The ability to self-inject in patients with multiple sclerosis (MS) has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patients' independence. However, injection anxiety, needle phobia and disease-related disability are major barriers to a patient's ability to self-administer treatment. Use of an autoinjector may improve patients' ability to self-inject. This study evaluated the safe and effective use of Avonex Pen™ (prefilled pen), a single use autoinjector, for intramuscular delivery of interferon beta-1a  in MS patients.This was a Phase IIIb, open-label, single-country, multicenter trial in MS patients currently using IM IFNβ-1a prefilled syringes. Patients received weekly 30 mcg IM IFNβ-1a treatment over 4 weeks. On Day 1, patients self-administered IM IFNβ-1a using a prefilled syringe at the clinic. On Day 8, patients received training on the prefilled pen and self-administered IM IFNβ-1a using the device. On Day 15, patients self-administered IM IFNβ-1a at home using the prefilled pen. A final injection occurred at the clinic on Day 22 when patients self-administered IM IFNβ-1a using the prefilled pen while clinic staff observed and completed a detailed questionnaire documenting patients' ability to self-inject with the device. Serum neopterin levels were evaluated pre and post-injection on Days 1 and 8. Adverse events were monitored throughout.Seventy-one (96%) patients completed the study. The overall success rate in safely and effectively using the prefilled pen was 89%. No device malfunctions occurred. One unsuccessful administration occurred at Day 22 due to patient error; no patient injury resulted. Patients gave the prefilled pen high ratings (8.7-9.3) on a 10-point scale for ease of use . Ninety-four percent of patients preferred the prefilled pen over the prefilled syringe. Induction of serum neopterin levels, serving as a biomarker for type 1 interferon action, was similar to that of the prefilled syringe. The prefilled pen demonstrated a safety profile comparable to the prefilled syringe.The prefilled pen is a safe and effective device for administration of IM IFNβ-1a and represents an alternative method for self-injection for MS patients using this therapy.NCT00828204This study is registered at clinicaltrials.gov, identifier:  Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that can lead to extensive neurodegeneration and subsequent irreversible disability. Symptoms of MS affect motor, sensory, visual, and autonomic systems but are not limited to these areas alone . While tFor patients prescribed injectable DMTs, self-administration has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patients' sense of independence -8. HowevThe clinical importance of enabling self-injection is supported by various studies that have shown that the injection process can be made easier for patients through the use of automated injectors -16. Auto® Prefilled Syringe for once-weekly intramuscular (IM) injection. The prefilled pen has been developed as the first IM autoinjector available for long-term treatment with IM IFNβ-1a. Features of the prefilled pen have been specifically designed to overcome the barriers to self-injection and facilitate the technical aspects of the injection process. These features include a protective sheath that conceals the needle within the device prior to injection, automated needle insertion and medication dispensing, a diameter and length designed to stabilize the device during the injection process, a safety mechanism which prevents accidental injection, and a visual indicator to confirm the full dose has been administered.The Avonex Pen™ (prefilled pen) is a single use autoinjector containing the commercially available AvonexThe prefilled pen has the potential to improve injection methods and simplify the self-injection process, thereby addressing an unmet need in patients using IM IFNβ-1a. This study was conducted to evaluate the safe and effective use of the prefilled pen for IM delivery of IFNβ-1a in patients with MS.This was a Phase IIIb, open-label, single-arm, multicenter study to evaluate the safe and effective use of the prefilled pen. A total of 17 sites in the United States participated. Investigators at each site obtained institutional review board (IRB) approval for the study protocol. This study was performed in accordance with all international, federal and local regulations, and written informed consent was obtained from each patient prior to eligibility evaluations. Study duration was 6 weeks, including a 14-day screening period and a 4 week IM IFNβ-1a treatment period. There were a total of 9 scheduled clinic visits per patient.Study participants were 18 to 65 years of age. Eligibility criteria required patients to have been self-administering the prefilled syringes to treat MS for the 12 weeks prior to the screening visit. Key exclusion criteria included concomitant treatment with prescribed immunomodulators or immunosuppressants, and unwillingness or inability to comply with the requirements of the protocol, including the presence of any condition  that was likely to affect a patient's ability to return for follow up visits on schedule.The prefilled pen is shown in Figure For the manual injection with the prefilled syringe (Injection 1), patients used their own supply of IM IFNβ-1a prefilled syringes. The needle size used for Injection 1 was not recorded for each patient since the needle size used for manual injection of the prefilled syringe can vary between patients. A 23 G × 1.25 inch (32 mm) needle is included in the commercially available IM IFNβ-1a prefilled syringe package, however a different needle size (25 G × 1 inch) is also approved for use with the IM IFNβ-1a prefilled syringe. The decision of which needle a patient should use is based on the needs of the patient and left to the discretion of the prescribing physician, per IM IFNβ-1a prescribing information.All patients received 30 mcg doses of IM IFNβ-1a once weekly over 4 weeks. Patients who were taking prophylactic therapy for flu-like symptoms at the start of the study continued the same medication and dose until their participation in the study was completed. If MS relapses occurred during the study, these were treated at the Investigator's discretion following standard medical practice, as long as treatment did not involve any of the protocol excluded concomitant medications. Treatment for spasticity, fatigue, or other MS associated symptoms was not restricted.Patients who met the eligibility criteria during the 14-day screening period entered into a 4-week IM IFNβ-1a treatment period. Injection 1 took place on Day 1 and was administered at the study clinic by the patient using a prefilled syringe from their own supply of IM IFNβ-1a prefilled syringes and needles as prescribed by their physician.Injection 2 occurred on Day 8 and was administered at the study clinic by the patient using the prefilled pen following training provided by the clinic site Trainer/Observer. During this injection, the Trainer/Observer observed patient use of the prefilled pen and reinforced training as needed. Injection 3 occurred on Day 15 and was self-administered by the patient at home using the prefilled pen. The final injection, Injection 4, occurred on Day 22 and was administered at the study clinic by the patient using the prefilled pen. At this clinic visit the Trainer/Observer observed patient use of the prefilled pen and completed a detailed questionnaire documenting patients' ability to self-inject with the device. The Trainer/Observer completed the observation in a hands off manner; no assistance or correction was provided to the patient during this final injection. In total, patients were to receive one injection with the prefilled syringe and three injections with the prefilled pen.Evaluations were made at various time points throughout the study. The treatment schedule and corresponding evaluations are displayed in Table The primary assessment of the safe and effective use of the prefilled pen was to evaluate the overall success rate as measured by the proportion of patients who successfully used the device. Data for determining the overall success rate were generated from an observation form that was completed by the Trainer/Observer during the final injection (Day 22). The observation form was composed of a series of questions organized around the three key steps of the injection process: device setup, self-administration of injection, and capping and disposal of the device. All actions captured in the observation form that would define the patient's handling of the prefilled pen as a failure were pre-defined in the protocol. Failure was further categorized as "failure patient induced" or "failure-possible device malfunction." Overall success was defined as no failures occurring during the patient's use of the device.Additional endpoints in this study included patient assessments, clinician assessments, a pharmacodynamic evaluation, and safety monitoring.A preference questionnaire was administered to the patients on the last clinic visit . The questionnaire investigated whether patients preferred the prefilled pen or the prefilled syringe, and scored patient preference for specific features of the prefilled pen compared to the prefilled syringe using a grading scale ranging from 0 (defined on the form as "much worse") to 10 (defined on the form as "much better"); definitions for integers 2-9 on the scale were not specified.The injection procedure was assessed by each patient in order to evaluate whether patients experienced any difficulty with the processes of preparing, injecting, removing, and disposing after each of the 4 injections .Injection site pain was evaluated pre and post injection by patients for each of the 4 injections . Pain was evaluated on a scale from 0 (no pain) to 10 (extremely painful).Patients evaluated the "ease of use" for each of the 4 injections performed  by using the Ease-of-Use Grading Scale to indicate how easy it was for the patient to perform the injection. The scale ranged from 0 (extremely difficult) to 10 (extremely easy).For each use of the prefilled pen , patients evaluated how easy or difficult it was to read and understand the training materials.Clinicians at the study site assessed injection sites 1 hour before injection and 24 hours following injection for each administration that took place at the clinic . The injection site was examined for erythema, induration, temperature, and tenderness.In order to evaluate levels of neopterin, a well-established biological marker of pharmacodynamic response to activation of the Type 1 interferon receptor, blood samples were collected from patients one hour prior to injection and 24 and 48 hours following injection for Injection 1  and Injection 2 .Adverse events were monitored throughout the study.A 10% dropout rate was assumed for this study. A sample size of 70 patients was required to provide a 95% confidence interval of the success rate  based on the assumption that 90% of patients would successfully use the prefilled pen. The population used to evaluate the primary outcome consisted of those patients who received Injection 1 with the prefilled syringe, received at least one injection with the prefilled pen, and had a completed observation form.Summary and descriptive statistics were used in this study. No formal statistical testing was preplanned in the protocol.2 (range: 17.9 to 42.2 kg/m2).Of the 74 enrolled patients, 64 (86%) were female. Mean patient age was 49.6 years (range: 22 to 65 years). The mean body mass index (BMI) of the study population was 28.92 kg/mOf 74 enrolled patients, 71 patients (96%) completed the study. All 74 enrolled patients received a self-injection using the prefilled syringe. Two patients discontinued from the study following the injection with the prefilled syringe prior to receiving an injection with the prefilled pen (one patient was withdrawn after missing two clinic visits and the other patient was withdrawn due to a MS relapse). Seventy two patients received at least one self- injection with the prefilled pen and 71 patients completed all three injections with the device. One patient completed the final injection but did not have a completed observation form. As a result, the observation form was only completed for 70 patients. In total, 215 injections were administered with the prefilled pen.The overall injection success rate was 89% (62/70 patients). No failures due to device malfunction and no damaged or bent needles were reported. Eight (11%) patient induced failures occurred, the majority of which took place during device setup . None of these events resulted in patient injury and all patients were able to complete administration with the prefilled pen. Patient-induced failures resulting in the device becoming unusable occurred in one patient. In this case the patient did not follow instructions and removed the device from the thigh prematurely before medication was administered; upon a second attempt the patient was able to successfully complete all steps of the injection process. Patient success at each observation of self-administration using the prefilled pen is described in Table The majority (94%) of patients indicated a preference for the prefilled pen over the prefilled syringe. Patients evaluated the prefilled pen in comparison to the prefilled syringe using a grading scale ranging from 0 (much worse) to 10 (much better). Across all domains, patient preference for the prefilled pen was strong Figure . PatientFollowing injection with the prefilled syringe, the mean pain score was low, 1.7 (out of 10). The mean pain score for each of the 3 injections with the prefilled pen was also low: 1.0, 1.3, and 0.7 for injections on Days 8, 15, and 22, respectively.Eighty-nine percent of patients reported having no difficulty with administration using the prefilled syringe. For each of the injections using the prefilled pen, 90% of patients reported having no difficulty.The mean ease of use score for the injection administered with the prefilled syringe was 8.1 (out of 10). For each administration with the prefilled pen, the mean ease of use score was as follows: 8.9 on Day 8, 8.7 on Day 15, and 9.3 for the final injection with the prefilled pen.Patients referred to the written instructions and DVD less with each subsequent injection using the prefilled pen. Of the patients who used the written instructions and DVD, the majority rated them as "very effective" in educating on how to use the prefilled pen .Clinical injection site assessments made before and after injection were similar between the prefilled syringe and the prefilled pen. For the majority of patients, the clinician found no presence of induration, no temperature variation, and no tenderness at the site following injection with the prefilled syringe or the prefilled pen. Mild erythema was reported in 26% of patients after using the prefilled syringe and in 25% and 23% of patients on Days 8 and 22 after using the prefilled pen. Mild induration and mild tenderness were reported in less than 8% of patients following injections with both the prefilled syringe and the prefilled pen. There were no severe reports of erythema, induration, tenderness and temperature following any injection.Similar increases in mean neopterin serum levels were observed over time following administration with the prefilled pen  as were seen with the injection using the prefilled syringe . The mean neopterin induction ratios were similar for injection with the prefilled syringe and the prefilled pen .All patients who received at least one dose of IM IFNβ-1a using either the prefilled syringe or the prefilled pen were included in the safety population. The overall incidence of AEs in this study was low and rates were similar between the prefilled syringe and the prefilled pen. One patient experienced a MS relapse during the study period. Eleven percent of patients reported an adverse event with use of the prefilled syringe (Day 1), and 17%, 18%, and 4% of patients reported an adverse event with each injection using the prefilled pen . No safety concerns potentially associated with the prefilled pen were observed. The incidence of injection site reactions was low and pain was infrequently reported with the prefilled pen Table .This open-label study evaluated the safe and effective use of the prefilled pen in patients currently self-administering IM IFNβ-1a via the prefilled syringe. These patients represent the population expected to use the prefilled pen and as such, were believed to be well suited to evaluate the prefilled pen.Safe and effective use of the prefilled pen was assessed from data captured in the observation form completed by the Trainer/Observer. The comprehensive list of questions in the observation form was developed to provide an overall evaluation of the patients' ability to properly self-inject with the device during the final injection using the prefilled pen. There were no device malfunctions and the overall success rate of the prefilled pen was high (89%), demonstrating that it provides a safe and effective alternative method of administering IM IFNβ-1a. Patients also gave high ratings to the related training materials and injection procedure.t test was performed to compare the ease of use assessment at Injection 1  with Injection 4 . Results demonstrated that patients found the prefilled pen statistically significantly easier to use after 3 injections compared to the prefilled syringe after at least 12 uses, as required by study entry criteria .The prefilled pen was specifically designed to overcome multiple challenges of self-injection faced by patients with MS. Features designed to reduce injection anxiety include a protective shield that conceals the needle and automated needle insertion and medication dispensing, which reduces the number of steps involved in the dosing process. Safety features include a mechanism to prevent early injection as well as a visual indicator that allows for confirmation of injection process completion. The diameter and length dimensions are designed to help stabilize the device during the injection process so as to improve ease of use for patients with impaired motor coordination. In this study, 94% of patients preferred the prefilled pen over the prefilled syringe. Reasons for patient preference for the prefilled pen were related to ease of holding and gripping, ease of injection, level of pain, and needle anxiety, confirming that the design of the prefilled pen was successful in making the injection process easier. In addition, although the study was not originally designed to compare the prefilled syringe to the prefilled pen, a post hoc paired t test and showed that patients experienced statistically significantly less pain with the prefilled pen by the third use than with the prefilled syringe after at least 12 uses, as required by study entry criteria . The incidence of pain through safety monitoring was also low for both methods of administration. Seven percent of patients reported an AE of pain related to use of the prefilled pen and none of the reports were severe. In addition to pain assessments, the injection site was assessed at multiple time points during the study by the clinician. Mild erythema was observed at a similar frequency following injection with the prefilled syringe and injection with the prefilled pen. The incidence of other injection site reactions such as temperature, induration, and tenderness were infrequent, and rates were similar for the two injection methods.Automated injection devices offer a means to potentially reduce injection site pain. In this study, patient assessment of pain was low for the injection with the prefilled syringe (1.7 out of 10), and numerically lower for each of the three injections with the prefilled pen. A post hoc comparison of the pain assessment at Injection 1  and Injection 4  was performed by paired Importantly, there were no new safety concerns raised in this study. The safety profile observed with the prefilled pen was similar to the known safety profile of IM IFNβ-1a from the prescribing information and post marketing data.Although IM injections are frequently administered via a manual syringe with a longer needle, the 25 G × 5/8 inch (16 mm) needle was determined to be the appropriate size for use with the prefilled pen. Earlier development of the prefilled pen using a 23 G × 1.25 inch (30 mm) needle indicated that this length was not appropriate for use with the device due to needle bends, which did not occur in this study with use of the shorter needle. The ability of the needle used in this study to deliver an IM injection is supported by published reports indicating that a 5/8 inch needle (16 mm) can be expected to access the IM space in the majority of patients when applied with a manual syringe -23. ConsAs discussed earlier, reduction in needle anxiety and injection pain were amongst the subjective benefits specifically sought in the design of the prefilled pen. We note that the shorter needle length of the prefilled pen may, in addition to its other features, contribute to the observed patient preferences for this device over the prefilled syringe. Our observation that neopterin induction was similar following injection with the prefilled syringe and with the prefilled pen further supports that the 25 G × 5/8 inch (16 mm) needle is the appropriate size to effectively deliver the full dose of IM IFNβ-1a with the prefilled pen as designed.There are limitations to consider when interpreting the results of this study. First, we acknowledge that the questionnaires and assessments used in the study have not been formally validated. However, they were specifically developed to capture information relevant to the robust evaluation of the safety and efficacy of the prefilled pen.In addition, several features of the study design and population should be emphasized. We enrolled only patients actively interested in the prefilled pen. In this regard, we are not able to speculate on the outcomes of a similar study conducted in patients who were not interested in a self-injection device. Given the nature of the study, it was also impossible to blind patients and study staff regarding injection method. As such, the data derived from the subjective assessments made in this study may partially reflect patients' and clinicians' expectations for the prefilled pen. The partial crossover study design in which patients switched from injections with the prefilled syringe to injections with the prefilled pen (and not from the prefilled pen to the prefilled syringe) does not allow us to exclude an impact of treatment order on our findings. Additionally, patients evaluated the prefilled syringe injection experience only once, whereas they evaluated the prefilled pen injection experience a total of three times. It could be argued that patient responses may have varied when assessing the different methods since there were repeat evaluations for only one of the methods. However, since the patients in the population selected for this study were currently using the prefilled syringe, it is unlikely that the single assessment of the prefilled syringe would have differed significantly if that assessment had been repeated.While we acknowledge that this study evaluated the prefilled pen in patients currently self-administering IM IFNβ-1a via the prefilled syringe and therefore does not address its suitability in treatment-naïve patients or when utilized by caregivers, the patient preference and ease of use results indicate the prefilled pen would also be an attractive option for use in these populations.Injection anxiety and physical limitations are major barriers to self-injection for many patients with MS. These barriers may contribute to poor treatment adherence that may result in a reduction in the clinical benefits of MS therapy.Results from this study support the safe and effective use of the prefilled pen for self-administration of IM IFNβ-1a by patients with MS. Patients preferred the prefilled pen over the prefilled syringe for reasons related to ease of use, injection pain, needle anxiety, and sense of independence. Data from this study demonstrate the potential for the prefilled pen to fulfil an unmet need in patients using IM IFNβ-1a by offering an alternative method for IM delivery that simplifies the injection process. The prefilled pen provides patients the opportunity to gain the clinical benefits of IM IFNβ-1a treatment while improving their ability to independently manage their disease.JTP has participated in consulting and/or speakers' bureau with Biogen Idec, Genzyme, Novartis, and Teva Neuroscience, and has participated in clinical research with Biogen Idec.EF has participated in consulting and/or speakers' bureau with Bayer, Biogen Idec, EMD Serono, Genzyme, Opexa, Novartis, Pfizer, and Teva Neuroscience, and has participated in research studies involving Biogen Idec, Eli Lilly, EMD Serono, Genzyme, Ono, Roche, Sanofi Aventis, and Teva Neuroscience.WG has participated in consulting, speakers' bureaus, and clinical research with Biogen Idec and Teva Neuroscience.DT, SL, and AD are employees of Biogen Idec.All authors contributed to the manuscript and have read and approved the final version. JTP served as the principal investigator and participated in the study design. JTP, EF, and WG served as study site investigators. DT participated in the conduct of the study and data analysis. SL participated in the study design and performed the statistical analysis. AD participated in the data analysis.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/11/126/prepub


Impairment of endothelial progenitor cells (EPCs) has been shown to contribute to the development of bronchopulmonary dysplasia (BPD). In the current study, the relationship between EPC changes of after birth and the development of BPD was investigated, and the effects of inhaled nitric oxide (iNO) on EPCs were evaluated.Sixty infants with a gestational age of less than 32 weeks and a birth weight of less than 1500 g were studied. NO was administered to infants who were receiving mechanical ventilation or CPAP for at least 2 days between the ages of 7 and 21 days. EPC level was determined by flow cytometry at birth, 7, 21 and 28 days of age and 36 weeks’ postmenstrual age (PMA), before and after the iNO treatment. Plasma concentrations of vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 and granulocyte-macrophage colony-stimulating factor were determined via immunochemical assay.+CD133+ and CD34+KDR+CD133+ EPC numbers along with increasing the level of plasma VEGF.Twenty-five neonates developed BPD, 35 neonates survived and did not develop BPD. EPC level was decreased on day 7 and 21 in infants who later developed BPD compared with infants that did not develop BPD. From birth to 21 days of age, BPD infants had a persistently lower VEGF concentration compared with non-BPD infants. No difference was found between the two groups at day 28 or 36 weeks PMA. In infants that later developed BPD, iNO raised the KDREPC level was reduced at 7 days of age in infants with BPD, and iNO increased the EPC number along with increasing the level of VEGF. Further studies are needed to elucidate the mechanism leading to the decrease of EPCs in infants with BPD and to investigate the role of iNO treatment in the prevention of BPD. Bronchopulmonary dysplasia (BPD) is the main chronic respiratory disorder following premature birth and is diagnosed in approximately one quarter of infants less than 1500 g at birth Endothelial progenitor cells (EPCs) can migrate from bone marrow to the peripheral circulation, where they contribute to the repair of injured endothelium and to the formation of new blood vessels in vitro study reported that NO gas treatment, during hyperoxia exposure, increased the growth of preterm cord blood-derived EPCs In recent years, many studies have focused on the role of inhaled nitric oxide (iNO) for the prevention and treatment of BPD. A number of multicenter clinical trials have shown that iNO therapy reduces the incidence of BPD The aim of this study was to investigate the dynamic changes of EPCs after birth and to evaluate the effects of iNO on peripheral EPC number and on the prevention and/or treatment of BPD.The Ethics Committees of Children’s Hospital of Fudan University approved this study . Written informed consent was obtained from the parents of infants prior to NO inhalation and blood collection.Preterm infants with a gestational age of less than 32 weeks and a birth weight of less than 1500 g, were included in the study. All infants had been admitted within the first 6 hours of life to the tertiary neonatal intensive care unit between October 2010 and June 2011. Infants with congenital anomalies were excluded from the study. The infants were followed up until 36 weeks’ postmenstrual age (PMA). At the same time, the initiation of iNO was recorded. The iNO treatment was given to infants according to physician’s experience and infant’s condition, especially for infants who were receiving assisted ventilation for lung disease (not apnea) between 7 and 21 days Clinical and outcome data were prospectively collected from the study population. The Clinical Risk Index for Babies-II score (CRIB-II) for the prediction of neonatal mortality and morbidity was calculated. The cumulative oxygen exposure value was calculated as reported previously Peripheral blood samples were collected during routine laboratory exams at the following time points: birth (within the first 12 h of life), 7 days, 21 days, 28 days of age and 36 weeks’ PMA. Blood samples were also obtained in infants who received iNO therapy before the initial iNO treatment and again after 7 days of inhalation. Blood samples were collected in heparinized tubes. About 0.1 ml of fresh whole blood was used for flow cytometry. Plasma was collected and stored at −20°C for further analysis.+ or CD133+ cells were gated and the resulting population was examined for dual expression of KDR, and triple positive cells were identified by the dual expression of KDR and CD133 in the CD34 gate. Approximately 500,000 cells were acquired. The EPC levels were expressed as the percentage of total mononuclear cells (MNC). The same trained operator performed all the tests throughout the study and was blind to the experiment.Cells were assessed in fresh whole blood samples as previously described Plasma levels of VEGF, granulocyte-macrophage colony-stimulating factor (GM-CSF), stromal cell-derived factor-1 (SDF-1) and eNOS  were assessed using enzyme-linked immunosorbent assay kits. The procedures were performed according to the manufacturer’s instructions.2−/NO3− using the Griess reaction .NO concentration in plasma was evaluated by measuring the total NOP value <0.05 was considered statistically significant.The parametric and nonparametric continuous variables are reported as mean ± standard deviation (SD) and the median and interquartile range or range, respectively. Categorical variables are described by count and relative frequency (%). Comparison between groups of continuous parametric and nonparametric variables was carried out using the Student’s t-test and the nonparametric Mann-Whitney U-test, respectively. Categorical variables were compared between groups using the Fisher’s exact test. A Of the 60 infants that were included in the study, 25 developed BPD, 35 survived without BPD. The clinical characteristics, including maternal data and incidence of complications are displayed in Infants with BPD had a longer duration of exposure to oxygen, nasal continuous positive airway pressure and mechanical ventilation. The cumulative oxygen exposure value was significantly higher for infants who developed BPD compared with those who did not. The incidence of patent ductus arteriosus (PDA) and ROP was significantly higher in infants who developed BPD vs. those that did not.Of the infants who developed BPD, 20 infants received iNO therapy, with a mean GA of 28.1±1.3 weeks, and a mean BW of 1166±198 g. The starting time of the NO treatment was 17.0±8.1 days of age.9 per L, P = 0.153). EPC levels at different time points after birth were compared. In both the BPD and non-BPD groups, the number of CD34+ cells were highest at birth, but were markedly decreased by day 7 (P = 0.003). There was a slight trend for CD34+ and CD133+ cells to be decreased during different time points after day 7, although this was not significant.There was no difference in the WBC counts at birth between infants who subsequently developed BPD and those who did not  and CD34+KDR+CD133+ cells   . There w9 per L, P>0.05). However, the number of KDR+CD133+ and CD34+KDR+CD133+ increased after iNO therapy  also tended to increase after the iNO therapy. Interestingly, inhaled NO also increased the plasma VEGF  and NO  concentrations , CD133+ , and CD34+CD133+ cells . However, there were no significant differences in the concentration of VEGF between the two groups . Conversely, no differences were observed between infants with and without IVH, PDA and NEC in any of the studied cell subsets studied.We also assessed whether different cell phenotypes were correlated with the presence of other diseases in preterm infants. We found that infants who later developed ROP tended to have higher levels of circulating progenitor cells at birth than infants who did not, which was statistically significant for CD34The contribution of impaired vascular growth to the development of BPD has been extensively studied. Several studies have demonstrated that EPCs may contribute to angiogenesis in the developing lung and have shown promise for the prevention and treatment of BPD. In the current study, we found that infants with lower EPC levels during early days after birth had higher risk of developing BPD. Furthermore, we found that iNO treatment could increase the level of circulating EPCs.+KDR+, KDR+CD133+ and CD34+KDR+CD133+ cells) have been used for EPC enumeration, and have been shown to correlate with the severity of the disease state It should be acknowledged that no consensus has yet been reached regarding methods for EPC identification. Flow cytometry is a convenient, rapid, and purely quantitative method used for population based studies. In many studies, three surface antigens and the corresponding subpopulations of EPCs (CD34Recent studies have reported somewhat contradictory results as to whether EPC number is related to the development of BPD. A previous study using flow cytometry showed that infants who had a lower number of EPC colonies in cord blood and circulating EPCs at birth were at an increased risk of developing BPD In the study, we report a higher incidence of BPD. This in an observational study instead of a randomized control trial, the iNO treatment depends on the clinical factors rather than randomize to iNO therapy according to the inclusion criteria. This might result in the more severe degree of lung condition and higher incidence of BPD in iNO group.It has been recognized that VEGF signaling plays a crucial role during alveolar development in early postnatal life No difference was found in SDF-1 and GM-CSF, though both have been reported to be involved in the EPC mobilization In recent years, inhaled NO has been used as prophylactic treatment for the prevention of BPD. Experimental studies have suggested that iNO treatment, after neonatal VEGF receptor inhibition, preserves normal alveolar and vascular growth and reduces endothelium apoptosis We did not observe a difference in EPCs between infants with and without PDA, though this finding is not incompatible with a previous study In conclusion, we found a decrease in the EPC level on day 7 in infants who later developed BPD compared to infants that did not develop BPD. We also found that iNO raised the circulating EPC level along with the level of plasma VEGF. Further studies are needed to elucidate the mechanism for the development of BPD and to clarify the effects of VEGF signal regulation and circulating EPC alteration.


There is a need to reduce the number of cystoscopies on patients with haematuria. Presently there are no reliable biomarkers to screen for bladder cancer. In this paper, we evaluate a new simple in–house fabricated, GC-sensor device in the diagnosis of bladder cancer based on volatiles. Sensor outputs from 98 urine samples were used to build and test diagnostic models. Samples were taken from 24 patients with transitional  cell carcinoma  and 74 controls presenting with urological symptoms, but without a urological malignancy ; results were analysed using two statistical approaches to assess the robustness of the methodology. A two-group linear discriminant analysis method using a total of 9 time points (which equates to 9 biomarkers) correctly assigned 24/24 (100%) of cancer cases and 70/74 (94.6%) controls. Under leave-one-out cross-validation 23/24 (95.8%) of cancer cases were correctly predicted with 69/74 (93.2%) of controls. For partial least squares discriminant analysis, the correct leave-one-out cross-validation prediction values were 95.8% (cancer cases) and 94.6% (controls). These data are an improvement on those reported by other groups studying headspace gases and also superior to current clinical techniques. This new device shows potential for the diagnosis of bladder cancer, but the data must be reproduced in a larger study. Over 10,000 patients are diagnosed with bladder cancer in the UK annually and half will die of the disease . Of thosBladder cancer cases presenting at an early stage can be treated by transurethral resection without the need for major extirpative surgery. Furthermore this early stage disease has an excellent 5-year survival rate >94%) compared to <50% 5-year survival for more advanced disease, so a non-invasive screening test that identifies cancer at an early stage from urine headspace has the potential to revolutionise patient care. Despite resection, the majority 50-70%) will recur and 10-30% progress to advanced disease . These f0% will r4% compar1, G2) and at an early stage (Ta) confined to the bladder lining. There were 74 controls, patients who were undergoing investigation for symptoms of bladder outflow obstruction and or haematuria; their symptoms and relevant co-morbidities included: 31 had raised PSA without malignancy, 24 had hypertension, 19 had visible haematuria, 15 had bladder outflow symptoms, 7 diabetes, 4 non-visible haematuria, 2 had renal tract stones and 1 had undergone renal transplant surgery.A total of 98 male patients, aged 27-91 years, presenting to urology clinics in Bristol were recruited after obtaining informed consent. All had undergone a clinical assessment for their symptoms. Demographics for the patient groups studied are given in Ethical approval for the study was obtained from the Wiltshire Research Ethics Committee; each participant reviewed an information sheet and gave written consent.Aliquots of fresh urine (0.75 ml) were transferred to septum-topped, glass headspace vials  and were frozen at -20oC until analysis. In a previous study we found that freezing had no detectable effect on the volatile composition of the samples [ samples .oC for 30 seconds. Thereafter, each sample was treated with an equal volume (0.75 ml) of sodium hydroxide  and the mixture equilibrated at 60oC in a water bath for 50 minutes prior to extraction of 2cm3 of headspace air. Headspace air was extracted using an airtight Hamilton gas syringe  and was then immediately injected into the inlet of a gas chromatograph coupled to a sensor detection system.Each urine sample was defrosted by immersing the vial in a water bath at 60TM-1 SULFUR capillary column with an inner diameter of 0.32 mm and a film thickness of 4 μm ) which was interfaced to a heated (450oC) metal oxide sensor used as the detector. The metal oxide sensor consisted of a tin oxide, zinc oxide mix (50: 50 wt%). The sensor preparation and characterisation has been reported elsewhere [oC and was fitted with a 1mm quartz liner. Compressed air  was used as the carrier gas at a pressure of 35 psi and was passed through an air purifier . The GC temperature programme used was as follows: initial GC oven temperature held at 30oC for 6 minutes, then ramped at a rate of 5oC/min to 100oC with a 22 minute hold, giving a total run time of 42 minutes.The VOCs from urine samples were analyzed using an in-house fabricated sensor system. The device comprised of a conventional gas chromatography oven  fitted with a commercially available capillary column  of 50 ppm ethanol in blended air .3) was injected into the device the volatile compounds were separated according to their chemical properties and eluted from the column at specific times. Volatiles eluted from the column and impinged on the sensor. The volatile compounds adsorbed and reacted on the heated metal oxide surface of the sensor concomitantly producing a reversible change in the electrical resistance. The change in electrical resistance versus time profile for the sensor produced a sample specific chromatogram. These resistance time chromatograms were then interpreted statistically based on their group membership.After headspace gas . The utility of highly specific features of the profiles, low order frequencies in the profiles, and broader profile features of the data in developing a good classifier was investigated. As there is no gold standard approach to data of this kind, we investigated two independent methods of statistical analysis.Methods 1 and 2 were based on standardizing each resistance profile so that each had a mean value of 0 and a standard deviation of 1 . This trThis was based on a between-groups comparison of the standardized resistance profiles using two-group linear discriminant analysis implementing the forward stepwise selection algorithm to ensure a) the number of predictors in the model does not exceed the smallest group size and b) the inclusion of a predictor variable does not result in multi-collinearity problems. The within-sample robustness of the predictive properties of the derived model was assessed using leave-one-out cross validation. This modelling strategy was designed to investigate whether a simple parsimonious description of between-groups separation existed based upon highly specific differences in profiles between groups.Partial least squares discriminant analysis (PLS-DA) was used to build a two group classifier for the discrimination of bladder cancer cases from controls. PLS-DA is an established supervised classification technique used in sensormetric analyses and is an information extraction and data reduction technique designed to maximally separate two or more groups and is particularly suited to high dimensional and multi-collinear data. This approach is considered to be better than alternative approaches using principal components analysis over a wide range of classification problems . In thisSensor outputs were compared in the two groups; patients with bladder cancer (24) and patients without cancer (74). Two independent statistical approaches were taken to determine whether there were differences in the sensor output. For each method, patients with cancer were compared with those without; the sample size was too small to be able to compare patterns with grade or stage , in line with the results from the in sample peaks. The average width of the peaks is circa 100 half seconds and can be up to 200 half seconds at higher retention times. Therefore, variability of approximately ±1% was found to have a negligible effect on the predictive accuracy of the statistical models .0-Rg/R0 ×100, where R0 is the baseline resistance and Rg is the resistance when exposed to ethanol). Although the sensitivity of the sensor was maintained at a reasonably constant level the baseline resistance was subject to drift. To counteract this effect and to aid visual and statistical comparison of the results the resistance scale was standardised using the methodology described above.The average sensitivity to ethanol over a two month period was 98.5% (S.D. 10.6)  = 117, 153, 174, 201, 359, 1073, 1162, 1362, 3204). Within samples 24/24 (100%) of bladder cancer cases and 70/74 (94.6%) controls were correctly assigned. This means the model detected the cancer in all patients, irrespective of the grade or stage. Under leave-one-out cross validation these values fell to 23/24 (95.8%) and 69/74 (93.2%) correct classification, respectively  use of the chromatography separation step and 2) the adjustment of pH using base. Base would have had several effects, the high ionic strength would have driven VOCs into the headspace and it would also have suppressed acids, increasing the concentration of basic compounds in the headspace. Previous work by our group has found that base treatment of urine samples (compared to acid treatment or untreated samples), enabled the identification of biomarkers that allowed differentiation between prostate cancer and controls .Sensor outputs were analyzed using two different, independent data analysis techniques each of which showed significant discrimination of samples from patients with and without bladder cancer. Control samples were collected from patients who had attended clinic with urological problems that were later found to be non-malignant. The choice of controls is important to assess the clinical usefulness of such a test. Patients without cancer may present similar symptoms to those with cancer and it is differentiating these that are the clinical challenge. Others  have repTwo different statistical approaches were used, linear discriminant analysis and partial least squares discriminant analysis, however, both techniques used slices of the time profile (bins). The results were similar; using 6 or more components in the PLS-DA correctly identified over 90% of cases and controls, while the simple linear DA correctly classified over 93% of cases and controls.A review of biomarkers for the detection and surveillance of bladder cancers  gave senThe reason for the presence of volatile biomarkers is probably a change in metabolism by malignant cells. There is evidence for oxidative stress and induction of cytochrome P450 by lung, breast, and prostate cancers -27; thisThe identity of the VOCs that contribute to the biomarker profile has yet to be determined. Their characterisation may be defined in future work using gas chromatography mass spectrometry techniques and this will provide further insight into bladder cancer induced biochemical changes.The study is a small scale prospective investigation based around the intuitively appealing proposition of the existence of some systematic compositional differences in urine samples between those patients with, and those patients without, bladder cancer. In this research the treated urine samples are quantitatively characterised using a reliable in-house fabricated sensor coupled with gas chromatographic separation.The research is particularly challenging and retains good ecological validity by not using healthy controls. Results are extremely encouraging. However, the relatively small sample size is based on patients from a single centre and population coverage and external validity cannot be assured; consequently some caution must be exercised with regard to generalising beyond the sample. It is also recognised that the robustness of statistical models based on small sample sizes could be prone to the presence of any chance idiosyncratic sample features, and the relatively small sample sizes do not readily permit stratification on potentially important patient features (e.g. tumour size). Equally the small sample size does not allow a proper statistical assessment of the effects of other confounding factors such as smoking status, drug treatments, ethnicity etc. In addition an all male cohort was selected as the basis of the study, this removes a confounding factor but is a limitation of the current study despite a much higher incidence of this cancer in the male vs. female population (circa 2.5:1). Another limitation of the current study concerns the use of frozen samples, although we have collected robust data from GC-MS studies that freezing does not have a marked effect on the volatile profile . In termprima facie support for the broad claim of differences between groups within the collected samples.Leave-one-out cross validation coupled with the triangulation of results from markedly different statistical analysis techniques provide good The novel combination of a GC and a unique metal oxide sensor based device has provided data to underpin a new instrument for the diagnosis of bladder cancer. The statistical model could be easily used to write an algorithm that will display the diagnosis. Both of the models tested were 96% accurate in diagnosing bladder cancer. These data must now be reproduced in larger studies.


SLC52A3 gene which encodes the intestinal (hRFT2) riboflavin transporter. In these patients riboflavin deficiency is the cause of the BVVL/FL syndrome and supplementation of riboflavin proved a life saving treatment. Mutations in the SLC52A2 gene and the SLC52A1 (GPR172B) gene, coding for human riboflavin transporters hRFT3 and hRFT1 have been associated with the BVVL syndrome as well. We performed a review of the literature, with emphasis on the natural history and the effects of treatment in these patients. A total of 35 publications were traced reporting on the clinical presentation of 74 patients who presented before age 18. The most prevalent symptoms were bulbar palsy, hearing loss, facial weakness and respiratory compromise. Death was reported in 28 of the 61 untreated patients, with a very low survival in patients presenting before age 4. All 13 patients who were treated with riboflavin survived, with a strong clinical improvement after days to months of treatment in eight patients. Three patients demonstrated a stable clinical course and treatment was stopped early in two patients. Abnormalities in plasma flavin levels and/or plasma acylcarnitine profiles were observed in some but not in all patients, and also patients with normal plasma flavin levels and acylcarnitine profiles demonstrated a striking clinical improvement on riboflavin supplementation. It is now clear that proper diagnosis requires mutation analysis of all three transporter genes and treatment should be started immediately without first awaiting results of molecular analysis. Clinical improvement may be rapid or gradual over a period of more than 12 months.The Brown-Vialetto-Van Laere syndrome is a rare neurological disorder which may present at all ages with sensorineural deafness, bulbar palsy and respiratory compromise. Fazio-Londe syndrome is considered to be the same disease entity. Recently it was demonstrated that in some patients the disease is caused by mutations in the  The Brown-Vialetto-Van Laere syndrome (BVVL)  is a rare neurological disorder first described by Brown in 1894 and later by Vialetto and Van Laere. The prevalence is very low and only fifty-eight patients were reported by 2008[SLC52A3 gene [In 2008 a detailed review of the literature was published by Sathasivam in this journal. HoweverSLC52A2 gene  coding for another human riboflavin transporter (hRFT3) have been associated with the BVVL syndrome as well, again with favorable clinical effects of oral riboflavin supplementation[SLC52A1 gene  which encodes another riboflavin transporter. The infant fully recovered after riboflavin treatment[Recently, mutations in the entation,9. Furthentation reportedentation. The motreatment,11.Awareness of these new insights and therapeutic options among professionals is essential, especially since treatment appears to be lifesaving with obvious consequences for the outcomes of these patients. Therefore, we performed a review of the literature, with particular emphasis on the natural history and the effects of treatment in these patients, and provide advice on diagnostics and treatment based on the present knowledge.A search was done in Pubmed using the search terms ‘Brown-Vialetto-Van Laere’ and ‘Fazio-Londe’. As these disorders are considered to be the same disease entity we will report all patients as having BVVL syndrome in this article,3. We seA total of 34 accessible publications was retrieved. Of one more article only the abstract was available but this provided enough information to be useful. In thesSeventy-four case reports were analyzed. The group consisted of 23 males and 51 females. Because the incidence within this group varied with age, we decided to divide the patients in three age groups . In group 1 (N=21) the age at presentation was known for 20 patients and the mean presenting age was 1.4 years. In group 2 (N=21) and in group 3 (N=28) the mean presenting ages were 7.9 years and 13.3 years respectively  which was increased to 450 mg/day after 3 months, five with a dose of 10 mg/kg/day, and one patient with a dose of and 25 mg/kg/day. One patient was treated intravenously with 200 mg/day at age 9 (less than 10 mg/kg/day). The first signs of improvement were seen within days in some patients. ImproveIn 6 of 8 riboflavin responsive patients MADD-like abnormalities were found in the acylcarnitine profile before treatment,5,8,9 anSLC52A3 gene, whereas in 2 patients mutations were demonstrated in the SLC52A2 gene[In all 8 patients who improved on riboflavin supplementation mutations were found in riboflavin transporter genes: in 6 patients mutations were demonstrated in the 2A2 gene.In 5 patients no improvement was demonstrated with riboflavin supplementation. Two of these patients were treated for a very short period: 1 discontinued treatment because of intolerance to oral riboflavin, and in SLC52A1, SLC52A2, or SLC52A3.Mutations in the hRFT2 gene were found in two patients who did not improve on riboflavin: one of the patients with a stable clinical course and the patient in whom treatment was stopped after 1 week for lack of effect. The two patients with a stable condition but no clinical improvement after treatment, and the patient reported to be intolerant of riboflavin supplementation did not demonstrate mutations in This review of the literature demonstrates that - when untreated - BVVL is a severe disorder with a variable but mostly rapid downhill progression, especially in the younger age groups. Outcome is often fatal. As the diagnosis in the group of patients reported before 2010 was based on symptoms only, the disease in these patients may well result from a very diverse etiology.Since 2010, a much more defined group of patients has been reported. The first publication reported only mutations in the hRFT2 gene and all patients demonstrated abnormalities in acylcarnitine profiles and flavin levels. Since tThe abnormalities in the acylcarnitine profiles in the first reported patients are explained by the fact that riboflavin is the precursor of FAD, which acts as an electron acceptor in a number of acyl-CoA dehydrogenation reactions involved in mitochondrial fatty acid oxidation and branched-chain amino acid catabolism. From thIt is now clear that proper diagnosis requires mutation analysis of all three transporter genes. As we reported before, patients will not be detected by newborn screening with abnormal acylcarnitine profiles, probably because of supplementation of flavins from the mother. BecauseIn spite of the success of treatment in this first small group of patients, very little is yet known of the pathophysiology of the disorder, nor of the optimal dose, frequency or mode of administration of the riboflavin supplementation. Further studies into the riboflavin transport by the different transporters are urgently needed.Untreated BVVL is a severe and often fatal disorder. In most patients with a proven hRFT defect riboflavin is highly effective and life saving, both in patients with and without a plasma flavin deficiency. The diagnosis can only be made or rejected by mutation analysis of all 3 genes encoding the hRFT family, and treatment should be started immediately without first awaiting results of molecular analysis. Clinical improvement may be rapid or gradual over a period of more than 12 months. We do recommend to rename this disease after its mechanism: Riboflavin transporter deficiency, type 1(hRFT1), 2 (hRFT2) and 3 (hRFT3).The authors declare that they have no competing interests.AB was involved in design, acquisition and anaylsis of data, drafting of the manuscript. KS was involved in acquisition and analysis of data and drafting of the manuscript. NA was involved in design, analysis of data and critical revision of the manuscript. HW was involved in design, acquisition and analysis of data, drafting of the manuscript. LIJ was involved in design and critical revision of the manuscript. RW was involved in design, analysis of data and critical revision of the manuscript. All authors read and approved the final manuscript.This study was funded by “Stichting Metakids”, The Netherlands.


We set out to examine whether structured professional judgement instruments DUNDRUM-3 programme completion (D-3) and DUNDRUM-4 recovery (D-4) scales along with measures of risk, mental state and global function could distinguish between those forensic patients detained in a secure forensic hospital  who were subsequently discharged by a mental health review board. We also examined the interaction between these measures and risk, need for therapeutic security and eventual conditional discharge.A naturalistic observational cohort study was carried out for 56 patients newly eligible for conditional discharge. Patients were rated using the D-3, D-4 and other scales including HCR-20, S-RAMM, START, SAPROF, PANSS and GAF and then observed over a period of twenty three months during which they were considered for conditional discharge by an independent Mental Health Review Board.The D-3 distinguished which patients were subsequently discharged by the Mental Health Review board  as did the D-4 . Item to outcome analysis showed each item of the D-3 and D-4 scales performed significantly better than random. The HCR-20 also distinguished those later discharged  as did the S-RAMM, START, SAPROF, PANSS and GAF. The D-3 and D-4 scores remained significantly lower (better) for those discharged even when corrected for the HCR-20 total score. Item to outcome analyses and logistic regression analysis showed that the strongest antecedents of discharge were the GAF and the DUNDRUM-3 programme completion scores.Structured professional judgement instruments should improve the quality, consistency and transparency of clinical recommendations and decision making at mental health review boards. Further research is required to determine whether the DUNDRUM-3 programme completion and DUNDRUM-4 recovery instruments predict those who are or are not recalled or re-offend after conditional discharge. The Butler Report  describeRisk assessment is a key part of the process when making decisions regarding a patient’s readiness for discharge to the community. Dolan and Khawja  showed tThe DUNDRUM toolkit is a set of five structured professional judgement instruments developed at the Central Mental Hospital Dundrum, the Republic of Ireland’s only secure forensic hospital . The firThe Criminal Law (Insanity) Act 2010  was intrIn this prospective cohort study we examined whether the DUNDRUM-3 programme completion and DUNDRUM-4 recovery instruments  measuredThis was a naturalistic prospective observational cohort study. Data were gathered as part of the routine clinical audit of service delivery and outcomes. The study was approved by the research ethics, audit and effectiveness committee of the Central Mental Hospital. All participants were given information about the nature and purpose of the assessments and gave informed consent.Structured professional judgement instruments and measures of mental state and global function were assessed at baseline in February 2011 just before the commencement of the Criminal Law (Insanity) Act 2010 which permitted conditional discharge for the first time. This allowed the MHRB to grant conditional discharge where appropriate and safe to do so, and subject to conditions regarding both treatment adherence and supports according to the individual’s risks and needs.The Mental Health Review Board was supplied with a report from the treating consultant psychiatrist, had access to all clinical notes, assessments and reports and heard oral evidence from the patient, the treating consultant psychiatrist and the patient’s lawyer, and any other evidence the MHRB wished to hear. The clinicians and MHRB were blind to the assessments reported here, carried out independently of the treating clinicians prior to the commencement of the new legislation. However neither the clinicians nor the members of the MHRB could be blinded to the unstructured factual clinical information used to make the ratings for the various instruments, nor could they have been blinded to such information. Clinicians decided to recommend or not to recommend absolute or conditional discharge in accordance with their normal practice, a synthesis of the results of structured professional judgement instruments such as the HCR-20 (rated by themselves) and broad unstructured bio-psycho-social assessment including reports of progress in hospital. The MHRB received reports from the treating psychiatrists and other clinicians and was independent in the exercise of its powers .The Central Mental Hospital is the only secure forensic psychiatric hospital in the state, providing high, medium and low secure therapeutic wards for a population of 4.6 million. It is the only hospital designated under the Criminal Law (Insanity) Acts 2006 & 2010 for the reception and treatment of patients found unfit to stand trial or not guilty by reason of insanity, or transferred from prison to hospital for psychiatric treatment. Male patients in the Central Mental Hospital are admitted to a high secure admission ward. The hospital is organised into a series of progressively less secure wards and patients are moved from ward to ward along this recovery pathway, progressing from high secure admission units, through medium secure units and on to low secure pre-discharge rehabilitation units . These pDecisions to offer conditional or unconditional discharges to patients detained under the Criminal Law (Insanity) Acts 2006 & 2010 on the grounds of unfitness to stand trial (UST) or not guilty by reason of insanity (NGRI) were made by a Mental Health  Review Board (MHRB). Those detained under the Mental Health Act 2001 were reviewed by a different body, the Mental Health Tribunal  that couAll patients in the hospital were assessed between February and March 2011 of whom 56 were newly eligible for conditional discharge to the community by the mental health review board. Data on the eligible patients and their subsequent discharges from the hospital were then gathered up to 31st December 2012. Those detained because UST (8 patients) were eligible for conditional discharge by the MHRB in the same way as those detained because found NGRI (48 patients), though those detained because UST could also be returned to court by the treating consultant if they regained fitness.The primary outcome measure was absolute or conditional discharge by the MHRB from this high and medium secure forensic hospital setting following the commencement of the Criminal Law (Insanity) Act 2010 on 8th February 2011. Patient discharges were documented up to 31st December 2012, an observation period of twenty three months. During this period each of the 56 patients eligible for discharge had at least three Criminal Law Review Board hearings thus ensuring that each patient had the opportunity to be granted a conditional or absolute discharge.The DUNDRUM-1 triage security instrument, DUNDRUM-3 programme completion (D-3) and DUNDRUM-4 recovery (D-4) scales are part of a set of four structured professional judgement instruments for the assessment of need for therapeutic security . The DUNWe have previously shown that the DUNDRUM-3 programme completion and the DUNDRUM-4 recovery scales have excellent psychometric properties  and distAs part of the hospital’s routine data gathering for audit and outcome measures, all in-patients were assessed at baseline prior to the commencement of the Criminal Law (Insanity) Act 2010 by MD using the DUNDRUM-1 triage security instrument, DUNDRUM-3 programme completion instrument and DUNDRUM-4 recovery instrument between February and March 2011. All patients were also assessed for the Positive and Negative Symptom Score (PANSS)  by post Possible sources of confounding and bias were considered, including the need for therapeutic security at baseline measured by the DUNDRUM-1 triage security instrument  since hiNo data were missing. All data were entered in SPSS-18 .Association with outcome was tested using the receiver operating characteristic (ROC) area under the curve (AUC), where a significant result for the AUC is one that differs significantly from the ‘random’ AUC of 0.5 - as a minimum the 95% confidence interval for the AUC does not overlap 0.5.Where analysis of variance was carried out, differences between groups can be assessed from the over-lap of confidence intervals. Univariate analysis of a general linear model was carried out for discharge, co-varying for the HCR-20 total score at the beginning of the period of observation because the HCR-20 measure of dynamic risk is already established as a predictor of success or failure in such discharges -8. SimilRegression analysis was used to examine the antecedent covariates of discharge. Discharge was treated as a binary variable, and binary logistic regression was used with either forward or backward stepwise likelihood ratios as appropriate.Covariates were chosen according to the results of the receiver operating characteristic.Unadjusted odds ratios were used as an indicator of the magnitude of effect of individual items, where these could be calculated.There were 56 eligible patients. The mean follow up period was 1.748 years (SD 0.248). Twelve were conditionally discharged and none were absolutely discharged as a first outcome during the follow up period  and mean length of stay was 11.1 years (SD 11.3) for the 56 eligible patients. All were Irish born. There were no significant differences between those discharged by the MHRB (n = 12) and those who were not discharged (n = 44) though there was a tendency for those conditionally discharged to be older (44.1(10.0) years vs 42.3(13.6)) and to have had longer lengths of stay (11.6(8.7) years vs 10.9(11.9)). Diagnosis according to ICD-10 criteria  was schiThe need for therapeutic security was assessed at baseline using the DUNDRUM-1 triage security scale . The meaOf the 8 patients admitted because they were deemed unfit to stand trial 5 remained as in-patients during the period of observation while three were found fit to stand trial in court and returned to prison or the community. All had been considered by the Mental Health Review Board but had not been discharged. Of the 48 patients who had the legal status of Not Guilty by Reason of Insanity (NGRI) 12 were discharged subject to conditions by the MHRB while the remaining 36 continued to be detained as in-patients in hospital at the end of the period of observation.For the 56 eligible for conditional or absolute discharge by the MHRB, Table Neither length of stay at baseline  nor age at baseline  was associated with subsequent discharge.The DUNDRUM-1 triage security scale was not associated with subsequent conditional discharge . The DUNDRUM-3 Programme completion scale distinguished which patients went on to receive a discharge from the Criminal Law  Review board  as did the DUNDRUM-4 Recovery Scale .The HCR-20 total score also distinguished which patients went on to receive a discharge  as did the HCR-20 historical items  and HCR-20 dynamic  items .The S-RAMM background items did not distinguish which patients went on to receive a discharge from the Criminal Law  Review board , however the S-RAMM dynamic (current and future) items  and S-RAMM total score  were significant.The START strengths distinguished which patients went on to receive a conditional discharge  as did the START vulnerabilities  and the SAPROF .The Global Assessment of Functioning (GAF) Scale distinguished which patients received a discharge from the Criminal Law  Review board .The PANSS positive scale distinguished which patients went on to receive a discharge  as did the PANSS negative scale , PANSS general symptoms score (AUC = 0.809. p = 0.001) and the total PANSS score .Table Table 2 = 8.45, df = 8, p = 0.391, Nagelkerke R2 = 0.610, and GAF odds ratio = 1.258  p = 0.002. This model correctly distinguished 95.1% of those not discharged, 83.1% of those who were discharged and 92.5% overall. This model was not robust with backwards logistic regression yielding a different result, resolving in five steps .Binary logistic regression was performed using forward stepwise likelihood ratios for the variables with significant areas under the curve. These were the DUNDRUM-3, DUMDRUM-4, HCR-20 total score, S-RAMM current score, START-S, SAPROF, GAF and PANSS total scores. The START-V was omitted and HCR-20 sub-scales combined to reduce multiple co-linearity while the START-S was also omitted to avoid co-linearity with SAPROF. The iterative process resolved in one step for the GAF as the only significant variable remaining in the regression equation. The model was acceptable with Hosmer and Lemeshow X2 = 0.603, Hosmer and Lemeshow X2 = 6.05, df = 8, p = 0.642, with 97.6% correct for those not discharged, 66.7% correct for those discharged and 90.6% correct overall. The model included two variables DUNDRUM-3 OR = 0.717, 95% CI 0.561 – 0.916, p = 0.008 and PANSS total score which did not reach significance OR = 0.913, 95% CI 0.821 – 1.016, p = 0.097. This model was reasonably robust and when repeated by forward logistic regression yielded a model in one iteration with Nagelkerke R2 = 0.525, Hosmer and Lemeshow X2 = 2.37, df = 7, p = 0.927, 92% correct for those not discharged, 66.7% correct for those discharged and 86.8% correct overall and included a single variable, DUNDRUM-3 odds ratio = 0.698, 95% CI 0.563 – 0.866, p < 0.001.Because the model was not robust, the logistic regression was repeated, this time omitting the GAF. This was done because of the apparent interactive effects between the GAF and SAPROF, evident also when the START-S was included instead of the SAPROF. Backward logistic regression resolved in five iterations, Nagelkerke ROn an item to outcome analysis, all items of the DUNDRUM-3 programme completion scale and all items of the DUNDRUM-4 recovery scale were significantly related to eventual discharge  items only low scores on H3 ‘relationship instability’ and H4 ‘employment problems’ distinguished subsequent discharge, though H7 psychopathy was omitted. Amongst the dynamic items the associations of subsequent discharge were lower scores for C1 ‘lack of insight’, C3 ‘active symptoms of major mental illness’, C5 ‘unresponsiveness to treatment’ and R1 ‘plans lack feasibility’  than others.This study occurred as a result of an experiment of nature. In February 2011, legislation was introduced for the first time in the Republic of Ireland, granting to the Mental Health Review Board the power to grant conditional discharge to patients who were detained in a forensic hospital having been found unfit to stand trial or not guilty by reason of insanity. We were therefore able to test the relevance of the content of structured professional judgement instruments assessing need for therapeutic security, risk assessment, assessment of progress in treatment, recovery, symptoms and global function by assessing these prior to the first hearings under the new legislation. During the period of observation, the DUNDRUM-3 programme completion and the DUNDRUM-4 recovery scales distinguished which patients later received a conditional discharge. The DUNDRUM-1 assessment of need for therapeutic security - a static measure - did not distinguish subsequent conditional discharge apart from a low score on ‘specialist forensic need’, an item describing arson, sadism, paraphilias and lack of cooperation. Low scores on the HCR-20 scales for risk of violence also distinguished which patients received a conditional discharge, as did low scores on the S-RAMM for assessing risk of self-harm and suicide. High (better) scores for the Global Assessment of Function (GAF) had a better AUC than any of the risk assessment scales. Low scores on the PANSS scales for positive, negative and general symptoms also distinguished subsequent conditional discharge.Co-varying for the HCR-20 score left only the DUNDRUM-3 and DUNDRUM-4 as significantly associated with conditional discharge, and the DUNDRUM-4 was eliminated when its risk item was omitted. However when the HCR-20 scales were co-varied for either the DUNDRUM-3 or the DUNDRUM-4 (omitting its risk item) the HCR-20 was no longer statistically significant for conditionally discharged patients.It is particularly interesting that the Global Assessment of Function (GAF) emerged as one of the strongest precursors of conditional discharge, and dominated the logistic regression models. The DUNDRUM-3 and DUNDRUM-4 correlated strongly with the GAF  and the DUNDRUM-3 programme completion scale emerged as the next strongest statistical precursor. It is possible that the items of these scales represent elements of what is taken into account when rating the GAF, or it may be that an element in the rating of all of these items, like the GAF, is a rating of some ‘structured intuition’ as recently suggested . The ratOn an item to outcome analysis all items of the DUNDRUM-3 programme completion scale and of the DUNDRUM-4 recovery scale significantly predicted conditional discharge while five of the HCR-20 items, four of the SAPROF items, seven of the START-S items, nine of the START-V items, five of the S-RAMM items and six PANSS items contributed to the statistical relationship with the outcome.The ratings of the instruments and their component items were carried out by researchers who were blind to each others’ ratings and the research ratings were not provided to the clinicians or MHRBs. The clinicians and MHRB were therefore blind to the baseline ratings. The success or failure of the instruments as statistical predictors depends on the extent to which they emulate the ways in which the clinicians and MHRBs make their recommendations and decisions. The clinical information contained in the structured professional judgement instruments was inevitably available in unstructured form to the clinicians and MHRBs who could not be deprived of it. What was studied is the extent to which the structured instruments and their contents at baseline, were associated with the later behaviour of the decision makers. The statistical inference is that the decision makers relied to a greater or lesser extent on this information (in unstructured form). This was an observational study and therefore no special effort could be made to blind clinicians who gave evidence or the members of the MHRB to such unstructured information. Since the purpose of the study was to identify in a defined structured form those clinical facts that influence conditional discharge, it would be self-defeating and probably impossible to blind clinicians and MHRB members to such unstructured information.This study did not attempt to distinguish between the recommendations of the treating psychiatrists and the decisions of the mental health review board (MHRB) since that would have required greater numbers and access to the deliberations of a judicial body.A further limitation of this study is that many of the measures are dynamic. Ratings made up to 18 months before a hearing may therefore be attenuated by subsequent change. Significant associations  are therefore conservative estimates.This was a study of factors influencing the decision by a mental health review board (MHRB) to conditionally discharge, it was not a study of adverse outcomes following discharge. One of the weaknesses of this study is that a number of patients had been considered ready for conditional discharge for some time prior to this being introduced into Irish legislation. Because these patients had been delayed so long, many of the patients achieving conditional discharge had near perfect scores on the DUNDRUM-3 and DUNDRUM-4 scales. We believe this problem has to an extent been overcome by the period of follow-up, examining conditional discharges after three MHRB hearings rather than just the first hearing under new legislation. In the future patients may be offered a conditional discharge with less perfect scores.This is a study of the overall process by which clinicians make recommendations and MHRB members decide who to discharge. We have shown that clinicians and decision makers appear to take into account more than risk alone when deciding to release a patient from a secure hospital setting.A thematic analysis of the items listed in Table The handbook of the DUNDRUM toolkit  emphasisThe DUNDRUM-3 programme completion and the DUNDRUM-4 recovery scales appear to predict moves to the community from the forensic hospital setting. In another naturalistic prospective cohort study in the same population but a year earlier we reported that the DUNDRUM-1 triage security scale and the HCR-20 measure of risk of violence predicted which patients would be moved from more secure to less secure wards within the hospital, and who would be moved back from less secure to more secure wards . The HCRThe development of structured professional judgement instruments to assist decision making in areas other than risk assessment should be of broad interest to clinicians other than forensic psychiatrists. The decision to discharge any in-patient is among the most professionally challenging in any medical or psychiatric setting, accompanied as it is by risks of subsequent self neglect, relapse, social and environmental hazards, suicide and in rare cases harm to others. The efforts here to describe this decision making process, leading to future validation of those factors other than risk that might be associated with positive or adverse outcomes, is of benefit for a range of applications. Such structured professional judgement may be a way of containing naturally occurring bias in decision making . MedicalThe DUNDRUM-3 and DUNDRUM-4 structured professional judgement instruments were designed to compliment risk assessment instruments as a means of guiding the clinicians and decision makers concerning those who are ready for the move from secure forensic hospitals to the community. In this naturalistic observational study of a cohort of patients with measured needs for therapeutic security at medium secure level (using the DUNDRUM-1 triage security measure), the DUNDRUM-3 and DUNDRUM-4 appear to capture information relevant to the decision to discharge, adding significantly to the information gained from risk assessment alone. Whether they also predict those who are not recalled or do not reoffend after conditional discharge remains to be studied.The authors declare that they have no competing interests.MD rated patients using the DUNDRUM-1, DUNDRUM-3 and DUNDRUM-4, revised drafts of the article and collated the database with ZA; LN and OG rated patients using the PANSS and GAF. The HCR-20 and S-RAMM were rated by the treating clinicians and collated by AN. ZA rated all patients using the START and SAPROF. HGK wrote the first draft of the handbook, designed the study and carried out the data analysis with MD. All contributed to the authorship of the paper. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/13/185/prepub


Background: It was hypothesized that the use of Pentoxifylline would increase arterial O2 saturation and increase exercise tolerance in patients with Chronic Obstructive Pulmonary Disease (COPD).Methods: We tested this hypothesis in 23 patients with COPD and pulmonary hypertension. Patients were randomized to receive Pentoxifylline or placebo, each for a 12-week period, in a prospective, double-blind study to assess the effects of Pentoxifylline on oxygen saturation and exercise tolerance via pulse oximetry and the 6-Minute Walk Test (6MWT).Results: At the end of the 12 weeks, the six-minute walk distance rose from 351.9±65 meters to 393±67 meters in the Pentoxifylline group (10 patients) and increased from 328±79 meters to 353±66 meters in the placebo group (10 patients) (P=0.142). Resting oxygen saturation by pulse oximetry changed from 87±4% to 85±14% in the Pentoxifylline group and from 88±3% to 88±2% in the placebo group (P=0.676). There were no significant changes in dyspnea severity index and heart rate before and after the 6MWT.Conclusion: Pentoxifylline does not seem to improve exercise capacity and dyspnea in patients with severe and very severe COPD. In the past, a few studies demonstrated some beneficial effects of Pentoxifylline on pulmonary hypertension and pulmonary gas exchange.1,3,4 In contrast, Scott et al.19 failed to show any benefits of Pentoxifylline on oxygenation and exercise tolerance in COPD patients. Pentoxifylline is a methylxanthine and possesses several properties that could have beneficial effects for patients with Chronic Obstructive Pulmonary Disease (COPD) and pulmonary hypertension.The exact role which Pentoxifylline can play in COPD is still a subject for debate. We investigated the effects of Pentoxifylline in patients with severe to very severe COPD alongside pulmonary hypertension, using arterial oxygenation, the 6-Minute Walk Test (6MWT), and dyspnea score in this prospective, randomized, double-blind, placebo-controlled study. The participants in this study were recruited from the Outpatient Pulmonary Clinic at Shiraz Medical Center. The study was approved by the Ethics Committee of Shiraz University of Medical Sciences, and informed consent was obtained from all the individuals before their participation.Patient SelectionA total of 37 clinically stable patients with severe to very severe COPD were recruited. Patients were selected for the study if they had forced expiratory volume in 1 second (FEV1) of less than 50% of their predicted value and systolic pulmonary artery pressure greater than 40 mm Hg by color Doppler echocardiography. Seven patients did not meet the echocardiographic inclusion criterion and were, therefore, excluded. Patients were excluded from the study if they had systolic blood pressure more than 180 mm Hg, diastolic blood pressure more than 120 mm Hg, evidence of left ventricular dysfunction or symptomatic coronary artery disease, inability to walk for 6 minutes due to musculoskeletal disorders, significant exertional dysrhythmias, or symptomatic peripheral vascular disease. Twenty-eight patients underwent randomization to receive either Pentoxifylline or placebo . Three pThe patients who qualified for the study underwent baseline spirometry and 6MWT in tandem with pulse oximetry and dyspnea rating before and after exercise with a standard Borg score questionnaire. Two patients in the case group stopped taking Pentoxifylline due to gastric complaints, and one patient in the placebo group withdrew from the study, after ICU admission due to COPD exacerbation. Finally, 10 patients in each group were analyzed.Two trained nurses performed the 6MWT, pulse oximetry, and other measurements. The referring physicians, nurses, and patients were unaware of the contents of the drug package. The patients received either 400 mg of Pentoxifylline orally three times a day for 12 weeks or an identical-appearing placebo tablet with exactly the same dosing regimen. The Pentoxifylline or placebo dosage was halved in the patients receiving Theophylline. At 6 and 12 weeks post-intervention, the patients were re-evaluated.Statistical Analysist test for mean comparisons, and the repeated measures ANOVA was employed to compare the differences between the two groups over the study period. All the measurements are expressed as mean±SD. A P value≤0.05 was considered significant.The SPSS (version 15) computer program was utilized for data entry and statistical analysis. The data were analyzed using the The study population comprised 23 patients, of whom 12 received Pentoxifylline and 11 received the placebo . One patThe mean 6-minute walk distance increased by 41 meters in the Pentoxifylline group , and increased by 25 meters in the placebo group . Despite the significant increase in the 6-minute walk distance in both groups, there was no statistically significant difference between the groups (P=0.142). After the administration of Pentoxifylline for 12 weeks, there was no increase (compared to the placebo) in the mean resting arterial oxygen saturation and heart rate, or nor was there a decrease in dyspnea score . The ind20COPD is characterized by dyspnea-induced impairment and as such can significantly limit the performance of everyday tasks. Hence, a primary goal in the management of COPD is to improve dyspnea with a view to facilitating physical activities irrespective of the severity of the disease if the patient’s health-related quality of life is to be enhanced.21 It also increases cardiac output and O2 consumption and attenuates systemic vasoconstriction.22 The drug is currently used in patients with peripheral vascular disease to increase blood perfusion and improve oxygen delivery. In addition, Pentoxifylline has been reported to increase the cardiac index and there is preliminary evidence that it can reduce hypoxia-induced pulmonary vasoconstriction.6Pentoxifylline is a xanthine-derived agent, which possesses several properties that could have beneficial effects for the patient with COPD. It improves the flow properties of blood by decreasing blood viscosity and reducing RBCs and platelet aggregation.3 demonstrated that Pentoxifylline improved treadmill walk time, arterial saturation, and pulmonary gas exchange in patients with moderate to severe COPD. Why did we obtain such disparate results relative to that study? There are a number of possible explanations. First, there are methodological differences between the two studies. Our study was double-blinded and placebo-controlled, which lessened any bias that might have occurred during the exercise testing. We also compared our exercise indices after the administration of Pentoxifylline for 12 weeks to the indices after the administration of the placebo for 12 weeks, whereas the previous investigators compared the exercise indices after Pentoxifylline administration with their baseline indices. Second, the patient populations may have been slightly different. In the study by Haas et al.3 the patients who received Pentoxifylline had a mean Hb saturation of oxygen of 92.8% with a range of 89 to 96%, while in our study, the mean Hb saturation of oxygen was 87.5% with a range of 83 to 91% with pulmonary hypertension; consequently, failure of Pentoxifylline to improve oxygenation and 6-minute walk distance in our COPD patients may have been caused by the recruitment of previously unrecruited capillaries as a result of hypoxemia. All the COPD patients in the study by Haas et al.3 who received Pentoxifylline for 12 weeks, had ceased smoking a minimum of five years earlier; while all our patients were smokers at the time of examination. In agreement with our results, Scott et al.19 in a double-blind study did not find evidence of improvement in oxygenation, resting diffusion capacity of lung for carbon monoxide (DLco), exercise tolerance, and dyspnea after a 12-week course of Pentoxifylline in individuals with moderate to severe COPD. Finally, the patients included in this trial had pulmonary hypertension at rest. Therefore, the current results are only generalizable to patients with severe COPD in tandem with mild to moderate pulmonary hypertension at rest and may not as such apply to patients with less severe COPD. In this context, these findings do not rule out the notion that Pentoxifylline may be efficacious in patients with less severe airflow obstruction.In the current study, the hypothesis that the net effect of this constellation of pharmacologic properties would improve gas exchange in COPD patients was tested in a group of patients with severe and very severe COPD in conjunction with pulmonary hypertension immediately after exercise. Haas et al.Despite the potential advantageous properties of Pentoxifylline in this randomized, double-blind, placebo-controlled study on 23 patients with severe to very severe COPD receiving Pentoxifylline for 12 weeks, we found no improvement in oxygenation, 6MWT, or dyspnea score.