Safety and efficacy of turoctocog alfa (NovoEight®) during surgery in patients with haemophilia A: results from the multinational guardian™ clinical trials.

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prevention and treatment of bleeding episodes in patients with haemophilia A. The present investigations from the multinational, open-label guardian(™) clinical trials assessed the haemostatic response of turoctocog alfa (NovoEight(®)), a rFVIII product, in patients with severe haemophilia A (FVIII ≤ 1%) undergoing surgery. All patients had a minimum of 50 exposure days to any FVIII product prior to surgery and no history of inhibitors. A total of 41 procedures (13 orthopaedic, 19 dental and 9 general) were performed in 33 patients aged 4-59 years. Of the 41 procedures, 15 were major surgeries in 13 patients and 26 were minor surgeries in 21 patients. The success rate for haemostatic response was 100% (success was defined as 'excellent' or 'good' haemostatic outcome). Turoctocog alfa consumption on the day of surgery ranged from 27 to 153 IU kg(-1). The mean daily dose declined over time, while retaining adequate FVIII coverage as measured by trough levels. Overall, no safety issues were identified. No thrombotic events were observed and none of the patients developed FVIII inhibitors. In conclusion, the present results show that turoctocog alfa was effective in controlling blood loss by obtaining a sufficient haemostatic response in patients with severe haemophilia A undergoing surgery.

Distinctive Characteristics of Thoracolumbar Junction Region Stenosis.

STUDY DESIGN: Retrospective case series and systemic literature meta-analysis. BACKGROUND: Thoracolumbar junction region stenosis produces spinal cord compression just above the conus and may manifest with symptoms that are not typical of either thoracic myelopathy or neurogenic claudication from lumbar stenosis. OBJECTIVE: As few studies describe its specific pattern of presenting symptoms and neurological deficits, this investigation was designed to improve understanding of this pathology. METHODS: A retrospective review assessed surgically treated cases of T10-L1 degenerative stenosis. Clinical outcomes were evaluated with the thoracic Japanese Orthopedic Association score. In addition, a systematic review and meta-analysis was performed in accordance with guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Of 1069 patients undergoing laminectomy at 1477 levels, 31 patients (16M/15F) were treated at T10-L1 a mean age 64.4 (SD=11.8). Patients complained of lower extremity numbness in 29/31 (94%), urinary dysfunction 11/31 (35%), and back pain 11/31 (35%). All complained about gait difficulty and objective motor deficits were detected in 24 of 31 (77%). Weakness was most often seen in foot dorsiflexion 22/31 (71%). Deep tendon reflexes were increased in 10 (32%), decreased in 11 (35%), and normal 10 (32%); the Babinski sign was present 8/31 (26%). Mean thoracic Japanese Orthopedic Association scores improved from 6.4 (SD=1.8) to 8.4 (SD=1.8) ( P <0.00001). Gait subjectively improved in 27/31 (87%) numbness improved in 26/30 (87%); but urinary function improved in only 4/11 (45%). CONCLUSIONS: Thoracolumbar junction stenosis produces distinctive neurological findings characterized by lower extremity numbness, weakness particularly in foot dorsiflexion, urinary dysfunction, and inconsistent reflex changes, a neurological pattern stemming from epiconus level compression and the myelomeres for the L5 roots. Surgery results in significant clinical improvement, with numbness and gait improving more than urinary dysfunction. Many patients with thoracolumbar junction stenosis are initially misdiagnosed as being symptomatic from lumbar stenosis, thus delaying definitive surgery.

Fluticasone Furoate/Vilanterol Use Trends and Characteristics in Patients With Obstructive Airway Disease: A Real-World Study of 10,374 Patients From India.

Introduction Obstructive Airway Diseases (OADs) are the leading cause of death among chronic respiratory diseases worldwide, and novel therapies are direly needed. Fluticasone furoate/vilanterol (FF/Vi) (100/25 µg) is the first once-daily ICS/uLABA marketed in India for COPD since 2021. Considering its limited real-world experience in OAD patients in Indian clinical settings, a large drug utilization study (DUS) was planned. Methodology We conducted a cross-sectional, observational DUS at 1900 outpatient clinics in India from October 2021 to March 2022. Prescription data and medical history of patients who were prescribed the FF/Vi combination were collected. Results It was observed that FF/Vi was prescribed in an almost equal number of patients with COPD (44.2%) and asthma (42.9%). The majority of the patients (74%) were switched from previous ICS/LABA to this ICS/uLABA, while 26% of patients were treatment naïve. The average CAT score was 19.5±7.8 (43.2% GOLD Group C and 32.2% GOLD Group B) in COPD patients, while the average ACQ-5 score was 2.6±1.3 (33.1% GINA Step 3, 29.5% GINA Step 2) in asthmatic patients. Most of the patients (63.9%) had raised biomarkers (Blood eosinophil count >300 cells/µl). Prior history of exacerbation was present in 65% of patients with annual exacerbation rates of 1.2 in COPD, 1.1 in asthma, and 1.2 in asthma-COPD overlap syndrome (ACOS). Leukotriene inhibitors (42%) and LAMAs (30.8%) were common add-on medications. Conclusion We observed a trend towards a shift to once-daily ICS/uLABA (FF/Vi) by physicians, especially in symptomatic and exacerbating OAD patients with underlying comorbidities.

The Effectiveness of an Oral Fixed-Dose Combination of Netupitant and Palonosetron (NEPA) in Patients With Multiple Risk Factors for Chemotherapy-Induced Nausea and Vomiting: A Multicenter, Observational Indian Study.

Background Female gender, young age, first chemotherapy cycle, and low alcohol intake have all been linked to an increased risk of nausea and vomiting from chemotherapy. We intended to see if netupitant and palonosetron (NEPA) could prevent chemotherapy-induced nausea and vomiting (CINV) in patients with risk factors such as age, gender, chemotherapy cycle number, and alcohol consumption history. Methods In this retrospective study, chemotherapy-naïve patients who were prescribed netupitant (300 mg) and palonosetron (0.50 mg) (NEPA) before the first cycle of chemotherapy were analyzed for overall, acute, and delayed phases of complete response (CR), complete protection (CP), and control. Results In the acute phase (AP), delayed phase (DP), and overall phase (OP), complete response was 88.23%, 86.27%, and 86.27%, respectively; complete protection was 80.39%, 78.43%, and 76.47%, respectively; and complete control was 76.47%, 72.54%, and 70.58%, respectively, in the whole population (i.e., 51 patients). Complete response, protection, and control in the overall phase were achieved by 86.27%, 72.72%, and 68.18% of patients who received the highly emetogenic chemotherapy (HEC) regimen (i.e., 44 patients), respectively. Conclusion NEPA provided a consistent magnitude of benefit for patients who are at high risk, receiving HEC and moderately emetogenic chemotherapy (MEC), and having good control in the acute, delayed, and overall phases of CINV.

Dural Tear During Thoracic Laminectomy Using Craniotome With Footplate Attachment.

Laminectomy can be accomplished using the craniotome with a footplate attachment, and the technique has been advanced as a superior alternative to using a high-speed drill-driven burr and Kerrison rongeurs. Laminectomy can be accomplished more rapidly and with less bone destruction, an advantage when planning laminoplasty. There is, however, scant literature describing complications of dural laceration using this technique. A 48-year-old male underwent T7-10 laminectomy for resection of an intramedullary spinal cord tumor. During the upward cut of the hemi-lamina at T7-9, a dural laceration occurred that proved not amenable to direct suture closure. The dural was closed with a dural patch placed along the inner surface of the dura and a fat graft on the outer surface with adjunctive use of a lumbar drain. While the footplate laminectomy technique has merits touted in prior publications, including the ability to open the spinal canal quickly at numerous levels and an enhanced ability to achieve an osteoplastic laminoplasty, surgeons should be cognizant of the risk of associated dural laceration. We believe that it is important to emphasize that the initial placement of the lip of the footplate must be well-seated under the inferior aspect of the lowest lamina and over the ligamentum flavum and that the footplate should not be directed beyond the border of the laminae and facet, as this can result in dura and root injury.

Postoperative lumbar spine MRI: How well does a radiology report that raises suspicion for infection correlate with true clinical infection?

INTRODUCTION: Interpretation of a lumbar spine MRI in the immediate postoperative period is challenging, as postoperative tissue enhancement and fluid collections may be mistaken for infection. Radiology reports may use ambiguous language, creating a clinical problem for a surgeon in determining whether a patient needs treatment with antibiotics or revision surgery. Moreover, retrospective criticism of management in instances of a true infection may lead to medicolegal ramifications. METHODS: A retrospective review of patients undergoing posterior-approach lumbar decompressive surgery with or without fusion over a 30-month period identified those undergoing postoperative MRI within 10 weeks of surgery. Patients initially operated upon for infection were excluded. The MRI reports were analyzed for language describing findings suspicious for infection and those of these with true infections were identified. RESULTS: Of 487 patients undergoing posterior lumbar spine decompression surgery, 68 (14%) had postoperative MRI within 10 weeks. Of these, the radiology reports raised suspicion for infection in 20 (29%), of which 2 (10%) patients had a true infection. Two patients underwent reoperation for new motor deficit from seroma/hematoma. Of 63 patients who had MRI to evaluate complaints of back and/or leg pain without new motor deficits, the MRI significantly altered management in 3 patients (4.8%). CONCLUSION: Radiology reports of postoperative lumbar spine MRIs frequently use language that raises suspicion for infection; but it is uncommon, however, that these patients harbor true infections. A radiology report describing possible infectious findings may not be considered significant without corroboration with other laboratory and clinical data.

Properties and outcomes of spinal rehabilitation units in four countries.

OBJECTIVE: Compare rehabilitation after spinal cord lesions (SCL) in different countries. DESIGN: Multicenter comparative study. SETTING: Four spinal rehabilitation units, in Denmark, Russia, Lithuania and Israel. SUBJECTS: 199 SCL patients. INTERVENTIONS: Information was collected about unit properties, rehabilitation objectives, American Spinal Injury Association (ASIA) scale and spinal cord independence measure (SCIM) assessments, and patient data. chi (2)-test, t-test, ANOVA and ANCOVA were used for statistical analysis. MAIN OUTCOME MEASURES: Time from lesion onset to admission for rehabilitation (TAR), length of stay in rehabilitation (LOS), SCIM and spinal cord ability realization measurement index (SCI-ARMI) scores, SCIM gain, SCI-ARMI gain and rehabilitation efficiency (RE). RESULTS: Differences were found between the units in rehabilitation objectives, facilities and special equipment for rehabilitation. Staff/bed ratio was 1.7 in Lithuania and Denmark, 1.1 in Israel and 0.9 in Russia. Russian patients were the youngest and had the most severe lesions among participating units. Admission SCIM and SCI-ARMI were the lowest in Israel: 25.1+/-17.2 and 34.3+/-17.3. TAR was highest in Russia (12.4 month) and lowest in Israel (2 weeks; P<0.01). LOS was longest in Denmark (176.9 days; P<0.001). SCIM score at the end of rehabilitation was highest in Denmark (67.3+/-23). SCIM gain and SCI ARMI gain were highest in Israel (36.9+/-18.3 and 38.5+/-19.4, respectively) and lowest in Russia (P<0.001). RE was highest in Lithuania and lowest in Denmark (P<0.001). CONCLUSIONS: In the participating units, SCL rehabilitation outcomes depend on SCL severity and unit-specific properties. A moderately delayed rehabilitation with long LOS achieved high functioning, and early or slightly delayed rehabilitation combined with shorter LOS achieved high functional gain or efficiency.

Vaginal Migration of Ventriculoperitoneal Shunt Catheter and Cerebrospinal Fluid Leak as a Complication of Hysterectomy.

BACKGROUND: Ventriculoperitoneal (VP) shunting is a common neurosurgical procedure to treat hydrocephalus that diverts cerebrospinal fluid from the cerebral ventricles to the peritoneal cavity for reabsorption. The distal catheter may potentially migrate through any potential or iatrogenic opening in the peritoneal cavity. Increasingly successfully management of childhood hydrocephalus and adult-onset conditions leading to hydrocephalus, such as subarachnoid hemorrhage, is leading many adult female patients harboring VP shunts needing to undergo hysterectomy. Hysterectomy creates a potential defect though which a VP shunt catheter may migrate. It is not known whether the hysterectomy cuff closure technique may affect the likelihood of distal catheter migration though the repair site. CASE DESCRIPTION: We report the case of a 38-year-old woman with a VP shunt who underwent laparoscopic hysterectomy via an open vaginal cuff technique who subsequently presented with vaginal cerebrospinal fluid leakage secondary to migration of the distal shunt catheter through the hysterectomy cuff. CONCLUSIONS: Vaginal migration of the distal VP shunt catheter is a possible complication of hysterectomy. The authors postulate that an open cuff hysterectomy closure technique may increase the risk of catheter migration, an issue that may be better understood with further investigation.

Bilirubin-neural cell interaction: characterization of initial cell surface binding leading to toxicity in the neuroblastoma cell line N-115.

The toxicity of bilirubin to the nervous system might be due to its effect on several key enzyme reactions occurring in the intracellular compartment as suggested by in vitro studies. The question of how bilirubin, a molecule with poor solubility in water and organic solvents, interacts with the plasma membrane and reaches intracellular targets is unclear. In an attempt to get some insight into this problem, we have measured the uptake of bilirubin from bilirubin-albumin solutions by the murine neuroblastoma cell line N-115. At a constant total concentration of bilirubin, the initial rate, as well as the extent of uptake, increases with increasing bilirubin to albumin molar ratio (B/A). The binding is reversible, at least partially, as indicated by the ability of albumin to extract cell-bound bilirubin. The cellular uptake of bilirubin was found to depend also on the concentration of bilirubin, on temperature and on pH. The results are not consistent with either a carrier-mediated transport or passive diffusion across the plasma membrane. The data, however, seem to fit a multistep binding of bilirubin to the plasma membrane proposed for the interaction of bilirubin with synaptosomal plasma membrane vesicles, erythrocyte ghosts and lipid vesicles. These studies, thus, reveal the complexity of the binding interaction at the level of the plasma membrane and leave open the question of transport across the membrane.

Characterization of mutations causing factor VII deficiency in 61 unrelated Israeli patients.

Inherited factor (F)VII deficiency is rare in most populations but relatively common in Israel. The aim of this study was to characterize the molecular and functional defect in unrelated Israeli patients with FVII deficiency. Mutations were identified by direct sequencing of PCR-amplified genomic DNA fragments. Selected mutations were expressed in baby hamster kidney (BHK) cells and tested for binding to tissue factor (TF), activation by FXa and activation of FX. In 61 patients with FVII deficiency, the causative mutation in the FVII gene was discerned. The predominant mutation found in this and a previously reported cohort of 27 unrelated patients in Israel was Ala244Val substitution; of 121 independent mutant alleles defined in all 88 patients ascertained in Israel, 102 (84%) bore this alteration. Eleven additional mutations were identified of which one, Cys22Arg, is novel. Expression of the mutations in BHK cells revealed that four (Ala244Val, 11128delC, Leu300Pro and Cys22Arg) were cross-reacting material (CRM)- negative, and three (Ala294Val, Cys310Phe and Phe24del) were CRM-positive. As predicted by modeling, we observed no binding to TF of FVII Phe24del, diminished binding of FVII Cys310Phe and normal binding of FVII Ala294Val. The main defect of FVII Ala294Val was its inability to activate FX in the presence of TF. Coexpression of Ala294Val and Arg353Gln, a polymorphism known to affect FVII secretion, did not reveal an additive effect on FVII secretion, while coexpression of Ala244Val and Arg353Gln did yield an additive effect.

Combined treatment of severe hyponatremia due to inappropriate antidiuretic hormone secretion.

A 6-year-old girl developed generalized seizures followed by coma, five days after surgical removal of a craniopharyngioma. Low serum sodium levels and low serum osmolality with inappropriately high urinary sodium output confirmed the diagnosis of inappropriate antidiuretic hormone (ADH) secretion. Treatment with 3% hypertonic saline solution and repeated doses of furosemide (1 mg/kg) improved her clinical condition; serum sodium levels, however, rose slowly and urinary excretion remained high. Deoxycorticosterone acetate (DOCA), 4 mg/sq m/day, was added to the above regimen. A striking clinical improvement was noted. Serum sodium levels returned to normal with a concomitant sharp decline in urinary sodium output. The clinical course of this patient demonstrates the efficacy of the addition of deoxycorticosterone acetate to hypertonic saline and furosemide in the treatment of severe, life-threatening hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion.

Polysomnographic and actigraphic evidence of sleep fragmentation in patients with irritable bowel syndrome.

STUDY OBJECTIVE: To characterize the function and quality of sleep in patients with irritable bowel syndrome (IBS). DESIGN: A prospective study with a historic comparison group. SETTING: A regional hospital that also serves as a tertiary referral center. PATIENTS: Eighteen patients with IBS and a comparison group of 20 matched adults with mild benign snoring. INTERVENTIONS: A polysomnography study and a wrist actigraphy study. MEASUREMENTS: All subjects underwent sleep studies and completed self-report questionnaires (IBS severity, psychosocial variables, sleep function, and Epworth Sleepiness Scale). Fourteen IBS and 11 comparison patients underwent actigraphy. RESULTS: The IBS patients had more than 70% less slow-wave stage sleep (4.5 +/- 7.3% vs 19.3 +/- 12.9%; P = 0.006), compensated by increased stage 2 sleep (72.2 +/- 6.6% vs 60.1 +/- 16.8%; P = 0.01). The IBS group had significant sleep fragmentation with a significantly higher arousal and awakening index (P < 0.001), a longer wake period after sleep onset (P = 0.02), and more downward shifts to lighter sleep stages (P = 0.01). The 4-night actigraphy study supported the polysomnography findings. The sleep fragmentation index was significantly higher (P = 0.008) in the IBS group. The IBS patients reported greater daytime sleepiness (9.0 +/- 4.8 vs 6.4 +/- 4.8, Epworth Sleepiness Scale score, P < 0.01) and greater impairment in quality of life, which correlated significantly with the sleep fragmentation indexes. The difference between the groups was not due to differences in baseline anxiety/depression levels. CONCLUSIONS: Patients with IBS have impaired sleep quality, reduced slow-wave sleep activity, and significant sleep fragmentation. The cause-and-effect relationship of these findings with patients' daytime symptoms should be studied further.

Molecular characterization of four novel mutations causing factor VII deficiency.

INTRODUCTION: Hereditary deficiency of factor VII (FVII) is a rare coagulation defect. We previously studied the molecular basis of the FVII deficiency in Israeli patients and found that the majority of them bore the Ala244Val mutation. In the present study we further analysed FVII deficient patients. PATIENTS AND METHODS: Three patients with severe FVII deficiency (FVII activity < or =1%) and one with partial deficiency (25%) were studied. In all four patients, the FVII gene was amplified and sequenced. RESULTS: Four novel mutations have been identified: IVS 2+1G-->C Phe 24 deletion, Leu300Pro and Arg277His. Homozygosity for the IVS2+1G-->C mutation was lethal, whereas homozygosity for the Phe 24 deletion was accompanied by a severe bleeding tendency. FVII modeling showed that Phe 24 is located in the Gla domain. Both Arg 277 and Leu 300 are within the catalytic domain, although Arg 277 is also involved in tissue factor binding. CONCLUSION: We have analysed four mutations, two of which (IVS2+1G-->C, Phe 24 deletion) were associated with severe bleeding tendency in the homozygous state, facilitating prenatal diagnosis. Hypothetically, using FVII modeling, Arg 277 replacement by histidine may weaken the tissue factor, while deletion of Phe 24 and Leu300Pro mutation might be associated with abnormal folding of the Gla and catalytic domains, respectively.

Children's sleep under the threat of attack by ballistic missiles.

The present paper reports on the influence of the Scud missile attacks during the Gulf War on the sleep of Israeli children. Two studies were performed. In the first, sleep habits and sleep disturbances of 61 (mean age 20 months) infants were assessed by questionnaires completed by their parents 5 months before the war and immediately after the end of the War. Comparison of pre- and post-war data revealed no major changes in sleep habits or in sleep quality. In the second study, sleep of 55 children was monitored at home by actigraphs during the last month of the War. All children were aroused during missile attacks, but returned to sleep immediately, with no evidence of carry-over effects once the 'all clear' sign was given. Comparison of sleep quality measures obtained during the War with those of age- and sex-matched children monitored a year before the war did not reveal any significant differences apart from the immediate response to the attack.

Bilirubin inhibits protein kinase C activity and protein kinase C-mediated phosphorylation of endogenous substrates in human skin fibroblasts.

The primary target and molecular basis of bilirubin toxicity to cellular function are not known. We have studied the effect of bilirubin on protein kinase C activity in subcellular fractions of human skin fibroblasts and on protein kinase C-mediated phosphorylation of endogenous substrates. Bilirubin inhibited the kinase activity in a concentration-dependent manner: a 50% inhibition was achieved by 45 mumol/l in the homogenate and 75 mumol/l in both the cytosolic and membranous fractions. Inhibition of protein kinase C activity by bilirubin was reversed by increasing the concentrations of activating lipids in both the cytosolic and membranous fractions. Bilirubin-induced inhibition of phosphorylation of endogenous proteins, in both fractions, was noted in the presence of calcium and the activating lipids, but not in the absence of the activators. This inhibition may play a role in the pathogenesis of bilirubin toxicity.

Graphical shape templates for automatic anatomy detection with applications to MRI brain scans.

A new method of model registration is proposed using graphical templates. A decomposable graph of landmarks is chosen in the template image. All possible candidates for these landmarks are found in the data image using robust relational local operators. A dynamic programming algorithm on the template graph finds the optimal match to a subset of the candidate points in polynomial time. This combination--local operators to describe points of interest/landmarks and a graph to describe their geometric arrangement in the plane--yields fast and precise matches of the model to the data with no initialization required. In addition, it provides a generic tool box for modeling shape in a variety of applications. This methodology is applied in the context of T2-weighted magnetic resonance (MR) axial and sagittal images of the brain to identify specific anatomies.

Deformable template models for emission tomography.

The reconstruction of emission tomography data is an ill-posed inverse problem and, as such, requires some form of regularization. Previous efforts to regularize the restoration process have incorporated rather general assumptions about the isotope distribution within a patient's body. A theoretical and algorithmic framework is presented in which the notion of a deformable template can be used to identify and quantify brain tumors in pediatric patients. Patient data and computer simulation experiments are presented which illustrate the performance of the deformable template approach to single photon emission computed tomography.

Case study: persistent ankle pain- the os trigonurn duly considered.

All emergency wards are inundated with persons who have sustained a painful ankle sprain. Those without unstable joints and malleoli fractures are usually treated by some form of immobilization, analgesia, and ordered to rest with the foot elevated. The large majority of persons recover after this treatment regime but a few continue complaining of pain exacerbated by plantarflexion and a limitation of this movement. During the last year we have noticed a considerable number of patients that have a large os trigonum. A case is described to highlight the clinical significance, the treatment, and to reflect upon the pertinent literature. J Orthop Sports Phys Ther 1987;8(8):402-404.

Twenty-five years of clinical experience with bone banking in Israel.

BACKGROUND: Bone banking and the clinical use of banked tissue are the most common forms of allopreservation and transplantation in modern medicine. OBJECTIVES: This article reviews 25 years (1973-98) of experience in bone banking in Israel. METHODS: A nationwide survey on the clinical application of the banked musculoskeletal tissues during 1996 was conducted by means of a written questionnaire sent to all orthopedic departments in Israel. RESULTS: The response rate to the questionnaire was 84%. A total of 257 cases were allocated bone allografts: the majority comprised 225 spongy bones, 26 were massive bone allografts and 6 were soft tissue allografts. CONCLUSION: Improvement of quality control and quality assurance of the banked tissues, together with development of skills in the use of osteoinductive and osteoconductive materials, cast the future of musculoskeletal tissue banking.

Bone allograft in revision total knee replacement.

Revision total knee replacement (TKR) is often associated with the necessity to reconstruct a certain amount of bone loss. In a retrospective study we reviewed the records of 137 patients who had undergone revision TKR in our department between 1990 and 1996, due to loosening or inflection. Bone allografts were used in 91 patients (67%) to accomplish stable, new prostheses. Three types of bone loss were identified in this group: Type I - minor, Type II - moderate, and Type III - large bone defects, located on either side of the knee joint - A, or both sides - B.The treatment results of these 91 patients, according to the type of bone loss, are presented, showing good functional outcome when utilizing bone allografts in revision TKR. However, careful preoperative planning, identification of bone loss type, and a well-equipped bone bank are mandatory to the success of the operation.