1 8. Th e i m m u n o g e ni city of R eF a c t o AF (m o r o c t o c o g alf a AF-CC) in p r evi... more 1 8. Th e i m m u n o g e ni city of R eF a c t o AF (m o r o c t o c o g alf a AF-CC) in p r evio u sly u n t r e a t e d p a ti e n t s wi t h h a e m o p hili a A in t h e U nit e d Kin g d o m. H a e m o p hili a 2 4 (6) , p p.
The guideline group was selected to be representative of UKbased medical experts. MEDLINE and EMB... more The guideline group was selected to be representative of UKbased medical experts. MEDLINE and EMBASE were searched systematically for publications in English from 2002 using the key word Willebrand. The writing group produced the draft guideline, which was subsequently reviewed by the A United Kingdom Haemophilia Centre Doctors Organization (UKHCDO) advisory committee, a British Committee for Standards in Haematology (BCSH) sounding board of approximately 50 UK haematologists, and the BCSH executive; comments were incorporated where appropriate. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found in at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_ GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with von Willebrand disease. Guideline update This is a single guideline replacing two separate guidelines on diagnosis and management respectively, published in 2004 (Laffan et al, 2004; Pasi et al, 2004). Where there has been no significant change in understanding or practice, the reader is referred to the earlier guidelines.
Direct sequencing of VWF genomic DNA in 21 patients with type 3 von Willebrand disease (VWD) fail... more Direct sequencing of VWF genomic DNA in 21 patients with type 3 von Willebrand disease (VWD) failed to reveal a causative homozygous or compound heterozygous VWF genotype in 5 cases. Subsequent analysis of VWF mRNA led to the discovery of a deletion (c.221-977_532 ؉ 7059del [p.Asp75_Gly178del]) of VWF in 7 of 12 white type 3 VWD patients from 6 unrelated families. This deletion of VWF exons 4 and 5 was absent in 9 patients of Asian origin. We developed a genomic DNA-based assay for the deletion, which also revealed its presence in 2 of 34 type 1 VWD families, segregating with VWD in an autosomal dominant fashion. The deletion was associated with a specific VWF haplotype, indicating a possible founder origin. Expression studies indicated markedly decreased secretion and defective multimerization of the mutant VWF protein. Further studies have found the mutation in additional type 1 VWD patients and in a family expressing both type 3 and type 1 VWD. The c.221-977_532 ؉ 7059del mutation represents a previously unreported cause of both types 1 and 3 VWD. Screening for this mutation in other type 1 and type 3 VWD patient populations is required to elucidate further its overall contribution to VWD arising from quantitative deficiencies of VWF.
Bone marrow transplantation was carried out on 38 patients with mucopolysaccharidosis type I over... more Bone marrow transplantation was carried out on 38 patients with mucopolysaccharidosis type I over a period of 15 years. The donor was an HLA identical relative in 10 cases, an HLA non-identical relative in 16 cases, and an HLA identical unrelated volunteer donor in 12 cases. Ten patients received a second transplant. One patient received three transplants. Thirteen engrafted patients have survived five years or more. Most patients have shown an arrest or slowing down of psychomotor regression. However, dysostosis multiplex has progressed. Careful selection of patients may be necessary to ensure optimum results.
Epstein Barr Virus (EBV) associated Lymphoproliferative Disease (LPD) is a complication of alloge... more Epstein Barr Virus (EBV) associated Lymphoproliferative Disease (LPD) is a complication of allogeneic haemopoietic stem cell tranplantation (HSCT). In certain groups (congenital immunodeficiency, unrelated and mismatched donor transplants, T cell depletion) the risk may be as high as 25% with significant morbidity and mortality. Strategies to predict such illlness and allow early intervention have therefore assumed importance. We have routinely screened peripheral blood of paediatric, transplanted patients by quantitiative PCR. We report the results of such analysis of 28 successive patients and the EBV serial quantitation in 4 patients with EBV LPD. The median age at time of transplant was 6.5 years. 17 patients received an unrelated donor transplant and one patient received a haplo-identical transplant. The remainder (n=9) received a matched family donor transplant. 23 patients received either Alemtuzumab (n=19) or ATG (n=4). 13 patients had leukaemia, 5 had mucopolysaccharide syndrome, 4 for congential immune deficiency and 6 for non malignant haeamtological conditions. 9 (32%) patients showed no evidence of EBV reactivation using serial PCR monitoring. 10 patients had low level EBV reactivation as defined with a PCR log[copy number] <4.5 copies/ml. 9 patients had a higher level of EBV reactivation. 2 patients had clinical EBV LPD and 2 additional LPD patients with LPD and with archived serial blood samples were also analysed. All patients with clinical LPD fell in the high level reactivation group. All patients with high level reactivation had received either Alemtuzumab or ATG. Patients within this high level group with LPD had a higher PCR log value again than those without LPD (all patients with EBV LPD had levels > 6, whilst the highest level without disease was 5.2). All 4 patients responded to therapy for EBV LPD, with a combination of rituximab, withdrawal of immune suppression or administration of donor lymphocytes - DLI). At higher EBV levels the quantitative PCR had increasing positive predictive value for clinical LPD. We therefore conclude that EBV serial quantitative PCR is useful in discriminating those who will develop LPD from those that will not. Our data suggest that it is possible to use EBV PCR quantitation further to discriminate asymptomatic EBV reactivation that will resolve without therapy from EBV reactivation that will require intervention. This prevents over exposure of patients to treatments (rituximab, DLI, immune suppression withdrawal) with significant associated toxicity (prolonged B cell aplasia, graft versus host disease).
Spinal cord stimulation (SCS) utilizes the delivery of mild electrical pulses via epidural electr... more Spinal cord stimulation (SCS) utilizes the delivery of mild electrical pulses via epidural electrodes placed on the dorsal side of the spinal cord, typically to treat chronic pain. The first clinical use of SCS involved the delivery of paresthesia inducing, low-frequency waveforms to the neural targets corresponding to the painful areas. Contemporary SCS therapies now leverage novel therapeutic pathways to limit paresthesia and deliver superior clinical outcomes. Historically, SCS has largely been delivered with fixed stimulation parameters. This approach, referred to as open-loop (OL) SCS, does not account for the fluctuations in spacing-driven by postural changes and activity-between the electrodes and the cord. These fluctuations result in variability in the delivered dose and the volume of tissue activation (VTA) that manifests with each stimulation pulse. Inconsistent dosing may lead to suboptimal therapeutic efficacy and durability. To address this clinical need, closed-loop (CL) SCS systems have been developed to automatically adjust stimulation parameters to compensate for this variability. The evoked compound action potential (ECAP), a biopotential generated by the synchronous activation of dorsal column fibers, is indicative of the VTA resulting from the stimulation pulse. The ECAP may be utilized as a control signal in CL SCS systems to adjust stimulation parameters to reduce variability in the ECAP, and in turn, variability in the VTA. While investigational CL SCS systems with ECAP sensing have so far focused solely on managing paresthesia-based SCS, such systems must also incorporate the stimulation approaches that now define the contemporary clinical practice of SCS. Accordingly, we describe here a flexible, next-generation framework for neural responsive SCS that blends science-based methodologies for pain management with real-time CL control for biophysical variation. We conclude with a clinical example of such a system and the associated performance characteristics.
Objectives: Spinal cord stimulation (SCS) is a treatment for chronic neuropathic pain. Recently, ... more Objectives: Spinal cord stimulation (SCS) is a treatment for chronic neuropathic pain. Recently, SCS has been enhanced further with evoked compound action potential (ECAP) sensing. Characteristics of the ECAP, if appropriately isolated from concurrent stimulation artifact (SA), may be used to control, and aid in the programming of, SCS systems. Here, we characterize the sensitivity of the ECAP growth curve slope (S) to both neural response (|S resp |) and SA contamination (|S art |) for four spinal ECAP estimation methods with a novel performance measure (|S resp /S art |). Materials and Methods: We collected a library of 112 ECAP and associated artifact recordings with swept stimulation amplitudes from 14 human subjects. We processed the signals to reduce SA from these recordings by applying one of three schemes: a simple high-pass (HP) filter, subtracting an artifact model (AM) consisting of decaying exponential and linear components, or applying a template correlation method consisting of a triangularly weighted sinusoid. We compared these against each other and to P2-N1, a standard method of measuring ECAP amplitude. We then fit the ECAP estimates from each method with a function representing the growth curve and calculated the S resp and S art parameters following the fit. Results: Any SA reduction scheme selected may result in under-or overestimation of neural activation or misclassification of SA as ECAP. In these experiments, the ratio of neural signal preservation to SA misclassification (|S resp /S art |) on the ECAP estimate was superior (p < 0.05) with the HP and AM schemes relative to the others. Conclusions: This work represents the first comprehensive assessment of spinal ECAP estimation schemes. Understanding the clinically relevant sensitivities of these schemes is increasingly important, particularly with closed-loop SCS systems using ECAP as a feedback control variable where misclassification of artifact as neural signal may lead to suboptimal therapy adjustments.
Ketamine can be administered by the intravenous, intramuscular and oral routes. There are increas... more Ketamine can be administered by the intravenous, intramuscular and oral routes. There are increasing reports on safety and efficacy of oral ketamine for painful invasive procedures
SummaryCongenital factor XIII (FXIII) deficiency is a rare bleeding disorder, which in its severe... more SummaryCongenital factor XIII (FXIII) deficiency is a rare bleeding disorder, which in its severe form is associated with a significant bleeding phenotype, requiring regular prophylactic therapy. A recently developed recombinant FXIII (rFXIII) has demonstrated safety and efficacy in children aged ≥6 years and adults (mentor™1 trial). This article describes the mentor™4 trial, which has assessed the pharmacokinetics (PK) and safety of rFXIII in younger children (1 to &lt;6 years) with congenital FXIII deficiency, and compares extrapolated PK parameters with the mentor™1 trial. Six children with congenital FXIII A‐subunit deficiency received a single, 35 IU kg−1 rFXIII dose. PK properties were similar in all the children, with a mean area under the concentration vs. 30‐day time curve of 248.6 IU h−1 mL−1, maximal FXIII activity (30 min) of 0.67 IU mL−1, and mean 30‐day trough of 0.21 IU mL−1. All patients maintained FXIII activity above the lower target level (0.1 IU mL−1). rFXIII half‐life was 15.1 days (range, 10–25). No safety findings of clinical concern were observed. PK properties of rFXIII were similar in patients from both trials. The study demonstrated that a single dose of 35 IU kg−1 rFXIII maintained plasma FXIII levels above 0.1 IU mL−1 over a 30‐day period in young children with congenital FXIII deficiency, and is, therefore, likely to provide adequate prophylaxis in this age group. The study extends the previous findings of the mentor™1 trial and confirms that no dose adjustment is required for different age groups with congenital FXIII deficiency.
This retrospective study looked at all patients with Haemophilia A who attended Manchester Pendle... more This retrospective study looked at all patients with Haemophilia A who attended Manchester Pendlebury Childrens Hospital for their first and subsequent Factor replacement therapy between January 1980 and May 2005. The aim was to determine :- Does an increased number of different products used influence inhibitor formation. Does using a B domain deleted factor (Refacto) concentrate influence inhibitor formation. Does changing from plasma derived to recombinant factor influence inhibitor formation. A total of 107 patients who received a cumulative total of 65,102 trearment days were identified and the following information was recorded for each patient :-severity of haemophilia (mild, moderate or severe) and baseline factor VIII level, date and age of first product, all types of products used, number of treatment days used of each product, detection of inhibitor and if present date of ocurrence and age of patient. The policy of the unit was to test for inhibitors every six months, pre operatively or when clinically indicated. Thirteen different products were in use during the period of the study :- AHFC(anti haemophilic factor concentrate), Cryoprecipitate, 8Y, 8SM, Alphanate, Replenate, Monoclate P, Helixate, Refacto, Recombinate, Hemophil M, Advate and Haemate P. Only 4 patients out of 107 developed inhibitors and all were exposed to less than 4 products. Inhibitor patient demographics Haemophilia type and baseline factor VIII Number of treatment days before inhibitor Products used with respective treatment days Severe (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1%) 249 Cryoprecipitate (128) 8Y(121) Severe (1%) 75 Alphanate(34) 8SM(34) Replinate(7) Moderate (2%) 39 Alphanate(30) Helixate(9) Moderate (2%) 18 Refacto(2) Helixate(16) A total of 37 patients received 6 or greater factor products. The mean number of treatment days was 1224 (median 1285, SDV 863) and the mean number of factor products used was 6.8 (median 7, SDV 0.81). In severe patients (baseline factor VIII of 2% or less) a total of 31 patients received 4 or greater factor products. The mean number of treatment days was 1512 (median 1501, SDV 776) and the mean number of factor products used was 6.45 (median 6, SDV 1.31). A total of 23 patients received 6 or greater factor products. The mean number of treatment days was 1664 (median 1525, SDV 776) and the mean number of products used was 7.04 (median 7, SDV 0.93). There were 10443 exposure days of Refacto in those patients that did not develop an inhibitor. 69 out of 103 patients were exposed to the product with a mean number of treatment days of 151 (median 43, SDV 237). In the same population 29 out of 43 severe patients (baseline factor VIII of 2% or less) were exposed to the product with a total number of exposure days of 6464 with a mean number of treatment days of 222 (median 241, SDV 241). There were only 2 exposure days of ReFacto in just one of the inhibitor patients. 64 patient changed from using plasma to recombinant products. Only one of these patients developed an inhibitor. In this study the number of different factors used, use of a B deleted domain factor and change from plasma derived to recombinant factors did not appear to be factors in the formation of inhibitors.
Results: Twenty-two patients were eligible for inclusion, mean age at last assessment 12.2 (Range... more Results: Twenty-two patients were eligible for inclusion, mean age at last assessment 12.2 (Range 6.221.6) years. Age at BMT 1.3 (SD 0.6) years. Conditioning for first BMT included busulphan and cyclophosphamide with 5 out of 10 second transplants receiving total body ...
A 3-year-old boy was treated for acute lymphoblastic leukae-mia (ALL) according to the UK Medical... more A 3-year-old boy was treated for acute lymphoblastic leukae-mia (ALL) according to the UK Medical Research Council trial (XI) (Hill et al, 2004). At diagnosis, his family returned to the UK after living in Albania and Greece for several years. Remission induction was uncomplicated, but ...
Sequential reduced-and full-intensity allografting using same donor in a child with chronic granu... more Sequential reduced-and full-intensity allografting using same donor in a child with chronic granulomatous disease and coexistent, significant comorbidity
Acute myeloid leukaemia (AML) is an uncommon malignancy in childhood affecting approximately 60 c... more Acute myeloid leukaemia (AML) is an uncommon malignancy in childhood affecting approximately 60 children per year in the United Kingdom (Webb et al, 2001). In contrast, individuals with Fanconi anaemia (FA) have an extremely high risk of developing AML (Faivre et al, 2000; Alter, 2003; Kutler et al, 2003). FA is a rare inherited disease characterised by congenital and developmental abnormalities, bone marrow failure and cancer predisposition. AML is the most common malignancy in FA patients and develops much earlier in life than in the general population (Alter, 2003; Tischkowitz & Hodgson, 2003). At the cellular level, FA cells display chromosomal instability and hypersensitivity to DNA-damaging agents, such as mitomycin C (MMC; Joenje & Patel, 2001; D'Andrea & Grompe, 2003). FA can be caused by mutations in one of at least 12 genes. These encode for proteins that interact in a cellular pathway that appears to have a central role in maintaining DNA integrity and prevents malignant transformation. It consists of an FA-core complex comprising the
1 8. Th e i m m u n o g e ni city of R eF a c t o AF (m o r o c t o c o g alf a AF-CC) in p r evi... more 1 8. Th e i m m u n o g e ni city of R eF a c t o AF (m o r o c t o c o g alf a AF-CC) in p r evio u sly u n t r e a t e d p a ti e n t s wi t h h a e m o p hili a A in t h e U nit e d Kin g d o m. H a e m o p hili a 2 4 (6) , p p.
The guideline group was selected to be representative of UKbased medical experts. MEDLINE and EMB... more The guideline group was selected to be representative of UKbased medical experts. MEDLINE and EMBASE were searched systematically for publications in English from 2002 using the key word Willebrand. The writing group produced the draft guideline, which was subsequently reviewed by the A United Kingdom Haemophilia Centre Doctors Organization (UKHCDO) advisory committee, a British Committee for Standards in Haematology (BCSH) sounding board of approximately 50 UK haematologists, and the BCSH executive; comments were incorporated where appropriate. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found in at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_ GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with von Willebrand disease. Guideline update This is a single guideline replacing two separate guidelines on diagnosis and management respectively, published in 2004 (Laffan et al, 2004; Pasi et al, 2004). Where there has been no significant change in understanding or practice, the reader is referred to the earlier guidelines.
Direct sequencing of VWF genomic DNA in 21 patients with type 3 von Willebrand disease (VWD) fail... more Direct sequencing of VWF genomic DNA in 21 patients with type 3 von Willebrand disease (VWD) failed to reveal a causative homozygous or compound heterozygous VWF genotype in 5 cases. Subsequent analysis of VWF mRNA led to the discovery of a deletion (c.221-977_532 ؉ 7059del [p.Asp75_Gly178del]) of VWF in 7 of 12 white type 3 VWD patients from 6 unrelated families. This deletion of VWF exons 4 and 5 was absent in 9 patients of Asian origin. We developed a genomic DNA-based assay for the deletion, which also revealed its presence in 2 of 34 type 1 VWD families, segregating with VWD in an autosomal dominant fashion. The deletion was associated with a specific VWF haplotype, indicating a possible founder origin. Expression studies indicated markedly decreased secretion and defective multimerization of the mutant VWF protein. Further studies have found the mutation in additional type 1 VWD patients and in a family expressing both type 3 and type 1 VWD. The c.221-977_532 ؉ 7059del mutation represents a previously unreported cause of both types 1 and 3 VWD. Screening for this mutation in other type 1 and type 3 VWD patient populations is required to elucidate further its overall contribution to VWD arising from quantitative deficiencies of VWF.
Bone marrow transplantation was carried out on 38 patients with mucopolysaccharidosis type I over... more Bone marrow transplantation was carried out on 38 patients with mucopolysaccharidosis type I over a period of 15 years. The donor was an HLA identical relative in 10 cases, an HLA non-identical relative in 16 cases, and an HLA identical unrelated volunteer donor in 12 cases. Ten patients received a second transplant. One patient received three transplants. Thirteen engrafted patients have survived five years or more. Most patients have shown an arrest or slowing down of psychomotor regression. However, dysostosis multiplex has progressed. Careful selection of patients may be necessary to ensure optimum results.
Epstein Barr Virus (EBV) associated Lymphoproliferative Disease (LPD) is a complication of alloge... more Epstein Barr Virus (EBV) associated Lymphoproliferative Disease (LPD) is a complication of allogeneic haemopoietic stem cell tranplantation (HSCT). In certain groups (congenital immunodeficiency, unrelated and mismatched donor transplants, T cell depletion) the risk may be as high as 25% with significant morbidity and mortality. Strategies to predict such illlness and allow early intervention have therefore assumed importance. We have routinely screened peripheral blood of paediatric, transplanted patients by quantitiative PCR. We report the results of such analysis of 28 successive patients and the EBV serial quantitation in 4 patients with EBV LPD. The median age at time of transplant was 6.5 years. 17 patients received an unrelated donor transplant and one patient received a haplo-identical transplant. The remainder (n=9) received a matched family donor transplant. 23 patients received either Alemtuzumab (n=19) or ATG (n=4). 13 patients had leukaemia, 5 had mucopolysaccharide syndrome, 4 for congential immune deficiency and 6 for non malignant haeamtological conditions. 9 (32%) patients showed no evidence of EBV reactivation using serial PCR monitoring. 10 patients had low level EBV reactivation as defined with a PCR log[copy number] &amp;amp;amp;amp;amp;amp;amp;lt;4.5 copies/ml. 9 patients had a higher level of EBV reactivation. 2 patients had clinical EBV LPD and 2 additional LPD patients with LPD and with archived serial blood samples were also analysed. All patients with clinical LPD fell in the high level reactivation group. All patients with high level reactivation had received either Alemtuzumab or ATG. Patients within this high level group with LPD had a higher PCR log value again than those without LPD (all patients with EBV LPD had levels &amp;amp;amp;amp;amp;amp;amp;gt; 6, whilst the highest level without disease was 5.2). All 4 patients responded to therapy for EBV LPD, with a combination of rituximab, withdrawal of immune suppression or administration of donor lymphocytes - DLI). At higher EBV levels the quantitative PCR had increasing positive predictive value for clinical LPD. We therefore conclude that EBV serial quantitative PCR is useful in discriminating those who will develop LPD from those that will not. Our data suggest that it is possible to use EBV PCR quantitation further to discriminate asymptomatic EBV reactivation that will resolve without therapy from EBV reactivation that will require intervention. This prevents over exposure of patients to treatments (rituximab, DLI, immune suppression withdrawal) with significant associated toxicity (prolonged B cell aplasia, graft versus host disease).
Spinal cord stimulation (SCS) utilizes the delivery of mild electrical pulses via epidural electr... more Spinal cord stimulation (SCS) utilizes the delivery of mild electrical pulses via epidural electrodes placed on the dorsal side of the spinal cord, typically to treat chronic pain. The first clinical use of SCS involved the delivery of paresthesia inducing, low-frequency waveforms to the neural targets corresponding to the painful areas. Contemporary SCS therapies now leverage novel therapeutic pathways to limit paresthesia and deliver superior clinical outcomes. Historically, SCS has largely been delivered with fixed stimulation parameters. This approach, referred to as open-loop (OL) SCS, does not account for the fluctuations in spacing-driven by postural changes and activity-between the electrodes and the cord. These fluctuations result in variability in the delivered dose and the volume of tissue activation (VTA) that manifests with each stimulation pulse. Inconsistent dosing may lead to suboptimal therapeutic efficacy and durability. To address this clinical need, closed-loop (CL) SCS systems have been developed to automatically adjust stimulation parameters to compensate for this variability. The evoked compound action potential (ECAP), a biopotential generated by the synchronous activation of dorsal column fibers, is indicative of the VTA resulting from the stimulation pulse. The ECAP may be utilized as a control signal in CL SCS systems to adjust stimulation parameters to reduce variability in the ECAP, and in turn, variability in the VTA. While investigational CL SCS systems with ECAP sensing have so far focused solely on managing paresthesia-based SCS, such systems must also incorporate the stimulation approaches that now define the contemporary clinical practice of SCS. Accordingly, we describe here a flexible, next-generation framework for neural responsive SCS that blends science-based methodologies for pain management with real-time CL control for biophysical variation. We conclude with a clinical example of such a system and the associated performance characteristics.
Objectives: Spinal cord stimulation (SCS) is a treatment for chronic neuropathic pain. Recently, ... more Objectives: Spinal cord stimulation (SCS) is a treatment for chronic neuropathic pain. Recently, SCS has been enhanced further with evoked compound action potential (ECAP) sensing. Characteristics of the ECAP, if appropriately isolated from concurrent stimulation artifact (SA), may be used to control, and aid in the programming of, SCS systems. Here, we characterize the sensitivity of the ECAP growth curve slope (S) to both neural response (|S resp |) and SA contamination (|S art |) for four spinal ECAP estimation methods with a novel performance measure (|S resp /S art |). Materials and Methods: We collected a library of 112 ECAP and associated artifact recordings with swept stimulation amplitudes from 14 human subjects. We processed the signals to reduce SA from these recordings by applying one of three schemes: a simple high-pass (HP) filter, subtracting an artifact model (AM) consisting of decaying exponential and linear components, or applying a template correlation method consisting of a triangularly weighted sinusoid. We compared these against each other and to P2-N1, a standard method of measuring ECAP amplitude. We then fit the ECAP estimates from each method with a function representing the growth curve and calculated the S resp and S art parameters following the fit. Results: Any SA reduction scheme selected may result in under-or overestimation of neural activation or misclassification of SA as ECAP. In these experiments, the ratio of neural signal preservation to SA misclassification (|S resp /S art |) on the ECAP estimate was superior (p < 0.05) with the HP and AM schemes relative to the others. Conclusions: This work represents the first comprehensive assessment of spinal ECAP estimation schemes. Understanding the clinically relevant sensitivities of these schemes is increasingly important, particularly with closed-loop SCS systems using ECAP as a feedback control variable where misclassification of artifact as neural signal may lead to suboptimal therapy adjustments.
Ketamine can be administered by the intravenous, intramuscular and oral routes. There are increas... more Ketamine can be administered by the intravenous, intramuscular and oral routes. There are increasing reports on safety and efficacy of oral ketamine for painful invasive procedures
SummaryCongenital factor XIII (FXIII) deficiency is a rare bleeding disorder, which in its severe... more SummaryCongenital factor XIII (FXIII) deficiency is a rare bleeding disorder, which in its severe form is associated with a significant bleeding phenotype, requiring regular prophylactic therapy. A recently developed recombinant FXIII (rFXIII) has demonstrated safety and efficacy in children aged ≥6 years and adults (mentor™1 trial). This article describes the mentor™4 trial, which has assessed the pharmacokinetics (PK) and safety of rFXIII in younger children (1 to &lt;6 years) with congenital FXIII deficiency, and compares extrapolated PK parameters with the mentor™1 trial. Six children with congenital FXIII A‐subunit deficiency received a single, 35 IU kg−1 rFXIII dose. PK properties were similar in all the children, with a mean area under the concentration vs. 30‐day time curve of 248.6 IU h−1 mL−1, maximal FXIII activity (30 min) of 0.67 IU mL−1, and mean 30‐day trough of 0.21 IU mL−1. All patients maintained FXIII activity above the lower target level (0.1 IU mL−1). rFXIII half‐life was 15.1 days (range, 10–25). No safety findings of clinical concern were observed. PK properties of rFXIII were similar in patients from both trials. The study demonstrated that a single dose of 35 IU kg−1 rFXIII maintained plasma FXIII levels above 0.1 IU mL−1 over a 30‐day period in young children with congenital FXIII deficiency, and is, therefore, likely to provide adequate prophylaxis in this age group. The study extends the previous findings of the mentor™1 trial and confirms that no dose adjustment is required for different age groups with congenital FXIII deficiency.
This retrospective study looked at all patients with Haemophilia A who attended Manchester Pendle... more This retrospective study looked at all patients with Haemophilia A who attended Manchester Pendlebury Childrens Hospital for their first and subsequent Factor replacement therapy between January 1980 and May 2005. The aim was to determine :- Does an increased number of different products used influence inhibitor formation. Does using a B domain deleted factor (Refacto) concentrate influence inhibitor formation. Does changing from plasma derived to recombinant factor influence inhibitor formation. A total of 107 patients who received a cumulative total of 65,102 trearment days were identified and the following information was recorded for each patient :-severity of haemophilia (mild, moderate or severe) and baseline factor VIII level, date and age of first product, all types of products used, number of treatment days used of each product, detection of inhibitor and if present date of ocurrence and age of patient. The policy of the unit was to test for inhibitors every six months, pre operatively or when clinically indicated. Thirteen different products were in use during the period of the study :- AHFC(anti haemophilic factor concentrate), Cryoprecipitate, 8Y, 8SM, Alphanate, Replenate, Monoclate P, Helixate, Refacto, Recombinate, Hemophil M, Advate and Haemate P. Only 4 patients out of 107 developed inhibitors and all were exposed to less than 4 products. Inhibitor patient demographics Haemophilia type and baseline factor VIII Number of treatment days before inhibitor Products used with respective treatment days Severe (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1%) 249 Cryoprecipitate (128) 8Y(121) Severe (1%) 75 Alphanate(34) 8SM(34) Replinate(7) Moderate (2%) 39 Alphanate(30) Helixate(9) Moderate (2%) 18 Refacto(2) Helixate(16) A total of 37 patients received 6 or greater factor products. The mean number of treatment days was 1224 (median 1285, SDV 863) and the mean number of factor products used was 6.8 (median 7, SDV 0.81). In severe patients (baseline factor VIII of 2% or less) a total of 31 patients received 4 or greater factor products. The mean number of treatment days was 1512 (median 1501, SDV 776) and the mean number of factor products used was 6.45 (median 6, SDV 1.31). A total of 23 patients received 6 or greater factor products. The mean number of treatment days was 1664 (median 1525, SDV 776) and the mean number of products used was 7.04 (median 7, SDV 0.93). There were 10443 exposure days of Refacto in those patients that did not develop an inhibitor. 69 out of 103 patients were exposed to the product with a mean number of treatment days of 151 (median 43, SDV 237). In the same population 29 out of 43 severe patients (baseline factor VIII of 2% or less) were exposed to the product with a total number of exposure days of 6464 with a mean number of treatment days of 222 (median 241, SDV 241). There were only 2 exposure days of ReFacto in just one of the inhibitor patients. 64 patient changed from using plasma to recombinant products. Only one of these patients developed an inhibitor. In this study the number of different factors used, use of a B deleted domain factor and change from plasma derived to recombinant factors did not appear to be factors in the formation of inhibitors.
Results: Twenty-two patients were eligible for inclusion, mean age at last assessment 12.2 (Range... more Results: Twenty-two patients were eligible for inclusion, mean age at last assessment 12.2 (Range 6.221.6) years. Age at BMT 1.3 (SD 0.6) years. Conditioning for first BMT included busulphan and cyclophosphamide with 5 out of 10 second transplants receiving total body ...
A 3-year-old boy was treated for acute lymphoblastic leukae-mia (ALL) according to the UK Medical... more A 3-year-old boy was treated for acute lymphoblastic leukae-mia (ALL) according to the UK Medical Research Council trial (XI) (Hill et al, 2004). At diagnosis, his family returned to the UK after living in Albania and Greece for several years. Remission induction was uncomplicated, but ...
Sequential reduced-and full-intensity allografting using same donor in a child with chronic granu... more Sequential reduced-and full-intensity allografting using same donor in a child with chronic granulomatous disease and coexistent, significant comorbidity
Acute myeloid leukaemia (AML) is an uncommon malignancy in childhood affecting approximately 60 c... more Acute myeloid leukaemia (AML) is an uncommon malignancy in childhood affecting approximately 60 children per year in the United Kingdom (Webb et al, 2001). In contrast, individuals with Fanconi anaemia (FA) have an extremely high risk of developing AML (Faivre et al, 2000; Alter, 2003; Kutler et al, 2003). FA is a rare inherited disease characterised by congenital and developmental abnormalities, bone marrow failure and cancer predisposition. AML is the most common malignancy in FA patients and develops much earlier in life than in the general population (Alter, 2003; Tischkowitz & Hodgson, 2003). At the cellular level, FA cells display chromosomal instability and hypersensitivity to DNA-damaging agents, such as mitomycin C (MMC; Joenje & Patel, 2001; D'Andrea & Grompe, 2003). FA can be caused by mutations in one of at least 12 genes. These encode for proteins that interact in a cellular pathway that appears to have a central role in maintaining DNA integrity and prevents malignant transformation. It consists of an FA-core complex comprising the
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