Prevalence and mutational determinants of high tumor mutation burden in breast cancer.

BACKGROUND: High tumor mutation burden (TMB) can benefit immunotherapy for multiple tumor types, but the prevalence of hypermutated breast cancer is not well described. The aim of this study was to evaluate the frequency, mutational patterns, and genomic profile of hypermutated breast cancer. PATIENTS AND METHODS: We used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients' samples that underwent whole exome sequencing or gene panel sequencing. The samples were classified as having high TMB if they had ≥10 mutations per megabase (mut/Mb). An additional eight patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among the patients with high TMB, the mutational patterns and genomic profiles were determined. A subset of patients was treated with regimens containing PD-1 inhibitors. RESULTS: The median TMB was 2.63 mut/Mb. The median TMB significantly varied according to the tumor subtype (HR-/HER2- >HER2+ >HR+/HER2-, P < 0.05) and sample type (metastatic > primary, P = 2.2 × 10-16). Hypermutated tumors were found in 198 patients (5%), with enrichment in metastatic versus primary tumors (8.4% versus 2.9%, P = 6.5 × 10-14). APOBEC activity (59.2%), followed by mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumors. Three patients with hypermutated breast cancer-including two with a dominant APOBEC activity signature and one with a dominant MMRd signature-treated with pembrolizumab-based therapies derived an objective and durable response to therapy. CONCLUSION: Hypermutation occurs in 5% of all breast cancers with enrichment in metastatic tumors. Different mutational signatures are present in this population with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.

Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer.

BACKGROUND: Little is known about mechanisms of resistance to poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy in patients with metastatic breast cancer and BRCA1/2 mutations. Further investigation of resistance in clinical cohorts may point to strategies to prevent or overcome treatment failure. PATIENTS AND METHODS: We obtained tumor biopsies from metastatic breast cancer patients with BRCA1/2 deficiency before and after acquired resistance to PARPi or platinum chemotherapy. Whole exome sequencing was carried out on each tumor, germline DNA, and circulating tumor DNA. Tumors underwent RNA sequencing, and immunohistochemical staining for RAD51 foci on tumor sections was carried out for functional assessment of intact homologous recombination (HR). RESULTS: Pre- and post-resistance tumor samples were sequenced from eight patients (four with BRCA1 and four with BRCA2 mutation; four treated with PARPi and four with platinum). Following disease progression on DNA-damaging therapy, four patients (50%) acquired at least one somatic reversion alteration likely to result in functional BRCA1/2 protein detected by tumor or circulating tumor DNA sequencing. Two patients with germline BRCA1 deficiency acquired genomic alterations anticipated to restore HR through increased DNA end resection: loss of TP53BP1 in one patient and amplification of MRE11A in another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of HR. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy. CONCLUSIONS: Genomic reversion in BRCA1/2 was the most commonly observed mechanism of resistance, occurring in four of eight patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker.

Pseudo-anticipation in Creutzfeldt-Jakob disease is due to a rhomboid-shaped artifact.

BACKGROUND AND PURPOSE: Previous studies have reported conflicting results regarding possible anticipation in familial E200K Creutzfeldt-Jakob disease (fCJD). Our objective was to use a large database to assess the age of disease onset (AODO) in CJD. METHODS: The study population included 477 CJD patients [266 with fCJD, 145 with sporadic CJD (sCJD) and 66 patients of Libyan origin but negative family history] from the Israeli registry of CJD conducted since 1954. In all patients, AODO in relatives and family trees was documented. Comparison of AODO was done using a paired t test and regression using Pearson correlation for birth and year of onset. RESULTS: The initial analysis in 52/73 families in which more than one generation was affected revealed an AODO of 63.30 ± 9.44 in the first generation compared to 56.96 ± 8.99 in the second generation (P < 0.001). However, inspection of individual AODO values plotted by year of birth showed a clear rhomboid methodological artifact generated by missing data of many young onset CJD patients who died before the database began to function in 1954 and of many late onset CJD patients missing at the present time since they will only develop the disease in the future. The 'generation' effect completely disappears if analysis is performed by year of disease onset or for the periods in which complete data are available. CONCLUSIONS: In this very large dataset, true anticipation in fCJD patients was not detected. It is plausible that previous reports supporting the presence of anticipation are biased by a rhomboid-shaped data availability artifact.

Improving techniques for diagnostics of laser pulses by compact representations.

We propose and demonstrate, numerically and experimentally, use of sparsity as prior information for extending the capabilities and performance of techniques and devices for laser pulse diagnostics. We apply the concept of sparsity in three different applications. First, we improve a photodiode-oscilloscope system's resolution for measuring the intensity structure of laser pulses. Second, we demonstrate the intensity profile reconstruction of ultrashort laser pulses from intensity autocorrelation measurements. Finally, we use a sparse representation of pulses (amplitudes and phases) to retrieve measured pulses from incomplete spectrograms of cross-correlation frequency-resolved optical gating traces.

Anatomic variations of the paranasal sinuses in the general pediatric population.

BACKGROUND: The prevalence of sinuses' anatomic variations in the healthy pediatric population has not been studied. The study describes the prevalence of known anatomic variations with regard to gender and age in this population. METHODS: A single academic institute observational cohort study. A total of 200 head CT scans were reviewed, subdivided into five equal age subgroups (0-4.99; 5-7.99; 8-10.99; 11-13.99; 14-17 years), with an equal male to female ratio. Different subgroups were randomly assigned to two senior residents (100 CTs each). A senior rhinologist and radiologist were randomly selected to review 100 CTs each. Consensus was reached after a joint review. Each CT was evaluated for the presence of sinuses and the following variations: deviated septum, frontoethmoidal, infraorbital, posterior-ethmoid cells (Kuhn, Haller, and Onodi cells, respectively) and concha bullosa. Definitions were made according to the European Position on Rhinosinusitis 2012. RESULTS: Gender did not affect sinus development or anatomical variations. The frontal and sphenoid sinuses were significantly less developed in the 0-4.99 years group. The point prevalence of concha bullosa and deviated septum significantly increased with age. The point prevalence of Haller cells demonstrated borderline significance among age groups, with children 0-4.99 demonstrating the lowest point prevalence. A significant association was found between the existence of Haller cells to Kuhn and Onodi cells. CONCLUSIONS: Anatomical variations should be expected in the pediatric population. Familiarity with their point prevalence and associations may assist pediatric endoscopic sinus surgery planning.

Coherent quantum phase slip.

A hundred years after the discovery of superconductivity, one fundamental prediction of the theory, coherent quantum phase slip (CQPS), has not been observed. CQPS is a phenomenon exactly dual to the Josephson effect; whereas the latter is a coherent transfer of charges between superconducting leads, the former is a coherent transfer of vortices or fluxes across a superconducting wire. In contrast to previously reported observations of incoherent phase slip, CQPS has been only a subject of theoretical study. Its experimental demonstration is made difficult by quasiparticle dissipation due to gapless excitations in nanowires or in vortex cores. This difficulty might be overcome by using certain strongly disordered superconductors near the superconductor-insulator transition. Here we report direct observation of CQPS in a narrow segment of a superconducting loop made of strongly disordered indium oxide; the effect is made manifest through the superposition of quantum states with different numbers of flux quanta. As with the Josephson effect, our observation should lead to new applications in superconducting electronics and quantum metrology.

Intravenous opioid drug abuse as an independent risk factor for supraglottic squamous cell carcinoma-A case-control study.

OBJECTIVES: Intravenous opioid drug abuse (IVDA) was previously correlated with laryngeal cancer. However, discrimination of this correlation by anatomical subsites has not yet been described. In this study, we aim to further establish the association between IVDA and laryngeal squamous cell carcinoma (SCC) and to indicate the laryngeal subsites that are predisposed for this correlation. DESIGN: A retrospective matched case-control study. SETTING AND PARTICIPANTS: Patients diagnosed with supraglottic SCC (SG-SCC) between 1996 and 2016 treated in a tertiary academic referral centre were enrolled to the case group. The control group comprised of matched patients diagnosed with glottis SCC (G-SCC). Matching was based on gender, age and socio-economic rank. MAIN OUTCOME MEASURES: Variables studies as risk factors included the following: smoking, alcohol consumption, history of IVDA and infectious diseases. The variables were tested for association with the 2 groups and with each other. RESULTS: Forty-eight patients with SG-SCC were matched with 48 patients with G-SCC. IVDA rates significantly increased among patients with SG-SCC. Of the SG-SCC group, 18.8% had a positive history for IVDA compared with 2.1% of the G-SCC (P = .008). A history of IVDA was found to be a risk factor for SG-SCC, independent of smoking, excessive alcohol and socio-economic status. The odds ratio for patients with an IVDA history to have SG-SCC relatively to G-SCC was 10.846 (95% CI: 1.3-89.4). CONCLUSIONS: Intravenous opioid drug abuse represents an independent risk factor for SG-SCC. The pathogenesis should be investigated not just as a risk factor, as opioids are commonly used for pain management in oncologic patients.

Surgeon-performed thyroid ultrasound-proving utility and credibility in selecting patients for fine needle aspiration according to the American thyroid association guidelines. A retrospective study of 500 patients.

DESIGN: Case series with chart review. SETTING: Single academic centre. PARTICIPANTS: The data of all patients who underwent surgeon-performed ultrasound (SUS) between 7/2009 and 9/2012 were retrospectively reviewed. MAIN OUTCOME MEASURES: A correlation between sonographic features and a non-benign cytology\malignant pathology. RESULTS: Four hundred ninety-eight nodules were included. Solid texture, irregular margins, hypo-echogenicity and intranodular vascularity were significantly associated with malignancy when benign to non-benign cytology was compared, and when compared to malignant pathology. Lack of suspicious features was significantly associated with benign lesions, with a negative predictive value of 94%. Except for taller than wider shape, malignancy odds ratio was significantly higher for known suspicious features, reaching 4.81 for irregular borders (CI 2.42-9.55, P < .001). CONCLUSIONS: SUS has proven to be a reliable and consistent tool to assess the thyroid nodule risk stratification. Surgeons should recognise the potential of this tool and its implementation.

A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples.

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Temperature changes of one-piece implants during the setting of acrylic resin temporary crown. The effect of implant diameter. An in vitro study.

The purpose of this work is to evaluate changes in temperature of one-piece titanium implant surface during the setting of acrylic resin temporary crowns and to correlate thermal changes to implant diameter. Thirty-three one-piece implants (ARRP, Alpha-Biotec) were divided into 3 groups according to diameter size (G1=3 mm, G2=3.3 mm, G3=3.6 mm). Implants were mounted on an acrylic glass apparatus. Thermocouples were positioned at the most coronal thread. Lower incisor temporary polycarbonate crowns were filled with 80 µL of self-curing acrylic resin and positioned immediately on the implant abutment. Thermal changes of the implant surface were recorded continuously for 10 min. Data were statistically analyzed using one-way analysis of variance. The mean initial temperature (C0) of groups G1, G2 and G3 was similar (24.79±0.78ºC, 25.26±0.63ºC, 24.97±1.06ºC, respectively). The setting of the acrylic resin temporary crown resulted in a significant increase in the implant surface temperature of all groups. The mean thermal amplitude (ΔC) for groups G1, G2 and G3 were 6.79±1.02ºC, 6.61±0.94ºC, 6.65±1.26ºC, respectively. The mean time to maximum temperature (Tmax) for groups G1, G2 and G3 were 337.38±42.91 sec, 324.69±41.46 sec and 317.98±37.91 sec respectively (P>0.05). Direct application of auto-polymerizing resin to the titanium abutment of one-piece implants significantly increased the cervical implant surface temperature. Implant diameter did not influence the temperature changes.

Should high BMI be a reason for IVF treatment denial?

Our aim was to examine the influence of BMI on the live-birth rate following IVF/ICSI and evaluate its specific contribution among other factors thus enabling accurate reproductive policy development. All patients that underwent IVF/ICSI at our center during January 2012-July 2015 were included in this retrospective study. A total of 1654 ICSI cycles were divided into four groups according to the patient's BMI (kg/m2): group I (normal weight): <25 (943 cycles); group II (overweight): 25-30 (403 cycles); group III (obese): 30-35 (212 cycles); group IV (morbid obesity): >35 (96 cycles). Comparing the four groups of BMI, mean age and number of previous ART cycles was significantly lower in group I compared to groups II, III and IV. Length of treatment was significantly shorter in group I compared to groups II, III and IV. Ovarian response to COH was comparable in terms of mean estradiol and progesterone levels on the day of hCG administration mean number of oocytes retrieved, fertilized and number of embryos transferred. Endometrial thickness was significantly lower in group IV. Outcome measures, such as implantation rate, clinical pregnancy rate (CPR) per cycle and per ET, as well as live-birth rates did not differ significantly between the groups, although in group IV LBR per cycle and per ET was lower. Multivariate logistic regression stepwise analysis found a significant correlation between age and BMI but did not find correlation between BMI and clinical pregnancy (p = 0.436) or LB (p = 0.206). The results of our relatively large retrospective study did not demonstrate a significant impact of BMI on the ART cycle outcome. Therefore, BMI should not be a basis for IVF treatment denial.

Religiosity: Its Impact on Coping Styles Among Women Undergoing Fertility Treatment.

The Israeli worldview places great significance on childbearing. This could create emotional and ethical difficulties for women coping with fertility issues in addition to their treatments. This study examined the relations between coping strategies and level of religiosity in 159 women undergoing infertility treatment. Statistically significant relations were found between the problem-solving coping style and religious observance (p < 0.01) and religious beliefs (p < 0.05). An inverse correlation was found between the emotional coping style and religious beliefs (p < 0.001). Health professionals should recognize the patient's coping styles and understand the patient's religious belief system as part of an ongoing fertility treatment.

Sustained efficacy of insulin pump therapy compared with multiple daily injections in type 2 diabetes: 12-month data from the OpT2mise randomized trial.

AIMS: To compare insulin pump therapy and multiple daily injections (MDI) in patients with type 2 diabetes receiving basal and prandial insulin analogues. METHODS: After a 2-month dose-optimization period, 331 patients with glycated haemoglobin (HbA1c) levels ≥8.0% and ≤12% were randomized to pump therapy or continued MDI for 6 months [randomization phase (RP)]. The MDI group was subsequently switched to pump therapy during a 6-month continuation phase (CP). The primary endpoint was the between-group difference in change in mean HbA1c from baseline to the end of the RP. RESULTS: The mean HbA1c at baseline was 9% in both groups. At the end of the RP, the reduction in HbA1c was significantly greater with pump therapy than with MDI (-1.1 ± 1.2% vs -0.4 ± 1.1%; p < 0.001). The pump therapy group maintained this improvement to 12 months while the MDI group, which was switched to pump therapy, showed a 0.8% reduction: the final HbA1c level was identical in both arms. In the RP, total daily insulin dose (TDD) was 20.4% lower with pump therapy than with MDI and remained stable in the CP. The MDI-pump group showed a 19% decline in TDD, such that by 12 months TDD was equivalent in both groups. There were no differences in weight gain or ketoacidosis between groups. In the CP, one patient in each group experienced severe hypoglycaemia. CONCLUSIONS: Pump therapy has a sustained durable effect on glycaemic control in uncontrolled type 2 diabetes.

Unusual presentations in patients with E200K familial Creutzfeldt-Jakob disease.

BACKGROUND AND PROPOSE: Familial Creutzfeldt-Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the PRNP gene. The typical presenting symptoms include cognitive decline, behavioral changes and gait disturbances; however, some patients may have an unusual presentation such as a stroke-like presentation, alien hand syndrome or visual disturbances. The aim of this paper is to describe uncommon presentations in our series of consecutive patients with E200K fCJD. METHODS: The study group included consecutive fCJD patients followed up as part of a longitudinal prospective study ongoing since 2003 or hospitalized since 2005. The clinical diagnosis of probable CJD was based on accepted diagnostic criteria and supported by typical magnetic resonance imaging, electroencephalographic findings, elevated cerebrospinal fluid tau protein levels and by genetic testing for the E200K mutation. Disease symptoms and signs were retrieved from the medical files. RESULTS: The study population included 77 patients (42 men) with a mean age of disease onset of 60.6 ± 7.2 years. The most prevalent presenting symptoms were cognitive decline followed by gait impairment and behavioral changes. However, six patients had an unusual presentation including auditory agnosia, monoparesis, stroke-like presentation, facial nerve palsy, pseudobulbar syndrome and alien hand syndrome. CONCLUSIONS: Our case series illustrates the wide phenotypic variability of the clinical presentation of patients with fCJD and widens the clinical spectrum of the disease. A high level of clinical suspicion may prove useful in obtaining early diagnosis and therefore avoiding costly and inefficient diagnostic and therapeutic strategies.

CSF tau correlates with CJD disease severity and cognitive decline.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is the most common prion disease in humans. The clinical diagnosis of CJD is supported by a combination of electroencephalogram, MRI, and the presence in the CSF of biomarkers. CSF tau is a marker for neuronal damage and tangle pathology, and is correlated with cognitive status in Alzheimer's disease (AD). OBJECTIVES: The aim of this study was to test whether tau levels in the CSF also correlate with the degree of the neurological deficit and cognitive decline in patients with CJD as reflected by various clinical scales that assess disease severity and cognitive performance. METHODS: Consecutive patients with familial CJD (fCJD) were examined by a neurologist who performed several tests including minimental status examination (MMSE), frontal assessment battery (FAB), NIH stroke scale (NIHSS), CJD neurological scale (CJD-NS), and the expanded disability status scale (EDSS). CSF tau was tested as part of the workout, and the correlation was tested using Pearson correlation. RESULTS: Fifty-two patients with fCJD were recruited to the study (35 males, mean age 59.4 ± 5.7, range 48-75 years). A significant negative correlation was found between CSF tau levels and the cognitive performance of the patients as reflected by their MMSE and FAB scores. In addition, a significant positive correlation was found between tau levels and the clinical disease severity scales of CJD-NS, NIHSS, and EDSS. CONCLUSION: The correlation between tau levels and the disease severity and degree of cognitive decline in patients with fCJD suggests that tau can be a biomarker reflecting the extent of neuronal damage.

Adaptability of structured forms for CSII initiation in patients with type 2 diabetes the Getting2Goal(SM) concept.

BACKGROUND: The goal is to assess the usability and satisfaction of implementing the Getting2Goal(SM) protocol by physicians transitioning patients with type 2 diabetes (T2DM) from multiple daily injections (MDI) to continuous subcutaneous insulin infusion (CSII). METHODS: T2DM patients from three diabetes clinics were switched from MDI to CSII. Physicians used the Getting2Goal type 2 pumping protocol to prescribe and manage insulin pump therapy for T2DM. Surveys were conducted in which the physicians rated their feedback related to acceptability of the Getting2Goal on a 5-point Likert scale. RESULTS: 17 patients with T2DM were switched from MDI to CSII treatment. Mean (±standard deviation) age was 61.2 ± 7.7 (46-77) years, weight was 91.4 ± 21 (66-147) kg, BMI was 31.9 ± 7.6, A1C was 9.2 ± 1.4 % (7.2-12.3) and TDD on MDI was 109.1 ± 53.1 units. Surveys completed by physicians indicated Getting2Goal type 2 pumping protocol to be more efficient, time saving, and structured compared to their current processes. In addition, the primarily prescribed TDD on pump was 98.1 ± 50.0 units and the TDD at first download was 81.4 ± 36.4 units, representing a 25.4 % reduction in TDD At first download. The percentage of all blood glucose readings below 70 mg/dL was also very low. CONCLUSIONS: The data indicate Getting2Goal materials as a standard approach that is simple and efficient to initiate pump therapy for T2DM. At the same time, it is safe and a useful tool for physicians that are starting to prescribe pump therapy for T2DM.

Routine use of continuous glucose monitoring in 10 501 people with diabetes mellitus.

AIMS: To analyse blood glucose control according to continuous glucose monitoring use in data from the CareLink database, and to identify factors associated with continuation of sensor use during sensor-augmented pump therapy. METHODS: The analysis used data from 10 501 people with Type 1 and 2 diabetes mellitus, of whom 7916 (61.7%) had used glucose sensors for ≥ 15 days during any 6-month period over a 2-year observation period. Data were analysed according to the extent of sensor use ( < 25%, 25-49%, 50-74% and ≥ 75% of the time). Time to discontinuation of sensor use was also analysed in new users of glucose sensors. RESULTS: Compared with patients in the lowest sensor usage group and non-users, the highest glucose sensor usage group had significantly (P < 0.0001) lower mean blood glucose and blood glucose sd, were more likely to achieve a mean blood glucose concentration < 8.6 mmol/l, (odds ratio 1.5, 95% CI 1.3-1.7; P < 0.0001), and had 50% fewer hypoglycaemic (blood glucose concentration < 2.8 mmol/l) episodes. Among new users, sensor use during the first month of therapy was an important predictor of subsequent discontinuation. Lack of full reimbursement was also significantly associated with early discontinuation, whereas measures of glycaemic control were predictive of discontinuation during long-term treatment. CONCLUSIONS: The use of continuous glucose monitoring was significantly associated with reductions in hypoglycaemia and improved metabolic control during insulin pump therapy. Sensor use during the first month was strongly associated with long-term adherence; patient education and training may be helpful in achieving this.

Androgen Receptor CAG Repeat Length in Relation to Phenotype Among Females with Nonclassical 21-Hydroxylase Deficiency.

Nonclassical 21-hydroxylase deficiency (NC21OHD) manifests with various degrees of post natal virilization. The length of CAG repeats of the androgen receptor gene (AR) is inversely correlated to activity of the human androgen receptor (AR) and affects phenotype of several androgen-dependent disorders. The aim of the study was to investigate the associations between CAG repeat length and the phenotype of females with NC21OHD. CAG repeat length and AR inactivation were assessed in females with NC21OHD, and related to their clinical presentation. CAG repeat length and AR inactivation were assessed in 119 females with NC21OHD. Biallelic mean (BAM) of the CAG repeat length and the weighted BAM (WBAM) were related to various clinical parameters. Age at diagnosis and age of menarche positively correlated with BAM (r=0.22, p=0.02, and r=0.23, p=0.01, respectively). A shorter (<25) BAM was associated with younger age at diagnosis (14.8 vs. 21.4 years, p<0.01), at adrenarche (8.1 vs. 10.2 years, p<0.01) and gonadarche (9.9 vs. 11.2 years, p<0.01), and higher corrected height standard deviation score at diagnosis (0.77 vs. 0.15, p=0.01). Precocious pubarche and precocious puberty were more frequent in these with the shorter BAM. Results of WBAM were similar. The CAG repeat length of the AR gene contributes to the clinical diversity of the phenotype in females with NC21OHD.

Seizures in E200K familial and sporadic Creutzfeldt-Jakob disease.

BACKGROUND: Although seizures (other than myoclonus) are frequently reported in Creutzfeldt-Jakob disease (CJD), their frequency, clinical manifestations, and effect on the disease course is unknown. OBJECTIVES: To characterize the frequency of seizures in E200K familial and sporadic CJD, to describe its semiology, EEG and MRI findings. METHODS: In this retrospective study, we reviewed all patients with CJD who were seen in the Sheba Medical Center between the years 2003-2012 and underwent clinical evaluation, genetic testing, EEG and MRI studies. The diagnosis of seizures was carried out based on documentation of episodes consistent with seizures or episode of unresponsiveness correlated with ictal activity in EEG. RESULTS: Sixty-four probable patients with CJD were included in the study, 57 (89%) with E200K familial (fCJD) and 7 (11%) with sporadic (sCJD). Seizures occurred in 8 patients: 3 of 7 (43%) in patients with sCJD compared to 5/57 (9%) in patients with E200K fCJD (P = 0.04, chi-square test). Two of E200K fCJD patients with seizures had other non-prion etiologies for seizures (brain metastasis, known history of temporal lobe epilepsy which started 44 years before the diagnosis of CJD). Seizures occurred late in the course of the disease with an average of 12 days between the onset of seizures and death. CONCLUSION: Seizures in E200K fCJD were infrequent and occurred late in the disease course. This difference suggests that E200K fCJD represents a separate subtype of the disease with distinct clinical characteristics.