The Long-term Outcomes of Sacral Neuromodulation for Fecal Incontinence: A Single-Center Experience.

BACKGROUND: Sacral neuromodulation is an effective treatment for fecal incontinence. OBJECTIVE: To assess the long-term outcomes of sacral neuromodulation and establish the outcomes of patients with inactive devices. DESIGN: This is an observational study of patients treated for >5 years. A positive outcome was defined as a more than 50% reduction in fecal incontinence episodes or improvement in a symptom severity score. Data were reviewed from a prospectively managed database. SETTINGS: This study was conducted at a single tertiary referral center. PATIENTS: Data from 74 patients (72 women) were available at long-term follow-up. MAIN OUTCOME MEASURES: Bowel diary, St. Mark's incontinence score, and Manchester Health Questionnaire data were prospectively recorded at baseline, after percutaneous nerve evaluation, and at last follow-up. RESULTS: Patients were analyzed in cohorts based on time since sacral neuromodulation implantation: group 1: 5 to 10 years (n = 20), group 2: >10 years (n = 35), and group 3: inactive sacral neuromodulation devices (n = 19). Median St. Mark's incontinence score and Manchester Health Questionnaire improved from baseline to last follow-up in group 1 ( p ≤ 0.05) and group 2 ( p ≤ 0.05), but in group 3, results returned to baseline levels at the last follow-up. Similarly, weekly fecal incontinence episodes improved in both active device groups at the last follow-up. However, in group 3, incontinence episodes were no different from baseline ( p = 0.722). Despite active devices, fecal urgency episodes increased at the last follow-up after >10 years since percutaneous nerve evaluation ( p ≤ 0.05). Complete continence was reported by 44% of patients, and at least a 50% improvement was seen in 77% of patients with active devices. LIMITATIONS: This study is retrospective with some gaps in the available data at the last follow-up. CONCLUSIONS: Sacral neuromodulation is an effective treatment for fecal incontinence in the long term, but all outcomes are adversely affected by device inactivity. Therefore, ongoing stimulation is required for continued benefit. See Video Abstract. RESULTADOS A LARGO PLAZO DE LA NEUROMODULACIN SACRA PARA LA INCONTINENCIA FECAL EXPERIENCIA DE UN SOLO CENTRO: ANTECEDENTES:La neuromodulación sacra es un tratamiento eficaz para la incontinencia fecal.OBJETIVO:Este estudio tuvo como objetivo evaluar los resultados a largo plazo de la neuromodulación sacra y establecer los resultados de los pacientes con dispositivos inactivos.DISEÑO:Este es un estudio observacional de pacientes tratados durante más de 5 años. Un resultado positivo se definió como una reducción >50 % en los episodios de incontinencia fecal o una mejoría en la puntuación de gravedad de los síntomas. Los datos se revisaron a partir de una base de datos administrada prospectivamente.ENTERNO CLINICO:Este estudio se realizó en un solo centro de referencia terciario.PACIENTES:Los datos de 74 pacientes (72 mujeres) estaban disponibles en el seguimiento a largo plazo.PRINCIPALES MEDIDAS DE RESULTADO:Diario intestinal, puntuación de incontinencia de St. Mark y datos del Cuestionario de salud de Manchester se registraron prospectivamente al inicio, después de la evaluación de nervio periférico y en el último seguimiento.RESULTADOS:Los pacientes se analizaron en cohortes según el tiempo transcurrido desde la implantación de la neuromodulación sacra: Grupo 1: 5-10 años (n = 20), Grupo 2: >10 años (n = 35) y Grupo 3: dispositivos SNM inactivos (n = 19). La mediana de la puntuación de incontinencia de St. Mark y Questionnaire Cuestionario de salud de Manchester mejoraron desde el inicio hasta el último seguimiento en el Grupo 1 (p = < 0,05) y el Grupo 2 (p = < 0,05), pero en el Grupo 3 los resultados volvieron a los niveles iniciales en el último seguimiento. arriba. De manera similar, los episodios semanales de incontinencia fecal mejoraron en ambos grupos de dispositivos activos en el último seguimiento. Sin embargo, en el Grupo 3 los episodios de incontinencia no fueron diferentes de los basales (p = 0,722). A pesar de los dispositivos activos, los episodios de urgencia fecal aumentaron en el último seguimiento después de más de 10 años desde la evaluación del nervio periférico (p = < 0,05). Continencia completa se reportó en el 44 % de los pacientes, y al menos una mejora del 50 % en el 77 % con dispositivos activos.LIMITACIONES:Este estudio es retrospectivo con algunas vacíos en los datos disponibles en el último seguimiento.CONCLUSIONES:La neuromodulación sacra es un tratamiento eficaz para la incontinencia fecal a largo plazo, pero todos los resultados se ven afectados negativamente por la inactividad del dispositivo. Por lo tanto, se requiere estimulación continua para un beneficio continuo. (Traducción- Dr. Francisco M. Abarca-Rendon ).

The effects of a comparatively higher dose of 1000 mg/kg/d of oral L- or D-arginine on the L-arginine metabolic pathways in male Sprague-Dawley rats.

Oral L-arginine supplements are popular mainly for their nitric oxide mediated vasodilation, but their physiological impact is not fully known. L-arginine is a substrate of several enzymes including arginase, nitric oxide synthase, arginine decarboxylase, and arginine: glycine amidinotransferase (AGAT). We have published a study on the physiological impact of oral L- and D-arginine at 500 mg/kg/day for 4 wks in male Sprague-Dawley rats. We investigated the effects of oral L-arginine and D-arginine at a higher dose of 1000 mg/kg/d for a longer treatment duration of 16 wks in 9-week-old male Sprague-Dawley rats. We measured the expression and activity of L-arginine metabolizing enzymes, and levels of their metabolites in the plasma and various organs. L-arginine did not affect the levels of L-arginine and L-lysine in the plasma and various organs. L-arginine decreased arginase protein expression in the upper small intestine, and arginase activity in the plasma. It also decreased AGAT protein expression in the liver, and creatinine levels in the urine. L-arginine altered arginine decarboxylase protein expression in the upper small intestine and liver, with increased total polyamines plasma levels. Endothelial nitric oxide synthase protein was increased with D-arginine, the presumed metabolically inert isomer, but not L-arginine. In conclusion, oral L-arginine and D-arginine at a higher dose and longer treatment duration significantly altered various enzymes and metabolites in the arginine metabolic pathways, which differed from alterations produced by a lower dose shorter duration treatment published earlier. Further studies with differing doses and duration would allow for a better understanding of oral L-arginine uses, and evidence based safe and effective dose range and duration.

Removal of Sacral Neuromodulation Devices Is an Office Procedure.

OBJECTIVE: To present our experience removing sacral neuromodulation (SNM) components under local in the office. In some instances, SNM devices need to be removed. Traditionally, permanent lead and/or implantable pulse generator (IPG) removals are done in the operating room under sedation. However, it is our practice to perform this procedure in the office using only local anesthesia. MATERIALS AND METHODS: We performed a retrospective chart review from 2017 to 2022 of SNM lead and IPG removals performed under local anesthesia in the office by a single surgeon. Patient characteristics, outcomes, and complications were reported. RESULTS: From 2017 to 2022, 41 SNM leads with and without IPGs were removed in the office using local anesthesia. 88% were female, mean age 66 ± 15.8years, and mean body mass index 28.6 (19.1-49.4). The most common indications for SNM treatment were urgency incontinence (56%) and nonobstructive urinary retention (24%). 44% (18/41) of SNM device removals were leads removed after failed stage I and 56% (23/41) were leads with IPGs removed most commonly for decreased efficacy (52%). In the latter group, median time to removal was 3.1 (0.3-12.3) years, and 52% (12/23) required a separate medial incision for lead retrieval. 9% (2/23) required fluoroscopy, of which, one was planned secondary to body mass index 49.4, and the other needed secondary to excessive scar tissue. No stage I failures required fluoroscopy. 7% (3/41) of leads required cutdown to the sacrum for removal with leads in place between 3.1 and 3.9years. All leads were removed completely intact and there were no complications. CONCLUSION: Removal of SNM devices in the office using local anesthesia is effective, well-tolerated, and safe.

Feasibility and Acceptability of Online Recruitment and an Online Brief Mindfulness Intervention Among Patients With Sickle Cell Disease.

Background Pain among young adult patients with sickle cell disease (PWSCD) is a highly significant public health problem associated with reduced quality of life. Due to issues uniquely affecting PWSCD, including distrust of research, challenging life situations, debilitating pain, stigma, and logistical challenges (e.g., child or elder care and transportation), SCD researchers often find it challenging to meet sample size and enrollment targets. To our knowledge, all known SCD studies have solely recruited participants in person (e.g., clinics and local organizations) and utilized lengthy interventions with suboptimal recruitment and retention results. Newer recruitment methods, such as online recruitment, need to be explored for research among PWSCD. In this pilot project, we sought to address these challenges by investigating: 1) a novel method of using online outreach to recruit/enroll young PWSCD and 2) a novel, brief online mindfulness intervention adapted from Mindfulness-Oriented Recovery Enhancement (MORE): Mini-MORE designed to treat pain among PWSCD.  Methods Participants (N = 32) were recruited online (e.g., paid advertisements on Facebook and NextDoor; free advertisements on Facebook groups and Reddit) and screened by phone from October 25 to November 8, 2022. Participants watched an online Mini-MORE video. Immediately before and after watching the video, participants rated their pain intensity and unpleasantness on an 11-point numeric rating scale (NRS). Afterward, participants were emailed an individualized link to additional audio recordings for ongoing practice. Immediately before and after accessing the additional recordings, participants rated their pain intensity, anxiety, and depression on an 11-point NRS. T-tests were used to examine the impact of Mini MORE on outcomes at two-time points. Results A total of 84 participants completed the self-screening. The majority of self-screeners resulted from free posts in Facebook groups (77%), Reddit (1%), and Craigslist (6%). Thirty-two (32) eligible participants agreed to join a Zoom meeting to watch the video. The entire Mini-MORE video was viewed by 31 of 32 participants (97%). Pain intensity decreased by 1.7 points (p<0.001, Cohen's d=2.19), and pain unpleasantness decreased by 2.1 points (p<0.001, Cohen's d=2.20). Listening to the supplemental recordings was associated with significant, immediate decreases in pain intensity by 1.3 points (p=0.015, Cohen's d=2.05), anxiety by 1.8 points (p=0.022, Cohen's d=3.10), and depression by 1.74 points (p=0.019, Cohen's d=2.94). Conclusions Results suggest that online methods are feasible in recruiting and enrolling young PWSCD, and the online Mini-MORE intervention is acceptable among PWSCD. Future research is needed to assess whether Mini-MORE is associated with decreased pain symptomology in young PWSCD.

The Emergency Medical Services Sleep Health Study: A cluster-randomized trial.

BACKGROUND: Greater than half of emergency medical services (EMS) clinician shift workers report poor sleep, fatigue, and inadequate recovery between shifts. We hypothesized that EMS clinicians randomized to receive tailored sleep health education would have improved sleep quality and less fatigue compared to wait-list controls after 3 months. METHODS: We used a cluster-randomized, 2-arm, wait-list control study design (clinicaltrials.gov identifier: NCT04218279). Recruitment of EMS agencies (clusters) was nationwide. Our study was powered at 88% to detect a 0.4 standard deviation difference in sleep quality with 20 agencies per arm and a minimum of 10 individuals per agency. The primary outcome was measured using the Pittsburgh Sleep Quality Index (PSQI) at 3-month follow-up. Our intervention was accessible in an online, asynchronous format and comprised of 10 brief education modules that address fatigue mitigation topics prescribed by the American College of Occupational Environmental Medicine. RESULTS: In total, 36 EMS agencies and 678 individuals enrolled. Attrition at 3 months did not differ by study group (Intervention = 17.4% vs. Wait-list control = 18.2%; p = .37). Intention-to-treat analyses detected no differences in PSQI and fatigue scores at 3 months. Per protocol analyses showed the greater the number of education modules viewed, the greater the improvement in sleep quality and the greater the reduction in fatigue (p < .05). CONCLUSIONS: While intention-to-treat analyses revealed no differences in sleep quality or fatigue at 3 months, per protocol findings identified select groups of EMS clinician shift workers who may benefit from sleep health education. Our findings may inform fatigue risk management programs.

International perspective on integrated care models in child and adult mental health.

The dearth of child and adolescent mental health services (CAMHS) is a global problem. Integrating CAMHS in primary care has been offered as a solution. We sampled integrated care perspectives from colleagues around the world. Our findings include various models of integrated care namely: the stepped care model in Australia; shared care in the United Kingdom (UK) and Spain; school-based collaborative care in Qatar, Singapore and the state of Texas in the US; collaborative care in Canada, Brazil, US, and Uruguay; coordinated care in the US; and, developing collaborative care models in low-resource settings, like Kenya and Micronesia. These findings provide insights into training initiatives necessary to build CAMHS workforce capacity using integrated care models, each with the ultimate goal of improving access to care. Despite variations and progress in implementing integrated care models internationally, common challenges exist: funding within complex healthcare systems, limited training mechanisms, and geopolitical/policy issues. Supportive healthcare policy, robust training initiatives, ongoing quality improvement and measurement of outcomes across programs would provide data-driven support for the expansion of integrated care and ensure its sustainability.

Is sacral neuromodulation effective in patients with Parkinson's disease? A retrospective review.

INTRODUCTION AND OBJECTIVE: Parkinson's disease (PD) is the second-most common degenerative neurologic disease worldwide. Overactive bladder (OAB) is prevalent in this population but can be challenging to treat. Sacral neuromodulation (SNM) is an attractive option but remains understudied. We have utilized SNM in PD patients and herein describe our outcomes. METHODS: We performed a retrospective chart review of PD patients who underwent peripheral nerve evaluation (PNE) or Stage 1 SNM from 2000 to 2020. The primary outcome was progression to a permanent implant. The impact of PD stage and preprocedural urodynamic (UDS) parameters on test-phase outcome were investigated. Long-term efficacy was assessed using Wilcoxon matched-pairs test looking at a change in urinary symptoms (frequency, nocturia, incontinence episodes, and pad use) documented at follow-up visits and further need for treatment. RESULTS: Thirty-four patients underwent test phase SNM (7 PNE and 27 Stage 1). Median follow-up was 11 (interquartile range 5.8-29.8) months. Indications included refractory OAB (30/34) and nonobstructive urinary retention (4/34). Overall, 82% (28/34) of patients proceeded to a permanent implant. 71% (5/7) of PNEs were successful. Test-phase success did not differ based on PD disease severity or UDS parameters. In patients with OAB/urgency incontinence who progressed to the permanent implant, there was a statistically significant improvement in their urinary symptoms from baseline. Most (68%) patients were able to discontinue OAB medications post-implant. The overall lead revision rate was 14% (4/28) and 3 devices required removal. CONCLUSIONS: SNM is an efficacious treatment option for PD patients with a high percentage of patients having improvement in their urinary symptoms.

Stress and Resilience Among Healthcare Workers During the COVID-19 Pandemic: Consideration of Case Studies.

ABSTRACT: The COVID-19 pandemic has caused a significant increase in stress for frontline healthcare workers, including rehabilitation workers. Contributing factors include disrupted workflows, heavier workloads, increased time restraints, and fear of contracting/passing the virus. Prolonged high stress levels can produce adverse health outcomes when unaddressed. Resilience can mitigate the negative effects of prolonged stress. Four healthcare workers relate their experiences from the frontlines of the pandemic, discussing their strategies to build resilience and maintain health. Highlighted strategies include mindfulness (the purposeful act of paying attention to the present moment without judgment), gratitude (the practice of being grateful for the positive things in life), self-care (the maintenance of a healthy lifestyle using physical, psychological, and emotional tools), and social support (the sense of belonging that comes from being cared for and valued). These strategies reduce negative outcomes produced by elevated stress levels and promote resilience in frontline healthcare workers.

Building Nurses' Resilience to Trauma Through Contemplative Practices.

Nurses can benefit from strategies that build resilience to counterbalance trauma exposures. Adverse childhood experiences (ACEs) and adverse community environments are common; nurses frequently encounter trauma victims and hear trauma narratives in most care settings. Having skills to manage the triggers present in health-care environments is essential. Contemplative practices can help to meet these needs. Breathing exercises can be used as needed throughout the work day; gratitude practices are simple but powerful; and visual journaling can help nurses process experiences. These practices are easy to implement and can profoundly affect health outcomes for nurses.

Autonomically-mediated decrease in microvascular blood flow due to mental stress and pain in sickle cell disease: A target for neuromodulatory interventions.

Pain and vaso-occlusive crises (VOC) are hallmark complications of sickle cell disease (SCD) and result in significant physical and psychosocial impairment. The variability in SCD pain frequency and triggers for the transition from steady state to VOC are not well understood. This paper summarizes the harmful physiological effects of pain and emotional stressors on autonomically-mediated vascular function in individuals with SCD and the effects of a cognitive, neuromodulatory intervention (i.e. hypnosis) on microvascular blood flow. We reviewed recent studies from the authors' vascular physiology laboratory that assessed microvascular responses to laboratory stressors in individuals with SCD. Results indicate that participants with SCD exhibit marked neurally mediated vascular reactivity in response to pain, pain-related fear, and mental stress. Further, pilot study results show that engagement in hypnosis may attenuate harmful microvascular responses to pain. The collective results demonstrate that autonomically-mediated vascular responses to pain and mental stress represent an important SCD intervention target. This ongoing work provides physiological justification for the inclusion of cognitive, neuromodulatory and complementary treatments in SCD disease management and may inform the development of targeted, integrative interventions that prevent the enhancement of autonomic vascular dysfunction in SCD.

The effects of oral arginine on its metabolic pathways in Sprague-Dawley rats.

Oral arginine supplements are popular mainly for their presumed vasodilatory benefit. Arginine is a substrate for at least four enzymes including nitric oxide synthase (NOS) and arginase, but the impact of oral supplements on its different metabolic pathways is not clear. Deficiencies of arginine-metabolising enzymes are associated with conditions such as hyperammonaemia, endothelial dysfunction, central nervous system and muscle dysfunction, which complicate the use of oral arginine supplements. We examined the effect of l-arginine (l-Arg) and d-arginine (d-Arg), each at 500 mg/kg per d in drinking water administered for 4 weeks to separate groups of 9-week-old male Sprague-Dawley rats. We quantified the expression of enzymes and plasma, urine and organ levels of various metabolites of arginine. l-Arg significantly decreased cationic transporter-1 expression in the liver and the ileum and increased endothelial NOS expression in the aorta and the kidney and plasma nitrite levels, but did not affect the mean arterial pressure. l-Arg also decreased the expression of arginase II in the ileum, arginine:glycine amidinotransferase in the liver and the kidney and glyoxalase I in the liver, ileum and brain, but increased the expression of arginine decarboxylase and polyamines levels in the liver. d-Arg, the supposedly inert isomer, also unexpectedly affected the expression of some enzymes and metabolites. In conclusion, both l- and d-Arg significantly affected enzymes and metabolites in several pathways that use arginine as a substrate and further studies with different doses and treatment durations are planned to establish their safety or adverse effects to guide their use as oral supplements.

A Novel Approach to Managing Post Retropubic Vaginal Sling Pain.

OBJECTIVE: To describe a novel technique of using peripheral nerve neuromodulation (PNNM) for the treatment of refractory, mesh-induced chronic pelvic pain. Chronic pelvic pain associated with mesh can be a debilitating complication and there is currently no consensus on treatment. PNNM has been shown to be successful in the treatment of post-traumatic neuralgias but has yet to be studied in mesh complications. MATERIALS AND METHODS: We present a case of a 50-year-old woman who had unrelenting pelvic pain after retropubic sling placement. She failed multiple therapies including medications, mesh removal, pelvic floor physical therapy, pudendal neuromodulation, and pelvic floor onabotulinumtoxinA trigger point injections. RESULTS: The only treatment that provided temporary relief of this patient's pain was transvaginal trigger point injections along with a right pudendal nerve block using 40 mg triamcinolone and 0.5% ropivacaine. To help define if treatment at the site of her pain would provide relief, a series of blocks were done by advancing a needle retropubically to her area of pain and injecting triamcinolone and 0.5% ropivacaine. This injection, which corresponded to the previous tract of her retropubic sling, provided temporary, but profound, relief. PNNM was then done with placement of the electrode in the retropubic space at the site of her pain. This provided instantaneous relief of almost all of her pain symptoms. Twelve months postoperatively, the patient continued to have >90% improvement in her pain. CONCLUSION: Focused PNNM is a simple procedure and can provide symptomatic relief for refractory postvaginal mesh pain.

Feasibility and Acceptance Testing of a Mobile Application Providing Psychosocial Support for Parents of Children and Adolescents With Chronic Pain: Results of a Nonrandomized Trial.

Objective To conduct a single-arm pilot study assessing the feasibility and acceptability of a 30-day parent-focused mindfulness and psychosocial support mobile app intervention for parents of children with chronic pain. Methods Thirty parents completed the intervention, which included a mindfulness curriculum, peer support videos, and written psychoeducational content. Twelve healthcare providers also assessed the app and provided feedback. Feasibility was assessed by server-side documented usage on ≥50% of the days in the intervention period and completion of ≥70% of the mindfulness content. Parent and provider acceptance were assessed by ≥70% of participants rating each acceptance test question as ≥5 on a 7-point Likert scale. Parents completed measures of solicitousness, stress, mindful parenting, and resilience prior to and following the intervention. Results Feasibility results were mixed: parents completed mindfulness content on an average of 11.2 days during the intervention period, slightly under the pre-established criterion. However, parents completed an average of 72.1% of the content, which met feasibility criterion. Acceptance criteria were met for the majority of parent acceptance test questions and all of the provider acceptance test questions. Exploratory analyses of the psychosocial measures revealed significant decreases in parental solicitous behavior and perceived stress, and a significant increase in mindful parenting. Conclusions The current study extends the emerging body of research on mindfulness-based interventions for parents of children with chronic illness and suggests that it may be acceptable to deliver this content through a mobile device. Future research is needed to assess the intervention's efficacy compared to standard of care.

A Mobile-Based Mindfulness and Social Support Program for Adolescents and Young Adults With Sarcoma: Development and Pilot Testing.

BACKGROUND: Approximately 70,000 adolescents and young adults (AYA) are diagnosed with cancer each year in the United States. Sarcomas carry a particularly high symptom burden and are some of the most common cancers among AYA. Recent work has documented significant levels of unmet needs among AYA with cancer, particularly the need for psychosocial support. Mobile technology may be a cost-effective and efficient way to deliver a psychosocial intervention to AYA with cancer and cancer survivors. OBJECTIVE: The two aims of this study were to (1) develop a pilot version of a mobile-based mindfulness and social support program and (2) evaluate program usage and acceptability. An exploratory aim was to examine change in psychosocial outcomes. METHODS: Thirty-seven AYA with sarcoma or sarcoma survivors, parents, and health care providers participated in the study. Semistructured interviews were conducted with 10 AYA, parents of five of the adolescents, and six health care providers. Themes from the interviews helped to inform the development of a mobile-based mindfulness pilot program and a companion Facebook-based social support group. Twenty AYA consented to participate in a single-arm pre-post evaluation of the program; 17 downloaded the app and joined the Facebook group. Seven of these participants had participated in the semistructured interviews. Six additional health care providers consented to participate in the evaluation stage. RESULTS: On average, participants completed 16.9 of the 28 unique sessions and used the mindfulness app for a mean 10.2 (SD 8.2) days during the 28-day evaluation period. The majority of participants (16/17) engaged in the social group and posted at least one reply to the moderator's prompts. The mean number of responses per person to the moderator of the social group was 15.2 of 31 (49%, range 0%-97%). Both AYA and health care providers responded positively to the Mindfulness for Resilience in Illness program and offered useful recommendations for improvements. Exploratory psychosocial analyses indicated there were no significant differences from pretest to posttest on measures of perceived social support, mindfulness, body image, or psychological functioning. CONCLUSIONS: This study offers preliminary support for the feasibility and acceptability of a mobile-based mindfulness and Facebook-based social support program for AYA with sarcoma. The feedback from AYA and health care providers will assist in creating a fully developed intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT03130751; https://clinicaltrials.gov/ct2/show/NCT03130751.

Pediatric Irritable Bowel Syndrome: Perspectives on Pain and Adolescent Social Functioning.

OBJECTIVE: The goal of the study was to describe the experiences of adolescents with irritable bowel syndrome (IBS) from the perspective of adolescents, their parents, and health care providers who treat adolescents who have IBS. DESIGN: The study consisted of semistructured interviews. SETTING: Participants were recruited from multidisciplinary pain clinics. SUBJECTS: Thirty-six people participated in the study: 12 adolescents, 12 parents, and 12 health care providers. RESULTS: Two main themes associated with the impact of IBS on adolescents' social functioning emerged from the qualitative interview data: 1) disconnection from peers and 2) strain on family relationships, with subthemes reflecting the perspectives of adolescents, parents, and health care providers. CONCLUSIONS: Participants in our study described that adolescents with IBS encounter significant peer- and family-related social stress. Helpful interventions may be those that focus on social support from other adolescents with similar conditions, as well as family-based therapeutic interventions.

The effect of hypnosis on pain and peripheral blood flow in sickle-cell disease: a pilot study.

BACKGROUND: Vaso-occlusive pain crises (VOCs) are the "hallmark" of sickle-cell disease (SCD) and can lead to sympathetic nervous system dysfunction. Increased sympathetic nervous system activation during VOCs and/or pain can result in vasoconstriction, which may increase the risk for subsequent VOCs and pain. Hypnosis is a neuromodulatory intervention that may attenuate vascular and pain responsiveness. Due to the lack of laboratory-controlled pain studies in patients with SCD and healthy controls, the specific effects of hypnosis on acute pain-associated vascular responses are unknown. The current study assessed the effects of hypnosis on peripheral blood flow, pain threshold, tolerance, and intensity in adults with and without SCD. SUBJECTS AND METHODS: Fourteen patients with SCD and 14 healthy controls were included. Participants underwent three laboratory pain tasks before and during a 30-minute hypnosis session. Peripheral blood flow, pain threshold, tolerance, and intensity before and during hypnosis were examined. RESULTS: A single 30-minute hypnosis session decreased pain intensity by a moderate amount in patients with SCD. Pain threshold and tolerance increased following hypnosis in the control group, but not in patients with SCD. Patients with SCD exhibited lower baseline peripheral blood flow and a greater increase in blood flow following hypnosis than controls. CONCLUSION: Given that peripheral vasoconstriction plays a role in the development of VOC, current findings provide support for further laboratory and clinical investigations of the effects of cognitive-behavioral neuromodulatory interventions on pain responses and peripheral vascular flow in patients with SCD. Current results suggest that hypnosis may increase peripheral vasodilation during both the anticipation and experience of pain in patients with SCD. These findings indicate a need for further examination of the effects of hypnosis on pain and vascular responses utilizing a randomized controlled trial design. Further evidence may help determine unique effects of hypnosis and potential benefits of integrating cognitive-behavioral neuromodulatory interventions into SCD treatment.

The benefit of evolving multidisciplinary care in ALS: a diagnostic cohort survival comparison.

BACKGROUND: Care for people with amyotrophic lateral sclerosis (ALS) has altered at King's College Hospital over the last 20 years. The clinic has been a multidisciplinary, specialist, tertiary referral centre since 1995 with a large team with integrated palliative and respiratory care since 2006. We hypothesised that these changes would improve survival. METHODS: In this retrospective observational study, patients diagnosed with El Escorial definite, probable and possible ALS between 1995-1998 and 2008-2011 were followed up. The primary outcome measure was a chi-square test for the proportion of each cohort surviving. Kaplan-Meier survival analysis and Cox multivariate regression were secondary analyses. RESULTS: There was low reporting of some interventions. Five hundred and forty-seven people were included. Survival between the cohorts was significantly different (p = 0.022) with a higher proportion surviving during 2008-2011. Survival time was 21.6 (95% CI 19.2-24.0) months in the 2008-2011 cohort compared to 19.2 years (15.6-21.6) in the 1995-1998 cohort (log rank p = 0.018). Four hundred and ninety-three cases were included in the Cox regression. Diagnostic cohort was a significant predictor variable (HR 0.79 (0.64-0.97) p = 0.023). CONCLUSIONS: These results support the hypothesis that integrated specialist clinics with multidisciplinary input improve survival in ALS.

Rock geochemistry induces stress and starvation responses in the bacterial proteome.

Interactions between microorganisms and rocks play an important role in Earth system processes. However, little is known about the molecular capabilities microorganisms require to live in rocky environments. Using a quantitative label-free proteomics approach, we show that a model bacterium (Cupriavidus metallidurans CH34) can use volcanic rock to satisfy some elemental requirements, resulting in increased rates of cell division in both magnesium- and iron-limited media. However, the rocks also introduced multiple new stresses via chemical changes associated with pH, elemental leaching and surface adsorption of nutrients that were reflected in the proteome. For example, the loss of bioavailable phosphorus was observed and resulted in the upregulation of diverse phosphate limitation proteins, which facilitate increase phosphate uptake and scavenging within the cell. Our results revealed that despite the provision of essential elements, rock chemistry drives complex metabolic reorganization within rock-dwelling organisms, requiring tight regulation of cellular processes at the protein level. This study advances our ability to identify key microbial responses that enable life to persist in rock environments.

Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains.

Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromodomain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromodomain of BRD4 (BRD4(1)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(1) was increased. The optimized compound is highly potent (Kd = 21 nM) and selective, displaying 40-fold selectivity over BRD4(1). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nanomolar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromodomains as therapeutic targets.