Age and African-American race impact the validity and reliability of the asthma control test in persistent asthmatics.

BACKGROUND: The Asthma Control Test (ACT) is widely used to assess asthma control, yet the validity and reliability of the test have not been specifically evaluated in adolescents or African-Americans. We conducted a prospective psychometric study of the ACT in African-American (AA) and non-African-American (nAA) adolescents with persistent asthma, with emphasis on the clinical utility of the test for medical decision making. METHODS: Participants completed the ACT and performed spirometry. A physician conducted a guidelines-based assessment of asthma control, blinded to the ACT score. Study procedures were repeated 6-8 weeks later. The ACT-based asthma control assessment was compared to physician assessment. RESULTS: For baseline and follow-up visits, internal consistency, as measured using Cronbach's alpha, was 0.80 and 0.81 in AA teens and 0.80 and 0.83 in nAA teens. Intraclass correlation coefficients were 0.59 and 0.76 in AA and nAA teens, respectively, with stable asthma control over time. Agreement between ACT and physician assessment was moderate in AA teens and fair in nAA teens. An ACT score of ≤19 showed reduced sensitivity for not well controlled asthma in both groups, while a score of ≤21 had the greatest area under the ROC curve. ACT scores were marginally responsive to change in control status. CONCLUSIONS: Concerns for the ACT's ability to detect uncontrolled asthma in adolescents emphasizes the need for a more comprehensive evaluation of asthma control in clinical settings. A higher threshold ACT score to define not well controlled asthma may be needed if the ACT is to be used for medical decision making. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02671643 , NCT02662413 .

Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy.

BACKGROUND: Though peanut oral immunotherapy (OIT) is a promising investigational therapy, its potential is limited by substantial adverse events (AEs), which are relatively understudied. OBJECTIVE: A retrospective analysis was conducted, pooling data from 3 pediatric peanut OIT trials, comprising the largest analysis of peanut OIT safety to date. METHODS: We pooled data from 104 children with peanut allergy from 3 peanut OIT studies. We catalogued AEs from parental reports, daily symptom diaries, and dose escalations. We included events that were considered likely related to OIT and identified potential baseline predictors of higher AE rates using generalized linear regression models. RESULTS: Eighty percent of subjects experienced likely related AEs during OIT (72% during buildup and 47% during maintenance). Of these AEs, over 90% occurred while at home. Approximately 42% of subjects experienced systemic reactions, and 49% experienced gastrointestinal symptoms. Twenty percent of subjects dropped out, with half (10% of the overall group) due to persistent gastrointestinal symptoms. Baseline allergic rhinitis (AR) and peanut SPT wheal size were significant predictors of higher overall AE rates. SPT wheal size predicted increased gastrointestinal AEs, and AR predicted increased systemic reactions. Over the course of OIT, 61% of subjects received treatment for likely related AEs, 59% with antihistamines and 12% with epinephrine. CONCLUSIONS: Peanut OIT is associated with frequent AEs, with rates declining over time, and most graded mild. However, systemic reactions and intolerable gastrointestinal AEs do occur and are significantly associated with AR and peanut SPT wheal size, respectively. Further study is needed of predictive biomarkers and the overall risks and benefits of OIT.

Early oral immunotherapy in peanut-allergic preschool children is safe and highly effective.

BACKGROUND: Oral immunotherapy (OIT) is an effective experimental food allergy treatment that is limited by treatment withdrawal and the frequent reversibility of desensitization if interrupted. Newly diagnosed preschool children may have clinical and immunological characteristics more amenable to treatment. OBJECTIVE: We sought to test the safety, effectiveness, and feasibility of early OIT (E-OIT) in the treatment of peanut allergy. METHODS: We enrolled 40 children aged 9 to 36 months with suspected or known peanut allergy. Qualifying subjects reacted to peanut during an entry food challenge and were block-randomized 1:1 to receive E-OIT at goal maintenance doses of 300 or 3000 mg/d in a double-blinded fashion. The primary end point, sustained unresponsiveness at 4 weeks after stopping early intervention oral immunotherapy (4-SU), was assessed by double-blinded, placebo-controlled food challenge either upon achieving 4 prespecified criteria, or after 3 maintenance years. Peanut-specific immune responses were serially analyzed. Outcomes were compared with 154 matched standard-care controls. RESULTS: Of 40 consented subjects, 3 (7.5%) did not qualify. Overall, 29 of 37 (78%) in the intent-to-treat analysis achieved 4-SU (300-mg arm, 17 of 20 [85%]; 3000 mg, 12 of 17 [71%], P = .43) over a median of 29 months. Per-protocol, the overall proportion achieving 4-SU was 29 of 32 (91%). Peanut-specific IgE levels significantly declined in E-OIT-treated children, who were 19 times more likely to successfully consume dietary peanut than matched standard-care controls, in whom peanut-specific IgE levels significantly increased (relative risk, 19.42; 95% CI, 8.7-43.7; P < .001). Allergic side effects during E-OIT were common but all were mild to moderate. CONCLUSIONS: At both doses tested, E-OIT had an acceptable safety profile and was highly successful in rapidly suppressing allergic immune responses and achieving safe dietary reintroduction.

POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome.

Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome.

Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy.

BACKGROUND: Although peanut oral immunotherapy (OIT) has been conclusively shown to cause desensitization, it is currently unknown whether clinical protection persists after stopping therapy. OBJECTIVE: Our primary objective was to determine whether peanut OIT can induce sustained unresponsiveness after withdrawal of OIT. METHODS: We conducted a pilot clinical trial of peanut OIT at 2 US centers. Subjects age 1 to 16 years were recruited and treated for up to 5 years with peanut OIT. The protocol was modified over time to permit dose increases to a maximum of 4000 mg/d peanut protein. Blood was collected at multiple time points. Clinical end points were measured with 5000-mg double-blinded, placebo-controlled food challenges once specific criteria were met. RESULTS: Of the 39 subjects originally enrolled, 24 completed the protocol and had evaluable outcomes. Twelve (50%) of 24 successfully passed a challenge 1 month after stopping OIT and achieved sustained unresponsiveness. Peanut was added to the diet. At baseline and the time of challenge, such subjects had smaller skin test results, as well as lower IgE levels specific for peanut, Ara h 1, and Ara h 2 and lower ratios of peanut-specific IgE/total IgE compared with subjects not passing. There were no differences in peanut IgG4 levels or functional activity at the end of the study. CONCLUSIONS: This is the first demonstration of sustained unresponsiveness after peanut OIT, occurring in half of subjects treated for up to 5 years. OIT favorably modified the peanut-specific immune response in all subjects completing the protocol. Smaller skin test results and lower allergen-specific IgE levels were predictive of successful outcome.

Peanut oral immunotherapy modifies IgE and IgG4 responses to major peanut allergens.

BACKGROUND: Patients with peanut allergy have highly stable pathologic antibody repertoires to the immunodominant B-cell epitopes of the major peanut allergens Ara h 1 to 3. OBJECTIVE: We used a peptide microarray technique to analyze the effect of treatment with peanut oral immunotherapy (OIT) on such repertoires. METHODS: Measurements of total peanut-specific IgE (psIgE) and peanut-specific IgG(4) (psIgG(4)) were made with CAP-FEIA. We analyzed sera from 22 patients with OIT and 6 control subjects and measured serum specific IgE and IgG(4) binding to epitopes of Ara h 1 to 3 using a high-throughput peptide microarray technique. Antibody affinity was measured by using a competitive peptide microarray, as previously described. RESULTS: At baseline, psIgE and psIgG(4) diversity was similar between patients and control subjects, and there was broad variation in epitope recognition. After a median of 41 months of OIT, polyclonal psIgG(4) levels increased from a median of 0.3 µg/mL (interquartile range [25% to 75%], 0.1-0.43 µg/mL) at baseline to 10.5 µg/mL (interquartile range [25% to 75%], 3.95-45.48 µg/mL; P < .0001) and included de novo specificities. psIgE levels were reduced from a median baseline of 85.45 kU(A)/L (23.05-101.0 kU(A)/L) to 7.75 kU(A)/L (2.58-30.55 kU(A)/L, P < .0001). Affinity was unaffected. Although the psIgE repertoire contracted in most OIT-treated patients, several subjects generated new IgE specificities, even as the total psIgE level decreased. Global epitope-specific shifts from IgE to IgG(4) binding occurred, including at an informative epitope of Ara h 2. CONCLUSION: OIT differentially alters Ara h 1 to 3 binding patterns. These changes are variable between patients, are not observed in control subjects, and include a progressive polyclonal increase in IgG(4) levels, with concurrent reduction in IgE amount and diversity.

The safety and efficacy of sublingual and oral immunotherapy for milk allergy.

BACKGROUND: Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are potential therapies for food allergy, but the optimal method of administration, mechanism of action, and duration of response remain unknown. OBJECTIVE: We sought to explore the safety and efficacy of OIT and SLIT for the treatment of cow's milk (CM) allergy. METHODS: We randomized children with CM allergy to SLIT alone or SLIT followed by OIT. After screening double-blind, placebo-controlled food challenges and initial SLIT escalation, subjects either continued SLIT escalation to 7 mg daily or began OIT to either 1000 mg (the OITB group) or 2000 mg (the OITA group) of milk protein. They were challenged with 8 g of milk protein after 12 and 60 weeks of maintenance. If they passed the 60-week challenge, therapy was withdrawn, with challenges repeated 1 and 6 weeks later. Mechanistic correlates included end point titration skin prick testing and measurement of CM-specific IgE and IgG(4) levels, basophil histamine release, constitutive CD63 expression, CD203c expression, and intracellular spleen tyrosine kinase levels. RESULTS: Thirty subjects with CM allergy aged 6 to 17 years were enrolled. After therapy, 1 of 10 subjects in the SLIT group, 6 of 10 subjects in the SLIT/OITB group, and 8 of 10 subjects in the OITA group passed the 8-g challenge (P = .002, SLIT vs OIT). After avoidance, 6 of 15 subjects (3 of 6 subjects in the OITB group and 3 of 8 subjects in the OITA group) regained reactivity, 2 after only 1 week. Although the overall reaction rate was similar, systemic reactions were more common during OIT than during SLIT. By the end of therapy, titrated CM skin prick test results and CD63 and CD203c expression decreased and CM-specific IgG(4) levels increased in all groups, whereas CM-specific IgE and spontaneous histamine release values decreased in only the OIT group. CONCLUSION: OIT was more efficacious for desensitization to CM than SLIT alone but was accompanied by more systemic side effects. Clinical desensitization was lost in some cases within 1 week off therapy.

Barriers and Facilitators Associated With Remote Monitoring Adherence Among Veterans With Pacemakers and Implantable Cardioverter-Defibrillators: Qualitative Cross-Sectional Study.

BACKGROUND: The Heart Rhythm Society strongly recommends remote monitoring (RM) of cardiovascular implantable electronic devices (CIEDs) because of the clinical outcome benefits to patients. However, many patients do not adhere to RM and, thus, do not achieve these benefits. There has been limited study of patient-level barriers and facilitators to RM adherence; understanding patient perspectives is essential to developing solutions to improve adherence. OBJECTIVE: We sought to identify barriers and facilitators associated with adherence to RM among veterans with CIEDs followed by the Veterans Health Administration. METHODS: We interviewed 40 veterans with CIEDs regarding their experiences with RM. Veterans were stratified into 3 groups based on their adherence to scheduled RM transmissions over the past 2 years: 6 fully adherent (≥95%), 25 partially adherent (≥65% but <95%), and 9 nonadherent (<65%). As the focus was to understand challenges with RM adherence, partially adherent and nonadherent veterans were preferentially weighted for selection. Veterans were mailed a letter stating they would be called to understand their experiences and perspectives of RM and possible barriers, and then contacted beginning 1 week after the letter was mailed. Interviews were structured (some questions allowing for open-ended responses to dive deeper into themes) and focused on 4 predetermined domains: knowledge of RM, satisfaction with RM, reasons for nonadherence, and preferences for health care engagement. RESULTS: Of the 44 veterans contacted, 40 (91%) agreed to participate. The mean veteran age was 75.3 (SD 7.6) years, and 98% (39/40) were men. Veterans had been implanted with their current CIED for an average of 4.4 (SD 2.8) years. A total of 58% (23/40) of veterans recalled a discussion of home monitoring, and 45% (18/40) reported a good understanding of RM; however, when asked to describe RM, their understanding was sometimes incomplete or not correct. Among the 31 fully or partially adherent veterans, nearly all were satisfied with RM. Approximately one-third recalled ever being told the results of a remote transmission. Among partially or nonadherent veterans, only one-fourth reported being contacted by a Department of Veterans Affairs health care professional regarding not having sent a remote transmission; among those who had troubleshooted to ensure they could send remote transmissions, they often relied on the CIED manufacturer for help (this experience was nearly always positive). Most nonadherent veterans felt more comfortable engaging in RM if they received more information or education. Most veterans were interested in being notified of a successful remote transmission and learning the results of their remote transmissions. CONCLUSIONS: Veterans with CIEDs often had limited knowledge about RM and did not recall being contacted about nonadherence. When they were contacted and troubleshooted, the experience was positive. These findings provide opportunities to optimize strategies for educating and engaging patients in RM.

Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization.

BACKGROUND: There are no treatments currently available for peanut allergy. Sublingual immunotherapy (SLIT) is a novel approach to the treatment of peanut allergy. OBJECTIVE: We sought to investigate the safety, clinical effectiveness, and immunologic changes with SLIT in children with peanut allergy. METHODS: In this double-blind, placebo-controlled study subjects underwent 6 months of dose escalation and 6 months of maintenance dosing followed by a double-blind, placebo-controlled food challenge. RESULTS: Eighteen children aged 1 to 11 years completed 12 months of dosing and the food challenge. Dosing side effects were primarily oropharyngeal and uncommonly required treatment. During the double-blind, placebo-controlled food challenge, the treatment group safely ingested 20 times more peanut protein than the placebo group (median, 1,710 vs 85 mg; P = .011). Mechanistic studies demonstrated a decrease in skin prick test wheal size (P = .020) and decreased basophil responsiveness after stimulation with 10(-2) µg/mL (P = .009) and 10(-3) µg/mL (P = .009) of peanut. Peanut-specific IgE levels increased over the initial 4 months (P = .002) and then steadily decreased over the remaining 8 months (P = .003), whereas peanut-specific IgG4 levels increased during the 12 months (P = .014). Lastly, IL-5 levels decreased after 12 months (P = .015). No statistically significant changes were found in IL-13 levels, the percentage of regulatory T cells, or IL-10 and IFN-γ production. CONCLUSION: Peanut SLIT is able to safely induce clinical desensitization in children with peanut allergy, with evidence of immunologic changes suggesting a significant change in the allergic response. Further study is required to determine whether continued peanut SLIT is able to induce long-term immune tolerance.

A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.

BACKGROUND: Open-label oral immunotherapy (OIT) protocols have been used to treat small numbers of patients with peanut allergy. Peanut OIT has not been evaluated in double-blind, placebo-controlled trials. OBJECTIVE: To investigate the safety and effectiveness of OIT for peanut allergy in a double-blind, placebo-controlled study. METHODS: In this multicenter study, children ages 1 to 16 years with peanut allergy received OIT with peanut flour or placebo. Initial escalation, build-up, and maintenance phases were followed by an oral food challenge (OFC) at approximately 1 year. Titrated skin prick tests (SPTs) and laboratory studies were performed at regular intervals. RESULTS: Twenty-eight subjects were enrolled in the study. Three peanut OIT subjects withdrew early in the study because of allergic side effects. During the double-blind, placebo-controlled food challenge, all remaining peanut OIT subjects (n = 16) ingested the maximum cumulative dose of 5000 mg (approximately 20 peanuts), whereas placebo subjects (n = 9) ingested a median cumulative dose of 280 mg (range, 0-1900 mg; P < .001). In contrast with the placebo group, the peanut OIT group showed reductions in SPT size (P < .001), IL-5 (P = .01), and IL-13 (P = .02) and increases in peanut-specific IgG(4) (P < .001). Peanut OIT subjects had initial increases in peanut-specific IgE (P < .01) but did not show significant change from baseline by the time of OFC. The ratio of forkhead box protein 3 (FoxP3)(hi): FoxP3(intermediate) CD4+ CD25+ T cells increased at the time of OFC (P = .04) in peanut OIT subjects. CONCLUSION: These results conclusively demonstrate that peanut OIT induces desensitization and concurrent immune modulation. The current study continues and is evaluating the hypothesis that peanut OIT causes long-term immune tolerance.

Individualized IgE-based dosing of egg oral immunotherapy and the development of tolerance.

BACKGROUND: Hen's egg allergy is among the most common food allergies in childhood and predicts later development of allergic disease. The optimal efficacy and mechanism(s) of egg allergen immunotherapy are poorly understood. OBJECTIVE: To enhance immunologic and clinical outcomes of egg oral immunotherapy (OIT) using a conditionally increased dosing strategy. METHODS: In an open-label clinical trial of egg OIT, egg-allergic children ingested daily doses of egg protein that were gradually increased based on the egg white (EW) IgE level. Skin prick test reactivity and EW- and ovomucoid-specific cellular and humoral responses were measured longitudinally. To confirm clinical tolerance, patients underwent double-blinded, placebo-controlled food challenges 1 month after completing the dosing protocol. RESULTS: Children aged 3 to 13 years with characteristics of clinical egg allergy were enrolled. All 6 patients who completed the entire protocol developed clinical tolerance to egg during the study. The median wheal diameter on EW skin prick testing decreased from 10 to 2.5 mm during OIT (P = .03). Both EW and ovomucoid IgE levels significantly decreased during the study (median EW IgE level: from 18.8 kU/L at baseline to 3.9 kU/L, P = .03), and corresponding IgG4 levels increased (median EW IgG4 level: from 0.65 mg/L at baseline to 86.15 mg/L, P = .03). Transient increases were seen in egg-induced interleukin 10 (P = .06) and transforming growth factor ß (P = .18) levels, and the ratio of T(H)2:T(H)1 cytokine production was decreased (P = .25). CONCLUSIONS: Egg OIT is associated with tolerance acquisition in children with persistent egg allergy. Individualized dosing regimens may be necessary to achieve a full therapeutic effect in some patients.

Safety of a peanut oral immunotherapy protocol in children with peanut allergy.

BACKGROUND: Oral immunotherapy (OIT) offers a promising therapeutic option for peanut allergy. Given that during OIT an allergic patient ingests an allergen that could potentially cause a serious reaction, the safety of OIT is of particular concern. OBJECTIVE: The purpose of this study was to examine safety during the initial escalation day, buildup phase, and home dosing phase in subjects enrolled in a peanut OIT study. METHODS: Skin, upper respiratory tract, chest, and abdominal symptoms were recorded with initial escalation day and buildup phase dosings. Subjects also maintained daily diaries detailing symptoms after each home dosing. A statistical analysis of these data was performed. RESULTS: Twenty of 28 patients completed all phases of the study. During the initial escalation day, upper respiratory tract (79%) and abdominal (68%) symptoms were the most likely symptoms experienced. The risk of mild wheezing during the initial escalation day was 18%. The probability of having any symptoms after a buildup phase dose was 46%, with a risk of 29% for upper respiratory tract symptoms and 24% for skin symptoms. The risk of reaction with any home dose was 3.5%. Upper respiratory tract (1.2%) and skin (1.1%) symptoms were the most likely after home doses. Treatment was given with 0.7% of home doses. Two subjects received epinephrine after 1 home dose each. CONCLUSIONS: Subjects were more likely to have significant allergic symptoms during the initial escalation day when they were in a closely monitored setting than during other phases of the study. Allergic reactions with home doses were rare.

Clinical efficacy and immune regulation with peanut oral immunotherapy.

BACKGROUND: Oral immunotherapy (OIT) has been thought to induce clinical desensitization to allergenic foods, but trials coupling the clinical response and immunologic effects of peanut OIT have not been reported. OBJECTIVE: The study objective was to investigate the clinical efficacy and immunologic changes associated with OIT. METHODS: Children with peanut allergy underwent an OIT protocol including initial day escalation, buildup, and maintenance phases, and then oral food challenge. Clinical response and immunologic changes were evaluated. RESULTS: Of 29 subjects who completed the protocol, 27 ingested 3.9 g peanut protein during food challenge. Most symptoms noted during OIT resolved spontaneously or with antihistamines. By 6 months, titrated skin prick tests and activation of basophils significantly declined. Peanut-specific IgE decreased by 12 to 18 months, whereas IgG(4) increased significantly. Serum factors inhibited IgE-peanut complex formation in an IgE-facilitated allergen binding assay. Secretion of IL-10, IL-5, IFN-gamma, and TNF-alpha from PBMCs increased over a period of 6 to 12 months. Peanut-specific forkhead box protein 3 T cells increased until 12 months and decreased thereafter. In addition, T-cell microarrays showed downregulation of genes in apoptotic pathways. CONCLUSION: Oral immunotherapy induces clinical desensitization to peanut, with significant longer-term humoral and cellular changes. Microarray data suggest a novel role for apoptosis in OIT.

The people factor: An analysis of the human resources landscape for immunization supply chain management.

Human resources is the backbone of any system and the key enabler for all other functions to effectively perform. This is no different with the Immunization Supply Chain, more so in todays' complex operating environment with the increasing strain caused by new vaccines and expanding immunization programmes (Source: WHO, UNICEF). In order to drive the change that is required for sustainability and continuous improvement, every immunization supply chain needs an effective leader. A dedicated and competent immunization supply chain leader with adequate numbers of skilled, accountable, motivated and empowered personnel at all levels of the health system to overcome existing and emerging immunization supply chain (ISC) challenges. Without an effective supply chain leader supported by capable and motivated staff, none of the interventions designed to strengthen the supply chain can be effective or sustainable (Source: Gavi Alliance SC Strategy 2014). This landscape analysis was preceded by an HR Evidence Review (March 2014) and has served to inform global partner strategies and country activities, as well as highlight where most support is required. The study also aimed to define the status quo in order to create some form of baseline against which to measure the impact of interventions related to HR going forward. The analysis was comprised of a comprehensive desk review, a survey of 40 respondents from 32 countries and consultations with ISC practitioners in several forums. The findings highlight key areas that should inform the pillars of a HR capacity development plan. At the same time, it revealed that there are some positive examples of where countries are actively addressing some of the issues identified and putting in place mechanisms and structures to optimize the SC function.

Expression in human ocular surface tissues of the GalNAc-transferases that initiate mucin-type O-glycosylation.

PURPOSE: Mucins are highly glycosylated proteins that act as lubricants, protectants, and mediators of signal transduction. The UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase (ppGaNTase) family members initiate mucin-type O-glycosylation. Because O-glycosylation provides mucins with the viscoelastic properties required for proper mucin function, ppGaNTase expression is vital to the maintenance of healthy epithelial surfaces including the ocular surface. Differences of expression of ppGaNTase isoforms might be factors influencing susceptibility to dry eye disease. Therefore, we determined the expression of the ppGaNTase isoforms in normal human ocular surface tissues and the conjunctival epithelium from patients with aqueous-deficient dry eye. METHODS: Expression of ppGaNTase isoforms was quantitated by real-time reverse transcriptase polymerase chain rection (RT-PCR). RESULTS: Conjunctiva and cornea expressed multiple ppGaNTase isoforms, with isoforms T12 and T4 being the most strongly expressed in conjunctiva and T12 and T3 in the cornea. In contrast, lacrimal gland expressed fewer isoforms and had lower total ppGaNTase expression. Brush cytology was found to be superior to impression cytology for harvesting conjunctival epithelium in terms of ease of use, safety, and reproducibility of results. Similar to whole conjunctiva, the strongest isoforms in conjunctival epithelial cells were T12 and T4, followed by T3, T1, T5, and T2. No significant differences of ppGaNTase expression were found between the conjunctival epithelium of dry eye and normal control groups. CONCLUSION: Human ocular surface tissues express multiple ppGaNTase isoforms, suggesting a requirement for glycosylating diverse mucin-type substrates. However, there is no evidence to date to suggest that differences of ppGaNTase expression levels might contribute to susceptibility to dry eye disease.

Critical pathways for management of patients with acute coronary syndromes: an assessment by the National Heart Attack Alert Program.

BACKGROUND: The use of critical pathways for a variety of clinical conditions has grown rapidly in recent years, particularly pathways for patients with acute coronary syndromes (ACS). However, no systematic review exists regarding the value of critical pathways in this setting. METHODS: The National Heart Attack Alert Program established a Working Group to review the utility of critical pathways on quality of care and outcomes for patients with ACS. A literature search of MEDLINE, cardiology textbooks, and cited references in any article identified was conducted regarding the use of critical pathways for patients with ACS. RESULTS: Several areas for improving the care of patients with ACS through the application of critical pathways were identified: increasing the use of guideline-recommended medications, targeting use of cardiac procedures and other cardiac testing, and reducing the length of stay in hospitals and intensive care units. Initial studies have shown promising results in improving quality of care and reducing costs. No large studies designed to demonstrate an improvement in mortality or morbidity were identified in this literature review. CONCLUSIONS: Critical pathways offer the potential to improve the care of patients with ACS while reducing the cost of care. Their use should improve the process and cost-effectiveness of care, but further research in this field is needed to determine whether these changes in the process of care will translate into improved clinical outcomes.

MUC7 expression in the human lacrimal gland and conjunctiva.

PURPOSE: Several mucins including MUC1, MUC2, MUC4, and MUC5AC have been identified at the ocular surface and in tears. The lacrimal gland, however, is not generally considered a source of ocular mucin. Because the lacrimal glands are similar to the salivary glands, we hypothesized that the lacrimal gland would express MUC7, a distinctive salivary mucin. We report the presence of MUC7 RNA and protein in normal human lacrimal glands as determined by reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization, and Western blot analysis. METHODS: RNA from lacrimal glands and conjunctivae was isolated and subjected to RT-PCR with primers specific for MUC7. The identity of the PCR products was confirmed by sequencing. In situ hybridization with PCR product-based riboprobes was used to locate MUC7 transcripts in the lacrimal gland. MUC7 protein was detected by Western blot analysis. RESULTS: Of six normal human lacrimal glands from which relatively intact mRNA could be extracted, four expressed MUC7. Hybridization with an antisense riboprobe for MUC7 indicates the presence of MUC7 transcripts in the cytoplasm of acinar cells. Western blot analysis confirms expression of the protein in the lacrimal gland. The presence of MUC1, MUC4, and MUC5B was also demonstrated by RT-PCR in lacrimal gland tissue. MUC7 transcripts and protein were also detected in normal human conjunctivae. CONCLUSIONS: The mucin profile of the lacrimal gland resembles that of the salivary gland. Both RNA and protein corresponding to MUC7 are present in the normal human lacrimal gland. Reverse transcription-polymerase chain reaction indicates that other transcripts of MUC1, MUC4, and MUC5B are present as well. Ocular MUC7 is also produced by the conjunctival mucosa. The lacrimal gland, therefore, contributes not only to the aqueous component of tears but also, in concert with the conjunctiva, may contribute to the total pool of ocular surface mucins.