A Long-Term Safety and Tolerability Study of TV-46000 for Subcutaneous Use in Patients with Schizophrenia: A Phase 3, Randomized, Double-Blinded Clinical Trial.

BACKGROUND: TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone that is approved by the United States Food and Drug Administration for the treatment of schizophrenia in adults. In the phase 3, randomized, double-blind RIsperidone Subcutaneous Extended-release (RISE) study, TV-46000 once monthly (q1m) and once every 2 months (q2m) significantly prolonged time to impending relapse compared with placebo [5.0-fold (q1m) and 2.7-fold (q2m)]. This phase 3, randomized, double-blind Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) study was designed to evaluate the long-term safety, tolerability, and exposure of TV-46000 in schizophrenia. METHODS: Patients who completed RISE without relapse (rollover) or who were newly recruited (de novo) were eligible for the SHINE study. Patients were initially stabilized on oral risperidone for 12 weeks (completed in RISE for rollover, or in SHINE for de novo). Patients in the de novo cohort and patients who received placebo in RISE were randomized 1:1 in SHINE to receive TV-46000 q1m or q2m for up to 56 weeks. Primary endpoint for SHINE was frequency of reported adverse events (AEs); event rates [ER; events per 100 patient-years (PYs)] were calculated for each AE by patients upon general questioning. RESULTS: Overall, 336 patients were randomized in SHINE [TV-46000 q1m, n = 174; TV-46000 q2m, n = 162; of these, de novo, n = 109 and rollover, n = 227 (n = 172 patients were treated and n = 55 received placebo)]. A total of 334 patients were evaluated for safety [q1m, n = 172 (PY = 97.8); q2m, n = 162 (PY = 104.5)]. Proportions of patients (ER) with ≥ 1 AE and ≥ 1 treatment-related AE were 37% (180.0) and 21% (84.9) for TV-46000 q1m and 46% (157.9) and 20% (70.8) for TV-46000 q2m, respectively. Frequent treatment-related AEs [≥ 3% of patients in either group; proportion of patients (ER)] were injection site pain [q1m, 5% (24.5); q2m, 4% (22.0)] and injection site nodule [q1m, 2% (9.2); q2m, 6% (12.4)]. The proportions of patients with serious AEs was 5% for TV-46000 q1m and 7% for TV-46000 q2m; serious AEs reported for ≥ 2 patients overall were worsening schizophrenia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 2 (1%; ER, 1.91)] and hyperglycemia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 1 (< 1%; ER, 0.96)]. Of three reported deaths, none were related to treatment. Overall, eight patients discontinued treatment because of AEs. Similar or somewhat lower rates of AEs were reported for patients who rolled over from TV-46000 treatment compared with those who had no prior TV-46000 treatment (de novo and placebo rollover). Most AEs related to injection site reactions were mild; no patient had a severe reaction. CONCLUSION: Results from this long-term safety study add to the favorable safety profiles of TV-46000 q1m and q2m, consistent with other formulations of risperidone and previous studies with TV-46000. REGISTRATION: ClinicalTrials.gov, NCT03893825; 27 March 2019.

The United States Food and Drug Administration approved TV-46000 in April 2023 for the treatment of schizophrenia in adults. TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) that uses technology that allows for the slow release of risperidone. TV-46000 is injected under the skin once monthly or once every 2 months. When people start taking TV-46000, they do not need an additional injection or oral risperidone. The Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) was a clinical study in which patients with schizophrenia received TV-46000. SHINE was conducted in patients who completed the RIsperidone Subcutaneous Extended-release (RISE) study and new patients. All patients (TV-46000 once monthly, n = 162; TV-46000 once every 2 months, n = 172) received TV-46000 in SHINE to see whether safety results were the same long term compared with RISE. The proportions with more than one adverse event were 37% for TV-46000 once monthly and 46% for TV-46000 once every 2 months. The proportions with more than one adverse event related to treatment were 21% for TV-46000 once monthly and 20% for TV-46000 once every 2 months. Common adverse events related to treatment were injection site pain and small swelling. Serious adverse events were rare. None of the three reported deaths were related to treatment. Similar or lower rates of adverse events were reported for those who received TV-46000 in RISE compared with those with no prior TV-46000 treatment. The long-term safety results in SHINE were consistent with other forms of risperidone and previous studies with TV-46000.

Alterations in plasma endocannabinoid concentrations among individuals with major depression treated with electroconvulsive therapy.

The role of the endocannabinoid system (ECS) in depression and suicidality has recently emerged. The purpose of the study was to identify changes in plasma endocannabinoid concentrations of several endocannabinoids and correlate them with depressive symptoms and suicidality in patients with severe major depression undergoing electroconvulsive therapy (ECT). The study included 17 patients that were evaluated in four visits at different stages of therapy. At each visit depression, anxiety and suicidality symptoms were assessed and blood samples collected. Several endocannabinoid concentrations increased following six sessions of ECT, as 2-AG (p < 0.05) and LEA (p < 0.01), and following twelve sessions of ECT, as 2-AG (p < 0.05), AEA (p < 0.05), LEA (p < 0.05) and DH-Gly (p < 0.05). Endocannabinoids also correlated with symptoms of depression, anxiety and suicidality at baseline and at the sixth ECT session. Finally, we found one endocannabinoid, l-Gly, that differentiated between remitted and not-remitted patients at the seventh and thirteenth ECT sessions (p < 0.05). Our findings suggest that depression is markedly related to imbalance of the endocannabinoid system, and further regulated by ECT. Plasma endocannabinoids could be promising biomarkers for detection of depression response and remission.

Efficacy and safety of TV-46000, a long-acting, subcutaneous, injectable formulation of risperidone, for schizophrenia: a randomised clinical trial in the USA and Bulgaria.

BACKGROUND: TV-46000 is a long-acting, subcutaneous, antipsychotic agent that combines risperidone and an innovative, copolymer-based drug delivery technology in a suspension that was approved in April, 2023 for subcutaneous use. The aim of the phase 3 Risperidone Subcutaneous Extended-release (RISE) study was to evaluate the efficacy of TV­46000 in schizophrenia. METHODS: The RISE study consisted of two treatment stages: a 12-week, open-label stabilisation phase with oral risperidone (stage 1), and an open-ended, randomised, double-blind, placebo-controlled, relapse-prevention phase with subcutaneous TV-46000 (stage 2) done at 69 clinical sites across the USA and Bulgaria. Patients diagnosed with schizophrenia more than 1 year before screening by DSM-5 criteria and confirmed at screening by the Structured Clinical Interview for DSM-5 and who had at least one relapse within 24 months before screening were eligible for enrolment. Patients who were outpatients and stabilised in stage 1 continued to stage 2 and were randomly assigned 1:1:1 by a computer-generated randomisation list to receive either subcutaneous TV-46000 once monthly, TV-46000 once every 2 months, or placebo until relapse, early discontinuation, or the study was stopped because the prespecified stopping criterion of at least 90 relapse events was met. The primary endpoint was time to impending relapse of the intention-to-treat patient population in stage 2. This study is registered with ClinicalTrials.gov, number NCT03503318, and is complete. FINDINGS: The study enrolled the first patient on June 1, 2018, and the last patient completed on Dec 3, 2020. 1267 patients were screened, 863 enrolled, and 544 (male, n=332 [61%], female, n=212 [39%]; mean [SD] age, 49·3 [10·98] years; Black or African American, n=322 [59%]; White, n=206 [38%]; Asian, n=7 [1%]; Native Hawaiian or other Pacific Islander, n=2 [<1%]; race not reported, n=3 [<1%]; other race, n=4 [<1%]; Hispanic or Latinx, n=117 [22%]) randomly assigned to subcutaneous TV-46000 once monthly (n=183), TV-46000 once every 2 months (n=180), or placebo (n=181). Time to impending relapse was significantly prolonged by 5·0 times with TV-46000 once monthly (hazard ratio, 0·200 [95% CI 0·109-0·367]; p<0·0001) and by 2·7 times with TV-46000 once every 2 months (0·375 [0·227-0·618]; p<0·0001) versus placebo. Most frequently reported treatment-related adverse events (ie, ≥5% of patients in either TV-46000 group) that occurred more often in patients receiving TV-46000 (once monthly or once every 2 months) versus placebo were injection site nodules (7% for TV-46000 once monthly, 7% for TV-46000 once every 2 months, 3% for placebo), weight increased (4%, 6%, 2%, respectively), and extrapyramidal disorder (5%, 3%, 0% respectively). Serious adverse events were reported for eight (4%) patients in the TV-46000 once-monthly group, ten (6%) patients in the TV-46000 once-every-2-months group, and 14 (8%) patients in the placebo group. The safety profile of TV-46000 was consistent with other approved formulations of risperidone. No new safety signals were identified. INTERPRETATION: In patients with schizophrenia, subcutaneous TV-46000 once monthly and once every 2 months significantly delayed impending relapse versus placebo. TV-46000 is an effective long-acting, subcutaneous, antipsychotic agent treatment option in adult patients with schizophrenia, with a favourable benefit-risk profile. FUNDING: Teva Branded Pharmaceutical Products R&D.

Super-resolution multi-reference alignment.

We study super-resolution multi-reference alignment, the problem of estimating a signal from many circularly shifted, down-sampled and noisy observations. We focus on the low SNR regime, and show that a signal in ℝ M is uniquely determined when the number L of samples per observation is of the order of the square root of the signal's length ( L = O ( M ) ). Phrased more informally, one can square the resolution. This result holds if the number of observations is proportional to 1/SNR3. In contrast, with fewer observations recovery is impossible even when the observations are not down-sampled (L = M). The analysis combines tools from statistical signal processing and invariant theory. We design an expectation-maximization algorithm and demonstrate that it can super-resolve the signal in challenging SNR regimes.

Centering Noisy Images with Application to Cryo-EM.

We target the problem of estimating the center of mass of objects in noisy two-dimensional images. We assume that the noise dominates the image, and thus many standard approaches are vulnerable to estimation errors, e.g., the direct computation of the center of mass and the geometric median which is a robust alternative to the center of mass. In this paper, we define a novel surrogate function to the center of mass. We present a mathematical and numerical analysis of our method and show that it outperforms existing methods for estimating the center of mass of an object in various realistic scenarios. As a case study, we apply our centering method to data from single-particle cryo-electron microscopy (cryo-EM), where the goal is to reconstruct the three-dimensional structure of macromolecules. We show how to apply our approach for a better translational alignment of molecule images picked from experimental data. In this way, we facilitate the succeeding steps of reconstruction and streamline the entire cryo-EM pipeline, saving computational time and supporting resolution enhancement.

An Algorithm for Improving Non-Local Means Operators via Low-Rank Approximation.

We present a method for improving a non-local means (NLM) operator by computing its low-rank approximation. The low-rank operator is constructed by applying a filter to the spectrum of the original NLM operator. This results in an operator, which is less sensitive to noise while preserving important properties of the original operator. The method is efficiently implemented based on Chebyshev polynomials and is demonstrated on the application of natural images denoising. For this application, we provide a comparison of our method with other denoising methods.

A Randomized Controlled Study to Determine the Efficacy of Garlic Compounds in Patients With Hematological Malignancies at Risk for Chemotherapy-Related Febrile Neutropenia.

BACKGROUND: Patients receiving chemotherapy for hematological malignancies are at high risk for febrile neutropenia (FN). Garlic extracts (GEs) are natural food substances showing antimicrobial effects in vivo. OBJECTIVES: We explored whether adding GE may be efficacious in reducing the risk or severity of infections. DESIGN: This was a placebo-controlled double-blind randomized study. RESULTS: Of 95 patients randomized to receive GE or placebo following chemotherapy, a febrile episode was documented in 50% of patients receiving GE and 63.3% receiving placebo (P = .89). There was a higher risk of developing a third and fourth febrile episode in the GE group (P = .01). However, among those at a lower risk for FN, those receiving GE developed fewer FN episodes (P = .075), especially those with severe neutropenia (P = .05). Major adverse events were distributed equally, but nonadherence was more common in the GE than in the placebo group: 19.5% versus 4%, respectively (P = .05). CONCLUSIONS: GE was safe and did not reduce FN risk in the entire cohort, but yet appeared to exert a protective effect in the lower-risk subgroup. We do not recommend the use of GE for FN prevention in higher-risk patients. A larger-scale clinical trial for the lower-risk subgroup of patients is advocated. (This trial was registered at www.clinicaltrials.gov as NCT00247039.).

The effect of prolonged physical activity performed during extreme caloric deprivation on cardiac function.

BACKGROUND: Endurance exercise may induce transient cardiac dysfunction. Data regarding the effect of caloric restriction on cardiac function is limited. We studied the effect of physical activity performed during extreme caloric deprivation on cardiac function. METHODS: Thirty-nine healthy male soldiers (mean age 20 ± 0.3 years) were studied during a field training exercise lasted 85-103 hours, with negligible food intake and unlimited water supply. Anthropometric measurements, echocardiographic examinations and blood and urine tests were performed before and after the training exercise. RESULTS: Baseline VO(2) max was 59 ± 5.5 ml/kg/min. Participants' mean weight reduction was 5.7 ± 0.9 kg. There was an increase in plasma urea (11.6 ± 2.6 to 15.8 ± 3.8 mmol/L, p<0.001) and urine osmolarity (692 ± 212 to 1094 ± 140 mmol/kg, p<0.001) and a decrease in sodium levels (140.5 ± 1.0 to 136.6 ± 2.1 mmol/L, p<0.001) at the end of the study. Significant alterations in diastolic parameters included a decrease in mitral E wave (93.6 to 83.5 cm/s; p = 0.003), without change in E/A and E/E' ratios, and an increase in iso-volumic relaxation time (73.9 to 82.9 ms, p = 0.006). There was no change in left or right ventricular systolic function, or pulmonary arterial pressure. Brain natriuretic peptide (BNP) levels were significantly reduced post-training (median 9 to 0 pg/ml, p<0.001). There was no elevation in Troponin T or CRP levels. On multivariate analysis, BNP reduction correlated with sodium levels and weight reduction (R = 0.8, p<0.001). CONCLUSIONS: Exposure to prolonged physical activity performed under caloric deprivation resulted in minor alterations of left ventricular diastolic function. BNP levels were significantly reduced due to negative water and sodium balance.

Obesity and blood pressure in 17-year-old offspring of mothers with gestational diabetes: insights from the Jerusalem Perinatal Study.

OBJECTIVE: Gestational diabetes mellitus (GDM) influences fetal development and offspring's metabolic risk. We evaluated this association in 17-year-old offspring adjusting for birth weight (BW) and prepregnancy maternal BMI (mBMI). STUDY DESIGN: The JPS birth cohort contains extensive data on 92,408 births from 1964 to 1976. Offspring's BMI and blood pressure (BP) were obtained from military records. For a subcohort born between 1974 and 1976, prepregnancy mBMI was available. Offspring were classified as born to mothers with GDM (n = 293) or born to mothers without recorded GDM (n = 59,499). RESULTS: GDM offspring had higher mean BMI and systolic and diastolic BP compared to no-recorded-GDM offspring. After adjusting for BW, GDM remained significantly associated with offspring BMI and diastolic BP (ß = 1.169 and 1.520, resp.). In the subcohort, when prepregnancy mBMI was entered to the models, it markedly attenuated the associations with GDM. CONCLUSIONS: Maternal characteristics have long-term effects on cardiometabolic outcomes of their offspring aged 17 years.

Bupropion for smoking cessation in patients with acute coronary syndrome.

BACKGROUND: Smokers hospitalized with acute coronary syndrome (ACS) are at high risk for subsequent ischemic events. Nevertheless, over two-thirds of patients continue to smoke after an acute myocardial infarction. Bupropion hydrochloride has proven efficacy as a smoking cessation aid, but data regarding its safety and efficacy in ACS patients are limited. METHODS: In a double-blind, randomized controlled trial, we compared the safety and efficacy of 8 weeks of treatment with bupropion slow-release (SR) or placebo for smokers hospitalized with ACS as an adjunct to nurse-led hospital- and telephone-based support. Primary efficacy outcome was smoking abstinence at 1 year. Primary safety outcome was clinical events at 1 year. RESULTS: A total of 151 patients were enrolled; all but 2 completed follow-up. Abstinence rates at 3 months were 45% and 44% in the bupropion SR and placebo groups, respectively (P = .99); 37% vs 42% (P = .61) at 6 months; and 31% vs 33% (P = .86) at 1 year. On multivariate analysis, an invasive procedure performed during index hospitalization was an independent predictor for smoking abstinence at 1 year (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.22-14.19). Presence of adverse effects attributed to treatment was a negative predictor for smoking cessation (OR, 0.23; 95% CI, 0.07-0.78). Treatment with bupropion SR was not associated with an increase in clinical events or change in blood pressure or body mass index, but dizziness was more common compared with placebo (14% vs 1.4%; P = .005). CONCLUSION: In hospitalized patients with ACS who received continuous, intensive nurse counseling about smoking cessation, bupropion did not increase the rates of smoking abstinence.

Increased risk for atherosclerosis of various macrophage scavenger receptor 1 alleles.

AIMS: Macrophage scavenger receptor 1 (MSR1) mediates the uptake of modified low density lipoprotein (LDL)-cholesterol. The significance of MSR1 in atherosclerosis development in animal models is uncertain. In this study we sought to determine the significance of MSR1 polymorphisms in its encoding gene in susceptibility to atherosclerosis. METHODS: We genotyped three polymorphic sites in the MSR1 gene including a 3-bp "TTA" insertion-deletion in intron 7 (rs3036811, Indel 7), an intron 5 SNP (rs33959637, IVS5-59), and a missense coding single nucleotide polymorphism (SNP) in exon 6 (rs3747531, P275A) in 136 nondiabetic Ashkenazi men under age 55 years (mean = 47.3 +/- 4.8 years) undergoing coronary angiography. Assessment of coronary disease was done by the number of segments with stenosis greater than 20% (coronary artery narrowing greater than 20% [CAGE > 20%]), greater than 50% (CAGE > 50%), and total number of diseased vessels. Linear regression modeling was used to define associations between atherosclerotic burden and MSR1 SNPs and haplotypes. RESULTS: Significant associations were noted between IVS5-59 and number of diseased vessels (p = 0.009) and CAGE > 20% (p = 0.017), which remained significant upon controlling for age, cholesterol level, hypertension, and smoking. CONCLUSION: This study demonstrates an association between MSR1 polymorphisms and atherosclerosis, suggesting that atherosclerotic risk associated with classic risk factors may be modified by MSR1 polymorphisms. These findings point to a significant role of MSR1 in atherosclerosis.

Estrogen receptor beta gene variant is associated with vascular dementia in elderly women.

OBJECTIVE: Alzheimer's disease (AD) and vascular dementia (VaD) are the main causes of dementia. Postmenopausal estrogen deficiency was suggested as a contributor to cognitive decline; however, replacement therapy failed to prove beneficial in its prevention or therapy. Sequence variants in the estrogen receptor alpha gene (ESR1) and beta gene (ESR2) may alter the effects of estrogen. METHODS: This is a case-control association study of sporadic AD, VaD, and single-nucleotide polymorphisms in ESR1 (rs2234693 and rs9340799), the TA dinucleotide repeat in the ESR1 promoter, and the rs4986938 single-nucleotide polymorphism in ESR2. Two hundred forty-six women (118 AD, age 83 +/- 7; 60 VaD, age 82 +/- 6; and 68 cognitively intact, age 81 +/- 7) residing in nursing homes were studied. The association of genotypes and AD or VaD was determined by logistic regression analysis adjusted for age and ethnic origin. RESULTS: An association of VaD and ESR2 rs4986938 was found. Carriers of each A allele had a 1.7 increased risk compared to carriers of the G allele (odds ratio 1.71, 95% confidence interval 1-2.95). The ApoE epsilon 4 allele was associated with AD (odds ratio 3.35, confidence interval 1.44-7.82), but not with VaD. No association of AD or VaD with ESR1 genotypes or haplotypes was detected. CONCLUSIONS: The ESR2 rs4986938 polymorphism is associated with susceptibility for VaD in elderly Jewish women. These results need to be confirmed in replicate studies in other populations.

Leptin, insulin, and obesity-related phenotypes: genetic influences on levels and longitudinal changes.

This study estimated the genetic and environmental determinants of plasma leptin and insulin levels and of obesity-related phenotypes. Included in this analysis were family members from 80 families living in kibbutz settlements, who participated in two examinations 8-10 years apart. We estimated that polygenes explained 30-50% of the adjusted leptin and insulin levels and 30-70% of the anthropometric phenotypes. This study demonstrated a significant genetic influence on longitudinal changes in leptin and BMI (h(2) = 0.45) and small-to-moderate heritability estimates for changes in insulin and other obesity-related phenotypes. In bivariate genetic analyses, we observed positive genetic correlations between leptin and anthropometric phenotypes, suggesting that shared effects of the same sets of loci account for 20-30% of the additive genetic variance in these pairs of variables. Shared genetic factors also account for 20-25% of the additive genetic variance in insulin-anthropometric pairs of variables.

Birth weight of offspring, maternal pre-pregnancy characteristics, and mortality of mothers: the Jerusalem perinatal study cohort.

PURPOSE: To explore the association between birth weight in offspring, a marker of the intrauterine environment, and mortality in their mothers, taking into account maternal pre-pregnancy characteristics, including maternal body mass index (BMI), smoking, and socioeconomic status. Distinguishing the effects of offspring's birth weight and pre-pregnancy characteristics on maternal outcome may provide clues regarding mechanisms underlying the association between birth weight and maternal mortality. METHODS: We studied long-term total mortality (average follow-up period, 29.1 years) in a population-based cohort of 13,185 mothers, aged 15 to 48 years at their offspring's birth, who delivered in West Jerusalem during 1974 through 1976. RESULTS: Univariate and multivariate Cox-proportional hazard models used to estimate the hazard of overall mortality among mothers indicated a nonlinear relationship with birth weight of offspring when introduced into the models as a continuous variable, and a linear positive association with maternal pre-pregnancy BMI. Inclusion of maternal BMI and other pre-pregnancy characteristics in the model did not alter the association between offspring's birth weight and mothers' all-cause mortality. When birth weight was introduced as a categorical variable, higher mortality was observed among mothers who gave birth to babies with birth weight less than 2500 g (hazard ratio [HR] = 1.90; 95% confidence interval [95%CI], 1.23-2.94) as compared to mothers whose offspring had birth weight between 3000 and 3499 g. The HR for mothers who gave birth to babies with birth weight 4000 g or more was 1.30 (95%CI, 0.88-1.91). CONCLUSIONS: Independent of pre-pregnancy maternal BMI and other characteristics, birth weight of offspring was associated with mortality in their mothers, suggesting that intrauterine metabolic events reflected by birth weight and not explained by maternal obesity, smoking, and socioeconomic status have remote consequences for maternal health. These findings underline the need to explore specific genetic and/or environmental mechanisms that account for these associations.

Effects of the single nucleotide polymorphism at MDM2 309 on breast cancer patients with/without BRCA1/2 mutations.

BACKGROUND: A germ line single nucleotide polymorphism (SNP) in the first intron of the gene encoding MDM2 at position 309, an important modulator of p53, has been described. BRCA1/2 mutation have been associated with increased rates of breast cancers with mutated P53. It was shown that the presence of MDM2 309 SNP correlated with younger cancer onset age in individuals with a p53 mutations. The differential effects of this SNP were also linked to estrogen receptor activation. Here we report on our study of 453 Ashkenazi breast cancer patients of whom 180 were positive for the known Ashkenazi BRCA1/2 mutations METHODS: DNA from breast cancer patients was obtained for analysis of one of the three common BRCA1/2 mutations and MDM2 SNP309. Data regarding cancer onset and death ages was obtained from our database and Statistical analysis was performed using the SPSS statistical package (SPCC Inc., Chicago, IL), and JMP software (SAS Institute, Cary, NC). RESULTS: The percentage of MDM2 SNP309 in control and BRCA 1/2 population which is similar to that reported for other Jewish Ashkenazi populations at 52.2% for the heterozygotes and 25.0% for MDM2SNP309G/G and 22.8% for MDM2SNP309T/T.There was not a statistical significant difference in median age of disease onset in the different MDM2 SNP309 subgroups of the BRCA1/2 carriers. When we further divided the group into under and above 51 years old ( presumed menopause age) in the BRCA1 positive subset we found that there were less patients of the MDM2SNP309 G/G versus the MDM2SNP309 T/T in the over 51 patient group (p = 0.049). This result has been obtained in a relatively small subgroup and is of borderline statistical significance. Interestingly, in the BRCA1/2 mutation carriers, we found a survival advantage for patients harboring the SNP309 G/G genotype (p = 0.0086) but not for the 272 patients not harbouring this mutations. CONCLUSION: MDM2SNP309G/G main effect on BRCA1/2 positive mutation carriers is linked to its effect on patients survival. Further research is needed in order to understand the reason for this difference.

Beginning IVF treatments after age 30 increases the risk of breast cancer: results of a case-control study.

The long-term risks of in vitro fertilization (IVF) treatment remain unclear. This study was designed to determine breast cancer risk factors in women who underwent IVF, and to establish characteristics of these tumors. Records of 7,162 consecutive women who underwent IVF at a single center between 1984 and 2002 were linked with the Israel Cancer Registry to identify women who developed breast cancer. IVF-related parameters were compared between 28 breast cancer patients who had undergone IVF (IVF BC) and for whom complete IVF data were available with 140 women who underwent IVF and did not develop breast cancer (IVF non-BC). Tumor parameters were compared between 38 patients who developed breast cancer after IVF and 114 age-matched breast cancer patients who did not undergo IVF (non-IVF BC). Age over 30 at the time of first IVF treatment, even after controlling for age at first birth, was the only parameter significantly associated with increased breast cancer risk (RR = 1.24, p = 0.02, 95% CI = 1.03-1.48). There were no differences between IVF-BC and IVF non-BC patients in all other IVF-related parameters. The only statistically significant difference in tumors developing in IVF-BC patients compared with non-IVF BC patients was in grade distribution, particularly for grade II tumors. However, the significance of such a difference is unclear. Women who start IVF after the age of 30 appear to be at increased risk of developing breast cancer. The characteristics of breast tumors in women who underwent IVF are no different than in patients without previous exposure to IVF.

Very high birth weight of offspring is associated with an increased risk of leukemia in their mothers: results of a population-based cohort study.

Although the association between birth weight and childhood leukemia is well described, the relation between a child's birth weight and parental risk of leukemia is unknown. We linked data from the Jerusalem Perinatal Study to the Israel Cancer Registry to ascertain the incidence of leukemia in mothers and fathers in relation to their offspring's birth weight. Birth weight >or=4500 g in any of the offspring was associated with a >3-fold risk of leukemia in mothers, but not fathers. Potential mechanisms include shared exposures of high birth weight infants and their mothers, possibly to radiation or growth factors, or genetic pathways leading to both high birth weight and leukemia.

Genetic polymorphisms of vitamin D receptor (VDR) in Fabry disease.

Fabry disease, an X-linked inborn error of metabolism, is characterized by multi-organ involvement including cardiac signs of left ventricular hypertrophy and abnormal intima-medial (IMT) thickening of arteries, progressive renal failure, neurological involvement, and more. The vitamin D receptor (VDR) and an enzyme producing vitamin D3 result in an autocrine loop with direct effects on blood vessels. The purpose of this study is to assess VDR polymorphisms (BsmI, FokI, ApaI, and TaqI) relative to clinically important disease parameters using a disease-specific severity score (MSSI) and haplotype analysis. There were statistically significant differences between females (43% of 74 patients) and males in MSSI total scores, and in general and neurologic sub-scores. There appears to be a protective effect of the TaqI tt genotype so that there were significantly lower scores in clinical categories between those with the tt genotype versus those with the TT genotype. Multivariate models of haplotypes with MSSI scores reveal that T-A-f-B and t-a-F-b haplotypes of the VDR gene polymorphisms are significantly associated with variation in the Fabry phenotype. Despite the limitations of using the MSSI score as a clinical correlate, these results are provocative and further studies in larger cohorts with more males are recommended.