical weighting, the sample of nondonors increased to 928 and baseline characteristics were similar between the 2 groups. During a median follow-up of 7.3 years (IQR, 6.0-9.0), in weighted analysis, hypertension occurred in 161 of 924 donors (17%) and 158 of 928 nondonors (17%) (weighted hazard ratio, 1.11 [95% CI, 0.75-1.66]). The longitudinal change in mean blood pressure was similar in donors and nondonors. After the initial drop in donors' eGFR after nephrectomy (mean, 32 mL/min/1.73 m2), donors had a 1.4-mL/min/1.73 m2 (95% CI, 1.2-1.5) per year lesser decline in eGFR than nondonors. However, more donors than nondonors had an eGFR between 30 and 60 mL/min/1.73 m2 at least once in follow-up (438/924 [47%] vs 49/928 [5%]). Albuminuria occurred in 132 of 905 donors (15%) and 95 of 904 nondonors (11%) (weighted hazard ratio, 1.46 [95% CI, 0.97-2.21]); the weighted between-group difference in the albumin to creatinine ratio was 1.02 (95% CI, 0.88-1.19). Conclusions and Relevance: In this cohort study of living kidney donors and nondonors with the same follow-up schedule, the risks of hypertension and albuminuria were not significantly different. After the initial drop in eGFR from nephrectomy, donors had a slower mean rate of eGFR decline than nondonors but were more likely to have an eGFR between 30 and 60 mL/min/1.73 m2 at least once in follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT00936078.

Multicenter, Prospective Trial of Nonendoscopic Biomarker-Driven Detection of Barrett's Esophagus and Esophageal Adenocarcinoma.

INTRODUCTION: Preliminary data suggest that an encapsulated balloon (EsoCheck), coupled with a 2 methylated DNA biomarker panel (EsoGuard), detects Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) with high accuracy. The initial assay requires sample freezing upon collection. The purpose of this study was to assess a next-generation EsoCheck sampling device and EsoGuard assay in a much-enlarged multicenter study clinically enhanced by using a Clinical Laboratory Improvement Amendments of 1988-compliant assay and samples maintained at room temperature. METHODS: Cases with nondysplastic BE (NDBE), dysplastic BE (indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia), EAC, junctional adenocarcinoma, plus endoscopy controls without esophageal intestinal metaplasia, were prospectively enrolled. Medical assistants at 6 institutions delivered the encapsulated balloon per orally with inflation in the stomach. The inflated balloon sampled the distal 5 cm of the esophagus and then was deflated and retracted into the capsule, preventing sample contamination. EsoGuard bisulfite sequencing assayed levels of methylated vimentin and methylated cyclin A1. RESULTS: A total of 243 evaluable patients-88 cases (median age 68 years, 78% men, 92% White) and 155 controls (median age 57 years, 41% men, 88% White)-underwent adequate EsoCheck sampling. The mean procedural time was approximately 3 minutes. Cases included 31 with NDBE, 16 with indefinite for dysplasia/low-grade dysplasia, 23 with high-grade dysplasia, and 18 with EAC/junctional adenocarcinoma. Thirty-seven NDBE and dysplastic BE cases (53%) were short-segment BE (<3 cm). Overall sensitivity was 85% (95% confidence interval 0.78-0.93) and specificity was 85% (95% confidence interval 0.79-0.90). Sensitivity for NDBE was 84%. EsoCheck/EsoGuard detected 100% of cancers (n = 18). DISCUSSION: EsoCheck/EsoGuard demonstrated high sensitivity and specificity in detecting BE and BE-related neoplasia.