Recommendations on thromboprophylaxis in major joint arthroplasty - many guidelines, little consensus?

Venous thromboembolic events remain a concern in total hip and knee arthroplasty. Consequently, several guidelines on thromboprophylaxis have been established. However, despite similarities in methodology for evaluation of evidence, discrepancies in guideline recommendations continue to exist. Furthermore, the results of older randomized clinical trials still have significant influence despite major improvements in perioperative care. In contrast, the results of recent large cohort studies with fewer thromboembolic events are mostly used only for background data. Here we outline some of the differences between the guidelines on thromboprophylaxis from the American College of Chest Physicians, the National Institute for Health and Care Excellence and the American Academy of Orthopedic Surgeons. We discuss differences in the methodology and focus of the guidelines potentially influencing the final recommendations. Future analyses are required, including data from modern care with early mobilization and short length of stay.

Effect of pre-operative methylprednisolone on orthostatic hypotension during early mobilization after total hip arthroplasty.

BACKGROUND: Orthostatic hypotension (OH) and intolerance (OI) are common after total hip arthroplasty (THA) and may delay early mobilization. The pathology of OH and OI includes a dysregulated post-operative vasopressor response, by a hitherto unknown mechanism. We hypothesized that OI could be related to the inflammatory stress response which is inhibited by steroid administration. Consequently, this study evaluated the effect of a pre-operative high-dose methylprednisolone on OH and OI early after THA. METHODS: Randomized, double-blind, placebo-controlled study in 59 patients undergoing elective unilateral THA with spinal anesthesia and a standardized multimodal analgesic regime. Patients were allocated (1 : 1) to pre-operative intravenous (IV) methylprednisolone (MP) 125 mg or isotonic saline (C). OH, OI and cardiovascular responses to sitting and standing were evaluated using a standardized mobilization protocol pre-operatively, 6, and 24 h after surgery. Systolic and diastolic arterial pressure and heart rate were measured non-invasively (Nexfin® ). The systemic inflammation was monitored by the C-reactive protein (CRP) response. RESULTS: At 6 h post-operatively, 11 (38%) versus 11 (37%) patients had OH in group MP and group C, respectively (RR 1.02 (0.60 to 1.75; P = 1.00)), whereas OI was present in 9 (31%) versus 13 (43%) patients (RR 0.76 (0.42 to 1.36; P = 0.42)), respectively. At 24 h post-operatively, the prevalence of OH and OI did not differ between groups, though CRP levels were significantly reduced in group MP (P < 0.001). CONCLUSION: Pre-operative administration of 125 mg methylprednisolone IV did not reduce OH or OI compared with placebo despite a reduced inflammatory response.

Delirium after fast-track hip and knee arthroplasty - a cohort study of 6331 elderly patients.

BACKGROUND: Postoperative delirium (PD) is a well-known complication among elderly surgical patients and associated with increased morbidity, mortality and length of stay (LOS). In elective orthopedic surgery, including hip and knee arthroplasty (THA/TKA), most studies report incidences between 5% and 10%. The multimodal optimization of perioperative care (fast-track) aims to enhance recovery and reduce morbidity and LOS, but limited data are available on the effect on PD. Consequently, the study investigated signs of PD associated with LOS > 4 days. METHODS: Prospective risk assessment study with retrospective analysis of discharge notes or medical records of signs of PD in 6331 elective primary unilateral THA and TKA patients ≥ 70 years, and LOS > 4 days. Preoperative patient characteristics collected from eight high volume centers with similar standardized fast-track protocols from January 2010 to November 2013. RESULTS: We identified 43 (0.7%) cases of PD symptoms mentioned as a reason for LOS > 4 days among the 789 patients with LOS > 4 days (12.5% of all THA and TKA). PD patients had a mean age of 80.7 [[95% CI] 79.3-82.1] years, being 4.0 [[95% CI] 2.5-5.5] years older compared to patients without PD (P < 0.001). LOS was median 10 [[Q2-Q3] 7-14] days in the PD group vs. 3 [2-3] days in the non-PD group (P < 0.001), without differences in gender or site of arthroplasty (P = 0.139 and 0.499, respectively). CONCLUSION: Postoperative delirium symptoms contributing to LOS > 4 days in fast-track THA and TKA are rare in elderly patients.

Hydrogen bond breaking dynamics of the water trimer in the translational and librational band region of liquid water.

The effect of exciting each of the three classes of intermolecular vibrations on the hydrogen bond lifetime (tau(H)) of the isolated water trimer is investigated by far-infrared laser spectroscopy. Single excitation of a librational vibration decreases tau(H) by 3 orders of magnitude to tau(H) = 1-6 ps, comparable to the time scale of a number of important bulk water dynamical relaxation processes. In contrast, excitation of translational or torsional vibrations has no significant effect (tau(H) = 1-2 ns). Although such a dependence of tau(H) on intermolecular motions has also been proposed for liquid water via computer simulations, these are the first experiments that provide a detailed molecular picture of the respective motions without extensive interpretation.

Absence of linkage and linkage disequilibrium to chromosome 15q11-q13 markers in 139 multiplex families with autism.

Chromosomal region 15q11-q13 has been implicated to harbor a susceptibility gene or genes underlying autism. Evidence has been derived from the existence of cytogenetic anomalies in this region associated with autism, and the report of linkage in a modest collection of multiplex families. Most recently, linkage disequilibrium with the marker GABRB3-155CA2 in the candidate locus GABRB3, located in this region, has been reported. We searched for linkage using eight microsatellite markers located in this region of chromosome 15 in 147 affected sib-pairs from 139 multiplex autism families. We also tested for linkage disequilibrium in the same set of families with the same markers. We found no evidence for excess allele sharing (linkage) for the markers in this region. Also, we found no evidence of linkage disequilibrium, including for the locus GABRB3-155CA2. Thus, it appears that the role of this region of chromosome 15 is minor, at best, in the majority of individuals with autism.

A genomic screen of autism: evidence for a multilocus etiology.

We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps >/=15) and are less compatible with models specifying

Exclusion of linkage to the HLA region in ninety multiplex sibships with autism.

Several studies have suggested a role for the histocompatibility complex of loci (HLA) in the genetic susceptibility to autism. We have tested this hypothesis by linkage analysis using genetic marker loci in the HLA region on chromosome 6p in multiplex families with autism. We have examined sharing of alleles identical by descent in 97 affected sib pairs from 90 families. Results demonstrate no deviation from the null expectation of 50% sharing of alleles in this region; in fact, for most marker loci, the observed sharing was less than 50%. Thus, it is unlikely that loci in this region contribute to the genetic etiology of autism to any significant extent in our families.

[Indications for cataract surgery in Denmark in 1980 and 1992. Results from the Danish Cataract Surgery Outcomes Study]. / Indikationer for kataraktkirurgi i Danmark i 1980 og 1992. Resultater fra the Danish Cataract Surgery Outcomes Study.

In Denmark the number of cataract extractions has increased to 350% from 1980 to 1991. During the same period the elderly population at risk has only increased to 117%, and thus cannot account for the large increase in the number of extractions. In order to investigate whether more comprehensive clinical indications could be a possible explanation, we compared pre-operative visual acuity and visual impairment in two consecutive samples of Danish cataract surgery patients obtained in 1980 (n = 73) and in 1992 (n = 270). Criteria for inclusion were similar and both samples were representative for the whole country. During the period mean pre-operative visual acuity increased from 0.04 to 0.16 in the eye enlisted for surgery (p < 0.001). Visual functional impairment could be compared by using the same questionnaire for patient interview in 1992 as was used in 1980. In 1992, the degree of impairment was significantly less for reading, outdoor orientation and self care activities. A change in surgical threshold or clinical indications for surgery appears to be a major contributing factor to the large increase in surgical rates.

Autism and the X chromosome. Multipoint sib-pair analysis.

BACKGROUND: Genetic factors undoubtedly play a major etiologic role in autism, but how it is inherited remains unanswered. The increased incidence in males suggests possible involvement of the X chromosome. METHODS: Using data from 38 multiplex families with autism (2 or more autistic siblings), we performed a multipoint sib-pair linkage analysis between autism and 35 microsatellite markers located on the X chromosome. The model included a single parameter, the risk ratio lambda xs (i.e., ratio of risk to siblings compared with the population prevalence), owing to an X-linked gene. Different lambda xs values were assumed and regions of exclusion were established. RESULTS: The entire X chromosome could be excluded for a lambda xs value of 4. The ability to exclude an X-linked gene decreased with smaller lambda xs values, and some positive evidence was obtained with smaller values. A maximum lod score of 1.24 was obtained at locus DXS424 with a lambda xs value of 1.5. CONCLUSIONS: We were able to exclude any moderate to strong gene effect causing autism on the X chromosome. Smaller gene effects (lambda xs < 4) could not be excluded, in particular, a gene of small effect located between DXS453 and DXS1001.

Male-to-male transmission in extended pedigrees with multiple cases of autism.

Despite strong genetic influences in autism, the true mode of inheritance remains unknown. Sex differences in autism have been described in both singleton and multiplex families [Lord et al., 1982; Volkmar et al., 1993; McLennan et al., 1993; Lord, 1992]: Boys outnumber girls by 3 or 4 to 1, and so a sex-linked mode of transmission must also be considered. The key characteristic of X-linkage is that all sons of affected men are unaffected (no male-to-male transmission). In the present study, which is part of an ongoing linkage project in autism, we describe 77 multiplex autism families, 11 of who are affected cousin or half-sibling families. By using these families, it is possible to trace the path of genetic transmission and observe whether the hypothesis of X-linkage is tenable. Of 11 extended pedigrees from 77 multiplex families, six show male-to-male transmission; in these families, X-linkage can be excluded as the genetic basis for their autism. The data from the other five families are compatible with either an autosomal or an X-linked mode of transmission. The key point to emerge, then, is that autism cannot be exclusively an X-linked disorder; there must be an autosomal mode of transmission at least in some families. Thus we must consider the alternative hypotheses that autism is either entirely autosomal, or it is genetically heterogeneous, involving at least one autosomal locus with genderspecific expression, as well as a possible locus on the X-chromosome.

Molecular analysis and test of linkage between the FMR-1 gene and infantile autism in multiplex families.

Approximately 2%-5% of autistic children show cytogenetic evidence of the fragile X syndrome. This report tests whether infantile autism in multiplex autism families arises from an unusual manifestion of the fragile X syndrome. This could arise either by expansion of the (CGG)n trinucleotide repeat in FMR-1 or from a mutation elsewhere in the gene. We studied 35 families that met stringent criteria for multiplex autism. Amplification of the trinucleotide repeat and analysis of methylation status were performed in 79 autistic children and in 31 of their unaffected siblings, by Southern blot analysis. No examples of amplified repeats were seen in the autistic or control children or in their parents or grandparents. We next examined the hypothesis that there was a mutation elsewhere in the FMR-1 gene, by linkage analysis in 32 of these families. We tested four different dominant models and a recessive model. Linkage to FMR-1 could be excluded (lod score between -24 and -62) in all models by using probes DXS548, FRAXAC1, and FRAXAC2 and the CGG repeat itself. Tests for heterogeneity in this sample were negative, and the occurrence of positive lod scores in this data set could be attributed to chance. Analysis of the data by the affected-sib method also did not show evidence for linkage of any marker to autism. These results enable us to reject the hypothesis that multiplex autism arises from expansion of the (CGG)n trinucleotide repeat in FMR-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetics of autism: characteristics of affected and unaffected children from 37 multiplex families.

Evidence from twin and family studies strongly suggests that genetic factors play a prominent role in the etiology of some cases of infantile autism. Genetic factors would be expected to be especially strong in families with multiple autistic members (multiplex families). This report describes the identification and evaluation of 44 families with two or more autistic children collected as part of a genetic linkage study in autism. Families were referred with a presumptive classification of multiplex autism. Children referred as autistic, as well as their presumptively normal siblings, were assessed using the Autism Diagnostic Interview (ADI) and the Autism Diagnostic Observation Scale (ADOS). Thirty-seven of the 44 families (87%) had at least two children who met diagnostic criteria for autism on the ADI. Of the total group of 117 children evaluated in those families, 83 (71%) met all ADI criteria and could be unambiguously classified as autistic (affected), 26 (22%) met none of the ADI criteria and were classified as not autistic (unaffected), and 8 (7%) were classified as uncertain because they met one or more but not all of the ADI cutpoints. Autistic siblings were not significantly concordant for most autism characteristics, for IQ, or for verbal ability. Significant concordances were found, however, for behaviors related to rituals and repetitive play, and for social impairments in the expression and understanding of facial expressions of emotion.(ABSTRACT TRUNCATED AT 250 WORDS)

Fentanyl and sufentanil increase intracranial pressure in head trauma patients.

Although opioids frequently are administered to patients with severe head trauma, the effects of such drugs on intracranial pressure are controversial. Nine patients with severe head trauma were studied for the effects of fentanyl and sufentanil on intracranial pressure (ICP). In all patients, ICP monitoring was instituted before the study. Full neuromuscular blockade was achieved with vecuronium bromide before the administration of either fentanyl (3 micrograms.kg-1) or sufentanil (0.6 microgram.kg-1) as an intravenous bolus over a 1-min period in a masked and random fashion. Patients received the other opioid in the same fashion 24 h later. Arterial blood pressure, heart rate, and ICP were recorded continuously for the 1 h after drug administration. Fentanyl was associated with an average ICP increase of 8 +/- 2 mmHg, and sufentanil with an increase of 6 +/- 1 mmHg. These increases were statistically significant. Both drugs produced clinically mild decreases in mean arterial blood pressure (fentanyl, 11 +/- 6 mmHg; sufentanil, 10 +/- 5 mmHg) that nevertheless were statistically significant. No significant changes in heart rate occurred. These results indicate that modest doses of potent opioids can significantly increase ICP in patients with severe head trauma.

The UCLA-University of Utah epidemiologic survey of autism: the etiologic role of rare diseases.

Twelve rare diseases known to cause CNS pathology were found in 26 (11%) of 233 autistic probands identified during a recent epidemiologic survey of Utah. These 26 probands had significantly lower mean IQs than the remaining patients (43 versus 60) but similar sex distribution and prevalence of abnormal EEGs and seizures. The rarity and diversity of these 12 diseases make it highly unlikely that they randomly occurred with autism. Their presence in this epidemiologic survey is the most compelling evidence to date to support the hypothesis that different diseases producing different types of CNS pathology can play an etiologic role in autism.

The UCLA-University of Utah epidemiologic survey of autism: prenatal, perinatal, and postnatal factors.

In a recent epidemiologic survey conducted in Utah, 241 autistic patients (DSM-III criteria) were found. Medical records of 233 autistics were surveyed for the presence of 36 potentially pathologic prenatal, perinatal, and postnatal factors. These results were compared with those of an identical survey of 62 of their nonautistic siblings, with the results of four previously published surveys, and with normative data. No potentially pathologic factor or group of factors occurred significantly more frequently among the autistic patients. Also, previous observations of significant differences in the occurrence of certain factors in the histories single vs multiple siblings with autism were not confirmed, with the exception of increased viral-type illness during gestation in single-incidence cases. Thus, the etiology of the brain pathology that characteristically disrupts normal development and produces the syndrome of autism remains obscure. Other data from the epidemiologic survey, however, suggest that the role of genetic factors needs to be explored further.

The UCLA-University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling.

The authors recently reported, in this journal, an epidemiologic survey of autism in Utah. Twenty (9.7%) of the 207 families ascertained had more than one autistic child. Analyses of these data revealed that autism is 215 times more frequent among the siblings of autistic patients than in the general population. The overall recurrence risk estimate (the chance that each sibling born after an autistic child will develop autism) is 8.6%. If the first autistic child is a male the recurrence risk estimate is 7%, and if a female 14.5%. These new recurrence risk estimates should be made available to all individuals who have autistic children and are interested in family planning.

Psychometric assessment of first-degree relatives of 62 autistic probands in Utah.

The Wechsler Intelligence Scales, Wide Range Achievement Test, and the Shipley-Hartford Test were administered to 122 parents and 153 siblings of 62 autistic probands in Utah. Scores were distributed as expected within the published normative ranges for each scale. Parents' scores correlated with those of their nonautistic children, but neither parents' nor siblings' scores correlated with the IQ level of the autistic probands. These results do not confirm prior reports from England and the United States of a high rate of cognitive and learning problems in the siblings of autistic individuals, nor the aggregation of such problems in the siblings of probands with high or low levels of cognitive function.

The UCLA-University of Utah epidemiologic survey of autism: prevalence.

The authors conducted an epidemiologic survey in Utah using a four-level ascertainment system, blind current diagnostic assessments, and DSM-III criteria. Of 483 individuals ascertained, 241 were diagnosed as having autism. The best estimate for the prevalence rate was 4 per 10,000 population. Autism was not associated with parental education, occupation, racial origin, or religion. Sixty-six percent of the autistic subjects scored below 70 on standardized IQ tests, and females scored proportionately lower than males. Twenty (9.7%) of 207 families had more than one autistic sibling, which supports the authors' previous finding that there may be a familial subtype of autism.

Positive practice overcorrection combined with additional procedures to teach signed words to an autistic child.

The present study evaluated the effectiveness of using positive practice overcorrection in combination with other techniques to teach two manual signs ("milk" and "cookie") to an autistic boy. This boy had a great deal of difficulty in forming any type of discrimination and often became confused in learning the most simple simultaneous discrimination. Intervention primarily consisted of positive practice overcorrection in which the subject was physically guided to form a required hand sign 10 times when he responded incorrectly and was positively reinforced when he signed correctly. The study used a changing criterion within a multiple-baseline design across responses. The results indicated that overcorrection plus positive reinforcement was effective in teaching one sign (milk), however, and added contingent exercise (having to stand up and sit down 10 times for an incorrect response) was required to teach the second sign (cookie). Once the two signs were learned to a criterion level, it was a relatively easy task for the subject to respond correctly with the signs in a matching-to-sample task.