Impact of study design on adenoma detection in the evaluation of artificial intelligence-aided colonoscopy: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Randomized controlled trials (RCTs) have reported that artificial intelligence (AI) improves endoscopic polyp detection. Different methodologies-namely, parallel and tandem designs-have been used to evaluate the efficacy of AI-assisted colonoscopy in RCTs. Systematic reviews and meta-analyses have reported a pooled effect that includes both study designs. However, it is unclear whether there are inconsistencies in the reported results of these 2 designs. Here, we aimed to determine whether study characteristics moderate between-trial differences in outcomes when evaluating the effectiveness of AI-assisted polyp detection. METHODS: A systematic search of Ovid MEDLINE, Embase, Cochrane Central, Web of Science, and IEEE Xplore was performed through March 1, 2023, for RCTs comparing AI-assisted colonoscopy with routine high-definition colonoscopy in polyp detection. The primary outcome of interest was the impact of study type on the adenoma detection rate (ADR). Secondary outcomes included the impact of the study type on adenomas per colonoscopy and withdrawal time, as well as the impact of geographic location, AI system, and endoscopist experience on ADR. Pooled event analysis was performed using a random-effects model. RESULTS: Twenty-four RCTs involving 17,413 colonoscopies (AI assisted: 8680; non-AI assisted: 8733) were included. AI-assisted colonoscopy improved overall ADR (risk ratio [RR], 1.24; 95% confidence interval [CI], 1.17-1.31; I2 = 53%; P < .001). Tandem studies collectively demonstrated improved ADR in AI-aided colonoscopies (RR, 1.18; 95% CI, 1.08-1.30; I2 = 0%; P < .001), as did parallel studies (RR, 1.26; 95% CI, 1.17-1.35; I2 = 62%; P < .001), with no statistical subgroup difference between study design. Both tandem and parallel study designs revealed improvement in adenomas per colonoscopy in AI-aided colonoscopies, but this improvement was more marked among tandem studies (P < .001). AI assistance significantly increased withdrawal times for parallel (P = .002), but not tandem, studies. ADR improvement was more marked among studies conducted in Asia compared to Europe and North America in a subgroup analysis (P = .007). Type of AI system used or endoscopist experience did not affect overall improvement in ADR. CONCLUSIONS: Either parallel or tandem study design can capture the improvement in ADR resulting from the use of AI-assisted polyp detection systems. Tandem studies powered to detect differences in endoscopic performance through paired comparison may be a resource-efficient method of evaluating new AI-assisted technologies.

The development, implementation, and evaluation of an optimal model for the case detection, referral, and case management of Neglected Tropical Diseases.

BACKGROUND: People affected by Neglected Tropical Diseases (NTDs), specifically leprosy, Buruli ulcer (BU), yaws, and lymphatic filariasis, experience significant delays in accessing health services, often leading to catastrophic physical, psychosocial, and economic consequences. Global health actors have recognized that Sustainable Development Goal 3:3 is only achievable through an integrated inter and intra-sectoral response. This study evaluated existing case detection and referral approaches in Liberia, utilizing the findings to develop and test an Optimal Model for integrated community-based case detection, referral, and confirmation. We evaluate the efficacy of implementing the Optimal Model in improving the early diagnosis of NTDs, thus minimizing access delays and reducing disease burden. METHODS: We used a participatory action research approach to develop, implement, and evaluate an Optimal Model for the case detection, referral, and management of case management NTDs in Liberia. We utilized qualitative and quantitative methods throughout the cycle and implemented the model for 12 months. RESULTS: During the implementation of our optimal model, the annual number of cases detected increased compared to the previous year. Cases were detected at an earlier stage of disease progression, however; gendered dynamics in communities shape the case identification process for some individuals. Qualitative data showed increased knowledge of the transmission, signs, symptoms, and management options among community health workers (CHW). CONCLUSION: The results provide evidence of the benefits of an integrated approach and the programmatic challenges to improve access to health services for persons affected by NTDs. The effectiveness of an integrated approach depends on a high level of collaboration, joint planning, and implementation embedded within existing health systems infrastructure.

Perceived impacts of COVID-19 responses on routine health service delivery in Liberia and UK: cross-country lessons for resilient health systems for equitable service delivery during pandemics.

BACKGROUND: COVID-19 has caused significant public health problems globally, with catastrophic impacts on health systems. This study explored the adaptations to health services in Liberia and Merseyside UK at the beginning of the COVID-19 pandemic (January-May 2020) and their perceived impact on routine service delivery. During this period, transmission routes and treatment pathways were as yet unknown, public fear and health care worker fear was high and death rates among vulnerable hospitalised patients were high. We aimed to identify cross-context lessons for building more resilient health systems during a pandemic response. METHODS: The study employed a cross-sectional qualitative design with a collective case study approach involving simultaneous comparison of COVID-19 response experiences in Liberia and Merseyside. Between June and September 2020, we conducted semi-structured interviews with 66 health system actors purposively selected across different levels of the health system. Participants included national and county decision-makers in Liberia, frontline health workers and regional and hospital decision-makers in Merseyside UK. Data were analysed thematically in NVivo 12 software. RESULTS: There were mixed impacts on routine services in both settings. Major adverse impacts included diminished availability and utilisation of critical health services for socially vulnerable populations, linked with reallocation of health service resources for COVID-19 care, and use of virtual medical consultation in Merseyside. Routine service delivery during the pandemic was hampered by a lack of clear communication, centralised planning, and limited local autonomy. Across both settings, cross-sectoral collaboration, community-based service delivery, virtual consultations, community engagement, culturally sensitive messaging, and local autonomy in response planning facilitated delivery of essential services. CONCLUSION: Our findings can inform response planning to assure optimal delivery of essential routine health services during the early phases of public health emergencies. Pandemic responses should prioritise early preparedness, with investment in the health systems building blocks including staff training and PPE stocks, address both pre-existing and pandemic-related structural barriers to care, inclusive and participatory decision-making, strong community engagement, and effective and sensitive communication. Multisectoral collaboration and inclusive leadership are essential.

Qualitative study exploring lessons from Liberia and the UK for building a people-centred resilient health systems response to COVID-19.

INTRODUCTION: COVID-19 has tested the resilience of health systems globally and exposed existing strengths and weaknesses. We sought to understand health systems COVID-19 adaptations and decision making in Liberia and Merseyside, UK. METHODS: We used a people-centred approach to carry out qualitative interviews with 24 health decision-makers at national and county level in Liberia and 42 actors at county and hospital level in the UK (Merseyside). We explored health systems' decision-making processes and capacity to adapt and continue essential service delivery in response to COVID-19 in both contexts. RESULTS: Study respondents in Liberia and Merseyside had similar experiences in responding to COVID-19, despite significant differences in health systems context, and there is an opportunity for multidirectional learning between the global south and north. The need for early preparedness; strong community engagement; clear communication within the health system and health service delivery adaptations for essential health services emerged strongly in both settings. We found the Foreign, Commonwealth and Development Office (FCDO) principles to have value as a framework for reviewing health systems changes, across settings, in response to a shock such as a pandemic. In addition to the eight original principles, we expanded to include two additional principles: (1) the need for functional structures and mechanisms for preparation and (2) adaptable governance and leadership structures to facilitate timely decision making and response coordination. We find the use of a people-centred approach also has value to prompt policy-makers to consider the acceptance of service adaptations by patients and health workers, and to continue the provision of 'routine services' for individuals during health systems shocks. CONCLUSION: Our study highlights the importance of a people-centred approach, placing the person at the centre of the health system, and value in applying and adapting the FCDO principles across diverse settings.

The GoodHope Ehlers Danlos Syndrome Clinic: development and implementation of the first interdisciplinary program for multi-system issues in connective tissue disorders at the Toronto General Hospital.

Ehlers-Danlos Syndrome (EDS) are a heterogeneous group of genetic connective tissue disorders, and typically manifests as weak joints that subluxate/dislocate, stretchy and/or fragile skin, organ/systems dysfunction, and significant widespread pain. Historically, this syndrome has been poorly understood and often overlooked. As a result, people living with EDS had difficulty obtaining an accurate diagnosis and appropriate treatment, leading to untold personal suffering as well as ineffective health care utilization. The GoodHope EDS clinic addresses systemic gaps in the diagnosis and treatment of EDS. This paper describes a leap forward-from lack of awareness, diagnosis, and treatment-to expert care that is tailored to meet the specific needs of patients with EDS. The GoodHope EDS clinic consists of experts from various medical specialties who work together to provide comprehensive care that addresses the multi-systemic nature of the syndrome. In addition, EDS-specific self-management programs have been developed that draw on exercise science, rehabilitation, and health psychology to improve physical and psychosocial wellbeing and overall quality of life. Embedded into the program are research initiatives to shed light on the clinical presentation, underlying mechanisms of pathophysiology, and syndrome management. We also lead regular educational activities for community health care providers to increase awareness and competence in the interprofessional management of EDS beyond our doors and throughout the province and country.

The Role of Resilience in Irritable Bowel Syndrome, Other Chronic Gastrointestinal Conditions, and the General Population.

BACKGROUND & AIMS: Resilience is the ability to adapt positively to stress and adversity. It is a potential therapeutic target as it is reduced in irritable bowel syndrome (IBS) compared to healthy controls and associated with worse symptom severity and poorer quality of life. The aim of this study was to examine if these findings are generalizable by comparing resilience between IBS versus the general population and other chronic gastrointestinal (GI) conditions. METHODS: Participants in the general population completed an online survey containing questionnaires measuring demographics, diagnosis of IBS and other GI conditions, symptom severity, psychological symptoms, resilience, and early adverse life events (EALs). IBS was defined as having a physician diagnosis of IBS and/or meeting Rome criteria without co-morbid GI disease. All others were included in the general population group. The chronic GI conditions group included those with inflammatory bowel disease, celiac disease and/or microscopic colitis. RESULTS: Resilience was lower in IBS (n = 820) than the general population (n = 1026; p < 0.001) and associated with worse IBS symptom severity (p < 0.05). Global mental health affected resilience differently in IBS compared to the general population (all p's < 0.05). EALs were associated with decreased ability to bounce back from adversity in both IBS and the general population (p < 0.001). Resilience scores were similar in IBS and other chronic GI conditions that present with similar symptoms. CONCLUSIONS: Resilience is lower compared to the general U.S. population but does not appear to be specific to IBS as it is comparable to other chronic GI conditions. Low resilience negatively affects symptom severity and mental health and thus, may serve as a novel therapeutic target.

Patterns and trends of fish mercury in New York State.

In the mid-2000s a survey was conducted to evaluate fish mercury in lakes across New York State. Approximately 10 years later a second survey examining adult sportfish from 103 lakes and reservoirs was conducted to evaluate the response of fish mercury to recent declines in US mercury emissions. Of those lakes, 43 were part of the earlier survey and were examined to determine if mercury concentrations in four popular sport species, Yellow Perch, Walleye, and Small- and Largemouth Bass, declined in response to decreasing emissions. Water samples were also collected at 35 of these lakes and analyzed for mercury, methylmercury and other analytes. The Adirondack and Catskill regions remain biological mercury hotspots with elevated concentrations in fish. The most widely sampled species, Yellow Perch, showed significant increases in mercury in the Northeast and West regions of New York State over the past decade. The increases in Yellow Perch mercury is not consistent with significant reductions in water concentrations of both total and methylmercury observed corresponding in lake water samples. This discrepancy suggests watershed and in-lake processes beyond mercury emissions, such as recovery from acid deposition, impacts from climate change, or changes in food web structure may be controlling fish mercury concentrations. These results demonstrate a need for a consistent, long-term program to monitor fish mercury to inform the status of mercury contamination in New York State.

Efficacy of Biofeedback Therapy in Clinical Practice for the Management of Chronic Constipation and Fecal Incontinence.

BACKGROUND: Chronic constipation (CC) and fecal incontinence (FI) are often secondary to pelvic floor neuromuscular sensory or motor dysfunction. Biofeedback therapy (BFT) uses visual and verbal feedback to improve anorectal coordination, strength and sensation. In clinical trials, BFT demonstrated response rates between 70% and 80%. The purpose of this study is to determine the effectiveness of BFT in clinical practice. METHODS: In this retrospective observational cohort study, the charts of all patients who completed BFT at our centre were reviewed. A positive response to BFT was defined as improvement in ARM profile from baseline or subjective symptom improvement or both. Descriptive statistics were used to analyze the data. RESULTS: One hundred thirty patients with an average age of 57.5 ± 16.4 years and 79.2% female were included. Of all patients, 43.1% were referred for CC, 37.7% for FI, 16.9% for alternating CC and FI, and 2.3% for rectal pain. The overall response rate to BFT was 76.2% (n=99). Of those that responded, 64.6% (n=64) demonstrated both ARM and symptom improvement, 27.3% (n=27) had ARM improvement but no symptom improvement, and 8.1% (n=8) had symptom improvement but no ARM improvement. In patients with FI, the overall response rate was 79.6% (n=39) with symptom improvement in 67.3% (n=33). In those with CC with dyssynergic defecation (n=53), the overall response rate was 69.8% (n=37); however, only 45.3% (n=24) had symptomatic improvement. CONCLUSION: In our clinical practice, although overall response rates to BFT are similar to published reports, patients with CC with dyssynergic defecation are less likely to have symptomatic response compared with those with FI.

Influence of video-based feedback on self-assessment accuracy of endoscopic skills: a randomized controlled trial.

Background and study aims Novice endoscopists are inaccurate in self-assessment of procedures. One means of improving self-assessment accuracy is through video-based feedback. We aimed to determine the comparative effectiveness of three video-based interventions on novice endoscopists' self-assessment accuracy of endoscopic competence. Materials and methods Novice endoscopists (performed < 20 previous procedures) were recruited. Participants completed a simulated esophagogastroduodenoscopy (EGD) on a virtual reality simulator. They were then randomized to one of three groups: self-video review (SVR), which involved watching a recorded video of their own performance; benchmark review (BVR), which involved watching a video of a simulated EGD completed by an expert; and self- and benchmark video (SBVR), which involved both videos. Participants then completed two additional simulated EGD cases. Self-assessments were conducted immediately after the first procedure, after the video intervention and after the additional two procedures. External assessments were conducted by two experienced endoscopists, who were blinded to participant identity and group assignment through video recordings. External and self-assessments were completed using the global rating scale component of the Gastrointestinal Endoscopy Competency Assessment Tool (GiECAT GRS). Results Fifty-one participants completed the study. The BVR group had significantly improved self-assessment accuracy in the short-term, compared to the SBVR group ( P  = .005). The SBVR group demonstrated significantly improved self-assessment accuracy over time ( P  = .016). There were no significant effects of group or of time for the SVR group. Conclusions Video-based interventions, particularly combined use of self- and benchmark video review, can improve accuracy of self-assessment of endoscopic competence among novices.

Negative Events During Adulthood Are Associated With Symptom Severity and Altered Stress Response in Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a stress-sensitive disorder associated with dysregulation of the hypothalamic-pituitary-adrenal axis. We studied the cumulative effect of events during adulthood on this pathway in patients with IBS. METHODS: We studied 129 patients with IBS, based on Rome III criteria (mean age 28.1 years, 66% women), and 108 healthy individuals (controls; mean age 29.8 years, 60% women) who completed the Life Experiences Survey from August 2013 to September 2017. Data were collected on the presence and effects of events since age 18, IBS severity scores, and IBS-related quality of life. For a subset of subjects, we measured serum cortisol and adrenocorticotropic hormone (ACTH) production in response to administration of corticotropin-releasing factor and ACTH. RESULTS: Compared with controls, patients with IBS perceived more adulthood life events as negative and had a significantly higher negative life event impact score (14.17 ± 12.04 vs 10.83 ± 9.98; P=.022). In patients with IBS, the presence of more-negatively perceived adulthood life events was associated with worse IBS symptom severity (ß = 1.53, 95% CI, 0.21-2.84; P = .025) and IBS-related quality of life (ß = -0.70; 95% CI, -1.02 to -0.38; P < .001). Negatively perceived adulthood life events were associated with reduced production of ACTH in response to corticotropin-releasing factor in patients with IBS compared with controls (P < .05). CONCLUSION: In a study of more than 200 subjects, we associated more-negatively perceived events during adulthood with an increased risk for IBS, worse symptom severity and quality of life, and a dysregulated stress response. Understanding the effects of events that cause stress in adults and their perceived effects on IBS may help guide disease management.

The Use of Standardized Questions in Identifying Patients with Dyssynergic Defecation.

BACKGROUND: Dyssynergic defecation (DD) is present in approximately 30% of patients with idiopathic chronic constipation (CC). Diagnostic criteria for DD require objective testing such as anorectal manometry (ARM); yet, ARM remains a limited resource in Canada. The aim of this study is to determine the predictability of DD in patients with CC using a standardized self-reported symptom questionnaire. METHOD: In this study, 166 consecutive English-speaking patients with CC who were referred for ARM completed a symptom questionnaire. DD was diagnosed if pelvic floor dyssynergy was demonstrated by ARM and balloon expulsion time was more than one minute. Likelihood ratios (LRs) were calculated for individual symptoms and prespecified symptom combinations. Likelihood ratios greater than five or less than 0.2 were considered significant. A recursive partitioning tree was used to find the symptoms best able to predict DD. RESULTS: No single constipation symptom was sufficient to predict a diagnosis of DD. Patients who reported sometimes feeling an urge to defecate and a prolonged straining duration of greater than five minutes were more likely to have DD (LR = 7.74). In patients who reported straining often or always and had a short straining duration of less than two minutes, the diagnosis of DD was less likely (LR = 0.04). The recursive partitioning tree analysis similarly identified a sense of urge with a prolonged straining duration as predictor for DD, as well as an incomplete evacuation as another potential predictor. CONCLUSION: Questions regarding need to strain, duration of straining, urge to defecate, and incomplete evacuation are useful to predict the presence of DD in patients with CC. These questions will enable clinicians to make a clinical diagnosis of DD to guide treatment.

Linaclotide: a new option for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

Chronic idiopathic constipation (CC) and irritable bowel syndrome with predominant constipation (IBS-C) are the 2 most common conditions among functional gastrointestinal disorders. Despite current multiple therapeutic options, treatment remains challenging and dissatisfactory to many patients. Linaclotide is a novel therapeutic agent, which is a guanylate cyclase receptor agonist that stimulates water secretion from the intestinal epithelium by promoting chloride and bicarbonate efflux into the lumen through activation of the cystic fibrosis transmembrane conductance regulator. Clinical trials have demonstrated that linaclotide is effective, safe and well tolerated in patients with CC and IBS-C. This review article highlights the mechanism of action of linaclotide, reviews published literature based on a search of databases, including MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), up to February 2013, and compares its utility with other currently available agents.

Clonidine as an adjunct to intravenous regional anesthesia: A randomized, double-blind, placebo-controlled dose ranging study.

BACKGROUND: The addition of clonidine to lidocaine intravenous regional anesthesia (IVRA) has been previously reported to improve postoperative analgesia in patients undergoing upper extremity surgery. Our objective was to perform a dose ranging study in order to determine the optimal dose of clonidine used with lidocaine in IVRA. DESIGN #ENTITYSTARTX00026; SETTING: We performed a double-blinded randomized placebo-controlled study with 60 patients scheduled for elective endoscopic carpal tunnel release under IVRA with 50 ml lidocaine 0.5%. University-affiliated outpatient surgery center. Data collected in operating rooms, recovery room, and by telephone after discharge from surgery center. MATERIALS #ENTITYSTARTX00026; METHODS: Sixty adult ASA I or II patients undergoing outpatient endoscopic carpal tunnel release under intravenous regional anesthesia.Patients were randomized into five study groups receiving different doses of clonidine in addition to 50 ml 0.5% lidocaine in their IVRA. Group A received 0 mcg/kg, group B 0.25 mcg/kg, group C 0.5 mcg/kg, group D 1.0 mcg/kg and group E 1.5 mcg/kg of clonidine.Intraoperative fentanyl, recovery room pain scores, time to first postsurgical analgesic, total number of acetaminophen/codeine tablets consumed postsurgery, incidence of sedation, hypotension and bradycardia. RESULTS #ENTITYSTARTX00026; CONCLUSIONS: There was no benefit from any dose of clonidine compared to placebo. There were no clonidine-related side effects seen within the dose range studied. In short duration minor hand surgery, the addition of clonidine to lidocaine-based intravenous regional anesthesia provides no measurable benefit.

The cardiac (pro)renin receptor is primarily expressed in myocyte transverse tubules and is increased in experimental diabetic cardiomyopathy.

BACKGROUND: The pro(renin) receptor is a 350 amino acid transmembrane protein, that on ligand binding, increases the catalytic efficiency of angiotensinogen cleavage by both prorenin and renin, augmenting angiotensin I formation at the cell surface. While implicated in a broad range of diseases, studies to date have focused on the kidney, particularly in the diabetic context. We sought to examine the site-specific expression of the pro(renin) receptor within the heart. METHODS: Using confocal microscopy, site-specific markers and transmission electron microscopy we assessed the location of the pro(renin) receptor in the heart at both cellular/sub-cellular levels. We assessed pro(renin) receptor expression in the setting of disease and blockade of the renin-angiotensin system, using the TGR[m(Ren2)-27] model of diabetic cardiomyopathy and the direct renin inhibitor, aliskiren. RESULTS: The pro(renin) receptor was found predominantly at the Z-disc and dyad of cardiac myocytes coinciding closely with the distributions of the vacuolar H⁺-ATPase and ryanodine receptor, known to be located within T-tubules and the sarcoplasmic reticulum's terminal cisternae, respectively. Pro(renin) receptor mRNA/protein abundance were increased ∼3-fold in the hearts of diabetic rats in association with diastolic dysfunction, myocyte hypertrophy and interstitial fibrosis (all P < 0.01). Direct renin inhibition reduced cardiac pro(renin) receptor expression in association with improved cardiac structure/function (all P < 0.05). CONCLUSION: Together, these findings are consistent with the notion that the pro(renin) receptor is a component of the vacuolar H⁺-ATPase, and that like the latter, is increased in the setting of cardiac stress and lowered by the administration of an ostensibly cardioprotective agent.

Ketamine as an adjuvant in lidocaine intravenous regional anesthesia: a randomized, double-blind, systemic control trial.

BACKGROUND AND OBJECTIVES: Ketamine delays and minimizes intraoperative tourniquet pain when added to lidocaine-based intravenous regional anesthesia (IVRA). It is unclear if adding ketamine to the IVRA injectate is more efficacious compared with systemic administration. This study compares intraoperative tourniquet pain, postoperative analgesia, and side effects of systemic versus IVRA ketamine during outpatient hand surgery. METHODS: We conducted a randomized, double-blind, systemic control study of 40 patients undergoing hand surgery using lidocaine IVRA. In group IVRA, 0.1 mg/kg ketamine in 1 mL of normal saline was added to the IVRA lidocaine, and 1 mL of normal saline was administered via a peripheral IV line. In group systemic, 1 mL of normal saline was added to the IVRA syringe, and 0.1 mg/kg ketamine in 1 mL of normal saline was administered via a peripheral intravenous line. Ten minutes after proximal tourniquet inflation, the distal tourniquet was inflated, and the proximal tourniquet deflated. Tourniquet pain was measured every 10 mins. Need for intraoperative opioids was recorded. Recovery room pain scores, analgesic needs, and sedation scores were compared. Patients were contacted 24 hrs after surgery and reported their analgesic consumption, satisfaction scores, and the occurrence of any unpleasant psychologic effects. RESULTS: Groups IVRA and systemic were comparable in demographic and surgical parameters. There were no differences between groups in intraoperative tourniquet pain scores, intraoperative fentanyl requirements, recovery room pain or sedation scores, postsurgical analgesic needs, or patient satisfaction scores. CONCLUSIONS: In comparison to systemic administration, there is no selective benefit to adding ketamine to the IVRA injectate.

Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1.

BACKGROUND: The acute respiratory distress syndrome (ARDS), a clinical complication of severe acute lung injury (ALI) in humans, is a leading cause of morbidity and mortality in critically ill patients. ALI is characterized by disruption of the lung alveolar-capillary membrane barrier and resultant pulmonary edema associated with a proteinaceous alveolar exudate. Current specific treatment strategies for ALI/ARDS are lacking. We hypothesized that mesenchymal stem cells (MSCs), with or without transfection with the vasculoprotective gene angiopoietin 1 (ANGPT1) would have beneficial effects in experimental ALI in mice. METHODS AND FINDINGS: Syngeneic MSCs with or without transfection with plasmid containing the human ANGPT1 gene (pANGPT1) were delivered through the right jugular vein of mice 30 min after intratracheal instillation of lipopolysaccharide (LPS) to induce lung injury. Administration of MSCs significantly reduced LPS-induced pulmonary inflammation, as reflected by reductions in total cell and neutrophil counts in bronchoalveolar lavage (BAL) fluid (53%, 95% confidence interval [CI] 7%-101%; and 60%, CI 4%-116%, respectively) as well as reducing levels of proinflammatory cytokines in both BAL fluid and lung parenchymal homogenates. Furthermore, administration of MSCs transfected with pANGPT1 resulted in nearly complete reversal of LPS-induced increases in lung permeability as assessed by reductions in IgM and albumin levels in BAL (96%, CI 6%-185%; and 74%, CI 23%-126%, respectively). Fluorescently tagged MSCs were detected in the lung tissues by confocal microscopy and flow cytometry in both naïve and LPS-injured animals up to 3 d. CONCLUSIONS: Treatment with MSCs alone significantly reduced LPS-induced acute pulmonary inflammation in mice, while administration of pANGPT1-transfected MSCs resulted in a further improvement in both alveolar inflammation and permeability. These results suggest a potential role for cell-based ANGPT1 gene therapy to treat clinical ALI/ARDS.

Cell-based angiopoietin-1 gene therapy for acute lung injury.

RATIONALE: The acute respiratory distress syndrome is a significant cause of morbidity and mortality in critically ill patients. Angiopoietin-1 (Ang-1), a ligand for the endothelial Tie2 receptor, is an endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. OBJECTIVES: We hypothesized that Ang-1 counteracts vascular inflammation and pulmonary vascular leak in experimental acute lung injury. METHODS: We used cell-based gene therapy in a rat model of ALI. Transgenic mice overexpressing Ang-1 or deficient in the Tie2 receptor were also studied to better elucidate the mechanisms of protection. MEASUREMENTS AND MAIN RESULTS: The present report provides data that support a strong protective role for the Ang-1/Tie2 system in two experimental models of LPS-induced acute lung injury. In a rat model, cell-based Ang-1 gene transfer improved morphological, biochemical, and molecular indices of lung injury and inflammation. These findings were confirmed in a gain-of-function conditional, targeted transgenic mouse model, in which Ang-1 reduced endothelial cell activation and the expression of adhesion molecules, associated with a marked improvement in airspace inflammation and intraalveolar septal thickening. Moreover, heterozygous Tie2-deficient mice demonstrated enhanced evidence of lung injury and increased early mortality. CONCLUSIONS: These results support a critical role for the Ang-1/Tie2 axis in modulating the pulmonary vascular response to lung injury and suggest that Ang-1 therapy may represent a potential new strategy for the treatment and/or prevention of acute respiratory distress syndrome in critically ill patients.

CSHCN in Texas: meeting the need for specialist care.

OBJECTIVE: Assuring the sufficiency and suitability of systems of care and services for children with special health care needs (CSHCN) presents a challenge to Texas providers, agencies, and state Title V programs. To meet the need for specialist care, referrals from primary care doctors are often necessary. The objective of this study was to describe the factors associated with the need for specialist care and problems associated with obtaining referrals in Texas. METHODS: Bivariate and multivariate analyses were performed using the National Survey of Children with Special Health Care Needs (NS-CSHCN) weighted sample for Texas (n = 719,014) to identify variables associated with the need for specialist care and problems obtaining referrals for specialist care. RESULTS: Medical need of the CSHCN and sensitivity to family values/customs was associated with greater need for specialist care, and Hispanic ethnicity and lower maternal education were associated with less need. Medical need, amount of time spent with doctors and sensitivity to values/customs, living in a large metropolitan statistical area, and lack of medical information were associated with problems obtaining a specialist care referral. CONCLUSIONS: Findings revealed some similarities and differences with meeting the need for specialist care when comparing Texas results to other studies. In Texas, aspects of customer satisfaction variables, especially doctors' sensitivity to family values/customs and parents' not receiving enough information on medical problems, were significantly associated with problems obtaining specialist referrals. Findings indicate a need to further research relationships and communication among doctors, CSHCN, and their families.

Development of the self-efficacy for testicular self-examination scale.

BACKGROUND: Men between the ages of 20 and 34 years are at highest risk for testicular cancer yet many lack knowledge and confidence in performing self-examination. The Self-Efficacy to Perform Testicular Self-Examination Scale (SEPTSES) is a 7-item questionnaire to be completed by men, which is designed to measure their confidence in self-examining their testicles. The purpose of this methodological study was to determine the validity and reliability of this self-report measure. METHODS: Content validity of the scale and clarity of items were established with a panel of experts. The SEPTSES and three valid scales of related constructs were completed by two samples of men (homeless [n = 150] and non-homeless [n = 156]) aged 18-34 years. RESULTS: A single factor explained 51.5% of the variance of the scale and Cronbach's alpha was satisfactory (a = 0.84). Construct validity was further supported by significant correlations with the other three scales; further support was established by a significant difference in mean scores between the two samples [t (303) = -5.44, p < 0.001]. CONCLUSION: The SEPTSES is a valid, unidimensional scale and it can be used in further research and in clinical practice as an assessment of this aspect of men's health.