Decision-making preferences and regret in rectal cancer patients undergoing restorative proctectomy: A prospective cohort study.

BACKGROUND: How patients make treatment choices in rectal cancer is poorly understood and may affect long-term regret and satisfaction. The objective of this study is to characterize decision-making preferences and their effect on decisional regret in patients undergoing restorative proctectomy for rectal cancer. METHODS: A prospective cohort study was conducted in a single academic specialist rectal cancer center from October 2018 to June 2022. Adult patients who underwent restorative proctectomy at least one year prior were recruited. Health literacy was assessed using the BRIEF instrument. Decision-making preferences regarding cancer treatment were assessed using the Control Preferences Scale. Decisional regret regarding their choice of restorative proctectomy was assessed using the Decision Regret Score. Bowel dysfunction was measured using the low anterior resection syndrome score. RESULTS: Overall, 123 patients were included. Health literacy was categorized as adequate in 63%, marginal in 25%, and limited in 12%. Patients with adequate health literacy were more likely to prefer a collaborative decision-making role compared with those with low health literacy (86% vs 65%, P = .016). Patients with incongruence between preferred and actual decision-making roles were more likely to report high regret (56% vs 25%, P = .003). Patients with major low anterior resection syndrome were also more likely to experience high regret compared with patients with no/minor low anterior resection syndrome (44% vs 25%, P = .036). CONCLUSION: A significant proportion of patients with rectal cancer undergoing restorative proctectomy do not have a decision-making role that is congruent with their preferences, and these patients experience a high degree of regret.

How well do we measure the impact of bowel dysfunction on health-related quality of life after rectal cancer surgery?

BACKGROUND: Rectal cancer surgery risks causing bowel dysfunction, which has an important impact on health-related quality of life. The validity of generic tools used to measure health-related quality of life after bowel dysfunction is unclear. This study aimed to determine the content validity of health-related quality-of-life measurement tools in rectal cancer. METHODS: This was a qualitative single-center study in which adult patients who underwent rectal cancer surgery with sphincter preservation from July 2017 to October 2020 were recruited. Patients were excluded if they developed local metastasis, required a permanent stoma, or had surgery <1 year since recruitment. Telephone-based semi-structured interviews were conducted. Bowel dysfunction was measured using the Low Anterior Resection Syndrome score. Content analysis was achieved using the International Classification of Functioning framework. RESULTS: Recurrent bowel dysfunction-related concepts included "Mental functions," "Defecation functions," "Emotional functions," "Recreation and leisure," "Intimate relationships," and "Remunerative employment." A mean of 7.5 recurrent bowel dysfunction-related concepts were identified within the health-related quality of life instruments analyzed. The European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-C30 (n = 11) and the 36-Item Short Form Health Survey (n = 9) covered the greatest number of recurrent bowel dysfunction-related concepts. Concepts such as "Mental functions," "Urination functions," "Sexual functions," "Driving," and "Mobility" were not covered by any instrument. CONCLUSION: The content of traditional health-related quality-of-life instruments is missing important areas that represent the impact of bowel dysfunction after rectal cancer surgery on health-related quality of life. These findings could help improve patient-centered care in rectal cancer surgery.

The impact of patient activation on the effectiveness of digital health remote post-discharge follow-up and same-day-discharge after elective colorectal surgery.

BACKGROUND: Low patient activation (PA) is associated with worse postoperative outcomes, however, its impact on the effectiveness of digital health interventions is unknown. We sought to determine the impact of PA on the effectiveness of digital health application for remote post-discharge follow-up for patients undergoing elective colectomy. METHODS: Data analysis included a control cohort (CC) of patients undergoing elective colorectal surgery from 10/2017 to 04/2018 without the digital health intervention and a digital application cohort (DAC) that received a smart phone application for remote post-discharge follow-up from 03/2021 to 08/2022, including a subset of same-day discharge (SDD) patients. PA was measured using the Patient Activation Measure (PAM; score 0-100) and categorized into low (< 55.1) and high (≥ 55.1). The PAM was administered 4-6 weeks before surgery in the DAC group and on postoperative day (POD) 1 in the CC group. The main outcome measure was 30-day emergency department (ED) visits. RESULTS: A total of 164 patients were included (89DAC with 50 SDD, 75CC), with no differences in patient characteristics other than more stoma closures in the DAC group. Overall, 77% of patients had high PA level, with no difference between CC and DAC (77% vs. 81%, p = 0.25). There was no difference in ED visits between CC and DAC (19% vs. 18%, p = 0.90). Overall, low PA was associated more ED visits (29% vs 14%, p = 0.04). In the SDD subgroup, low PA patients had more ED visits (38% vs. 7%, p = 0.015). PA level did not affect app usage metrics. On multiple regression, only low PA remained independently associated with ED visits (OR 3.42, 95%CI 1.27, 9.24). CONCLUSION: Low PA remains an important predictor of surgical outcomes after elective colorectal surgery regardless of the use of a digital health application for remote post-discharge follow-up. This suggests that improving PA levels may improve postoperative outcomes.

Predictive Factors for Successful Same-Day Discharge After Minimally Invasive Colectomy and Stoma Reversal.

BACKGROUND: Same-day discharge after minimally invasive colorectal surgery is a safe, effective practice in specific patients that can enhance the efficiency of enhanced recovery pathways. OBJECTIVE: To identify predictive factors associated with success or failure of same-day discharge. DESIGN: Prospective cohort study from January 2020 to March 2023. SETTINGS: Tertiary colorectal center. PATIENTS: Adult patients eligible for same-day discharge with remote postdischarge follow-up included those with minimal comorbidities, residing near the hospital, having sufficient home support, and owning a mobile device. INTERVENTIONS: Patients were discharged on the day of surgery upon meeting specific criteria, including adequate pain control, tolerance of oral intake, independent mobility, urination, and the absence of complications. Successful same-day discharge was defined as discharge on the day of surgery without unplanned visits in the first 72 hours. MAIN OUTCOME MEASURES: Factors associated with successful or failed same-day discharge after minimally invasive colorectal surgery. RESULTS: A total of 175 patients (85.3%) were discharged on the day of surgery, with 14 patients (8%) having an unplanned visit within 72 hours. Overall, 161 patients (78.5%) were categorized as same-day discharge success and 44 patients (21.5%) as same-day discharge failure. The same-day discharge failure group had a higher Charlson Comorbidity Index (3.7 vs 2.8, p = 0.03). Mean length of stay (0.8 vs 3.0, p = 0.00), 30-day complications (10% vs 48%, p = 0.00), and readmissions (8% vs 27%, p = 0.00) were higher in the same-day discharge failure group. Regression analysis showed that failed same-day discharge was associated with higher comorbidities (OR 0.79; 95% CI, 0.66-0.95) and prolonged postanesthesia care unit time (OR 0.99; 95% CI, 0.99-0.99). Individuals who received a regional nerve block (OR 4.1; 95% CI, 1.2-14) and those who did not consume postoperative opioids (OR 4.6; 95% CI, 1-21) were more likely to have successful same-day discharge. LIMITATIONS: Single-center study. CONCLUSIONS: Our findings indicate that comorbidities and prolonged postanesthesia care unit stays were associated with same-day discharge failure, whereas regional nerve blocks and minimal postoperative opioids were related to success. These factors may inform future research aiming to enhance colorectal surgery recovery protocols. See Video Abstract . FACTORES PREDICTIVOS PARA UN ALTA EXITOSA EL MISMO DA DESPUS DE UNA COLECTOMA MNIMAMENTE INVASIVA Y REVERSIN DEL ESTOMA: ANTECEDENTES:El alta el mismo día después de una cirugía colorrectal mínimamente invasiva es una práctica segura y eficaz en pacientes específicos que puede mejorar la eficiencia de las vías de recuperación mejoradas.OBJETIVO:Identificar factores predictivos asociados con el éxito o fracaso del alta el mismo día.DISEÑO:Estudio de cohorte prospectivo del 01/2020 al 03/2023.AJUSTES:Centro colorrectal terciario.PACIENTES:Los pacientes adultos elegibles para el alta el mismo día con seguimiento remoto posterior al alta incluyeron aquellos con comorbilidades mínimas, que residían cerca del hospital, tenían suficiente apoyo en el hogar y poseían un dispositivo móvil.INTERVENCIONES:Los pacientes fueron dados de alta el día de la cirugía al cumplir con criterios específicos, incluido un control adecuado del dolor, tolerancia a la ingesta oral, movilidad independiente, micción y ausencia de complicaciones. El alta exitosa el mismo día se definió como el alta el día de la cirugía sin visitas no planificadas en las primeras 72 horas.PRINCIPALES MEDIDAS DE RESULTADO:Factores asociados con el alta exitosa o fallida el mismo día después de una cirugía colorrectal mínimamente invasiva.RESULTADOS:Un total de 175 (85,3%) pacientes fueron dados de alta el día de la cirugía y 14 (8%) pacientes tuvieron una visita no planificada dentro de las 72 horas. En total, 161 (78,5%) pacientes se clasificaron como éxito del alta el mismo día y 44 (21,5%) pacientes como fracaso del alta el mismo día. El grupo de fracaso del alta el mismo día tuvo un índice de comorbilidad de Charlson más alto (3,7, 2,8, p = 0,03). La duración media de la estancia hospitalaria (0,8, 3,0, p = 0,00), las complicaciones a los 30 días (10%, 48%, p = 0,00) y los reingresos (8%, 27%, p = 0,00) fueron mayores en el mismo día grupo de fallo de descarga. El análisis de regresión mostró que el alta fallida el mismo día se asoció con mayores comorbilidades (OR 0,79; IC del 95 %: 0,66; 0,95) y tiempo prolongado en la unidad de cuidados postanestésicos (OR 0,99; IC del 95 %: 0,99; 0,99). Las personas que recibieron un bloqueo nervioso regional (OR 4,1; IC del 95 %: 1,2, 14) y aquellos que no consumieron opioides posoperatorios (OR 4,6, IC del 95 %: 1-21) tuvieron más probabilidades de tener éxito en el mismo día -descarga.LIMITACIONES:Estudio unicéntrico.CONCLUSIONES:Nuestros hallazgos indican que las comorbilidades y las estancias prolongadas en la unidad de cuidados postanestésicos se asociaron con el fracaso del alta el mismo día, mientras que los bloqueos nerviosos regionales y los opioides postoperatorios mínimos se relacionaron con el éxito. Estos factores pueden informar investigaciones futuras destinadas a mejorar los protocolos de recuperación de la cirugía colorrectal. (Traducción-Yesenia Rojas-Khalil ).

The impact of restorative proctectomy versus permanent colostomy on health-related quality of life after rectal cancer surgery using the patient-generated index.

BACKGROUND: The impact of bowel dysfunction versus colostomy on quality of life after rectal cancer surgery is poorly understood. BACKGROUND: To evaluate the quality of life after rectal cancer surgery in patients with colostomy versus restorative proctectomy. METHODS: A mixed-methods study measuring quality of life using the Patient-Generated Index, patients were asked to list up to 5 areas of their life affected by their surgery. Areas were then weighted according to patients' preferences for improvement to generate a score from 0-100. The areas reported by patients were linked to the International Classification of Functioning for content analysis. Bowel dysfunction was measured using the low anterior resection syndrome score, and patients were then grouped according to (1) colostomy, (2) no/minor, or (3) major low anterior resection syndrome. Quality of life was compared between groups. RESULTS: Overall, 121 patients were included (colostomy n = 39, restorative proctectomy n = 82). There were no differences in demographics, neoadjuvant radiotherapy, or time to follow-up between groups. In the restorative proctectomy group, 53% had no/minor, and 47% had major low anterior resection syndrome. Overall, patients with colostomy had significantly lower quality-of-life scores than those with restorative proctectomy. However, patients with major low anterior resection syndrome scored similarly to those with colostomy. On content analysis, patients with colostomies reported more problems with sexual function, body image, and sports. Patients with restorative proctectomy reported more problems with sleep, using transportation, and taking care of themselves. CONCLUSION: Colostomy has a more detrimental impact on quality of life than restorative proctectomy. However, bowel dysfunction severity is important to consider. The patient experience between treatments differs.

Understanding the Impact of Bowel Dysfunction on Quality of Life After Rectal Cancer Surgery From the Patient's Perspective.

BACKGROUND: Bowel dysfunction is an important consequence of rectal cancer surgery' and the specific quality-of-life domains that are affected remain unclear and unaddressed by generic surveys. OBJECTIVE: This study aimed to identify quality-of-life domains most affected by rectal cancer surgery. DESIGN: Qualitative content analysis. SETTINGS: Semistructured interviews conducted by telephone with patients recruited from a single university-affiliated colorectal referral center. PATIENTS: Adult patients were included if they underwent rectal cancer surgery with sphincter preservation from July 2017 to July 2020. Patients were excluded if their surgery was <1 year since the recruitment date, received a permanent stoma, or developed recurrence or metastasis. MAIN OUTCOME MEASURES: Bowel dysfunction was evaluated via the low anterior resection syndrome score. Interview transcripts were coded by 2 independent reviewers and evaluated for concordance. Qualitative content analysis was used to identify themes, and their frequency of occurrence was quantified (percent total number of interviews). RESULTS: A total of 54 patient interviews were conducted. Analysis revealed 5 quality-of-life-related themes impacted by bowel dysfunction: experiencing psychological and emotional stress, challenging roles and relationships within society, encountering physical limitations, restricting leisure and recreational activities, and learning self-empowerment and adapting to change. Patients with minor and major bowel dysfunction were more likely to report disruption to their social activities and their role as a sexual partner versus those with no bowel dysfunction. Patients with major bowel dysfunction were more likely to report effects on sleep versus those with no and minor bowel dysfunction. LIMITATIONS: Single center, self-reported, and observer bias. CONCLUSION: The impact of bowel dysfunction on quality of life includes a wide range of themes that extend beyond traditional measures. These results may help better inform patients in the preoperative setting and serve as a basis for the development of a more patient-centered quality-of-life survey. COMPRENDER EL IMPACTO DE LA DISFUNCIN INTESTINAL EN LA CALIDAD DE VIDA DESPUS DE LA CIRUGA DE CNCER DE RECTO DESDE LA PERSPECTIVA DEL PACIENTE: ANTECEDENTES:La disfunción intestinal es una consecuencia importante de la cirugía del cáncer de recto y los dominios específicos de la calidad de vida que se ven afectados siguen sin estar claros y sin abordarse en las encuestas genéricas.OBJETIVO:Identificar los dominios de calidad de vida más afectados por la cirugía del cáncer de recto.DISEÑO:Análisis cualitativo de contenido.ÁMBITOS:Entrevistas semiestructuradas realizadas por teléfono con pacientes reclutados de un único centro de referencia colorrectal afiliado a una universidad.PACIENTES:Pacientes adultos intervenidos de cáncer de recto con preservación de esfínter del 07/2017 al 07/2020. Los pacientes fueron excluidos si su cirugía fue <1 año desde la fecha de reclutamiento, recibieron un estoma permanente o desarrollaron recurrencia o metástasis.PRINCIPALES MEDIDAS DE RESULTADO:La disfunción intestinal se evaluó a través de la puntuación del síndrome de resección anterior baja. Dos revisores independientes codificaron las transcripciones de las entrevistas y evaluaron su concordancia. Se utilizó el análisis de contenido cualitativo para identificar los temas, cuantificando su frecuencia de aparición (porcentaje del número total de entrevistas).RESULTADOS:Se realizaron un total de 54 entrevistas a pacientes. El análisis reveló cinco temas relacionados con la calidad de vida afectados por la disfunción intestinal: experimentar estrés psicológico y emocional, roles y relaciones desafiantes dentro de la sociedad, encontrar limitaciones físicas, restringir actividades recreativas y de ocio, y autoempoderamiento y adaptación al cambio. Los pacientes con disfunción intestinal menor y mayor tenían más probabilidades de informar la interrupción de las actividades sociales y el papel como pareja sexual en comparación con aquellos sin disfunción intestinal. Los pacientes con disfunción intestinal importante tenían más probabilidades de informar efectos sobre el sueño en comparación con aquellos sin disfunción intestinal o con disfunción intestinal menor.LIMITACIONES:Sesgo de un solo centro, autoinformado y observador.CONCLUSIÓN:El impacto de la disfunción intestinal en la calidad de vida incluye una amplia gama de temas que se extienden más allá de las medidas tradicionales. Estos resultados pueden ayudar a informar mejor a los pacientes en el entorno preoperatorio y servir como base para el desarrollo de una encuesta de calidad de vida más centrada en el paciente. (Traducción-Dr. Yesenia Rojas-Khalil ).

"Your child needs surgery": A survey-based evaluation of simulated expert consent conversations by key stakeholders.

BACKGROUND: Consent conversations in pediatric surgery are essential components of pre-operative care which, when inadequate, can lead to significant adverse consequences for the child, parents, surgeon, and others in the healthcare system. The aim of this study is to explore expert consenting practice from the key stakeholders' perspective. METHODS: Four senior attending pediatric surgeons obtained consent from a standardized mother of a child requiring surgery in two scenarios: a low-risk elective surgery (inguinal hernia repair - Video 1), and a high-risk emergency surgery (intestinal atresia - Video 2). All sessions were recorded. Families of children who had undergone minor or major surgery, families without medical or surgical background, and healthcare professionals were invited to view and evaluate the videos using a semi-structured questionnaire. RESULTS: Out of 251 distributed surveys, 56 complete responses were received. Thirty two participants (57.1%) evaluated video 1 and 24 (42.9%) evaluated. Overall, 22 (69%) respondents to video 1 and 20 (84%) respondents to video 2 were "very satisfied" with the recorded consent conversation. Qualitative responses shared common themes of valuing surgeon empathy, good surgeon communication, patient engagement, and adequate time and information. Suggestions for improvement included additional resources and visual aids, improved patient engagement, and discussion of post-operative expectations. CONCLUSION: Our data identifies strengths and gaps in the current consent process from the perspective of patient families and providers. Identified areas for improvement in the informed consent process based on multi-stakeholder input will guide the planned development of a consenting educational video resource. LEVEL OF EVIDENCE: IV.

A retrospective analysis of early discharge following minimally invasive colectomy in an enhanced recovery pathway.

BACKGROUND: There is increasing evidence to support discharge prior to gastrointestinal recovery following colorectal surgery. Furthermore, many patients are discharged early despite being excluded from an ambulatory colectomy pathway. The objective of this study was to determine the outcomes of patients discharged early following laparoscopic colectomy in an enhanced recovery pathway (ERP). METHODS: A retrospective review of all adult patients undergoing elective laparoscopic colectomy at a single university-affiliated colorectal referral center (08/2017-06/2021) was performed. Patients were included if they had undergone elective laparoscopic colectomy or ileostomy closure and excluded if they had been enrolled in an ambulatory colectomy pathway. Patients were then divided into three groups: LOS =1 day, LOS 2-3 days, and LOS 4+ days. The main outcomes were 30-day emergency room (ER) visits and readmissions. Reasons for inpatient stay per post-operative day (POD) were also recorded. RESULTS: A total of 497 patients were included [LOS1 n = 63 (13%), LOS2-3 n = 284 (57%), and LOS4+ n = 150 (30%)]. There were no differences in patient characteristics, diagnosis, or procedure between the groups. Patients were discharged with gastrointestinal recovery (GI-3) in 54% LOS1 vs. 98% LOS2-3 vs. 100% LOS4+ (p<0.001). Shorter procedure duration, transversus abdominus plane block, and lower opioid requirements were associated with shorter LOS (p<0.001). The absence of flatus was the most common reason to keep patients hospitalized: 61% on POD1, 21% on POD2, and 8% on POD3 (p<0.001). There were no differences in 30-day emergency visits, or readmission between the groups. In the LOS1 group, there were no differences in outcomes between patients with full return of bowel function at discharge compared to those without. CONCLUSION: Discharge on POD1 was not associated with increased emergency department use, complications, or readmissions. Importantly, full return of bowel function at discharge did not affect outcomes. There may be potential to expand eligibility criteria for ambulatory colectomy protocol.

Does the Low Anterior Resection Syndrome Score Accurately Represent the Impact of Bowel Dysfunction on Health-Related Quality of Life?

BACKGROUND: Bowel dysfunction after rectal cancer surgery is common, but its effect on health-related quality of life (HRQOL) is complex. Objective measures of bowel function may not be a good representation on the actual impact on HRQOL. Therefore, the objective of this study is to determine whether there are differences between patient-reported bowel-related impairment versus a standardized measure of bowel dysfunction on HRQOL. METHODS: A prospective database starting in September 2018 of adult patients who had undergone sphincter preserving rectal cancer surgery up to October 2021 was queried. Patients were excluded if they had local recurrence, metastasis, persistent stoma, or had less than 1-year follow-up. Patients were administered the study instruments at their standard surveillance visit: patient-reported bowel-related quality of life(BQOL) impairment, HRQOL using the Short Form-36 (SF-36), and bowel dysfunction using the low anterior resection syndrome(LARS) score. RESULTS: Overall, 136 patients were included. There were 43% with no LARS, 22% with minor LARS, and 35% with major LARS. For the BQOL, 26% of subjects reported no impairment, 57% minor impairment, and 17% major impairment. There was a high proportion of discordance between BQOL and LARS, with 23% minor or major LARS in patients with no BQOL impairment, and 32% with no or minor LARS with major BQOL impairment. The BQOL was associated with more changes in SF-36 scores compared to the LARS score. CONCLUSIONS: The patient-reported BQOL is likely to be a more relevant outcome of interest to patients than the objective LARS score. This has important implications for shared decision-making for rectal cancer treatments.

Predictors of pre- and post-treatment bowel dysfunction severity in patients with rectal cancer.

BACKGROUND: Treatment of rectal cancer is frequently associated with low anterior resection syndrome. However, data concerning the contribution rectal tumors have on pretreatment bowel-dysfunction is scarce. We sought to evaluate the impact of the untreated rectal cancer on bowel-dysfunction and the relationship of pretreatment and post-treatment function. METHODS: A prospective database of adults with rectal cancer at a single university-affiliated colorectal referral center from August 2018 to March 2022 was queried. Bowel-dysfunction was measured using the low anterior resection syndrome score questionnaire (categorized as no, minor, or major low anterior resection syndrome) which was provided to patients at their primary visit, and after treatment. Patients were included if they underwent rectal cancer treatment and had pre- and post-treatment low anterior resection syndrome measurements. Observed low anterior resection syndrome scores were compared to normative low anterior resection syndrome data for age and sex-specific distributions from published data. Multiple multinomial regression compared pre- and post-treatment low anterior resection syndrome scores. RESULTS: Overall, 121 patients were included with mean age 62.0 years (standard deviation 12.3), 74% male, and mean tumor height 8.7 cm (standard deviation 5.72). The proportion of pretreatment observed low anterior resection syndrome were 48% no low anterior resection syndrome, 28% minor, and 24% major. Male and older patients were more likely to have worse than predicted low anterior resection syndrome categories (P < .05). On average, low anterior resection syndrome category did not change after treatment (P = .618) and pretreatment low anterior resection syndrome category was a significant independent predictor of post-treatment category (P = .037). CONCLUSION: Pretreatment bowel-dysfunction in rectal cancer patients is common and significantly worse than predicted for older and male patients. Importantly, pretreatment bowel-dysfunction predicted postoperative function. These results may better inform the shared decision-making process.

A mobile device application (app) to improve adherence to an enhanced recovery program for colorectal surgery: a randomized controlled trial.

BACKGROUND: Increased adherence with enhanced recovery pathways (ERP) is associated with improved outcomes. However, adherence to postoperative elements that rely on patient participation remains suboptimal. Mobile device apps may improve delivery of health education material and have the potential to foster behavior change and improve patient compliance. The objective of this study was to estimate the extent to which a novel mobile device app affects adherence to an ERP for colorectal surgery in comparison to standard written education. METHODS: This was a superiority, parallel-group, assessor-blind, sham-controlled randomized trial involving 97 patients undergoing colorectal resection. Participants were randomly assigned with a 1:1 ratio into one of two groups: (1) iPad including a novel mobile device app for postoperative education and self-assessment of recovery, or (2) iPad without the app. The primary outcome measure was mean adherence (%) to a bundle of five postoperative ERP elements requiring patient participation: mobilization, gastrointestinal motility stimulation, breathing exercises, and consumption of oral liquids and nutritional drinks. RESULTS: In the intervention group, app usage was high (94% completed surveys on POD0, 82% on POD1, 72% on POD2). Mean overall adherence to the bundle on the two first postoperative days was similar between groups: 59% (95% CI 52-66%) in the intervention group and 62% (95% CI 56-68%) in the control group [Adjusted mean difference 2.4% (95% CI - 5 to 10%) p = 0.53]. CONCLUSIONS: In this randomized trial, access to a mobile health application did not improve adherence to a well-established enhanced recovery pathway in colorectal surgery patients, when compared to standard written patient education. Future research should evaluate the impact of applications integrating novel behavioral change techniques, particularly in contexts where adherence is low.

Methylmercury alters glutathione homeostasis by inhibiting glutaredoxin 1 and enhancing glutathione biosynthesis in cultured human astrocytoma cells.

Methylmercury (MeHg) is a neurotoxin that binds strongly to thiol residues on protein and low molecular weight molecules like reduced glutathione (GSH). The mechanism of its effects on GSH homeostasis particularly at environmentally relevant low doses is not fully known. We hypothesized that exposure to MeHg would lead to a depletion of reduced glutathione (GSH) and an accumulation of glutathione disulfide (GSSG) leading to alterations in S-glutathionylation of proteins. Our results showed exposure to low concentrations of MeHg (1µM) did not significantly alter GSH levels but increased GSSG levels by ∼12-fold. This effect was associated with a significant increase in total cellular glutathione content and a decrease in GSH/GSSG. Immunoblot analyses revealed that proteins involved in glutathione synthesis were upregulated accounting for the increase in cellular glutathione. This was associated an increase in cellular Nrf2 protein levels which is required to induce the expression of antioxidant genes in response to cellular stress. Intriguingly, we noted that a key enzyme involved in reversing protein S-glutathionylation and maintaining glutathione homeostasis, glutaredoxin-1 (Grx1), was inhibited by ∼50%. MeHg treatment also increased the S-glutathionylation of a high molecular weight protein. This observation is consistent with the inhibition of Grx1 and elevated H2O2 production however; contrary to our original hypothesis we found few S-glutathionylated proteins in the astrocytoma cells. Collectively, MeHg affects multiple arms of glutathione homeostasis ranging from pool management to protein S-glutathionylation and Grx1 activity.