Methionine Source and Level Modulate Gut pH, Amino Acid Transporters and Metabolism Related Genes in Broiler Chickens.

This study determined the effects of two methionine (Met) sources at three total sulfur amino acids (TSAA) to lysine ratios (TSAA/Lys) on gut pH, digestive enzyme activity, amino acid transporter expression, and Met metabolism of broilers. The birds were randomly assigned to a 2 × 3 factorial arrangement with Met sources (dl-Met and dl-2-hydroxy-4-(methylthio)-butanoic acid (OH-Met)) and TSAA/Lys (0.58, 0.73, and 0.88) from 1 to 21 days. The results demonstrated that dl-Met and OH-Met supported the same growth performance, but high TSAA/Lys ratio reduced the feed intake and body weight (P < 0.05). OH-Met reduced the crop chyme pH and enhanced the jejunal lipase activity (P < 0.05). ATB0,+ expression decreased with increased dl-Met levels in the duodenum; the low TSAA/Lys ratio induced a stronger mRNA expression of basolateral Met transporters. OH-Met resulted in an increase of cystathionine ß-synthase expression in the liver and a decrease in serum homocysteine levels at middle TSAA/Lys ratio compared with dl-Met treatment (P < 0.05). In conclusion, two Met sources support the same growth, but OH-Met acidified the crop chyme. The investigated transporter transcripts differed significantly along the small intestine. At the middle TSAA/Lys ratio, OH-Met showed a higher metabolic tendency of the trans-sulfuration pathway compared with dl-Met.

Multiple autoimmune disorders refractory to glucocorticoids after allogeneic hematopoietic stem cell transplantation: a case report and review of the literature.

We report here the case of a 50-year-old man who was first diagnosed with myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 2019, resulting in complete remission. However, he was diagnosed in 2021 with several autoimmune disorders, including autoimmune hepatitis (AIH), Hashimoto's thyroiditis (HT), and autoimmune hemolytic anemia (AIHA). This is referred as multiple autoimmune syndrome (MAS), which is a rare occurrence after allo-HSCT, as previously noted in the literature. Despite being treated with glucocorticoids, cyclosporine A, and other medications, the patient did not fully recover. To address the glucocorticoid-refractory MAS, a four-week course of rituximab (RTX) at a weekly dose of 100mg was administered, which significantly improved the patient's condition. Thus, this case report underscores the importance of implementing alternative treatments in patients with post-transplant autoimmune diseases, who are glucocorticoid-refractory or glucocorticoid-dependent, and highlights the effectiveness of RTX as second-line therapy.

Short-chain fatty and carboxylic acid changes associated with fecal microbiota transplant communally influence microglial inflammation.

The intestinal microbiota has been proposed to influence human mental health and cognition through the gut-brain axis. Individuals experiencing recurrent Clostridioides difficile infection (rCDI) frequently report depressive symptoms, which are improved after fecal microbiota transplantation (FMT); however, mechanisms underlying this association are poorly understood. Short-chain fatty acids and carboxylic acids (SCCA) produced by the intestinal microbiota cross the blood brain barrier and have been proposed to contribute to gut-brain communication. We hypothesized that changes in serum SCCA measured before and after successful FMT for rCDI influences the inflammatory response of microglia, the resident immune cells of the central nervous system. Serum SCCA were quantified using gas chromatography-mass spectroscopy from 38 patients who participated in a randomized trial comparing oral capsule-vs colonoscopy-delivered FMT for rCDI, and quality of life was assessed by SF-36 at baseline, 4, and 12 weeks after FMT treatment. Successful FMT was associated with improvements in mental and physical health, as well as significant changes in a number of circulating SCCA, including increased butyrate, 2-methylbutyrate, valerate, and isovalerate, and decreased 2-hydroxybutyrate. Primary cultured microglia were treated with SCCA and the response to a pro-inflammatory stimulus was measured. Treatment with a combination of SCCA based on the post-FMT serum profile, but not single SCCA species, resulted in significantly reduced inflammatory response including reduced cytokine release, reduced nitric oxide release, and accumulation of intracellular lipid droplets. This suggests that both levels and diversity of SCCA may be an important contributor to gut-brain communication.

Adoption of Two-Dimensional Ultrasound Gastrointestinal Filling Contrast on Artificial Intelligence Algorithm in Clinical Diagnosis of Gastric Cancer.

This research was aimed to explore the value of gastrointestinal filling contrast-enhanced ultrasound (CEUS) and computed tomography (CT-)-enhanced scanning based on artificial intelligence (AI) algorithm in the evaluation of gastric cancer staging. 102 patients with gastric cancer were selected as the research objects. All of them underwent CEUS of gastrointestinal filling and 64-slice spiral CT before surgery. In addition, an improved mean shift algorithm was proposed based on differential optical flow and deep convolutional neural network (D-CNN), which was applied in image processing. The predicted positive rate (PPR), sensitivity, specificity, and accuracy of gastric cancer in different stages by CEUS and CT were calculated using pathological diagnosis results as the gold standard. 17 patients with T1 stage, 41 patients with T2-T3 stage, and 35 patients with T4 stage were detected by CEUS. 13 patients with T1 stage, 34 patients with T2-T3 stage, and 30 patients with T4 stage were detected by CT enhanced examination. The PPRs of CEUS for T1, T2-T3, and T4 stages of gastric cancer were higher than those of CT enhanced (P < 0.05). The PPR of CEUS for N0 staging of gastric cancer was higher than that of CT enhanced (P < 0.05), and it for N3 staging of gastric cancer was lower than that of CT enhanced (P < 0.05). From the analysis of M staging of gastric cancer, the PPRs of CEUS for M0 and M1 staging of gastric cancer were not statistically different from the PPRs of CT enhanced (P > 0.05). The sensitivity (95.6%), specificity (81.82%), and accuracy (94.12%) of CEUS in assessing resectability were significantly higher than those of CT enhancement (89.01%, 63.67%, and 86.27%, respectively), and the differences were statistically significant (P < 0.05). In summary, CEUS gastrointestinal filling based on the D-CNN algorithm could better improve the display rate of the tissue lesions around the stomach. It also helped to judge the lesion progress, the depth of infiltration, and lymph node metastasis of the lesion. In addition, it had excellent performance in evaluating the resectability of gastric cancer before surgery and had clinical promotion value.

Phase 1 Study Evaluating the Effects of the Proton Pump Inhibitor Rabeprazole and Food on the Pharmacokinetics of Lorlatinib in Healthy Participants.

Lorlatinib is approved worldwide as treatment for anaplastic lymphoma kinase-positive and c-ros oncogene 1-positive non-small cell lung cancer. The objectives of this phase 1, open-label crossover study (NCT02569554) in healthy adult participants were to determine (1) the effects of the proton pump inhibitor (PPI) rabeprazole on lorlatinib pharmacokinetics (PK), (2) the effects of a high-fat meal on lorlatinib PK, and (3) the relative bioavailability of an oral solution to tablet formulation of lorlatinib under fasted conditions. Participants were followed on-study for ≥50 days after the first dose of lorlatinib. Participants received treatments over 4 periods, with a washout of ≥10 days between consecutive lorlatinib doses. Twenty-seven participants were enrolled and received lorlatinib, and all were assessed for PK and safety. Results showed no effect of multiple doses of rabeprazole on the total plasma exposure of a single oral dose of lorlatinib 100-mg tablets. The results also indicated that a high-fat meal had no effect on lorlatinib PK after a single 100-mg oral dose. In addition, the relative bioavailability of lorlatinib oral solution compared with lorlatinib tablets was complete (approximately 108%). The safety profile of lorlatinib was consistent with that reported in previous studies, and most treatment-related adverse events were mild to moderate. These data indicate that lorlatinib can be administered with drugs that modify gastric acid, including PPIs, without restriction. These results also confirm that lorlatinib can be administered regardless of food intake.

Underperformance of Contemporary Phase III Oncology Trials and Strategies for Improvement.

BACKGROUND: Statistical testing in phase III clinical trials is subject to chance errors, which can lead to false conclusions with substantial clinical and economic consequences for patients and society. METHODS: We collected summary data for the primary endpoints of overall survival (OS) and progression-related survival (PRS) (eg, time to other type of event) for industry-sponsored, randomized, phase III superiority oncology trials from 2008 through 2017. Using an empirical Bayes methodology, we estimated the number of false-positive and false-negative errors in these trials and the errors under alternative P value thresholds and/or sample sizes. RESULTS: We analyzed 187 OS and 216 PRS endpoints from 362 trials. Among 56 OS endpoints that achieved statistical significance, the true efficacy of experimental therapies failed to reach the projected effect size in 33 cases (58.4% false-positives). Among 131 OS endpoints that did not achieve statistical significance, the true efficacy of experimental therapies reached the projected effect size in 1 case (0.9% false-negatives). For PRS endpoints, there were 34 (24.5%) false-positives and 3 (4.2%) false-negatives. Applying an alternative P value threshold and/or sample size could reduce false-positive errors and slightly increase false-negative errors. CONCLUSIONS: Current statistical approaches detect almost all truly effective oncologic therapies studied in phase III trials, but they generate many false-positives. Adjusting testing procedures in phase III trials is numerically favorable but practically infeasible. The root of the problem is the large number of ineffective therapies being studied in phase III trials. Innovative strategies are needed to efficiently identify which new therapies merit phase III testing.

Fecal Microbiota Transplantation Is Safe and Effective in Patients With Clostridioides difficile Infection and Cirrhosis.

BACKGROUND & AIMS: Clostridioides difficile infection (CDI) harms a large proportion of patients with cirrhosis. Fecal microbiota transplantation (FMT) is recommended for recurrent CDI, but its effects in patients with cirrhosis have not been established. We performed a multicenter observational study to evaluate the efficacy and safety of FMT for CDI in patients with cirrhosis. METHODS: We performed a retrospective study of 63 adults with cirrhosis (median model for end-stage liver disease score, 14.5; 24 patients with decompensated cirrhosis) who underwent FMT for CDI from January 2012 through November 2018 at 8 academic centers in the United States, Canada, and Italy. We collected data on patient demographics and characteristics of cirrhosis, CDI, and FMT from medical records and compared differences among patients with different severities of cirrhosis, and FMT successes vs failures at the 8-week follow-up evaluation. We also obtained data on adverse events (AEs) and severe AEs within 12 weeks of FMT. RESULTS: Patients underwent FMT for recurrent CDI (55 of 63; 87.3%), severe CDI (6 of 63; 9.5%), or fulminant CDI (2 of 63; 3.2%) primarily via colonoscopy (59 of 63; 93.7%) as outpatients (47 of 63; 76.8%). FMT success was achieved for 54 patients (85.7%). Among FMT failures, a higher proportion used non-CDI antibiotics at the time of FMT (44.4% vs 5.6%; P < .001), had Child-Pugh scores of B or C (100% vs 37.7%; P < .001), used probiotics (77.8% vs 24.1%; P = .003), had pseudomembranes (22.2% vs 0; P = .018), and underwent FMT as inpatients (45.5% vs 19%; P = .039), compared with FMT successes. In multivariable analysis, use of non-CDI antibiotics at the time of FMT (odds ratio, 17.43; 95% CI, 2.00-152.03; P = .01) and use of probiotics (odds ratio, 11.9; 95% CI, 1.81-78.3; P = .01) were associated with a greater risk of FMT failure. FMT-related AEs occurred in 33.3% of patients (21 of 63)-most were self-limited abdominal cramps or diarrhea. There were only 5 severe AEs that possibly were related to FMT; none involved infection or death. CONCLUSIONS: In a retrospective study, we found FMT to be safe and effective for the treatment of CDI in patients with cirrhosis.

The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants.

INTRODUCTION: Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib. METHODS: This phase 1, open-label, two-period, crossover study estimated the effect of oral rifampin (a strong CYP3A inducer) on the pharmacokinetics and safety of oral lorlatinib (NCT02804399). Healthy participants received single-dose lorlatinib 100 mg in period 1 followed by rifampin 600 mg/day (days 1-12) and single-dose lorlatinib 100 mg (day 8) in period 2. Blood samples were collected for 120 h after each dose of lorlatinib. RESULTS: When a single dose of lorlatinib was administered during daily dosing with rifampin (period 2), the area under the plasma concentration-time profile extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of lorlatinib were 14.74% [90% confidence interval (CI) 12.78%, 17.01%] and 23.88% (90% CI 21.58%, 26.43%), respectively, of those in period 1 (lorlatinib alone). A single dose of lorlatinib was well tolerated in period 1, but elevations in transaminase values were observed in all participants (grade 2-4 in 11 participants) within 1-3 days after a single dose of lorlatinib was administered with ongoing rifampin in period 2. Rifampin dosing was therefore halted. Transaminase levels subsequently returned to normal (median time to recovery: 15 days). No elevations in bilirubin were observed. CONCLUSIONS: The addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02804399.

Risk Factors Associated With Upper Aerodigestive Tract or Coliform Bacterial Overgrowth of the Small Intestine in Symptomatic Patients.

INTRODUCTION: The clinical relevance of bacterial types identified in small bowel aspirate cultures during diagnostic evaluation of small intestinal bacterial overgrowth (SIBO) is unclear. AIM: The main purpose of this study was to assess associations between risk factors for upper aerodigestive tract (UAT) or coliform SIBO and SIBO diagnosis by culture. MATERIALS AND METHODS: Small bowel aspirates were cultured in patients with suspected SIBO, defined as ≥10 colony-forming units/mL coliform or ≥10 colony-forming units/mL UAT bacteria. History was reviewed for risk factors and potential SIBO complications. Symptoms, quality of life, psychological traits, and laboratory values were assessed. We compared groups by 2-sample t test, Wilcoxon rank sum test, and the Fisher exact test. Overall associations of primary and secondary endpoints with type of bacterial overgrowth were assessed by analysis of variance F-test, Kruskal-Wallis test, and the Fisher exact tests. Associations of risk factors with type of overgrowth were explored using multinomial logistic regression. RESULTS: Among 76 patients, 37 had SIBO (68% coliform, 33% UAT) and 39 did not. Conditions (P=0.02) and surgery (P<0.01) associated with decreased gastric acid were associated with SIBO. In multinomial logistic regression, conditions of decreased acid was associated with UAT SIBO [odds ratio (OR), 5.8; 95% confidence interval, 1.4-33.3]. Surgery causing decreased acid was associated with UAT [OR, 9.5 (1.4-106)] and coliform SIBO [OR, 8.4 (1.6-86.4)]. Three patients with discontinuous small bowel had coliform SIBO [OR, 17.4 (1.2-2515)]. There were no differences in complications, overall symptoms, quality of life, or psychological traits. CONCLUSIONS: Conditions or surgeries associated with decreased gastric acid are associated with SIBO diagnosis by culture.

Associations of chronic diarrhoea with non-alcoholic fatty liver disease and obesity-related disorders among US adults.

Mechanisms explaining observed associations between diarrhoea and obesity or increased body mass index (BMI) are unclear. OBJECTIVE: To assess associations of bowel patterns with BMI, metabolic syndrome (MS), non-alcoholic fatty liver disease (NAFLD) and other obesity-related disorders. DESIGN: We performed a cross-sectional analysis of data from adults who completed bowel health questions for the 2005 to 2010 cycles of the National Health and Nutrition Examination Surveys. Relationships were examined using multinomial logistic regression. Confounding effects of demographics, smoking, alcohol and BMI were examined by sequential modelling. RESULTS: Among 13 413 adults, weighted prevalence rates of constipation and diarrhoea were 8.9% and 6.6%, respectively. Mean BMI was associated with bowel patterns (p<0.001), and was higher with diarrhoea (30.3 kg/m2) versus normal bowel patterns (28.6 kg/m2) and with diarrhoea versus constipation (27.8 kg/m2). NAFLD was more prevalent (ORs, 95% CI) in diarrhoea versus normal bowel patterns (OR=1.34, 95% CI 1.01 to 1.78) or constipation (OR=1.45, 95% CI 1.03, 2.03) in adjusted analyses. The higher prevalence of MS in diarrhoea versus constipation (OR=1.27, 95% CI 0.97 to 1.67) was not independent of BMI. CONCLUSIONS: These findings suggest an association between diarrhoea and NAFLD that is independent of BMI.

MIND food and speed of processing training in older adults with low education, the MINDSpeed Alzheimer's disease prevention pilot trial.

BACKGROUND: Multiple national organizations and leaders have called for increased attention to dementia prevention in those most vulnerable, for example persons with limited formal education. Prevention recommendations have included calls for multicomponent interventions that have the potential to improve both underlying neurobiological health and the ability to function despite neurobiological pathology, or what has been termed cognitive reserve. OBJECTIVES: Test feasibility, treatment modifier, mechanism, and cognitive function effects of a multicomponent intervention consisting of foods high in polyphenols (i.e., MIND foods) to target neurobiological health, and speed of processing training to enhance cognitive reserve. We refer to this multicomponent intervention as MINDSpeed. DESIGN: MINDSpeed is being evaluated in a 2 × 2 randomized factorial design with 180 participants residing independently in a large Midwestern city. Qualifying participants are 60 years of age or older with no evidence of dementia, and who have completed 12 years or less of education. All participants receive a study-issued iPad to access the custom study application that enables participants, depending on randomization, to select either control or MIND food, and to play online cognitive games, either speed of processing or control games. METHODS: All participants complete informed consent and baseline assessment, including urine and blood samples. Additionally, up to 90 participants will complete neuroimaging. Assessments are repeated immediately following 12 weeks of active intervention, and at 24 weeks post-randomization. The primary outcome is an executive cognitive composite score. Secondary outcomes include oxidative stress, pro-inflammatory cytokines, and neuroimaging-captured structural and functional metrics of the hippocampus and cortical brain regions. SUMMARY: MINDSpeed is the first study to evaluate the multicomponent intervention of high polyphenol intake and speed of processing training. It is also one of the first dementia prevention trials to target older adults with low education. The results of the study will guide future dementia prevention efforts and trials in high risk populations.

Pathological risk factors for higher clinical stage in testicular seminomas.

AIMS: Testicular seminomas require accurate staging for effective management. Twenty per cent are metastatic at presentation, while 80% are clinical stage I, requiring only orchiectomy and surveillance. Tumour size, rete testis invasion, hilar soft tissue invasion and lymphovascular invasion have been shown to incur a higher risk of metastasis and recurrence in clinical stage I seminomas, with little congruence between studies. METHODS AND RESULTS: We reviewed 211 cases of testicular seminomas and recorded patient age, tumour size, lymphovascular invasion and rete testis, hilar soft tissue, epididymis, spermatic cord, tunica albuginea and tunica vaginalis involvement. A univariate and multivariate analysis was performed comparing clinical stage I to advanced clinical stage patients (stages II and III) in reference to these factors. We found that tumour size (P = 0.02), vascular invasion (P = 0.02) and invasion of rete testis stroma (P = 0.01), epididymis (P = 0.02), spermatic cord (P = 0.047) and hilar soft tissue (P = 0.04) were predictors of higher clinical stage at the univariate level. However, multivariate analysis showed that only tumour size and vascular invasion remained significant (P = 0.008 and 0.032, respectively). A tumour size of 4 cm was the cut-off size found to be significant. CONCLUSIONS: Tumour size and vascular invasion are the strongest predictors of higher clinical stage in testicular seminomas. Our univariate data suggest that rete testis and hilar soft tissue invasion relate to higher clinical stage. However, neither of these factors were found to be independent risk factors at multivariate analysis. Therefore, this study supports tumour upstaging based only upon size and vascular invasion.

Evaluation of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer.

PURPOSE: This phase 1 study evaluated the effect of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer. METHODS: Patients were dosed according to hepatic function classified by modified National Cancer Institute Organ Dysfunction Working Group criteria and group assignment [normal (A1 and A2), mild (B), moderate (C1 and C2), or severe (D)]. Primary pharmacokinetic endpoints included area under the concentration-time curve as daily exposure (AUCdaily) and maximum plasma concentration (Cmax) at steady state. Safety endpoints included types, incidence, seriousness, and relationship to crizotinib of adverse events. RESULTS: The AUCdaily and Cmax in patients with normal liver function were 7107 ng h/mL and 375.1 ng/mL (A1) and 5422 ng h/mL and 283.9 ng/mL (A2), respectively. The AUCdaily and Cmax ratios of adjusted geometric means for Groups B, C2, and D versus Group A1 were 91.12 and 91.20, 114.08 and 108.87, and 64.47 and 72.63, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 75% of patients; grade 3/4 TRAEs occurred in 25%, including fatigue (6%), hyponatremia (5%), and hyperbilirubinemia (3%). CONCLUSIONS: No adjustment to the approved 250 mg twice daily (BID) dose of crizotinib is recommended for patients with mild hepatic impairment. The recommended dose is 200 mg BID for patients with moderate hepatic impairment, and the dose should not exceed 250 mg daily for patients with severe hepatic impairment. Adverse events appeared consistent among the hepatic impairment groups. CLINICAL TRIAL REGISTRATION NO: NCT01576406.

The Significance of Spermatic Cord Involvement by Testicular Germ Cell Tumors: Should We Be Staging Discontinuous Invasion From Involved Lymphovascular Spaces Differently From Direct Extension?

The recent 8th edition of the American Joint Committee on Cancer (AJCC) staging manual had multiple changes concerning how pathologists should stage germ cell tumors (GCTs) of the testis. A significant one concerns the impact of different types of spermatic cord involvement, specifically direct tumor extension versus discontinuous involvement by invasion through lymphovascular spaces. We compared clinicopathologic findings and outcome data between 2 cohorts with these findings to evaluate the validity of the change in the AJCC 8th edition manual. GCTs (seminomatous and nonseminomatous) of the testis were identified that had previously been staged as pT3 due to involvement of the spermatic cord. Pathologic, radiographic, and clinical findings were reviewed. Tumors were restaged based on AJCC 8th edition criteria and the cohorts were split into direct extension by tumor into the spermatic cord (pT3), spermatic cord soft tissue invasion via spread from discontinuously involved lymphovascular spaces (pT2pM1), or a combination of both (pT3pM1). One hundred cases of primary GCTs of the testis, previously classified as pT3 by the AJCC 6th or 7th cancer staging manuals from 2007 to 2015, were selected. Mixed malignant GCTs were the predominant tumor type, comprising 66% of all cases. Pure tumor morphologies included embryonal carcinoma (n=17), seminoma (n=14), teratoma (n=2), and yolk sac tumor (n=1). The tumors either directly invaded into the spermatic cord (n=78), involved the cord discontinuously via spread from lymphovascular spaces (n=18), or had both findings (n=4). Overall, 93% of patients presented at advanced clinical stage (CS). Using the AJCC 8th parameters, 12% of all tumors were upstaged. Changes included CSI (n=1) and CSII (n=11) tumors being reclassified as prognostic stage group III. Clinical and/or pathologic recurrence was identified in 19% of all patients, including 12 pT3 and 7 pM1 patients (P=0.11). Overall mean time to recurrence was 24.6 months, with a mean of 28.0 months for pT3 tumors and 18.9 months for pM1 tumors. Five patients were dead at the time of this study, including 3 (4%) with pT3 tumors and 2 (9%) in the pM1 cohort. Our findings support that seminomatous and nonseminomatous GCTs with spermatic cord invasion have a high frequency of advanced CS at presentation, regardless of involvement by direct extension or discontinuous spread via invasion from lymphovascular spaces. By designating the latter as M1, a spurious upstaging to prognostic stage group III is required by the AJCC 8th edition. We were unable to identify statistically significant difference between the 2 groups as it pertained to CS at presentation and likelihood of recurrence. Conversely, statistical trends favor that pM1 patients have more likely recurrence and worse prognosis than pT3 patients.

Age and Dyssynergia Subtypes Associated With Normal Sphincter Pressures in Women With Fecal Incontinence.

OBJECTIVES: Fecal incontinence (FI) is frequently associated with low sphincter pressures, sensory abnormalities, and advanced age. Twenty-three percent of patients with FI and 22% of healthy patients demonstrate dyssynergic defecation (DD) on high-resolution anorectal manometry. Overflow incontinence occurs in some DD patients with normal resting and squeeze anal sphincter pressures. Our aim was to identify factors associated with normal sphincter pressures in women with FI. METHODS: We reviewed medical records of 134 women with FI. Patients with normal resting and squeeze anal pressures were compared with those with abnormal pressures using Wilcoxon rank sum test and Fisher exact. Multivariable logistic regression was performed to identify factors associated with normal resting and squeeze anal pressures. RESULTS: Among 134 women, abnormal resting and/or squeeze pressures were identified in 113 and normal pressures were identified in 21. Women with normal sphincter pressures were younger (mean age 52.7 ± 10.8 years vs 59.0 ± 14.0 years, P = 0.036), more often had abnormal defecation indices (100% vs 83.2%, P = 0.043) and higher rectal defecation pressures (30.8 ± 18.8 mm Hg vs 50.8 ± 22.6 mm Hg, P < 0.001). There was an overall association between DD subtype and normal and abnormal sphincter pressure groups (P = 0.021). Dyssynergia subtypes I or III (odds ratio, 7.2; 95% confidence interval, 1.8-28.8) and age younger than 67 years (odds ratio, 8.5; 95% confidence interval, 1.5-48.6) were associated with greater odds of having normal sphincter pressures. CONCLUSIONS: Female FI patients with normal anal sphincter pressures are younger, have higher rectal defecation pressures, and more often have type I or type III DD.

Provider-specific quality measurement for ERCP using natural language processing.

BACKGROUND AND AIMS: Natural language processing (NLP) is an information retrieval technique that has been shown to accurately identify quality measures for colonoscopy. There are no systematic methods by which to track adherence to quality measures for ERCP, the highest risk endoscopic procedure widely used in practice. Our aim was to demonstrate the feasibility of using NLP to measure adherence to ERCP quality indicators across individual providers. METHODS: ERCPs performed by 6 providers at a single institution from 2006 to 2014 were identified. Quality measures were defined using society guidelines and from expert opinion, and then extracted using a combination of NLP and data mining (eg, ICD9-CM codes). Validation for each quality measure was performed by manual record review. Quality measures were grouped into preprocedure (5), intraprocedure (6), and postprocedure (2). NLP was evaluated using measures of precision and accuracy. RESULTS: A total of 23,674 ERCPs were analyzed (average patient age, 52.9 ± 17.8 years, 14,113 were women [59.6%]). Among 13 quality measures, precision of NLP ranged from 84% to 100% with intraprocedure measures having lower precision (84% for precut sphincterotomy). Accuracy of NLP ranged from 90% to 100% with intraprocedure measures having lower accuracy (90% for pancreatic stent placement). CONCLUSIONS: NLP in conjunction with data mining facilitates individualized tracking of ERCP providers for quality metrics without the need for manual medical record review. Incorporation of these tools across multiple centers may permit tracking of ERCP quality measures through national registries.

Does a Program Based on Cognitive Behavioral Therapy Affect Kinesiophobia in Patients Following Total Knee Arthroplasty? A Randomized, Controlled Trial With a 6-Month Follow-Up.

BACKGROUND: To evaluate the effects of a cognitive behavioral therapy (CBT) program on kinesiophobia, knee function, pain and pain catastrophizing in patients following total knee arthroplasty (TKA). METHODS: This was a parallel-group, randomized, controlled pilot study in which 100 patients who exhibited kinesiophobia after TKA were randomly assigned to participate in a CBT (experimental group) or standard care (control group) program. Each group included 50 patients. Before intervention (preintervention), 4 weeks after intervention (postintervention), and 6 months after the end of intervention (follow-up), patients were assessed via the Tampa Scale for Kinesiophobia, the Pain Catastrophizing Scale, a numerical rating scale, and the Hospital for Special Surgery knee rating scale. Repeated-measures analysis of variance was used to test the significance of each outcome measure. RESULTS: The CBT program had significant group (P < .001), time (P < .001), and group-by-time interaction (P < .001) effects on kinesiophobia, pain catastrophizing, and knee function, and these effects lasted for at least 6 months after the end of the intervention. Pain was reduced in both groups after the intervention, but there were significant time and group effects (P = .003) in favor of the experimental group. CONCLUSION: The CBT program was superior to standard care in reducing kinesiophobia, pain catastrophizing, and knee pain and in enhancing knee function in patients who have a high level of kinesiophobia following TKA. The treatment effect was clinically significant and lasted for at least 6 months after the end of the intervention.

Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial.

Importance: Fecal microbiota transplantation (FMT) is effective in preventing recurrent Clostridium difficile infection (RCDI). However, it is not known whether clinical efficacy differs by route of delivery. Objective: To determine whether FMT by oral capsule is noninferior to colonoscopy delivery in efficacy. Design, Setting, and Participants: Noninferiority, unblinded, randomized trial conducted in 3 academic centers in Alberta, Canada. A total of 116 adult patients with RCDI were enrolled between October 2014 and September 2016, with follow-up to December 2016. The noninferiority margin was 15%. Interventions: Participants were randomly assigned to FMT by capsule or by colonoscopy at a 1:1 ratio. Main Outcomes and Measures: The primary outcome was the proportion of patients without RCDI 12 weeks after FMT. Secondary outcomes included (1) serious and minor adverse events, (2) changes in quality of life by the 36-Item Short Form Survey on a scale of 0 (worst possible quality of life) to 100 (best quality of life), and (3) patient perception on a scale of 1 (not at all unpleasant) to 10 (extremely unpleasant) and satisfaction on a scale of 1 (best) to 10 (worst). Results: Among 116 patients randomized (mean [SD] age, 58 [19] years; 79 women [68%]), 105 (91%) completed the trial, with 57 patients randomized to the capsule group and 59 to the colonoscopy group. In per-protocol analysis, prevention of RCDI after a single treatment was achieved in 96.2% in both the capsule group (51/53) and the colonoscopy group (50/52) (difference, 0%; 1-sided 95% CI, -6.1% to infinity; P < .001), meeting the criterion for noninferiority. One patient in each group died of underlying cardiopulmonary illness unrelated to FMT. Rates of minor adverse events were 5.4% for the capsule group vs 12.5% for the colonoscopy group. There was no significant between-group difference in improvement in quality of life. A significantly greater proportion of participants receiving capsules rated their experience as "not at all unpleasant" (66% vs 44%; difference, 22% [95% CI, 3%-40%]; P = .01). Conclusions and Relevance: Among adults with RCDI, FMT via oral capsules was not inferior to delivery by colonoscopy for preventing recurrent infection over 12 weeks. Treatment with oral capsules may be an effective approach to treating RCDI. Trial Registration: clinicaltrials.gov Identifier: NCT02254811.

Do Nonseminomatous Germ Cell Tumors of the Testis With Lymphovascular Invasion of the Spermatic Cord Merit Staging as pT3?

The staging of testicular nonseminomatous germ cell tumors (NSGCTs) with lymphovascular invasion (LVI) of the spermatic cord in the absence of cord parenchymal involvement remains controversial. Our previous study showed that tumors with spermatic cord LVI present at a higher clinical stage than tumors with LVI confined to the testis (pT2). We compared NSGCTs with LVI of the spermatic cord without direct involvement of the spermatic cord soft tissues to pT3 tumors to help clarify the appropriate staging of this histologic finding. A retrospective, multi-institutional review was performed to identify cases of NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord. The clinical-pathologic findings were compared with NSGCTs with spermatic cord soft tissue invasion (pT3). We identified 38 pT2 NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord and 89 pT3 tumors. There were no significant differences in patient age, tumor size, or clinical stage at presentation between the 2 groups. There were no significant differences in dominant histologic subtype, rete testis invasion, hilar soft tissue invasion, or margin status. There were no significant differences in disease recurrence/progression (P=0.63), recurrence/progression after chemotherapy (P=0.35), or death (P=0.51) between patients with only spermatic cord LVI versus patients with cord soft tissue invasion. In patients with pT2 NSGCTs according to the current staging, LVI in the spermatic cord without cord soft tissue invasion is comparable with pT3 tumors in terms of clinical stage at presentation as well as disease recurrence and survival.

Informative Patterns of Health-Care Utilization Prior to the Diagnosis of Pancreatic Ductal Adenocarcinoma.

Early-detection tests for pancreatic ductal adenocarcinoma (PDAC) are needed. Since a hypothetical screening test would be applied during antecedent clinical encounters, we sought to define the variability in health-care utilization leading up to PDAC diagnosis. This was a retrospective cohort study that included patients diagnosed with PDAC in the Indianapolis, Indiana, area between 1999 and 2013 with at least 1 health-care encounter during the antecedent 36-month period (n = 1,023). Patients were classified by unique patterns of health-care utilization using a group-based trajectory model. The prevalences of PDAC signals, such as diabetes mellitus (DM) and chronic pancreatitis, were compared. Four distinct trajectories were identified, the most common (42.0%) being having few clinical encounters more than 6 months prior to PDAC diagnosis (late acceleration). In all cases, a minority of persons had DM (30.6%, with 9.5% <1.5 years before PDAC) or any pancreatic disorder (39.9%); these were least common in the late-acceleration group (DM, 14.7%; any pancreatic disorder, 32.1% (P < 0.001)). The most common pattern of antecedent care was having few clinical encounters until shortly before PDAC diagnosis. Since the majority of patients diagnosed with PDAC do not have an antecedent PDAC signal, early-detection strategies limited to these groups may not apply to the majority of cases.