When and where do patients with bone metastases actually break their femurs?

AIMS: Accurate estimations of the risk of fracture due to metastatic bone disease in the femur is essential in order to avoid both under-treatment and over-treatment of patients with an impending pathological fracture. The purpose of the current retrospective in vivo study was to use CT-based finite element analyses (CTFEA) to identify a clear quantitative differentiating factor between patients who are at imminent risk of fracturing their femur and those who are not, and to identify the exact location of maximal weakness where the fracture is most likely to occur. METHODS: Data were collected on 82 patients with femoral metastatic bone disease, 41 of whom did not undergo prophylactic fixation. A total of 15 had a pathological fracture within six months following the CT scan, and 26 were fracture-free during the five months following the scan. The Mirels score and strain fold ratio (SFR) based on CTFEA was computed for all patients. A SFR value of 1.48 was used as the threshold for a pathological fracture. The sensitivity, specificity, positive, and negative predicted values for Mirels score and SFR predictions were computed for nine patients who fractured and 24 who did not, as well as a comparison of areas under the receiver operating characteristic curves (AUC of the ROC curves). RESULTS: The sensitivity of SFR was 100% compared with 88% for the Mirels score, and the specificity of SFR was 67% compared with 38% for the Mirels score. The AUC was 0.905 for SFR compared with 0.578 for the Mirels score (p = 0.008). CONCLUSION: All the patients who sustained a pathological fracture of the femur had an SFR of > 1.48. CTFEA was far better at predicting the risk of fracture and its location accurately compared with the Mirels score. CTFEA is quick and automated and can be incorporated into the protocol of CT scanners. Cite this article: Bone Joint J 2020;102-B(5):638-645.

A class of multivariate distribution-free tests of independence based on graphs.

A class of distribution-free tests is proposed for the independence of two subsets of response coordinates. The tests are based on the pairwise distances across subjects within each subset of the response. A complete graph is induced by each subset of response coordinates, with the sample points as nodes and the pairwise distances as the edge weights. The proposed test statistic depends only on the rank order of edges in these complete graphs. The response vector may be of any dimensions. In particular, the number of samples may be smaller than the dimensions of the response. The test statistic is shown to have a normal limiting distribution with known expectation and variance under the null hypothesis of independence. The exact distribution free null distribution of the test statistic is given for a sample of size 14, and its Monte-Carlo approximation is considered for larger sample sizes. We demonstrate in simulations that this new class of tests has good power properties for very general alternatives.

Glucose homeostasis abnormalities assessed by an OGTT in coronary artery disease patients during admission and follow-up at ambulation.

BACKGROUND: Most non diabetic patients admitted with acute coronary syndrome (ACS) demonstrate an abnormality in glucose homeostasis. It was claimed that an oral glucose tolerance test (OGTT) undertaken during the admission is a good indicator of the patient's glycemic status. AIM: The aim of this study was to examine the reproducibility of OGTT based dysglycemic diagnosis during the acute admission and during an ambulatory visit in patients with ischemic heart disease (IHD). METHODS: We have repeated an OGTT on 29 patients with IHD who had been tested with OGTT during hospitalization for ACS. RESULTS: In 20 of the 29 (69%) patients the OGTT results improved on the repeated ambulatory test. This improvement was evident in the post-prandial glucose level yet not in the fasting levels. There were no significant differences in beta-cell function or in insulin sensitivity between the OGTTs as assessed by HOMA calculations. However there was tendency for improvement in insulin sensitivity at 2 h when assessed by the SI120 formula. CONCLUSIONS: In this pilot study we found that impaired post-prandial glucose control in patients with ACS improves when retested at ambulation. Therefore, it is probably better to perform the OGTT as an ambulatory test and not during the acute admission for defining abnormalities in glucose homeostasis of patients with ACS.

Prediction of nonSVR to therapy with pegylated interferon-alpha2a and ribavirin in chronic hepatitis C genotype 1 patients after 4, 8 and 12 weeks of treatment.

In patients with chronic hepatitis C genotype 1, the current algorithm for treatment discontinuation is based on no early virological response (<2 log decline in hepatitis C virus (HCV)-RNA) at 12 weeks. It is important to determine whether prediction of nonsustained virological response (NR) before 12 weeks can be robustly obtained by statistical methods. We used longitudinal discriminant analysis (LDA) to build and cross-validate models including baseline patient characteristics and measurements of serum HCV-RNA in the first 4, 8 or 12 weeks of treatment. The performance of each model was evaluated by the partial AUC (PA) index, exploring the accuracy of prediction in the range of high negative predictive values. Models were compared by computing 95% confidence intervals for the difference in PA indices. NR was best predicted before week 12 by a single HCV-RNA measurement at week 8 taken together with gender, BMI and age (W8 model, PA index = 0.857). This model was not inferior to models that included a measurement at week 12 (PA index = 0.831). The best model obtained with LDA within the first 4 weeks, which included measurements at days 4, 8 and at week 4, was found to be inferior to the week 8 model (PA index = 0.796). These results indicate that lack of sustained viral response is best predicted after 8 weeks of treatment and that waiting until 12 weeks does not improve the prediction.

Estimation of a secondary parameter in a group sequential clinical trial.

In this article, we investigate estimation of a secondary parameter in group sequential tests. We study the model in which the secondary parameter is the mean of the normal distribution in a subgroup of the subjects. The bias of the naive secondary parameter estimator is studied. It is shown that the sampling proportions of the subgroup have a crucial effect on the bias: As the sampling proportion of the subgroup at or just before the stopping time increases, the bias of the naive subgroup parameter estimator increases as well. An unbiased estimator for the subgroup parameter and an unbiased estimator for its variance are derived. Using simulations, we compare the mean squared error of the unbiased estimator to that of the naive estimator, and we show that the differences are negligible. As an example, the methods of estimation are applied to an actual group sequential clinical trial, The Beta-Blocker Heart Attack Trial.

An open trial of plant-source derived phosphatydilserine for treatment of age-related cognitive decline.

We assessed whether the efficacy of plant-source derived phosphatydilserine (one of the phospholipids which play an important functional role in membrane-related processes in the brain) for treatment of age related cognitive decline is consistent with previous (placebo controlled) positive findings with bovine derivative of PS (BC-PS). Eighteen healthy elderly volunteers meeting Age Associated Memory Impairment inclusion and exclusion criteria were treated for 12 weeks with plant-source derived phosphatydilserine (PS) (100 mg x 3/day p.o.) and evaluated at base line, after 6 weeks of treatment and at the end of the trial. Fifteen concluded the study. All but two outcome measures elicited a significant drug over time effect. Post-hoc paired t-tests showed that the significant effect was attributable to an improvement from base line to week 6 and that effect was maintained at week 12. These results are encouraging. However, they await double-blind controlled verification in a large sample before suggesting that this may be a viable approach to the treatment of age-related cognitive decline, without exposing the patients to possible hazards involved in the treatment with bovine derivative of PS (BC-PS).

5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: blunted temperature and hormone responses to ipsapirone challenge.

Serotonergic receptors of the 5-HT1A subtype have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, including specific serotonin reuptake inhibitors (SSRIs). We examined the effect of clinical doses of the SSRI, fluoxetine, on 5-HT1A receptor function in 15 normal volunteers. Hypothermic and hormone responses to the 5-HT1A receptor agonist, ipsapirone (0.3 mg per kg, per os) were examined after two weeks of placebo and again, after the subjects had been receiving fluoxetine for four weeks. On fluoxetine, the hypothermic response to ipsapirone was significantly blunted, as were ACTH, cortisol and growth hormone release. Ipsapirone plasma levels were significantly increased by fluoxetine but a pharmacokinetic effect could not have accounted for the observed blunting of 5-HT1A receptor mediated effects. These findings confirm and extend previous observations in rodents and humans and indicate that both post-synaptic 5-HT1A receptors in the hypothalamus, which mediate hormone responses to 5-HT1A agonists, and pre-synaptic 5-HT1A receptors which (putatively) mediate the hypothermic response, are rendered subsensitive by chronic SSRI administration. Since fluoxetine did not have significant effects on mood and other psychological variables in these subjects, alterations in 5-HT1A receptor function induced by SSRIs may have psychotropic relevance only in the context of existing perturbations of serotonergic function which underlie the psychopathological states in which these drugs are therapeutically effective.

Social adjustment and self-esteem in remitted patients with unipolar and bipolar affective disorder: a case-control study.

To evaluate social adjustment and self-esteem in patients with unipolar (UP) and bipolar (BP) affective disorder and to examine demographic and clinical correlates of these variables, outpatients with UP and BP disorder in remission for at least 12 months were consecutively recruited and individually matched to control subjects with no personal or family history of psychiatric illness (UP-control matched pairs, n = 23; BP-control matched pairs, n = 27). Subjects completed the Rosenberg Self-Esteem scale (SES) and the self-report version of the Social Adjustment Scale (SAS). UP patients reported significantly worse overall social adjustment than their matched controls (P = .009), specifically in the area of social and leisure activities (P = .0003) and poorer self-esteem (P = .02). When separated by gender, only the female UP group manifested significant findings on the SAS. BP patients reported poorer self-esteem than their controls (P = .04), but were not significantly different on the SAS. Although the patients were not clinically depressed, a worse social adjustment was significantly associated with a higher score on the Hamilton Depression Scale (HAM-D) in both groups. In the UP group, this association was absent when the analysis was limited to patients receiving antidepressant pharmacotherapy. The findings indicate that (1) UP patients, particularly women, experience substantial difficulties in social adjustment, primarily in social and leisure activities, even during stable clinical remission, and (2) in both UP and BP patients, adjustment problems are related to depressive symptoms even though these are minimal in severity.

Age-related changes in brain perfusion of normal subjects detected by 99mTc-HMPAO SPECT.

Previous functional imaging data generally show impairment in global cerebral blood flow (CBF) with age. Conflicting data, however, concerning age-related changes in regional CBF (rCBF) have been reported. We examined the relative rCBF in a sample of healthy subjects of various ages, to define and localize any age-related CBF reduction. Twenty-seven healthy subjects (17 male, 10 female; mean age 49 +/- 15, range 26-71, median 47 years) were studied by 99mTc-HMPAO brain SPECT. The younger age group consisted of subjects below, the older group above 47 years of age, respectively. Analysis was performed by applying three preformed templates, each containing delineated regions of interest (ROIs), to three transaxial brain slices at approximately 4, 6, and 7 cm above the orbitomeatal line (OML). The average number of counts for each ROI was normalized to mean uptake of the cerebellum and of the whole brain slice. Globally, 99mTc-HMPAO uptake ratio normalized to cerebellum was significantly decreased in older subjects, affecting both hemispheres. A slight left-to-right asymmetry was observed in HMPAO uptake of the whole study group. It did not, however, change with age. Regionally, both cortical and subcortical structures of older subjects were involved: uptake ratio to cerebellum was significantly lower (after correction for multiple testing) in the left basal ganglia and in the left superior temporal, right frontal and bilateral occipital cortices at 4 cm above the OML. At 6 cm above the OML, reduced uptake ratios were identified in the left frontal and bilateral parietal areas. At 7 cm, reduced uptake was detected in the right frontal and left occipital cortices. Most of these differences were reduced when uptake was normalized to whole slice, whereas an increase in uptake ratios was observed in the cingulate cortex of the elderly. An inverse correlation between age and HMPAO uptake ratios normalized to cerebellum was observed in a number of brain regions. These findings suggest that advancing age has a differential effect on cerebral perfusion reflected in brain 99mTc-HMPAO uptake.

Effect of clinical doses of fluoxetine on psychological variables in healthy volunteers.

OBJECTIVE: The authors sought to determine the effect of clinically equivalent doses of fluoxetine on mood and other psychological variables in normal subjects. METHOD: Fifteen healthy volunteers received placebo for 2 weeks; fluoxetine, 10 mg/day, for 1 week; fluoxetine, 20 mg/day, for 5 weeks; and then an additional 2 weeks of placebo in the context of a single-blind study. The subjects were evaluated with a series of self- and observer-rated instruments. RESULTS: No significant effects attributable to fluoxetine were observed on any of the psychological variables examined. Minimal adverse effects were reported. CONCLUSIONS: Significant mood-elevating and other psychological effects of fluoxetine would appear to be induced only when symptomatic targets exist.

Schizophrenia, chronic hospitalization and the 5-HT2C receptor gene.

Frequency of a polymorphism in the coding region of the 5-hydroxytryptamine2C (5-HT2C) receptor gene (HTR2C Xq24) was not significantly different in 122 unrelated Israeli schizophrenia patients compared with 180 control subjects matched for gender and ethnicity. However, proportion of time spent in hospital since the first admission was significantly greater in patients hemi- of homozygous for the 5-HT2Cser allele than in patients carrying other genotypes (p = 0.006). The 5-HT2Cser genotype conferred a 3.3-fold increased risk for lifetime hospitalization exceeding 10 years. Genetically determined variation in the 5-HT2C receptor may influence the clinical course and phenotypic expression of schizophrenia.

Cerebral hypoperfusion in medication resistant, depressed patients assessed by Tc99m HMPAO SPECT.

Functional imaging studies generally show decreased cerebral metabolism and perfusion in depressed patients relative to normal controls, although the location of the deficits varies. We used Tc99m HMPAO SPECT to compare cerebral blood flow in medication resistant, depressed patients and a normal control group. HMPAO uptake ratios (adjusted for age) were significantly lower in the depressed patients in the transaxial slices 4 cm and 6 cm above the orbitomeatal line (OML) on the left side. Examining individual regions of interest (corrected for age and multiple testing), we found significantly lower perfusion in the left superior temporal, right parietal and bilateral occipital regions in the patient group. These findings are in limited agreement with previous HMPAO SPECT studies. Methodological differences between studies, particularly variability in adjusting data for age, lead to a divergence in findings. Future research should seek to standardize protocols and data analysis in order to generate comparable results.

Increased cerebral blood flow in depressed patients responding to electroconvulsive therapy.

UNLABELLED: Considerable data support the existence of impaired regional cerebral blood flow (rCBF) in major depression. We compare rCBF in depressed patients before and after electroconvulsive therapy (ECT) to define whether the impairment is a "state"-related property or a trait phenomenon. METHODS: Twenty patients with a major depressive disorder were studied by 99mTc-HMPAO brain SPECT, 2-4 days before and 5-8 days after a course of ECT. Three transaxial brain slices delineating anatomically defined regions of interest at approximately 4, 6 and 7 cm above the orbitomeatal line were used, with the average number of counts for each region of interest normalized to the area of maximal cerebellar uptake. RESULTS: Technetium-99m-HMPAO uptake significantly increased in patients who responded to ECT but remained unchanged in patients who did not respond to the treatment (response defined as a reduction of at least 60% on the Hamilton Depression Rating Scale). An inverse correlation was observed between severity of depression and HMPAO uptake, and clinical improvement was positively correlated with the increase in tracer uptake. CONCLUSIONS: These findings imply that reduced rCBF in depression, as reflected in brain 99mTc-HMPAO uptake, is a "state"-related property and is reversible by successful treatment. Technetium-99m-HMPAO uptake may serve as an objective state marker for depression, an an indicator of the severity of depression and as an objective means of evaluating response to treatment.

Electroconvulsive therapy and resistant depression: clinical implications of seizure threshold.

BACKGROUND: Patients with major depressive disorder (MDD) were treated with electroconvulsive therapy (ECT) to determine (1) variability of initial seizure threshold, (2) factors that influence seizure threshold, (3) change in seizure threshold during the ECT course, and (4) relationship of seizure threshold to antidepressant effects. METHOD: Seizure threshold was measured by a stimulus titration technique during the first, eighth, and final ECT of medication-free patients who had MDD, endogenous subtype based on Research Diagnostic Criteria and were randomly assigned to three-times-weekly, bilateral, brief pulse ECT (N = 24) or twice-weekly ECT plus one simulated treatment per week (N = 23). Subsequent to the first ECT, stimulus intensity was 1.3 to 1.8 (median = 1.5) times threshold. The Hamilton Rating Scale for Depression (HAM-D) was the primary clinical outcome measure. RESULTS: Initial seizure threshold varied by 594%. Gender (p = .03), total strength of pre-ECT pharmacotherapy trials (p = .02), and age (p = .12) accounted for 23.9% of the variance. Threshold increased by 42% +/- 26% (p = .0001) from the first to the final ECT, and seizure duration decreased by 33% +/- 28% (p = .0001). Seizure duration and mean stimulus intensity were negatively associated over all treatments (r = -.49, p = .0003). Change in HAM-D score was related to duration of the current depressive episode (r = -.39, p = .006) and total strength of pre-ECT pharmacotherapy trials (r = -.39, p = .008), but not to seizure threshold or duration. CONCLUSION: (1) Initial seizure threshold for pulse bilateral ECT is highly variable and not yet amenable to accurate prediction. (2) Stimulus titration allows threshold to be determined on an individual basis and dosage for subsequent treatments to be defined. (3) Seizure duration is of limited value as a sole criterion for the adequacy of treatment when initial threshold is unknown and/or electrical doses that substantially exceed threshold are used. (4) With moderately suprathreshold bilateral ECT, a relationship of seizure threshold to antidepressant response is not demonstrable.

Interrelationship of age, depression, and central serotonergic function: evidence from fenfluramine challenge studies.

The purpose of this study was to examine the relationship between age-associated changes in central serotonergic function and abnormalities associated with major depression. Under randomized double-blind conditions, prolactin and cortisol responses to the serotonin-releasing agent d,l-fenfluramine hydrochloride (60 mg orally) and placebo were examined in 30 normal subjects (15 men, 15 women; age range 21-84 years) and 39 patients with major depressive disorder, endogenous subtype (14 men, 25 women; age range 29-72 years). In the normal subjects, a significant Age x Challenge x Time interaction was observed in the prolactin response (p = .03). This was primarily due to the elevated prolactin responses of the younger healthy women. Peak minus baseline (delta) prolactin responses were negatively correlated with age (women, p = .004; men, p = .06). In the depressed patients there was no age-related decline in prolactin response to fenfluramine. When depressed and healthy younger subjects were compared, delta prolactin responses to fenfluramine were significantly blunted in young patients with depression (p = .003) irrespective of the significant effect of gender (p = .01), but not in older depressed patients. Cortisol responses to fenfluramine did not reveal consistent effects of age, gender, or diagnosis. Age-related decline in central serotonergic function may make older individuals more vulnerable to depression and possibly render depressive episodes more frequent, more severe, and less amenable to treatment.

Complex effects of age and gender on hypothermic, adrenocorticotrophic hormone and cortisol responses to ipsapirone challenge in normal subjects.

The effects of a challenge dose of the 5-HT1A agonist, ipsapirone (0.3 mg per kg body weight), or placebo on body temperature and on adrenocorticotrophic hormone (ACTH) and cortisol release, were examined in 30 normal subjects (14 males, 19-74 years and 16 females, 22-69 years) using a randomized, double blind design. Irrespective of age or gender, ipsapirone induced a significant reduction in body temperature relative to placebo and a significant increase in ACTH and cortisol release. Maximal temperature reduction by ipsapirone was significantly blunted in older subjects and was inversely related to age. There was no gender difference in the hypothermic response to ipsapirone. ACTH and cortisol responses showed an opposite impact of aging in males and females. Whereas both responses diminished with age in male subjects, they increased with age in females. The cortisol response of older females was significantly larger than that of all the other subjects. Adverse effects of ipsapirone were also more marked in elderly females and were correlated with ACTH and cortisol responses. These findings should be taken into consideration in the use of ipsapirone and other 5-HT1A agonists as challenge procedures for studying central serotonergic function in depression and other disorders. Careful matching of control and experimental subjects is indicated so as to avoid spurious results which reflect the effects of age and gender rather than the pathophysiology of the disorders being investigated.

A prospective study of lithium continuation therapy in depressed patients who have responded to electroconvulsive therapy.

Twenty-eight of 34 patients with major depression who completed a course of electroconvulsive therapy (ECT) and were classified as responders were administered lithium carbonate (Li) continuation therapy in the context of an open, prospective study. Twenty-four patients were followed for 6 months or until relapse; four patients dropped out of follow-up while still in remission. The probability of completing 6 months without relapse (by survival analysis, including the patients who dropped out as censored observations) was 65%. The eight patients who relapsed into depression all did so within 13 weeks. They were characterized by a shorter duration of their index depressive episode, a greater likelihood of having suffered an additional depressive episode in the preceding 12 months, and failure of an adequate trial of antidepressant medication before the ECT course. Novel pharmacological strategies may be needed in the post-ECT continuation therapy of patients who have a prior history of relapse and are demonstrably resistant to antidepressant medication.

Onset and time course of antidepressant action: psychopharmacological implications of a controlled trial of electroconvulsive therapy.

Onset and time course of antidepressant effect were examined in 47 patients with major depressive disorder who had been randomly assigned to twice weekly bilateral, brief pulse electroconvulsive therapy plus one simulated treatment per week (ECTx2) or to a three times weekly schedule of administration (ECTx3). Rapid improvement was observed in the ECTx3 group in whom the number of real ECTs to 30% reduction on the Hamilton Depression Scale (HAM-D) was 3.2 +/- 1.90, administered over 7.3 +/- 4.43 days and to 60% reduction, 5.9 +/- 3.09 real ECTs over 13.7 +/- 7.21 days. Among the responders in both groups combined, 24.3 +/- 29.58% of the overall improvement in HAM-D was contributed by the first real ECT, 60.9 +/- 28.13% by the first four real ECTs and 91.6 +/- 25.82% by the first eight. Although 85.3% of the responders had reached 60% HAM-D improvement after eight ECTs, a clinically significant minority (14.7%) responded later in the course (ECT 9-12). However, response was predictable on the basis of symptomatic improvement (30% on the HAM-D) by the sixth real ECT. Thirty-three out of 34 responders would have been correctly identified by this criterion and only 2 out of 13 non-responders mis-identified (P < 0.000001). Once achieved, the antidepressant effect was stable, without continuation pharmacotherapy, until 1 week after the last treatment and on lithium carbonate (Li) or Li plus clomipramine for a further 3 weeks. These findings confirm the clinical impression that ECT is a rapidly effective treatment for major depression with a shorter latency than generally reported for antidepressant drugs.(ABSTRACT TRUNCATED AT 250 WORDS)