Official Position of the American Academy of Clinical Neuropsychology Social Security Administration Policy on Validity Testing: Guidance and Recommendations for Change.

UNLABELLED: The milestone publication by Slick, Sherman, and Iverson (1999) of criteria for determining malingered neurocognitive dysfunction led to extensive research on validity testing. Position statements by the National Academy of Neuropsychology and the American Academy of Clinical Neuropsychology (AACN) recommended routine validity testing in neuropsychological evaluations. Despite this widespread scientific and professional support, the Social Security Administration (SSA) continued to discourage validity testing, a stance that led to a congressional initiative for SSA to reevaluate their position. In response, SSA commissioned the Institute of Medicine (IOM) to evaluate the science concerning the validation of psychological testing. The IOM concluded that validity assessment was necessary in psychological and neuropsychological examinations (IOM, 2015 ). OBJECTIVE: The AACN sought to provide independent expert guidance and recommendations concerning the use of validity testing in disability determinations. METHOD: A panel of contributors to the science of validity testing and its application to the disability process was charged with describing why the disability process for SSA needs improvement, and indicating the necessity for validity testing in disability exams. RESULTS: This work showed how the determination of malingering is a probability proposition, described how different types of validity tests are appropriate, provided evidence concerning non-credible findings in children and low-functioning individuals, and discussed the appropriate evaluation of pain disorders typically seen outside of mental consultations. CONCLUSIONS: A scientific plan for validity assessment that additionally protects test security is needed in disability determinations and in research on classification accuracy of disability decisions.

Common acute childhood infections and appendicitis: a historical study of statistical association in 27 English public boarding schools, 1930-1934.

Although the involvement of common childhood infections in the aetiology of acute appendicitis has long been conjectured, supporting evidence is largely restricted to a disparate set of clinical case reports. A systematic population-based analysis of the implied comorbid associations is lacking in the literature. Drawing on a classic epidemiological dataset, assembled by the School Epidemics Committee of the United Kingdom's Medical Research Council (MRC) in the 1930s, this paper presents a historical analysis of the association between termly outbreaks of each of six common childhood infections (chickenpox, measles, mumps, rubella, scarlet fever and whooping cough) and operated cases of acute appendicitis in 27 English public boarding schools. When controlled for the potential confounding effects of school, year and season, multivariate negative binomial regression revealed a positive association between the level of appendicitis activity and the recorded rate of mumps (beta=0.15, 95% CI 0.07-0.24, P<0.001). Non-significant associations were identified between appendicitis and the other sample infectious diseases. Subject to data caveats, our findings suggest that further studies are required to determine whether the comorbid association between mumps and appendicitis is causal.

Comparison of hypoxia transcriptome in vitro with in vivo gene expression in human bladder cancer.

Hypoxia-inducible genes have been linked to the aggressive phenotype of cancer. However, nearly all work on hypoxia-regulated genes has been conducted in vitro on cell lines. We investigated the hypoxia transcriptome in primary human bladder cancer using cDNA microarrays to compare genes induced by hypoxia in vitro in bladder cancer cell line EJ28 with genes upregulated in 39 bladder tumour specimens (27 superficial and 12 invasive). We correlated array mRNA fold changes with carbonic anhydrase 9 (CA IX) staining of tumours as a surrogate marker of hypoxia. Of 6000 genes, 32 were hypoxia inducible in vitro more than two-fold, five of which were novel, including lactate transporter SLC16A3 and RNAse 4. Eight of 32 hypoxia-inducible genes in vitro were also upregulated on the vivo array. Vascular endothelial growth factor mRNA was upregulated two-fold by hypoxia and 2-18-fold in 31 out of 39 tumours. Glucose transporter 1 was also upregulated on both arrays mRNA, and fold changes on the in vivo array significantly correlated with CA IX staining of tumours (P=0.008). However, insulin-like growth factor binding protein 3 mRNA was the most strongly differentially expressed gene in both arrays and this confirmed its upregulation in urine of bladder cancer patients (n=157, P<0.01). This study defines genes suitable for an in vivo hypoxia 'profile', shows the heterogeneity of the hypoxia response and describes new hypoxia-regulated genes.

Phase I trial of intravesical Suramin in recurrent superficial transitional cell bladder carcinoma.

Suramin is an antitrypanosomal agent with antineoplastic activity, but with serious systemic side effects. We administered Suramin intravesically to determine a concentration with low toxicity but with evidence of a pharmacodynamic effect, to recommend a dose level for phase II trials. This was an open-labelled, non-randomized dose-escalation phase I study. In all, 12 patients with a history of recurrent superficial bladder cancer were grouped into four dose levels (10-150 mg ml(-1) in 60 ml saline). Six catheter instillations at weekly intervals were used. Cystoscopy and biopsy were performed before and 3 months after the start of treatment. Suramin was assayed using high-performance liquid chromatography, vascular endothelial growth factor (VEGF) using ELISA (enzyme-linked immunosorbent assay), and urinary protein profile using surface-enhanced laser desorption ionisation mass spectroscopy (SELDI). Minimal systemic absorption of Suramin was found at the highest dose of 150 mg ml(-1). Urinary VEGF was affected by Suramin at doses above 50 mg ml(-1), corresponding to the estimated threshold of saturation of Suramin binding to urine albumin. SELDI showed a specific disappearance of urinary protein peaks during treatment. Intravesical Suramin shows lack of toxicity and low systemic absorption. The results of this phase I trial support expanded clinical trials of efficacy at a dose of 100 mg ml(-1) intravesically.

Bladder management and risk of bladder stone formation in spinal cord injured patients.

PURPOSE: We determined by statistical analysis whether method of management is associated with risk of bladder stone formation in spinal cord injured patients. MATERIALS AND METHODS: A retrospective cohort study was performed of 457 patients admitted to Stoke Mandeville Hospital Spinal Injuries Center between 1985 and 1990 with more than 6 months of followup. Analysis included Cox regression and Poisson regression. RESULTS: Relative to those patients treated with intermittent self-catheterization, the hazard ratio was 10.5 (p <0.0005, 95% confidence interval 4.0-27.5) for patients with suprapubic catheters and it was 12.8 (p <0.0005, 95% confidence interval 5.1-31.9) for those with indwelling urethral catheters. The absolute annual risk of stone formation in patients with a catheter was 4% compared with 0.2% for those on intermittent self-catheterization. However, having formed a stone, the risk of forming a subsequent stone quadrupled to 16% per year. Bladder stones were no more likely to form in patients with suprapubic catheters compared to those with indwelling urethral catheters (hazard ratio 1.2, p = 0.6). CONCLUSIONS: In spinal cord injured patients long-term catheterization is associated with a substantial increased risk of bladder stone formation. This increased risk occurs independently of age, sex and injury level. Degree of injury (complete or incomplete) was considered in the model. Catheter type (suprapubic or urethral) did not change this risk significantly if at all.

Ureteric obstruction caused by pelvic actinomycosis.

Ureteric obstruction is a well-known complication of actinomycosis, however its management in previous case reports has been very variable and sometimes mutilating. We report a rare case presenting with ischiorectal abscess that was successfully treated by JJ stenting and penicillin.

A study of waiting time for surgery in elderly patients with hip fracture and subsequent in-patient hospital stay.

OBJECTIVE: To establish whether increased waiting time to operation in elderly patients with hip fracture significantly affects postoperative time to discharge. METHODS: Combined prospective and retrospective analysis of theatre logbooks and in-patient data to determine the type, time and date of operation and subsequent in-patient stay. SETTING: A busy district general hospital in the South East Thames Valley area with changing availability of a dedicated trauma list. PATIENTS: 441 elderly patients undergoing hip surgery between May 1995 and March 1997. MAIN OUTCOME MEASURES: Waiting time from booking of operation to surgery and length of postoperative hospital stay. RESULTS: Increased pre-operative wait for emergency hip surgery in elderly patients significantly increases postoperative stay. Roughly doubling pre-operative wait increases postoperative stay by 19% (P < 0.01).

Antenatal management of severe feto-maternal alloimmune thrombocytopenia: HLA incompatibility may affect responses to fetal platelet transfusions.

In feto-maternal alloimmune thrombocytopenia (FMAIT), severe hemorrhage, particularly intracranial haemorrhage (ICH), may occur before delivery. Management strategies to prevent ICH in high-risk pregnancies include maternal administration of intravenous Ig with or without steroids and fetal platelet transfusions. This report describes a patient who lost three fetuses with ICH because of FMAIT due to anti-HPA-1a. ICH occurred earlier in successive pregnancies (at 28, 19, and 16 weeks of gestation) despite maternal treatment with intravenous Ig and steroids from 14 weeks of gestation in the third pregnancy. The fourth pregnancy was managed by administering weekly intraperitoneal injections of Ig to the fetus from 12 to 18 weeks of gestation. At 18 weeks, there was no evidence of ICH, but the fetal platelet count was only 12 x 10(9)/L. Serial fetal platelet transfusions were started, but there were poor responses because of immune destruction of the transfused platelets by maternal HLA antibodies. There were improved responses to transfusions prepared from the mother and from HLA-compatible HPA-1a-negative donors. At 35 weeks of gestation, a normal infant was delivered by Caesarean section after 20 platelet transfusions. There was prolonged thrombocytopenia in the baby for 15 weeks after birth, probably due to transfer of HPA-1a antibodies in the transfusions of unwashed maternal platelets. The optimal management of pregnancies likely to be severely affected by FMAIT is still evolving. Intensive management was successful in this case, but a successful outcome cannot be guaranteed in severely affected cases. This is the first time that HLA incompatibility has been found to complicate fetal transfusion therapy.

The histocompatibility antigen in asbestos related disease.

Thirty nine phenotypes of human leucocyte antigens (HLA)-A-B-DR and DQ were obtained from 99 asbestos workers (one woman and 98 men). Presence or absence of antinuclear antibodies and rheumatoid factor was determined in 91 of them. Workers were divided into five groups: asbestos workers with no apparent disease (AW; n = 17), diffuse benign pleural disease (PD; n = 31), asbestosis (AS; n = 24), asbestosis with lung cancer (AS-CA; n = 14), and mesothelioma (M; n = 13). Compared with AW, several trends of differences of HLA antigen prevalence were found in patients with asbestos related disease, but these did not achieve statistical significance when p was corrected (pcorr) by number of analyses undertaken. Analysis of the results obtained in previous studies together with the results of this study showed that compared with AW, AS patients had decreased prevalence of HLA-DR5 (pcorr < 0.02). Reasons for the differences in results of previous studies and statistical methods commonly used to compare prevalences of HLA antigen are discussed.

Imaging of thrombi with tissue-type plasminogen activator rendered enzymatically inactive and conjugated to a residualizing label.

BACKGROUND: Contemporary cardiovascular practice relies increasingly on thrombolysis as a therapeutic modality. Its optimal use requires prompt, noninvasive delineation of thrombotic occlusion in arterial beds and rapid detection of reocclusion after initially successful thrombolysis. METHODS AND RESULTS: We have been developing an approach to noninvasively image thrombi in which plasminogen-activating properties of tissue-type plasminogen activator (t-PA) are attenuated by treatment with D-Phe-L-Pro-L-Arg-chloromethyl ketone (PPACK) and have shown that the inactive t-PA avidly and promptly binds to clots in vitro. In the present study, we conjugated this material to a residualizing label, radioiodinated dilactitol tyramine (*I-DLT), and characterized the potential use of the inactivated, conjugated t-PA as a radiopharmaceutical for imaging thrombi in vivo. The approach developed requires not only avid binding of the tracer to thrombi but also rapid clearance from plasma and a lack of prompt release of radiolabeled degradation products from the liver. The rapid clearance of unaltered or PPACK-treated t-PA was not influenced by conjugation to *I-DLT, but the release of radioiodinated degradation products into plasma after injection of *I-DLT-conjugated t-PA was markedly less than release of degradation products of directly radioiodinated t-PA. When 131I-DLT-PPACK-t-PA was infused for 15 minutes intravenously after a bolus injection of 20% in dogs with coronary, pulmonary, or carotid artery thrombi, clearance was rapid. Mean +/- SEM thrombus-to-blood ratios of radioactivity were high, ranging from 37 +/- 9:1 and 2.8 +/- 0.6:1 with carotid thrombi formed concomitantly or approximately 30 minutes before infusion of tracer, respectively, to 35:1 for concomitantly formed coronary thrombi, 42 +/- 7:1 and 8.1 +/- 0.8:1 for concomitantly formed and preformed pulmonary thrombi, respectively, and 18:1 for a preformed femoral artery thrombus. Thrombi were detectable by planar gamma scintigraphy even though image quality was affected adversely by low concentrations of radioactivity that in aggregate composed a relatively large amount of radioactivity in underlying and overlying tissues. This limitation was overcome by tomographic imaging, which was used to detect both femoral and pulmonary thrombi. CONCLUSIONS: Use of enzymatically inactivated t-PA coupled to a residualizing label permits rapid detection and localization of thrombi in vivo.

Are certain HLA haplotypes responsible for low testosterone levels in males?

The level of testosterone on 138 HLA typed healthy males and 71 male rheumatoid arthritis patients were analysed. HLA-B15 was associated with a lower mean serum testosterone level in males than any other tissue type. This was observed in both the normal and RA groups.

Detection of granulocyte antibodies using flow cytometric analysis of leucocyte immunofluorescence.

Antigranulocyte antibodies are involved in the pathophysiology of a number of clinical disorders, which include: febrile transfusion reactions, severe pulmonary reactions to transfusion, auto-immune neutropenia, drug-induced neutropenia, and iso-immune neonatal neutropenia. Owing to the inherent difficulties of manipulating granulocytes in vitro, many of the serological techniques described for the detection of antigranulocyte antibodies are complex and sometimes difficult to reproduce. We describe the detection of alloreactive granulocyte antibodies using flow cytometric analysis of donor leucocyte suspensions in an indirect immunofluorescent test. The technique provides a semiquantitative detection of granulocyte antibodies in two groups of patients studied and, by providing as a comparison the reactivity on the corresponding mononuclear leucocytes, allows the distinction between granulocyte-specific antibodies and antibodies directed against the histocompatibility antigens.

Disappearance of HLA and platelet-specific antibodies in acute leukaemia patients alloimmunized by multiple transfusions.

Alloimmunization by platelet transfusions was studied in 154 patients with acute leukaemia. 17 patients had HLA antibodies at initial presentation induced by previous transfusions or pregnancies; one of these also had platelet-specific antibodies and one other patient had platelet-specific antibodies alone. A further 38 patients developed HLA antibodies during therapy; three also had platelet-specific antibodies and two patients developed platelet-specific antibodies alone. Of these, 37 patients with HLA antibodies including three with platelet-specific antibodies and one patient with platelet-specific antibodies alone survived their initial therapy and formed the basis of this study. Antibodies once detected persisted throughout the study in seven of the 37 patients with HLA antibodies including one patient with platelet-specific antibodies and in the patient with platelet-specific antibodies alone. HLA antibodies disappeared after discontinuation of transfusions in six patients, and after switching to HLA matched platelet transfusions and leucocyte-poor blood in eight patients; two of the latter patients also had platelet-specific antibodies which disappeared. The other 16 patients with HLA antibodies lost their antibodies despite continued transfusions.

Post-transfusion purpura associated with anti-Baka and anti-PIA2 platelet antibodies and delayed haemolytic transfusion reaction.

The occurrence of post-transfusion purpura (PTP) in a 16-year-old girl with sickle/beta-thalassaemia is described. Clinically this was a typical case of PTP, but it was unusual serologically. Anti-Baka and anti-PIA2 platelet-specific antibodies were identified and the patient's platelets were typed as homozygous PIA1-positive and Baka-negative. The patient also developed red-cell, granulocyte and lymphocytotoxic antibodies in response to the blood transfusion and had a delayed haemolytic transfusion reaction.

Use of leucocyte-poor blood components and HLA-matched-platelet donors to prevent HLA alloimmunization.

Recent studies have shown that the incidence of alloimmunization due to repeated platelet transfusions from random donors may be reduced by the use of leucocyte-poor blood components. These results were confirmed by this study, where 16% of patients with acute leukaemia undergoing initial chemotherapy and receiving leucocyte-poor blood components developed lymphocytotoxic antibodies, compared with 48% of patients in a control group receiving standard (non-leucocyte-depleted) blood components. In a third group, who received leucocyte-poor blood components and HLA-matched platelets, none of the patients developed lymphocytotoxic antibodies. There was a low incidence of platelet-specific antibodies (8%) but no difference between the three groups. Improved methods of removing leucocytes from blood components appear to offer the best approach for minimizing HLA alloimmunization, as the provision of HLA-matched platelet donors for prophylactic platelet support of all patients is not feasible.

The role of lysosomes and microtubules in cardiac protein degradation.

The mechanisms and regulatory factors involved in cardiac proteolysis are incompletely understood. Agents that interfere with lysosomal function (e.g., chloroquine, leupeptin, methyladenine) cause a 25-30% reduction in the overall rate of protein degradation. In the same hearts, however, the rate of myosin breakdown remains unchanged. Disaggregation of micro-tubules with colchicine is accompanied by a 15% reduction in the rate of degradation of total protein and of myosin. In the same hearts, the degradation of "organellar" protein, including mitochondrial cytochromes, is reduced by over 30%. Thus, it appears that the degradation of different classes of cardiac proteins may be accomplished and regulated by different processes. Lysosomes are important in overall proteolysis, but appear not to be involved in the regulation of myosin breakdown. Microtubules are also involved in the proteolytic process, and appear to be especially important for the breakdown of proteins from mitochondria and perhaps other organelles.

Forecasting epidemic pathways for measles in Iceland: the use of simultaneous equation and logit models.

Six measles transmission chains between pairs and triplets of medical districts in Iceland are identified using monthly data for the 26 years from 1945 to 1970. The years studied are divided into two halves, a calibration period (1945-1957) and a forecast period (1958-1970). Some simultaneous equation models of the chains are developed and fitted using three-stage least squares. The resulting one month ahead forecasts are presented in terms of the expected case levels and as the probability of epidemics occurring. A single equation probability model using a logistic transformation is then formulated and compared with the simultaneous equation approach. The results obtained from the Icelandic study confirm in practice the advantages theoretically expected from setting up forecasting models containing geographically based chain transmission components.