Assessing the profile and utility of diplomates in occupational medicine.

BACKGROUND: The utility of the occupational medicine diploma in the UK is yet to be explored. The NHS 'Growing Occupational Health (OH) and Wellbeing' programme provides opportunities for diplomates to increase their OH work. AIMS: To assess what proportion of diplomates carry out OH work, the type of work being undertaken, to identify obstacles impeding OH work, to capture their interest in future work opportunities and what additional support they require. METHODS: A link to an online questionnaire was sent to diplomates via several professional bodies; we estimate that 2428 diplomates received this. The survey was open from 24 March to 31 May 2022. RESULTS: Replies were received from 310/2428 (13%) diplomates. Fifty-two per cent of respondents were males and 35% were female. Respondents were diverse in terms of age and geographical region. Main employment settings: 13% primary care, 43% secondary care, 31% private sector, 24% public sector and 20% self-employed. Seventy-two per cent of diplomates had undertaken OH clinical work since completion of their diploma, and 90% of those were undertaking OH clinical work at the time of the survey. Specific obstacles to accessing OH work highlighted included existing workload constraints, lack of employment opportunities with OH providers and lack of time. CONCLUSIONS: Many (126/310; 41%) respondents had considered increasing their OH work in the previous 12 months. Increasing mentorship from senior OH clinicians to diplomates was suggested by 4% of respondents to enhance the utility of diplomates.

Contribution of Noncanonical Antigens to Virulence and Adaptive Immunity in Human Infection with Enterotoxigenic E. coli.

Enterotoxigenic Escherichia coli (ETEC) contributes significantly to the substantial burden of infectious diarrhea among children living in low- and middle-income countries. In the absence of a vaccine for ETEC, children succumb to acute dehydration as well as nondiarrheal sequelae related to these infections, including malnutrition. The considerable diversity of ETEC genomes has complicated canonical vaccine development approaches defined by a subset of ETEC pathovar-specific antigens known as colonization factors (CFs). To identify additional conserved immunogens unique to this pathovar, we employed an "open-aperture" approach to capture all potential conserved ETEC surface antigens, in which we mined the genomic sequences of 89 ETEC isolates, bioinformatically selected potential surface-exposed pathovar-specific antigens conserved in more than 40% of the genomes (n = 118), and assembled the representative proteins onto microarrays, complemented with known or putative colonization factor subunit molecules (n = 52) and toxin subunits. These arrays were then used to interrogate samples from individuals with acute symptomatic ETEC infections. Surprisingly, in this approach, we found that immune responses were largely constrained to a small number of antigens, including individual colonization factor antigens and EtpA, an extracellular adhesin. In a Bangladeshi cohort of naturally infected children <2 years of age, both EtpA and a second antigen, EatA, elicited significant serologic responses that were associated with protection from symptomatic illness. In addition, children infected with ETEC isolates bearing either etpA or eatA genes were significantly more likely to develop symptomatic disease. These studies support a role for antigens not presently targeted by vaccines (noncanonical) in virulence and the development of adaptive immune responses during ETEC infections. These findings may inform vaccine design efforts to complement existing approaches.

Breast cancer and work outcomes in health care workers.

BACKGROUND: Cancer survivors are at a higher risk of leaving the labour market prematurely than healthy individuals or those with other chronic conditions. They continue to report difficulty in re-entering the workplace after diagnosis and treatment. AIMS: To investigate return to work in health care staff with a diagnosis of breast cancer and the adjustments required to assist them. METHODS: We identified health care workers with a diagnosis of breast cancer, seen by occupational physicians in a National Health Service occupational health (OH) service, between 2000 and 2012. Review of OH records was conducted and information relating to return to work and sick leave was recorded. RESULTS: One hundred and seventeen staff members were identified, and 111 (95%) returned to work. Almost all (109) required workplace adjustments to do so: 97 had temporary adjustments and 12 permanent changes. The majority of those who returned to work (98) did so within 1 year. CONCLUSIONS: This study showed a higher return to work rate in the first year, following treatment for breast cancer, than described previously. Workplace adjustments, recommended by an occupational physician, were provided for the majority.

Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection.

RATIONALE: Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. OBJECTIVES: To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. METHODS: 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R). RESULTS: The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs -0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). CONCLUSIONS: Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

The association of month of birth with atopy in adult patients with asthma and rhinitis in Anatolia, Turkey.

BACKGROUND: Exposure to allergens in early life may predispose subjects to develop allergies and diseases related to allergic sensitisation. OBJECTIVE: To determine the association between month of birth and atopic sensitisation in adult Turkish patients with rhinitis and/or asthma using the diagnostic method of skin prick tests. METHODS: This prospective cross-sectional study included all adult patients who underwent skin prick testing with rhinitis and asthma from November 2009 to June 2010. Sensitisation was categorised as any sensitisation, pollen sensitisation, and house dust mite sensitisation. Multivariate logistic regression model was employed with the primary predictor being month of birth. Diagnosis (asthma, rhinitis and both), age, gender and family history of atopy were considered as potential confounders in the model. The associations were presented with both unadjusted and adjusted odds ratios (OR) and their 95% confidence interval (CI). RESULTS: A total of 616 subjects were evaluated. Three-hundred and forty-one subjects had sensitisation to allergens according to skin prick tests. Analyses showed that subjects born in September were less likely to have documented skin test positively with pollen sensitisation [0.27 (0.09-0.84), p=0.023]. CONCLUSION: The results support the hypothesis that being born at the end of the pollen season may protect subjects from pollen sensitisation.

Association of site of treatment with clinical outcomes following intravenous antimicrobial treatment of a pulmonary exacerbation.

BACKGROUND: In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital. METHODS: Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location. RESULTS: In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV1 improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only. CONCLUSIONS: Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF treated at home.

C-reactive protein (CRP) as a biomarker of pulmonary exacerbation presentation and treatment response.

BACKGROUND: C-reactive protein (CRP) has been proposed as a biomarker for pulmonary exacerbation (PEx) diagnosis and treatment response. CRP >75mg/L has been associated with increased risk of PEx treatment failure. We have analyzed CRP measures as biomarkers for clinical response during the STOP2 PEx study (NCT02781610). METHODS: CRP measures were collected at antimicrobial treatment start (V1), seven to 10 days later (V2), and two weeks after treatment end (V3). V1 log10CRP concentrations and log10CRP change from V1 to V3 correlations with clinical responses (changes in lung function and symptom score) were assessed by least squares regression. Odds of intravenous (IV) antimicrobial retreatment within 30 days and future PEx hazard associated with V1 and V3 CRP concentrations and V1 CRP >75 mg/L were studied by adjusted logistic regression and proportional hazards modeling, respectively. RESULTS: In all, 951 of 982 STOP2 subjects (92.7%) had CRP measures at V1. V1 log10CRP varied significantly by V1 lung function subgroup, symptom score quartile, and sex, but not by age subgroup. V1 log10CRP correlated moderately with log10CRP change at V3 (r2=0.255) but less so with lung function (r2=0.016) or symptom (r2=0.031) changes at V3. Higher V1 CRP was associated with greater response. CRP changes from V1 to V3 only weakly correlated with lung function (r2=0.061) and symptom (r2=0.066) changes. However, V3 log10CRP was associated with increased odds of retreatment (P = .0081) and future PEx hazard (P = .0114). DISCUSSION: Despite consistent trends, log10CRP change was highly variable with only limited utility as a biomarker of PEx treatment response.

Antipseudomonal treatment decisions during CF exacerbation management.

BACKGROUND: Cystic fibrosis (CF) pulmonary exacerbation (PEx) treatment guidelines suggest that Pseudomonas aeruginosa (Pa) airway infection be treated with two antipseudomonal agents. METHODS: We retrospectively studied treatment responses for STOP2 PEx treatment trial (NCT02781610) participants with a history of Pa infection. Mean lung function and symptom changes from intravenous (IV) antimicrobial treatment start to Visit 2 (7 to 10 days later) were compared between those receiving one, two, and three+ antipseudomonal classes before Visit 2 by ANCOVA. Odds of PEx retreatment with IV antimicrobials within 30 days and future IV-treated PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively. Sensitivity analyses limited to the most common one-, two-, and three-class regimens, to only IV/oral antipseudomonal treatments, and with more stringent Pa infection definitions were conducted. RESULTS: Among 751 participants, 50 (6.7%) were treated with one antipseudomonal class before Visit 2, while 552 (73.5%) and 149 (19.8%) were treated with two and with three+ classes, respectively. Females and participants with a negative Pa culture in the prior month were more likely to be treated with a single class. The most common single, double, and triple class regimens were beta-lactam (BL; n = 42), BL/aminoglycoside (AG; n = 459), and BL/AG/fluoroquinolone (FQ; n = 73). No lung function or symptom response, odds of retreatment, or future PEx hazard differences were observed by number of antipseudomonal classes administered in primary or sensitivity analyses. CONCLUSIONS: We were unable to identify additional benefit when multiple antipseudomonal classes are used to treat PEx in people with CF and Pa.

Changes in symptom scores as a potential clinical endpoint for studies of cystic fibrosis pulmonary exacerbation treatment.

INTRODUCTION: Symptom improvement was assessed as changes in the Chronic Respiratory Infection Symptom Score (CRISS) during intravenous antimicrobial exacerbation treatments among subjects from study NCT02109822. METHODS: Median daily CRISS reduction (i.e., improvement) and covariates associated with CRISS reduction by Day 14 were assessed by logistic regression. RESULTS: Among 173 subjects, median baseline CRISS was 49 [IQR 41, 56]; 93.6% had a CRISS reduction of ≥11 (minimal clinically important difference); median time to -11 reduction was 2 days [95% CI 2, 3]. The greatest median CRISS difference from baseline, on Day 17, was -26 [-29, -23]. Odds of -26 CRISS change by Day 14 were greater in subjects with higher baseline CRISS (P=.006) and younger ages (P=.041). CONCLUSIONS: CRISS response has good dynamic range and may be a useful efficacy endpoint for PEx interventional trials. The optimal use of CRISS change as an endpoint remains uncharacterized.

The evaluation of training in patient-centred interviewing skills for psychiatric residents.

BACKGROUND: Communication skills are considered 'core skills' in the curriculum of psychiatry but studies evaluating the effectiveness of a time-limited training course in interviewing skills in psychiatry have remained rare. The aim was to assess the effectiveness of training in patient-centred interviewing on the interview performance of psychiatric residents. METHOD: Psychiatric residents (n=10) each interviewed 12 different anonymized standardized patients (SPs), eight before and another four after training. SPs simulated psychiatric out-patients who attended for a first visit to the psychiatric out-patient clinic. The consultations were videotaped, transcribed and coded with a classification scheme developed for psychiatric consultations from which an interview performance index was derived. An interrupted time-series design and a segmented regression analysis with multilevel analysis explored the performance trend within the series of consultations. RESULTS: The regression model evidenced a horizontal slope at pre- and post-training, with a significant level change. These findings excluded the presence of a practice effect and indicated a significant effect of training. Performance variability between and within residents over the series of consultations increased at post-training. CONCLUSIONS: The training improved patient-centred interviewing performance. More post-training exercise time and supervised practice are necessary to establish consistent performance patterns at a higher skill level.

Building global development strategies for cf therapeutics during a transitional cftr modulator era.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Duration of antibiotic therapy in non-cystic fibrosis bronchiectasis.

PURPOSE OF REVIEW: a)We conducted a review of the current evidence relating to antibiotic duration in the short and long-term management of non-cystic fibrosis bronchiectasis. RECENT FINDINGS: b)In non-cystic fibrosis pulmonary exacerbations, evidence is primarily based on expert consensus and recent guidelines recommend antibiotic durations of approximately 14 days. Chronic antibiotics (oral or inhaled) are recommended in patients with frequent exacerbations or with chronic Pseudomonas aeruginosa airways infection. Macrolides are the best studied therapies for long-term use with evidence for effect limited to a 12 month duration. Encouragingly, there are increased efforts to develop registries and conduct larger population level studies to improve patient care. SUMMARY: c)There is a paucity of evidence for optimal antibiotic strategies in exacerbations and chronic maintenance in persons with non-cystic fibrosis bronchiectasis. Rationally designed studies which utilize a registry and population-based approach will be critical to build evidence-based strategies to optimize management of non-cystic fibrosis bronchiectasis.

Experience using centralized spirometry in the phase 2 randomized, placebo-controlled, double-blind trial of denufosol in patients with mild to moderate cystic fibrosis.

BACKGROUND: Centralized spirometry may significantly improve quality of spirometry and reduce variability of this outcome measure in clinical trials in cystic fibrosis (CF). METHODS: Spirometry was performed during the phase 2 randomized, placebo-controlled, double-blind clinical trial of denufosol in patients with mild to moderate CF using American Thoracic Society guidelines. Uniform spirometers were used with electronic data transmission of all the data to a reading center. Spirometry was evaluated for quality by a central reader based on start of test, cough during the test, and evidence of a plateau. RESULTS: A total of 1418 spirometry values were assessed in 89 subjects during the trial. In only 5 instances did the central reading center need to give feedback to sites regarding the quality of spirometry. The study site data matched the central reading center's data for all but 78 (6%) spirometry values in 33 patients. Many of these differences were small with only 35 (3%) values differing by more than 50 mL in 26 patients. CONCLUSION: Spirometry in this clinical trial was of high quality with low rate of significant centralized over-read.

Efforts to link declarations to actions: Italian experiences of shared decision making in clinical settings.

The Italian National Health Plan 2006-08 acknowledges the importance of patient/citizen participation, highlighting that health services have to involve patients by means of a shared decision-making (SDM) approach. The present study aims at examining the implementation of SDM in clinical settings in Italy, describing some experiences, practical difficulties and potential solutions. We found that the majority of patients want to participate in decision-making, but substantial knowledge gaps represent a barrier. Small proportions of patients express opinions and questions during the medical encounter, with a lack of facilitating questions by physicians, indicating a limited degree of involvement. The project Partecip a Salute is an initiative aiming at involving citizens, patient associations and scientific-medical professionals in the health and clinical research debate. The literature review on Italian SDM experiences has shown a limited number of publications, with the majority being commentaries or letters. In conclusion, in order to put SDM into practice more organizational and educational efforts are needed directed to both health professionals and patients/consumers. Documenting and sharing experiences is a fundamental prerequisite for progressing in the field.

Initial development and pilot testing of observer-reported outcomes (ObsROs) for children with cystic fibrosis ages 0-11years.

PURPOSE: Patient-reported outcomes are important clinical trial endpoints. Young children may not be able to reliably report on how they feel or function, so observer-reported outcomes (ObsROs) may be more appropriate for them. The purpose of this study was to develop and pilot field test electronic parent-reported observational instruments for children with cystic fibrosis (CF) 0-6 and 7-11years of age. METHODS: We performed concept elicitation interviews with parents of children with CF ≤11years of age to elicit the respiratory signs they could observe at baseline and during an acute respiratory illness. The resulting instruments were refined based on interviews with parents and clinicians. We conducted a pilot field test to evaluate test-retest reliability and the ability of items to distinguish well and sick periods. RESULTS: The instruments consist of 17 items assessing respiratory signs and observable CF-related impacts. Test-retest reliability was acceptable for both age groups but discrimination was low for ages 7-11, likely reflecting less direct observation of older children by their parents. CONCLUSIONS: An ObsRO for children with CF ages 0-6 appears promising, while self-report may be more appropriate for children >6years of age. Next steps for the 0-6year old instrument will be utilizing it as an exploratory endpoint in clinical trials to enable item reduction, scale development, and further reliability and validity testing. Ultimately, this ObsRO could be a promising endpoint for early intervention trials in young children with CF.

Comparison of three solid phase extraction sorbents for the isolation of THM precursors from manitoban surface waters.

Three prepackaged solid phase extraction (SPE) cartridges: two modified styrene divinylbenzene, Bond Elut ENV and Bond Elut PPL (Varian), and one N-vinylpyrrolidone (Strata-X, Phenomenex), were assessed for isolation of THM precursors from three surface waters in Manitoba, Canada. The dissolved organic matter (DOM) from the La Salle River (LR), Lake Winnipegosis (LW) and the Waterhen River (WR) were fractionated into hydrophobic (HPO) and hydrophilic (HPI) parts. ENV isolated less DOM (LR = 46.6 ± 1.5%; LW = 36.2 ± 1.4%; WR = 28.6 ± 2.2%) compared to PPL (LR = 50.2 ± 4.4%; LW = 47.9 ± 2.2%; WR = 37.3 ± 2.8%) and Strata (LR = 46.4% ± 1.0; LW = 51.6 ± 0.3%; WR = 31.9 ± 3.9%). The HPO fraction isolated by each SPE was characterized using Fourier Transform Infrared (FTIR) spectrochemical imaging. The FTIR spectra confirmed the HPO fractions were typical of humic-material and largely resembled fulvic acids; however, the PPL and Strata HPO isolates contained slightly more polysaccharides. The THM formation potential (THMFP) confirmed that the HPO fraction formed more THMs than the HPI. The HPO fraction isolated using ENV was found to have the lowest THMFP of all three SPEs in each waterbody; however, the specific THMFP (µgTHM/mgDOM) results indicated that ENV isolated THM precursors more effectively, as the Strata and PPL isolated a greater amount of non-THM forming material. All three SPE showed significant potential for implementation at water treatment plants as a simple tool to monitor THM precursors in source waters, enabling operators to adapt processes to improve drinking water quality.

Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis.

BACKGROUND: Given the variability in pulmonary exacerbation (PEx) management within and between Cystic Fibrosis (CF) Care Centers, it is possible that some approaches may be superior to others. A challenge with comparing different PEx management approaches is lack of a community consensus with respect to treatment-response metrics. In this analysis, we assess the feasibility of using different response metrics in prospective randomized studies comparing PEx treatment protocols. METHODS: Response parameters were compiled from the recent STOP (Standardized Treatment of PEx) feasibility study. Pulmonary function responses (recovery of best prior 6-month and 12-month FEV1% predicted and absolute and relative FEV1% predicted improvement from treatment initiation) and sign and symptom recovery from treatment initiation (measured by the Chronic Respiratory Infection Symptom Score [CRISS]) were studied as categorical and continuous variables. The proportion of patients retreated within 30days after the end of initial treatment was studied as a categorical variable. Sample sizes required to adequately power prospective 1:1 randomized superiority and non-inferiority studies employing candidate endpoints were explored. RESULTS: The most sensitive endpoint was mean change in CRISS from treatment initiation, followed by mean absolute FEV1% predicted change from initiation, with the two responses only modestly correlated (R2=.157; P<0.0001). Recovery of previous best FEV1 was a problematic endpoint due to missing data and a substantial proportion of patients beginning PEx treatment with FEV1 exceeding their previous best measures (12.1% >12-month best, 19.6% >6-month best). Although mean outcome measures deteriorated approximately 2-weeks post-treatment follow-up, the effect was non-uniform: 62.7% of patients experienced an FEV1 worsening versus 49.0% who experienced a CRISS worsening. CONCLUSIONS: Results from randomized prospective superiority and non-inferiority studies employing mean CRISS and FEV1 change from treatment initiation should prove compelling to the community. They will need to be large, but appear feasible.

Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial.

PURPOSE: To evaluate the effects of oral N-acetylcysteine (NAC), which replenishes systemic glutathione, on decreasing inflammation and improving lung function in CF airways. METHODS: A multicenter, randomized, double-blind proof of concept study in which 70 CF subjects received NAC or placebo orally thrice daily for 24 weeks. ENDPOINTS: primary, change in sputum human neutrophil elastase (HNE) activity; secondary, FEV(1) and other clinical lung function measures; and safety, the safety and tolerability of NAC and the potential of NAC to promote pulmonary hypertension in subjects with CF. RESULTS: Lung function (FEV(1) and FEF(25-75%)) remained stable or increased slightly in the NAC group but decreased in the placebo group (p=0.02 and 0.02). Log(10) HNE activity remained equal between cohorts (difference 0.21, 95% CI -0.07 to 0.48, p=0.14). CONCLUSIONS: NAC recipients maintained their lung function while placebo recipients declined (24 week FEV1 treatment effect=150 mL, p<0.02). However no effect on HNE activity and other selected biomarkers of neutrophilic inflammation were detected. Further studies on mechanism and clinical outcomes are warranted.

The cystic fibrosis therapeutics development network (CF TDN): a paradigm of a clinical trials network for genetic and orphan diseases.

Clinical trials have become critical to the advancement of medical science and to the evolution of patient care in medicine. The science of clinical research has advanced from early studies in which treatment was assessed without controls to sophisticated multinational collaborative randomized, double-blind, placebo controlled trials of therapeutic interventions. To facilitate the advancement of clinical research, clinical trials networks have been developed to conduct multicenter studies. This review describes the history of clinical trials, clinical trials networks, and the goals of such networks in the United States. The Cystic Fibrosis Therapeutics Development Network, a network that represents the paradigm for genetic and orphan diseases, is described in detail. This network has been extremely successful in its first 3.5 years of existence conducting 18 different clinical trials in patients with Cystic Fibrosis. Unique aspects of the network include the use of internet applications for study conduct and communication, the development of statistical methodology to enhance the efficiency of clinical trial design, the development of outcome measures specific to Cystic Fibrosis, and the development of infrastructure necessary for expediting protocol development. In the current environment, clinical research faces significant challenges related to ensuring the safe and ethical conduct of clinical research while promoting fast and efficient clinical trials. To succeed and move forward to provide treatments and find cures for diseases, clinical trials networks must continue to evolve. The Cystic Fibrosis Therapeutics Development Network represents a network that has met this challenge and will continue to provide a venue for the safe and efficient conduct of clinical trials in Cystic Fibrosis.

Case of enantiomer impurity identification by normal-phase chiral high-performance liquid chromatography with optical rotation and mass spectrometric detection.

An impurity produced in the synthesis of compound I is separated and identified as its enantiomer II using normal-phase chiral high-performance liquid chromatography (HPLC) with UV absorbance, optical rotation (OR) and mass spectrometric (MS) detection. The results show that the impurity II and compound I have equal and opposite specific rotations, identical MS spectra and the same MS-MS fragmentation pattern, as required for enantiomers. The procedures presented demonstrate a novel combination of methods for enantiomer identification and characterization that do not require the preparation of individual enantiomer markers or even the racemic mixture, thus reducing the need for additional synthetic work.