The Patient Reported Outcomes, Burdens and Experiences (PROBE) Project: development and evaluation of a questionnaire assessing patient reported outcomes in people with haemophilia.

BACKGROUND: The interest of health care agencies, private payers and policy makers for patient-reported outcomes (PRO) is continuously increasing. There is a substantial need to improve capacity to collect and interpret relevant PRO data to support implementation of patient-centered research and optimal care in haemophilia. The Patient Reported Outcomes, Burdens and Experiences (PROBE) Project aims to develop a patient-led research network, to develop a standardized questionnaire to gather patient-reported outcomes and to perform a feasibility study of implementing the PROBE questionnaire. METHODS: A pilot questionnaire was developed using focus group methodology. Content and face validity were assessed by a pool of persons living with haemophilia (PWH) and content experts through interactive workshops. The PROBE questionnaire was translated with the forward-backward approach. PROBE recruited national haemophilia patient non-governmental organizations (NGOs) to administer the questionnaire to people with and without haemophilia. PROBE measured the time to complete the questionnaire and gathered feedback on its content and clarity; staff time and cost required to implement the questionnaire were also collected. RESULTS: The PROBE questionnaire is comprised of four major sections (demographic data, general health problems, haemophilia-related health problems and health-related quality of life using EQ-5D-5L and EQ-VAS). Seventeen NGOs participated in the pilot study of the PROBE Project, recruiting 656 participants. Of these, 71% completed the questionnaire within 15 min, and all participants completed within 30 min. The median total staff and volunteer time required for the NGOs to carry out the study within their country was 9 h (range 2 to 40 h). NGO costs ranged from $22.00 to $543.00 USD per country, with printing and postage being the most commonly reported expenditures. CONCLUSIONS: The PROBE questionnaire assesses patient-important reported outcomes in PWH and control participants, with a demonstrated short completion time. PROBE proved the feasibility to engage diverse patient communities in the structured generation of real-world outcome research at all stages. TRIAL REGISTRATION: Trial registration: NCT02439710.

Identifying information needs among children and teens living with haemophilia.

Transitioning from one life stage to the next can be difficult, but for those living with a chronic condition, it can be even more challenging. Children and adolescents with haemophilia need help to manage transitions while dealing with the complications of their disorder. The National Haemophilia Foundation (NHF), headquartered in New York City, has an extensive information centre on bleeding disorders, but it was not clear how much material existed on the topic of transition. The objectives of this project were to (i) assess the availability of literature about transition for children and adolescents living with haemophilia, (ii) determine which transition issues were the most relevant and (iii) develop and test information products that would address those transition issues. An inventory of NHF's resources and an environmental scan over the Internet was performed. Focus groups were conducted to determine messaging. Video prototypes containing messages were created, tested by focus groups and revised. The literature search yielded limited information available on transition for children and adolescents with haemophilia. Results of the formative research indicated that adolescents wanted more information on sports participation and disclosure of their condition (e.g. to peers, teachers, coaches, health care providers). Video was found to be the preferred delivery format. Children and adolescents living with haemophilia need information to help them transition through life. As a result of this study, two educational products were produced, but several more are recommended to guide these individuals in making healthy transitions into adulthood.

MASAC Consensus Conference: impediments to conducting clinical research in persons with haemophilia, von Willebrand's disease and rare bleeding disorders.

A consensus conference conducted by the Medical and Scientific Advisory Council of the National Hemophilia Foundation was held in New Orleans, LA, on November 11, 2010, to discuss the impediments to conducting clinical research in persons with haemophilia, von Willebrand's disease and rare bleeding disorders. The conference combined presentations providing academic, non-profit and industry perspectives with periods of open discussion. The objective of this conference was to identify the many challenges involved in facilitating U.S. Food and Drug Administration approval of innovative products for these patient populations.

Outcomes of mentored, grant-funded fellowship training in haemostasis /thrombosis: findings from a nested case-control survey study.

Successful strategies by which to effectively recruit and retain academic subspecialists in benign haematology have not been established. To evaluate the effectiveness of a grant-funded, mentored fellowship with respect to retention and early career goals in haemostasis/thrombosis, we sought to compare outcomes for graduates of a grant-funded, mentored fellowship training programme in haemostasis/thrombosis [the National Hemophilia Foundation (NHF)-Baxter Clinical Fellowship Award] during conventional haematology/oncology fellowship training (cases), vs. their training peers who were graduates of conventional haematology/oncology fellowship training alone (controls), via a nested case-control survey study. Survey response rate was 85% (11/13) for cases and 90% (9/10) for controls. All respondents had pursued careers in academic haematology/oncology. Median (range) percent time spent in benign haematology postfellowship was 98% (70-100%) for cases vs. 0% (0-20%) for controls. Time spent in research was significantly greater among cases than controls (median 80% [range: 42-90%] vs. 55% [10-80%], respectively; P = 0.01). By years 3-4 postfellowship, median annual number of peer-reviewed publications was higher for cases than controls (3.5 vs. 1.0; P = 0.01). Cases were also more successful in grant funding (including K-awards). These data suggest that a grant-funded, mentored fellowship training programme in haemostasis/thrombosis may be superior to conventional haematology/oncology fellowship training alone with respect to outcomes of retention in clinical care/research, early-career grant funding and publication productivity.

Cytochrome c oxidase is regulated by modulations in protein expression and mitochondrial membrane phospholipid composition in estivating African lungfish.

We examined some of the potential mechanisms lungfish (Protopterus dolloi) use to regulate cytochrome c oxidase (CCO), during metabolic depression. CCO activity was reduced by 67% in isolated liver mitochondria of estivating fish. This was likely accomplished, in part, by the 46% reduction in CCO subunit I protein expression in the liver. No change in the mRNA expression levels of CCO subunits I, II, III, and IV were found in the liver, suggesting CCO is under translational regulation; however, in the kidney, messenger limitation may be a factor as the expression of subunits I and II were depressed ( approximately 10-fold) during estivation, suggesting tissue-specific mechanisms of regulation. CCO is influenced by mitochondrial membrane phospholipids, particularly cardiolipin (CL). In P. dolloi, the phospholipid composition of the liver mitochondrial membrane changed during estivation, with a approximately 2.3-fold reduction in the amount of CL. Significant positive correlations were found between CCO activity and the amount of CL and phosphatidylethanolamine within the mitochondrial membrane. It appears CCO activity is regulated through multiple mechanisms in P. dolloi, and individual subunits of CCO are regulated independently, and in a tissue-specific manner. It is proposed that altering the amount of CL within the mitochondrial membrane may be a means of regulating CCO activity during metabolical depression in the African lungfish, P. dolloi.

Failure to up-regulate gill Na+,K+-ATPase alpha-subunit isoform alpha1b may limit seawater tolerance of land-locked Arctic char (Salvelinus alpinus).

Many populations of Arctic char (Salvelinus alpinus) are land-locked, physically separated from the ocean by natural barriers and unable to migrate to sea like anadromous populations. Previous studies which experimentally transferred land-locked Arctic char to seawater report high mortality rates due to osmoregulatory failure and an inability to up-regulate gill Na(+),K(+)-ATPase activity. This study examined the mRNA expression of two recently discovered alpha-subunit isoforms of gill Na(+)K(+)-ATPase (alpha1a and alpha1b) during seawater exposure of land-locked Arctic char. mRNA levels of these gill Na(+),K(+)-ATPasealpha-subunit isoforms were compared to Na(+),K(+)-ATPase activity and protein levels and related to osmoregulatory performance. Land-locked Arctic char were unable to regulate plasma osmolality following seawater exposure. Seawater exposure did not induce an increase in gill Na(+),K(+)-ATPase activity or protein levels. Na(+),K(+)-ATPase isoform alpha1a mRNA quickly decreased upon exposure to seawater, while isoform alpha1b levels were unchanged. These results suggest the inability of land-locked Arctic char to acclimate to seawater is due a failure to up-regulate gill Na(+),K(+)-ATPase activity which may be due to their inability to increase Na(+),K(+)-ATPase alpha1b mRNA expression.

Intermediary metabolism of Arctic char Salvelinus alpinus during short-term salinity exposure.

The migration of Arctic char Salvelinus alpinus from freshwater to seawater requires a substantial reorganization of the osmoregulatory tissues to regulate plasma ion levels. These modifications have an inherent metabolic cost, which must be met through the upregulation of intermediary metabolism. Arctic char intermediary metabolism was monitored during the initial 96 h of seawater acclimation through measurement of key enzymes in gill, liver, red and white muscle as well as tissue and blood free amino acid (FAA) levels, and plasma glucose and non-esterified fatty acid content. In general, seawater exposure stimulated large changes in amino acid metabolism, but no change in lipid or carbohydrate metabolism. White muscle FAA content increased significantly following seawater exposure, with levels of essential FAAs doubling after 96 h. Similar increases were seen in the plasma, suggesting a rapid mobilization of FAAs to the circulation. These changes were accompanied by significant increases in the activities of enzymes involved in amino acid metabolism in the gill, liver, red and white muscle, suggesting seawater-acclimated fish have an enhanced capacity for energy production from amino acids. Increased energy requirements were evident in the gill of seawater-acclimated char, as citrate synthase activity increased significantly. The results of this study suggest a rapid upregulation of amino acid metabolism may be critical for the successful acclimation of Arctic char to seawater.

Wild Arctic char (Salvelinus alpinus) upregulate gill Na+,K+-ATPase during freshwater migration.

The successful acclimation of eurhyhaline fishes from seawater to freshwater requires the gills to stop actively secreting ions and start actively absorbing ions. Gill Na(+),K(+)-ATPase is known to be an integral part of the active ion secretion model of marine fishes, but its importance in the active ion uptake model of freshwater fishes is less clear. This study, conducted in the high Arctic, examines gill Na(+),K(+)-ATPase regulation in wild anadromous arctic char returning to freshwater from the ocean. Gill Na(+),K(+)-ATPase activity, protein expression, and mRNA expression of Na(+),K(+)-ATPase isoforms alpha 1a and alpha 1b were monitored in arctic char at three points along their migration route to and from Somerset Island, Nunavut, Canada: out at sea (Whaler's Point), in seawater near the river mouth (Nat's Camp), and after entering the Union River. Arctic char collected from the Union River had more than twofold greater gill Na(+),K(+)-ATPase activity. This was associated with a significant increase (threefold) in Na(+),K(+)-ATPase isoform alpha 1a mRNA expression and a significant increase in plasma sodium and osmolality levels compared with seawater char. Compared with char sampled from Whaler's Point, Na(+),K(+)-ATPase isoform alpha 1b mRNA expression was decreased by approximately 50% in char sampled at Nat's Camp and the Union River. These results suggest that the upregulation of gill Na(+),K(+)-ATPase activity is involved in freshwater acclimation of arctic char and implicate a role for Na(+),K(+)-ATPase isoform alpha 1a in this process. In addition, we discuss evidence that arctic char go through a preparatory phase, or "reverse smoltification," before entering freshwater.

Nitrogen metabolism and excretion in the mangrove killifish Rivulus marmoratus I. The influence of environmental salinity and external ammonia.

At a field site in Belize, mangrove killifish Rivulus marmoratus inhabit hypersaline waters (up to 48 per thousand containing approximately 1 mmol l(-1) ammonia. We tested the hypotheses that R. marmoratus modify their nitrogen metabolism and excretion (i) by accumulating free amino acids (FAAs) and urea in the tissues during hyperosmotic stress and (ii) by shifting to ureotelism and accumulating FAAs during hyperammonia stress. Urea excretion (J(Urea)) (but not ammonia excretion, J(Amm)) displayed a diurnal pattern, with significantly less (75 %) urea excreted at night than during the day in both laboratory-reared clones and wild-caught killifish. When fish were exposed to hypersaline conditions (45 per thousand sea water), J(Urea) was significantly reduced and tissue urea and FAA levels were elevated compared with those of control fish (15 per thousand sea water). When R. marmoratus were exposed to 0, 1, 2, 5 and 10 mmol l(-1) NH(4)Cl (pH 8) for 48 h, no differences were found in J(Urea). Remarkably, prolonged exposure (10 days) to 5 mmol l(-1) NH(4)Cl (pH 8) did not result in an elevation of tissue ammonia levels. In addition, tissue urea and total FAA levels did not differ between control and ammonia-exposed fish after > or =4 days. We propose that the euryhaline R. marmoratus retain urea and FAAs within their tissues in response to extreme osmotic stress. In contrast to many ammonia-tolerant fishes, R. marmoratus do not shift to ureotelism during prolonged hyperammonia stress, nor do they convert nitrogenous wastes into FAAs. The data suggest that killifish continue to eliminate ammonia despite an unfavourable blood-to-water gradient, thereby avoiding accumulation of ammonia.

Nitrogen metabolism and excretion in the mangrove killifish Rivulus marmoratus II. Significant ammonia volatilization in a teleost during air-exposure.

The mangrove killifish Rivulus marmoratus can tolerate prolonged periods of air-exposure (>1 month). During these periods of emersion, we hypothesized that R. marmoratus would convert potentially toxic ammonia into urea and free amino acids (FAAs). In air-exposed fish, both ammonia (J(Amm)) and urea (J(Urea)) excretion continued at approximately 57 % and 39 %, respectively, of submerged rates. Remarkably, approximately 42 % of the total ammonia excreted during air-exposure was through NH(3) volatilization. Ammonia did not accumulate in whole-body tissues of air-exposed fish, but levels of both urea and some FAAs (primarily alanine and glutamine) were up to twofold higher after 10 days. The activities of the ornithine-urea cycle enzymes carbamoyl phosphate synthetase III and ornithine transcarbamylase increased (by approximately 30 % and 36 %, respectively) in whole-body tissues of air-exposed fish, while levels of arginase remained unchanged. The activities of enzymes involved in amino acid and oxidative metabolism were not significantly different between control and air-exposed fish. Partitioning of the anterior and posterior ends of immersed fish revealed that just over half (57 %) of the total nitrogen (ammonia+urea) was excreted through the anterior end of the fish, presumably via the branchial tissues, while emersed fish increased excretion via the posterior end (kidney+skin). R. marmoratus do not undergo a shift towards ureotelism during air-exposure. Rather, we propose that R. marmoratus are able to survive on land for extended periods without significant ammonia accumulation because they continuously release ammonia, partially by NH(3) volatilization.

Parallels between post-polio fatigue and chronic fatigue syndrome: a common pathophysiology?

Fatigue is the most commonly reported and most debilitating of post-polio sequelae affecting the >1.8 million North American polio survivors. Post-polio fatigue is characterized by subjective reports of difficulty with attention, cognition, and maintaining wakefulness. These symptoms resemble those reported in nearly 2 dozen outbreaks of post-viral fatigue syndromes (PVFS) that have recurred during this century and that are related clinically, historically, anatomically, or physiologically to poliovirus infections. This article reviews recent studies that relate the symptoms of post-polio fatigue and chronic fatigue syndrome (CFS) to clinically significant deficits on neuropsychologic tests of attention, histopathologic and neuroradiologic evidence of brain lesions, impaired activation of the hypothalamic-pituitary-adrenal axis, increased prolactin secretion, and electroencephalogram (EEG) slow-wave activity. A possible common pathophysiology for post-polio fatigue and CFS, based on the Brain Fatigue Generator Model of PVFS, and a possible pharmacotherapy for PVFS based on replacement of depleted brain dopamine, will be described.

Bromocriptine in the treatment of post-polio fatigue: a pilot study with implications for the pathophysiology of fatigue.

Fatigue is the most commonly reported and most disabling of all post-polio sequelae (PPS). Bromocriptine mesylate (Parlodel) was employed in a placebo-controlled trial in five survivors of paralytic polio who continued to report moderate to severe daily fatigue after complying with the conservative treatments prescribed for PPS. Placebo was given for 4 wk followed by increasing doses of bromocriptine mesylate, administered at 12:00 pm for 28 days, which reached a total dose of 12.5 mg/day. Three subjects reported marked symptom improvement on bromocriptine but not on placebo. Their reported difficulty with attention, concentration, word finding, mind wandering, memory, thinking clearly, and fatigue on awakening was significantly negatively correlated with days on bromocriptine but not with days on placebo. Before the drug trial began, responders had clinically impaired performance on neuropsychologic tests of attention and information processing speed, more than twice as many hyperintensities on magnetic resonance imaging of the brain, abnormally low fasting adrenocorticotropic hormone levels, and nearly double the mean plasma prolactin level compared with nonresponders. The implications of these findings for the pathophysiology of fatigue are discussed. A double-blind, placebo-controlled, multicenter study will be needed to confirm bromocriptine's efficacy in treating attentionally and neurophysiologically impaired polio survivors whose severe and disabling fatigue does not respond to conservative therapies.

The neuroanatomy of post-polio fatigue.

Fatigue is the most commonly reported, most debilitating, and most poorly understood Post-Polio Sequelae (PPS). Postmortem studies of 50 years ago documented frequent and severe poliovirus-induced lesions within the Reticular Activating System (RAS). Recently, neuropsychological testing has documented marked attention deficits in polio survivors reporting severe fatigue. However, neither of these findings has yet been related to the pathophysiology of post-polio fatigue. Magnetic resonance imaging of the brain was performed in 22 polio survivors carefully screened to eliminate the effect of comorbidities. Subjects rated the severity of their daily fatigue and subjective problems with attention, cognition, and memory. Small discrete or multiple punctate areas of hyperintense signal (HS) in the reticular formation, putamen, medial leminiscus, or white matter tracts were imaged in 55% of the subjects reporting high fatigue and in none of those reporting low fatigue. The presence of HS significantly correlated with fatigue severity and subjective problems in attention, concentration, staying awake, recent memory, and thinking clearly. The lack of significant correlations between HS or fatigue severity and age, severity of the acute polio, depressive symptoms, or difficulty sleeping militates against these factors as either causing HS or producing fatigue. These preliminary findings suggest that poliovirus-induced lesions in the Brain Activating System may underlie the subjective fatigue and attention deficits reported by polio survivors.

The psychology of polio as prelude to post-polio sequelae: behavior modification and psychotherapy.

Even as the physical causes and treatments for post-polio sequelae (PPS) are being identified, psychological symptoms--chronic stress, anxiety, depression, and compulsive, Type A behavior--are becoming evident in polio survivors. Importantly, these symptoms are not only causing marked distress but are preventing patients from making the lifestyle changes necessary to treat their PPS. Neither clinicians nor polio survivors have paid sufficient attention to the acute polio experience, its conditioning of life-long patterns of behavior, its relationship to the development of PPS, and its effect on the ability of individuals to cope with and treat their new symptoms. We describe the acute polio and post-polio experiences on the basis of patient histories, relate the experience of polio to the development of compulsive, Type A behavior, link these behaviors to the physical and psychological symptoms reported in the National Post-Polio Surveys, and present a multimodal behavioral approach to treatment.

Polioencephalitis, stress, and the etiology of post-polio sequelae.

Post-mortem neurohistopathologies that document polio virus-induced lesions in reticular formation and hypothalamic, thalamic, peptidergic, and monoaminergic neurons in the brain are reviewed from 158 individuals who contracted polio before 1950. This polioencephalitis was found to occur in every case of poliomyelitis, even those without evidence of damage to spinal motor neurons. These findings, in combination with data from the 1990 National Post-Polio Survey and new magnetic resonance imaging studies documenting post-encephalitis-like lesions in the brains of polio survivors, are used to present two hypotheses: 1) polioencephalitic damage to aging reticular activating system and monoaminergic neurons is responsible for post-polio fatigue, and 2) polioencephalitic damage to enkephalin-producing neurons is responsible for hypersensitivity to pain in polio survivors. In addition, the antimetabolic action of glucocorticoids on polio-damaged, metabolically vulnerable neurons may be responsible for the fatigue and muscle weakness reported by polio survivors during emotional stress.

Post-polio sequelae and the psychology of second disability.

Thousands of persons who had poliomyelitis are reporting new physical symptoms that are eroding physical abilities, regained only after strenuous and lengthy rehabilitation, that were thought to have been permanently restored. These symptoms are causing persons to feel they are becoming disabled for a second time by the same disease. These new symptoms are psychologically traumatic also because they are unexpected, their cause is unknown and there is a lack of knowledge and understanding concerning them within the medical community. Society's negative and pejorative attitude toward the disabled is discussed to explain the psychological trauma associated with any first or second disability. Psychological processes that promote acceptance of disability are outlined with special emphasis on the post-polio experience. Post-polio support groups are described as one means to obtain the resources necessary to surmount the physical and psychological difficulties associated with post-polio sequelae.