Lack of proton pump inhibitor trial prior to commencing therapy for eosinophilic esophagitis is common in the community.

Eosinophilic esophagitis is characterized by eosinophil inflammation restricted to the esophagus and the resulting symptoms of esophageal dysfunction. Critical to the diagnosis of eosinophilic esophagitis is a trial of proton pump inhibitor therapy to exclude alternative causes of esophageal eosinophilia such as proton pump inhibitor-responsive esophageal eosinophilia. While consensus guidelines recommend a proton pump inhibitor trial prior to diagnosis, little is known about its implementation in clinical practice. The primary aim of this study is to assess the frequency of proton pump inhibitor trial prior to the diagnosis of eosinophilic esophagitis in community practice. The secondary aim is to assess the frequency of other treatments for eosinophilic esophagitis, including topical steroids and/or dietary therapy, in patients who did not undergo a proton pump inhibitor trial prior to diagnosis or who had an alternative diagnosis to eosinophilic esophagitis upon completed workup. We conducted a single-center, case series of patients referred to the Hospital of the University of Pennsylvania for eosinophilic esophagitis management between 2010 and 2015. This case series consisted of 125 patients who were referred from community practitioners with a presumptive diagnosis of eosinophilic esophagitis. Upon review, 90 out of 125 (72%) patients had not had a proton pump inhibitor trial or esophageal pH testing prior to the diagnosis of eosinophilic esophagitis being made. Of these patients, 77.8% (70/90) had already received either topical steroid or dietary therapy for presumed eosinophilic esophagitis. Of the 125 patients initially diagnosed with eosinophilic esophagitis, 32 (25.6%) were found to have an alternative diagnosis, and 79.2% of this subset of patients (25/32) had previously received topical steroid or dietary therapy. This study demonstrates that a substantial number of patients with presumed eosinophilic esophagitis have not had a proton pump inhibitor trial prior to diagnosis in community practice. This led to the misclassification of patients and potentially to the use of less optimal medical therapies in a substantial number of these patients.

Clinical presentation and disease course of patients with esophagogastric junction outflow obstruction.

Esophagogastric junction outflow obstruction, characterized by preserved peristalsis in conjunction with an elevated integrated relaxation pressure, can result from specific anatomic variants or may represent achalasia in evolution. There is limited information on the clinical significance of this diagnosis. The aim of this study is to describe the clinical characteristics and outcomes in our cohort of patients with esophagogastric junction outflow obstruction.Consecutive adult patients who had undergone high-resolution esophageal manometry between February 2013 and November 2015 with a diagnosis of esophagogastric junction outflow obstruction were identified. Electronic medical records were reviewed to determine: (1) secondary causes of esophagogastric junction outflow obstruction; (2) treatment; and (3) natural history. Improvement in symptoms noted during follow-up evaluation was considered to be a favorable outcome. Worsening of symptoms or no change in symptoms was considered to be an unfavorable outcome.Of 874 manometries performed during this time period, 83 met the criteria for esophagogastric junction outflow obstruction. Of these patients, 11 had secondary causes: paraesophageal hernia (4), Nissen fundoplication (2), esophageal stricture (3), prior laparoscopic band placement (1), and diverticulum (1). All of these secondary causes were identified by barium esophagram. The remaining 72 patients were categorized as idiopathic esophagogastric junction outflow obstruction. Two patients developed type II achalasia on follow-up. An additional two patients had no symptoms as testing was performed for preoperative evaluation prior to bariatric surgery, leaving 68 patients for symptom follow-up analysis. Of these, 19 had a favorable outcome, 18 had an unfavorable outcome, and 31 were lost to follow-up. Of those with a favorable outcome, 6 patients underwent treatment: medication (3), botulinum toxin injection followed by laparoscopic Heller myotomy (1), botulinum toxin injection and medication (1), and bougie dilation (1). Of the 18 patients with an unfavorable outcome, 6 patients underwent treatment: botulinum toxin injection (5) and medication (1). Computed tomography scan or endoscopic ultrasound was performed in 40% of patients with available follow-up and none of these studies revealed secondary causes. The overall median follow-up time was 5 months.Esophagogastric outflow obstruction is a manometric finding of unclear significance. Secondary causes should first be excluded with structural studies. The evolution of esophagogastric junction outflow obstruction to achalasia is rare. Symptoms in patients with esophagogastric junction outflow obstruction do not always require treatment and treatment response is variable. The challenge in managing these patients lies in distinguishing which patients will need intervention. Further studies are needed for consideration of subgrouping this disease or modifying the categorization into clinically relevant entities.

Esophageal distensibility measurement: impact on clinical management and procedure length.

Luminal distensibility measurement has demonstrated relevance to various disease processes, though its effects on clinical decision-making have been less well understood. This study aims to characterize the clinical impact of impedance planimetry measurement as well as the learning curve associated with its use in the esophagus. A single provider performed distensibility measurement in conjunction with upper endoscopy for a variety of clinical indications with the functional lumen imaging probe (FLIP) over a period of 21 months. Procedural data were prospectively collected and, along with medical records, retrospectively reviewed. Seventy-three procedures (70 patients) underwent esophageal distensibility measurement over the timeline of this study. The most common procedural indications were known or suspected achalasia (32.9%), dysphagia with connective tissue disease (13.7%), eosinophilic esophagitis (12.3%), and dysphagia with prior fundoplication (9.6%). FLIP results independently led to a change in management in 29 (39.7%) cases and supported a change in management in an additional 15 (20.5%) cases. The most common change in management was a new or amended therapeutic procedure (79.5%). Procedural time added by distensibility measurement was greater among earlier cases than among later cases. The median time added overall was 5 minutes and 46 seconds. Procedural time added varied significantly by procedural indication, but changes in management did not. Distensibility measurement added meaningful diagnostic information that impacted therapeutic decision-making in the majority of cases in which it was performed. Procedural time added by this modality is typically modest and decreases with experience.

Gender is a determinative factor in the initial clinical presentation of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease resulting in symptoms of esophageal dysmotility. Abnormalities include dysphagia, food impaction and reflux. Although men appear to comprise a majority of the EoE population, few studies have directly assessed gender-associated clinical differences. The aim of this study is to identify the effect of gender on the initial clinical presentation of adult-onset EoE patients. We reviewed our electronic medical record database from January 2008 to December 2011 for adults diagnosed with EoE per the 2011 updated consensus guidelines. Patient demographics, presenting symptoms, endoscopy findings and complications were recorded. Proportions were compared using chi-squared analysis, and means were compared using the Student's t-test. A total of 162 patients met the inclusion criteria and 71 (44%) were women. Women were more likely to report chest pain (P = 0.03) and heartburn (P = 0.06), whereas men more commonly reported dysphagia (P = 0.04) and a history of food impaction (P = 0.05). Endoscopic findings were similar between groups. No patients suffered esophageal perforations. These data suggest that men report more fibrostenotic symptoms and women report more inflammatory symptoms at the time of diagnosis. There was no difference in endoscopic findings between genders. This is one of the only reviews comparing differences in clinical presentation, endoscopic findings and complications between gender for EoE. The current recommended guidelines state that any patient with symptoms of esophageal dysfunction should be biopsied for EoE. Our findings support biopsying patients with typical and atypical symptoms of dysmotility including heartburn and chest pain.

The influence of sporadic anovulation on hormone levels in ovulatory cycles.

STUDY QUESTION: Do ovulatory hormone profiles among healthy premenopausal women differ between women with and without sporadic anovulation? SUMMARY ANSWER: Women with one anovulatory cycle tended to have lower estradiol, progesterone and LH peak levels during their ovulatory cycle. WHAT IS KNOWN ALREADY: Anovulation occurs sporadically in healthy premenopausal women, but the influence of hormones in a preceding cycle and the impact on a subsequent cycle's hormone levels is unknown. STUDY DESIGN, SIZE, DURATION: The BioCycle Study was a prospective cohort including 250 healthy regularly menstruating women, 18-44 years of age, from Western New York with no history of menstrual or ovulation disorders. The women were followed with up to eight study visits per cycle for two cycles, most of which were consecutive. PARTICIPANTS/MATERIALS, SETTING AND METHODS: All study visits were timed to menstrual cycle phase using fertility monitors and located at the University at Buffalo women's health research center from 2005 to 2007. The main outcomes measured were estradiol, progesterone, LH and follicle-stimulating hormone levels in serum at up to 16 visits over two cycles. Anovulation was defined as peak serum progesterone concentrations ≤5 ng/ml and no serum LH peak detected during the mid- or late-luteal phase visit. MAIN RESULTS AND THE ROLE OF CHANCE: Reproductive hormone concentrations were lower during anovulatory cycles, but significant reductions were also observed in estradiol (-25%, P = 0.003) and progesterone (-22%, P = 0.001) during the ovulatory cycles of women with one anovulatory cycle compared with women with two ovulatory cycles. LH peak concentrations were decreased in the ovulatory cycle of women with an anovulatory cycle (significant amplitude effect, P = 0.004; geometric mean levels 38% lower, P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Follow-up was limited to two menstrual cycles, and no ultrasound assessment of ovulation was available. Data were missing for a total of 168 of a possible 4072 cycle visits (4.1%), though all women had at least five visits per cycle (94% had seven or more per cycle). WIDER IMPLICATIONS OF THE FINDINGS: These results suggest a possible underlying cause of anovulation, such as a longer-term subclinical follicular, ovarian or hypothalamic/pituitary dysfunction, even among healthy, regularly menstruating women.

Synaptotagmin C2A loop 2 mediates Ca2+-dependent SNARE interactions essential for Ca2+-triggered vesicle exocytosis.

Synaptotagmins contain tandem C2 domains and function as Ca(2+) sensors for vesicle exocytosis but the mechanism for coupling Ca(2+) rises to membrane fusion remains undefined. Synaptotagmins bind SNAREs, essential components of the membrane fusion machinery, but the role of these interactions in Ca(2+)-triggered vesicle exocytosis has not been directly assessed. We identified sites on synaptotagmin-1 that mediate Ca(2+)-dependent SNAP25 binding by zero-length cross-linking. Mutation of these sites in C2A and C2B eliminated Ca(2+)-dependent synaptotagmin-1 binding to SNAREs without affecting Ca(2+)-dependent membrane binding. The mutants failed to confer Ca(2+) regulation on SNARE-dependent liposome fusion and failed to restore Ca(2+)-triggered vesicle exocytosis in synaptotagmin-deficient PC12 cells. The results provide direct evidence that Ca(2+)-dependent SNARE binding by synaptotagmin is essential for Ca(2+)-triggered vesicle exocytosis and that Ca(2+)-dependent membrane binding by itself is insufficient to trigger fusion. A structure-based model of the SNARE-binding surface of C2A provided a new view of how Ca(2+)-dependent SNARE and membrane binding occur simultaneously.

Mars Extant Life: What's Next? Conference Report.

On November 5-8, 2019, the "Mars Extant Life: What's Next?" conference was convened in Carlsbad, New Mexico. The conference gathered a community of actively publishing experts in disciplines related to habitability and astrobiology. Primary conclusions are as follows: A significant subset of conference attendees concluded that there is a realistic possibility that Mars hosts indigenous microbial life. A powerful theme that permeated the conference is that the key to the search for martian extant life lies in identifying and exploring refugia ("oases"), where conditions are either permanently or episodically significantly more hospitable than average. Based on our existing knowledge of Mars, conference participants highlighted four potential martian refugium (not listed in priority order): Caves, Deep Subsurface, Ices, and Salts. The conference group did not attempt to reach a consensus prioritization of these candidate environments, but instead felt that a defensible prioritization would require a future competitive process. Within the context of these candidate environments, we identified a variety of geological search strategies that could narrow the search space. Additionally, we summarized a number of measurement techniques that could be used to detect evidence of extant life (if present). Again, it was not within the scope of the conference to prioritize these measurement techniques-that is best left for the competitive process. We specifically note that the number and sensitivity of detection methods that could be implemented if samples were returned to Earth greatly exceed the methodologies that could be used at Mars. Finally, important lessons to guide extant life search processes can be derived both from experiments carried out in terrestrial laboratories and analog field sites and from theoretical modeling.

What is the clinical significance of esophagogastric junction outflow obstruction? evaluation of 60 patients at a tertiary referral center.

BACKGROUND: Esophagogastric junction (EGJ) outflow obstruction (EGJOO) is characterized by impaired EGJ relaxation with intact or weak peristalsis. Our aims were to evaluate: (i) prevalence, (ii) yield of fluoroscopy, endoscopy, and endoscopic ultrasound (EUS), (iii) outcomes, and (iv) whether this data differed based on quantitative EGJ relaxation. METHODS: Studies that met criteria for EGJOO were identified. Demographics, encounters, endoscopy, radiology, treatment decisions, and outcomes were extracted. KEY RESULTS: Sixty studies were identified. Dysphagia was the most common symptom. Forty patients underwent barium esophagram (BE): normal (11), hiatal hernia (20), spasm/dysmotility (17), EGJ narrowing (10), compression (2), Schatzki's ring (5), malrotation (1), gastric volvulus (1), mass (1). Esophagogastroduodenoscopy (EGD) was performed in 41 patients: normal (19), hiatal hernia (13), Schatzki's ring (6), esophagitis (3), esophageal candidiasis (3), mass (1). EUS was performed in 20 patients and was frequently normal. Twenty-two patients underwent intervention. While transient improvement was noted in the majority, persistent improvement was seen in only one of nine patients (dilatation), four of six patients (botulinum toxin), and three patients who underwent per-oral endoscopic myotomy. No patients treated with medical therapy alone had improvement in dysphagia. There was no difference in symptoms or outcomes based on quantitative EGJ relaxation. CONCLUSIONS & INFERENCES: The manometric criterion EGJOO defines a heterogeneous clinical group. While BE, EGD, and EUS all provide complementary information, a significant percentage of these studies will be normal. For patients with dysphagia, outcome may depend on EGJ disruption. There were no differences in symptoms our outcomes based on quantitative EGJ relaxation.

Fibrous structure in the intervertebral disk: correlation of MR appearance with anatomic sections.

To correlate the MR appearance of the disk with its fibrous structure, we studied the lumbar intervertebral disks in 10 cadavers with MR, CT, cryomicrotome anatomic sections, and, in selected disks, with histologic and dried sections. In MR images the predominantly fibrous tissues such as Sharpey's fibers had a low signal intensity while the fibrocartilagenous tissues with a mucoid matrix in the intervertebral disk had a high signal intensity. In the equator of the adult disk was a well-defined fibrous plate that contained collagenous, elastic, and reticular fibers with little ground substance. This plate appeared to develop progressively from the periphery of the nucleus toward the center, starting in the second decade of life. The fibrous plate was also distinguished as a lower signal intensity in the MR images.

Preliminary clinical studies of bioceramic in periodontal osseous defects.

In six patients, porous tricalcium phosphate ceramic (400 to 500 micrometer pore diameter and 50% pore volume) was used to repair naturally occurring periodontal osseous defects. These patients were evaluated clinically, radiographically and hematologically. The clinical evaluation indicated that there was no adverse inflammatory response at the implant site except the anticipated immediate postsurgical trauma. Radiographically, there was a significant increase in bone height with a mean gain of 5.2 mm. Whether or not this gain consisted of bone and/or ceramic is yet to be conclusively determined. The SMA-12 blood chemistry study revealed that no significant change occurred pre- or post-operatively (P less than 0.01). Although the number of patients in our study was limited, the results are very promising. The ceramic is nontoxic to human tissue and repair of the periodontium is most likely obtainable, the desired objective being the restoration of the natural state of the periodontium.

Tissue response to biphasic calcium phosphate ceramic with different ratios of HA/beta TCP in periodontal osseous defects.

The purpose of this study was to determine the optimal ratio of calcium hydroxyapatite (HA) to beta tricalcium phosphate (beta TCP) in a biphasic porous calcium phosphate (BCP) ceramic for effective repair of periodontal osseous defects. Defects were surgically produced in beagle dogs and made chronic for 4 months to simulate periodontal disease. Mucoperiosteal periodontal flaps were reflected, followed by osseous defect debridement and root planing. Specially prepared ceramic with different HA/beta TCP ratios were implanted into the prepared defects. The sites were allowed to heal for 6 months, animals were euthanized, and site-blocks were removed for histological study. During the follow-up phase, scaling and polishing were done once a month, and standardized probing attachment levels were recorded pre- and 6-months postoperatively. The Duncan's multiple range test showed that all the treatments produced statistically significant higher gain in probing attachment levels than the control group (0HA/0 beta TCP) (P < 0.05). Among the 7 "active" treatment groups, 2 (65/35 and 85/15) had significantly higher gain in probing attachment levels than those in 3 groups (50/50, 100/0, and 0/100) (P < 0.05). Histologically, higher HA ratio (but not 100% HA) showed accelerated new bone formation and new attachment levels. Based on histological results, the 85HA/15 beta TCP ratio appears to demonstrate greater gain in attachment level and bone regeneration in the treatment of periodontal osseous defects.

Bioceramic implants in surgically produced infrabony defects.

Tricalcium phosphate ceramic of hydroxyapatite structure with 50% porosity and 800- to 1000-mum pore diameter was implanted in surgically produced infrabony defects in dogs. The defects were evaluated histologically at different time intervals, 1, 2, 4, 8, 16, and 24 weeks. The results show that the ceramic is well tolerated by the tissue and yields no toxic reactions. Bone ingrowth into the pores and repair of the periodontium are clearly demonstrated. No significant hematological changes were observed.

Evaluation of porous biphasic calcium phosphate ceramics for anterior cervical interbody fusion in a caprine model.

STUDY DESIGN: This study compared the efficacy of characterized 50/50 hydroxyapatite/beta-tricalcium phosphate ceramics of 30%, 50%, and 70% porosity and autograft to promote interbody spinal fusion at C2-C3 and C5-C6 in 24 goats: 12 at 3 months and 12 at 6 months. OBJECTIVES: Radiographs, histology, dual energy x-ray absorptiometry analysis, and biomechanical testing were used to evaluate the ability of the 30%, 50%, and 70% porous 50/50 hydroxyapatite/beta-tricalcium phosphate ceramics and autograft to promote cervical interbody fusion. SUMMARY OF BACKGROUND DATA: The conundrum in the use of calcium phosphates for interbody fusion is what porosity is most effective to promote ingrowth yet strong enough to resist compressive stresses found in the spine? It is known that the ability for bone ingrowth increases and the compressive strength decreases as porosity of the ceramic is increased. Dense ceramics remain intact but may be surrounded by fibrous tissue. Porous ceramics have good ingrowth but may fracture. METHODS: Radiographs were evaluated for fusion and fracture or collapse of the ceramics or autograft. Dual energy x-ray absorptiometry was used to evaluate the fusion mass. Treated motion segments underwent biomechanical testing to quantify the flexibility of the segment. Undecalcified and decalcified histologic analysis were performed to evaluate the presence or absence of a bony union. RESULTS: Thirty percent, 50%, and 70% porous ceramics had better radiographic fusion scores than the autograft at 3 and 6 months. Incidence of ceramic fracture did not increase with porosity and was equivalent to the collapse of autograft, although ceramics maintained disc height when fracture occurred. No statistically significant differences were found between autograft and the porous ceramics with biomechanical testing and peri-implant bone mineral density values as measured by dual energy x-ray absorptiometry. At 3 months, histologic analysis showed a union rate of 0% for autograft and 30% porous ceramic, 67% for 50% porous ceramic, and 83% for 70% porous ceramic. At 6 months, the union rate was 67% for the 30%, 50%, and 70% porous ceramics and 50% for autograft. CONCLUSIONS: Thirty percent, 50%, and 70% porous ceramics performed equal to or better than autogenous bone after 3 and 6 months. There may be promise for the use of 50/50 hydroxyapatite/beta-tricalcium phosphate in spine surgery as the need to harvest autograft from the iliac crest is obviated, and complications and cost associated with the harvest are avoided.

Cross-reactivity studies and predictive modeling of "Bath Salts" and other amphetamine-type stimulants with amphetamine screening immunoassays.

INTRODUCTION: The increasing abuse of amphetamine-like compounds presents a challenge for clinicians and clinical laboratories. Although these compounds may be identified by mass spectrometry-based assays, most clinical laboratories use amphetamine immunoassays that have unknown cross-reactivity with novel amphetamine-like drugs. To date, there has been a little systematic study of amphetamine immunoassay cross-reactivity with structurally diverse amphetamine-like drugs or of computational tools to predict cross-reactivity. METHODS: Cross-reactivities of 42 amphetamines and amphetamine-like drugs with three amphetamines screening immunoassays (AxSYM(®) Amphetamine/Methamphetamine II, CEDIA(®) amphetamine/Ecstasy, and EMIT(®) II Plus Amphetamines) were determined. Two- and three-dimensional molecular similarity and modeling approaches were evaluated for the ability to predict cross-reactivity using receiver-operator characteristic curve analysis. RESULTS: Overall, 34%-46% of the drugs tested positive on the immunoassay screens using a concentration of 20,000 ng/mL. The three immunoassays showed differential detection of the various classes of amphetamine-like drugs. Only the CEDIA assay detected piperazines well, while only the EMIT assay cross-reacted with the 2C class. All three immunoassays detected 4-substituted amphetamines. For the AxSYM and EMIT assays, two-dimensional molecular similarity methods that combined similarity to amphetamine/methamphetamine and 3,4-methylenedioxymethampetamine most accurately predicted cross-reactivity. For the CEDIA assay, three-dimensional pharmacophore methods performed best in predicting cross-reactivity. Using the best performing models, cross-reactivities of an additional 261 amphetamine-like compounds were predicted. CONCLUSIONS: Existing amphetamines immunoassays unevenly detect amphetamine-like drugs, particularly in the 2C, piperazine, and ß-keto classes. Computational similarity methods perform well in predicting cross-reactivity and can help prioritize testing of additional compounds in the future.

Measurement of the muon capture rate in hydrogen gas and determination of the proton's pseudoscalar coupling gP.

The rate of nuclear muon capture by the proton has been measured using a new technique based on a time projection chamber operating in ultraclean, deuterium-depleted hydrogen gas, which is key to avoiding uncertainties from muonic molecule formation. The capture rate from the hyperfine singlet ground state of the microp atom was obtained from the difference between the micro(-) disappearance rate in hydrogen and the world average for the micro(+) decay rate, yielding Lambda(S)=725.0+/-17.4 s(-1), from which the induced pseudoscalar coupling of the nucleon, g(P)(q(2)=-0.88m(2)(micro))=7.3+/-1.1, is extracted.

Gross and microscopic anatomical studies of palate structure and osteotomy site.

A normal 1-year-old infant palate and a newborn cleft palate were studied grossly, radiographically, and microscopically for histological structure in hard palate osteotomy sites. A correlated study of biopsies from an osteotomy site seven days postoperatively and another at twelve months following osteotomy was also made. The findings showed that successful osteotomy in infant cleft palate surgery translocates autogenous fibrous bone and osteogenic cells into a cleft-bridging position. Woven fibrous bone rapidly forms across the cleft, and then matures by lamellar bone replacement and haversian system remodeling. Both normal and cleft palates have a rich anastomosis of microscopic blood supply that is vitally important in the remodeling process. These factors may help to explain successful long-term results in early cleft palate osteotomy surgery.

Effects of chelates in chemotherapy of experimental gas-gangrene toxemia.

The relative ability of the calcium chelates of calcium disodium ethylenediaminetetraacetate (EDTA) and calcium trisodium ethylenetriaminepentaacetate (DTPA) to protect mice against lethal doses of Clostridium perfringens alpha-toxin was investigated. Their protective ability was assayed by the increase in survival time of mice which had been given large doses of toxin, and by determining the median protective dose of chelate that would protect mice against toxin at a minimum lethal dose of two. In both assay procedures, intraperitoneal, intravenous, and intracutaneous injections of toxin were utilized, and with each toxin injection route the protective ability of the chelate was determined with the three routes of injection. DTPA was 10 to 20 times more effective than EDTA with both types of assay procedure and with all injection routes. DTPA may be superior to EDTA as a protective agent not only because it binds zinc to a greater extent, but also because of its greater retention in the body and its ability to gain entrance into cells. It appears that DTPA may be of value as a therapeutic agent in gas-gangrene.

Relationship of route of inoculation and nature of toxin preparation to bioassay of Clostridium perfringens alpha-toxin in mice.

The toxicity of Clostridium perfringens was determined in mice utilizing three different routes of inoculation. There was marked variation in the minimum lethal dose with the different routes; the largest amount was required for the intracutaneous route, less for the intravenous route, and least with the intraperitoneal route. The relationship of toxicity to the lecithinase content of different toxin preparations was assayed. It was found that the toxicity of toxin preparations in different states of purification was not correlated with their lecithinase content.