The longitudinal structure of negative symptoms in treatment resistant schizophrenia.

BACKGROUND AND HYPOTHESIS: The negative symptoms of schizophrenia are strong prognostic factors but remain poorly understood and treated. Five negative symptom domains are frequently clustered into the motivation and pleasure (MAP) and emotional expression (EE) 'dimensions', but whether this structure remains stable and behaves as a single entity or not remains unclear. STUDY DESIGN: We examined a cohort of 153 patients taking clozapine for treatment-resistant schizophrenia in a regional mental health clinic. Patients were assessed longitudinally over a mean period of 45 months using validated scales for positive, negative and mood symptoms. Network analyses were performed to identify symptom 'communities' and their stability over time. The influence of common causes of secondary negative symptoms as well as centrality measures were also examined. STUDY RESULTS: Across patients at baseline, two distinct communities matching the clinical domains of MAP and EE were found. These communities remained highly stable and independent over time. The communities remained stabled when considering psychosis, depression, and sedation severity, and these causes of secondary negative symptoms were clustered into the MAP community. Centrality measures also remained stable over time, with similar centrality measures across symptoms. CONCLUSIONS: Our results suggest that MAP and EE are independent dimensions that remain highly stable over time in chronic schizophrenia patients treated with clozapine. Common causes of secondary negative symptoms mapped onto the MAP dimension. Our results emphasise the need for clinical trials to address either MAP or EE, and that treating causes of secondary negative symptoms may improve MAP.

Mechanical failure of distal femur mega prosthesis due to polyaryl-ether-ether-ketone (PEEK) hinge component.

BACKGROUND: Polyaryl-ether-ether-ketone (PEEK) has gained popularity as a substrate for orthopaedic hardware due to its desirable properties such as heat and deformation resistance, low weight, and ease of manufacturing. However, we observed a relatively high failure rate of PEEK-based hinges in a distal femur reconstruction system. In this study, we aimed to evaluate the proportion of patients who experienced implant failure, analyse the mechanism of failure, and document the associated clinical findings. METHODS: We conducted a retrospective cohort study, reviewing the medical charts of 56 patients who underwent distal femur resection and reconstruction with a PEEK Optima hinge-based prosthesis between 2004 and 2018. Concurrently, we performed a clinical and biomechanical failure analysis. RESULTS: PEEK component failure occurred in 21 out of 56 patients (37.5%), with a mean time to failure of 63.2 months (range: 13-144 months, SD: 37.9). The survival distributions of PEEK hinges for males and females were significantly different (chi-square test, p-value = 0.005). Patient weight was also significantly associated with the hazard of failure (Wald's test statistic, p-value = 0.031). DISCUSSION: Our findings suggest that PEEK hinge failure in a distal femur reconstruction system is correlated with patient weight and male gender. Retrieval analysis revealed that failure was related to fretting and microscopic fractures due to cyclic loading, leading to instability and mechanical failure of the PEEK component in full extension. Further assessment of PEEK-based weight bearing articulating components against metal is warranted.

The COVID-19 pfizer BioNTech mRNA vaccine and the frequency of seizures.

OBJECTIVE: A nationwide vaccination operation against Coronavirus disease 2019 (COVID-19) using the BNT162b2 mRNA vaccine commenced in Israel in December 2020. People older than 60 were prioritized, and most were vaccinated shortly after. Seizures are not infrequently attributed to the vaccine despite a lack of supporting evidence. People with epilepsy (PWE) are often reluctant to get the vaccine due to concerns of seizure aggravation. We aim to examine the effect of the vaccine effort on the frequency of both new-onset seizures and recurrent seizures in PWE. METHODS: All adults who presented to the emergency department (ED) of Tel Aviv Sourasky Medical Center between January 1st and May 31st, 2017-2021, and were diagnosed with seizures were included. Demographic, clinical, and vaccination status parameters were collected using MDClone, a data acquisition tool. Vaccination rates in the general population were obtained from official governmental publications. Statistics included a sub-analysis of patients with the highest vaccination rate, people older than 60. RESULTS: 1675 cases were included. The numbers of ED visits and hospital admissions due to seizures in 2021 were comparable to preceding years after adjusting for the total number of ED visits at the same time. Out of 339 cases in 2021, 134 patients older than 60 years old presented to the ED (39.5%) compared to 124-151 in 2017-2019 (37-44%) and 103 in 2020 (33%). The vaccination rate among patients hospitalized due to seizures was similar to the general population of the same age group during the same period in Israel. There was no temporal relation between vaccination and hospitalization due to a seizure. SIGNIFICANCE: Despite very high vaccination rates in the general population in Israel and especially among people older than 60 years, no increase was observed in ED presentations due to seizures. No temporal relation was observed between vaccination and hospitalization due to a seizure. We conclude that the mass vaccination with the Pfizer BioNTech mRNA vaccine is not associated with increased seizure propensity.

α-methylacyl-CoA racemase (AMACR) expression in chordomas differentiates them from chondrosarcomas.

AIMS: Chordomas and chondrosarcomas are malignant mesenchymal tumours with overlapping morphological and immunohistochemical (IHC) characteristics. Our aim was to evaluate the IHC expression of α-methylacyl-CoA racemase (AMACR/P504S), ß-catenin and E-cadherin in chordomas relative to chondrosarcomas and assess the utility of these markers for differential diagnosis. METHODS: Archival sections of 18 chordomas, 19 chondrosarcomas and 10 mature cartilage samples were immunostained and scored for AMACR, ß-catenin and E-cadherin and the relative differential capacity of each marker was calculated. In addition, AMACR mRNA level was assessed in 5 chordomas by RT-PCR and evaluated by comparative CT method. RESULTS: AMACR and ß-catenin stained 88.9% and 94.1% of the chordomas respectively, 21.1% and 10.5% of the chondrosarcomas correspondingly and none of the mature cartilage samples. E-cadherin stained positively 82.4% of the chordomas, 36.8% of the chondrosarcomas and 42.9% of the mature cartilage cases. Both AMACR and ß-catenin showed statistically significant difference between chordomas and chondrosarcomas (p < 0.001 for both), unlike E-cadherin. AMACR was detected at the mRNA level. CONCLUSIONS: AMACR is expressed in most of the chordomas but only in a minority of chondrosarcomas. AMACR may serve as IHC marker of chordoma with differentiating ability comparable to that of ß-catenin.

Klotho expression in cervical cancer: differential expression in adenocarcinoma and squamous cell carcinoma.

AIMS: Klotho is a trans-membrane protein that serves as a tumour suppressor in a wide array of malignancies. Recent data suggest it as an epigenetically silenced tumour suppressor in cervical cancer. Yet, the expression pattern of klotho in cervical cancer has not been determined. We aimed to study the expression of klotho in squamous cell carcinomas (SQCC) and adenocarcinoma (ADC) of the cervix. METHODS: Klotho expression was analysed by immunohistochemistry in 44 SQCC samples, 38 ADC samples and the adjacent normal tissue. For each sample, percentage of positive stained cells, staining intensity and a combined staining score were recorded. Staining was validated by measuring klotho mRNA levels, using quantitative RT-PCR, in 18 of the samples. RESULTS: Klotho expression was high in all endocervical and exocervical normal tissues adjacent to tumour. No expression of klotho was noted in 7 out of 38 (18.4%) ADC samples and in 2 out of 44 (4.5%) SQCC samples. Staining intensity, number of positively stained cells and combined intensity score were all lower in tumours compared with normal adjacent tissues in ADC and SQCC. Klotho mRNA levels highly correlated with immunohistochemical (IHC) staining (p=0.008). CONCLUSIONS: We found reduced klotho expression in cervical carcinoma, especially in ADC, compared with normal adjacent tissue. Our results support the role of klotho as a potential tumour suppressor in cervical cancer. Further studies are required in order to establish the therapeutic role of klotho in cervical carcinoma and identify patients who may benefit from it.

Surgically treated ovarian endometriosis association with BRCA1 and BRCA2 mutations.

Endometriosis is associated with an increased risk of ovarian cancer. Few studies have also shown increased risk of breast cancer. BRCA1/2 mutations are linked to an increased risk of breast and ovarian cancers but their relation to endometriosis is unknown. The objective of this study was to examine the mutation rate of BRCA1/2 among women with surgically treated ovarian endometriosis. We collected 126 specimens from Jewish Ashkenazi women with endometriotic (76) and control non-endometriotic (50) ovarian cysts, reviewed the pathological diagnoses and extracted DNA from all samples. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), samples were examined for the founder germline mutations of BRCA1/2, most common among Ashkenazi Jews. The rate of mutations in each group was calculated and compared. BRCA1/2 mutation rate was 1/76 (1.3%) in the endometriotic cyst study group and 1/50 (2%) in the control non-endometriotic cysts, showing no statistically significant difference between the groups (p=0.84). BRCA1/2 mutation rate was similar to the previously reported rate among Jewish Ashkenazi women. BRCA1/2 mutation rates in patients with endometriotic ovarian cysts and with non-endometriotic ovarian cysts are similar. A larger cohort is required to completely exclude the possibility of an association between BRCA1/2 mutations and surgically treated endometriosis.

Sequence variants in SLC6A3, DRD2, and BDNF genes and time to levodopa-induced dyskinesias in Parkinson's disease.

Levodopa-induced dyskinesias (LID) present a common but elusive complication of levodopa therapy in Parkinson's disease (PD). In order to identify genetic factors associated with LID, 352 (213 males) levodopa-treated Israeli PD patients were genotyped for 34 polymorphisms within three candidate genes affecting dopaminergic activity and synaptic plasticity: dopamine transporter gene (DAT1 or SLC6A3) [14 single nucleotide polymorphisms (SNPs) and 40-bp variable number tandem repeat (VNTR)], DRD2 [11 SNPs and dinucleotide CA short tandem repeat (STR)], and BDNF (7 SNPs). A comparison of patients with and without LID was performed by applying a time-oriented approach, with survival analyses evaluating LID development hazard rate over time [Cox proportional hazards and accelerated failure time (AFT) lognormal models]. Overall, 192 (54.5 %) participants developed LID, with a mean latency of 5.0 (±4.5) years. After adjusting for gender, age at PD onset, duration of symptoms prior to levodopa exposure, and multiple testing correction, one SNP in SLC6A3 (with 81 % genotyping success) was significantly associated with LID latency: the C allele of the rs393795 extended the time to LID onset, time ratio = 4.96 (95 % CI, 2.3-10.9; p = 4.1 × 10(-5)). This finding should be validated in larger, ethnically diverse PD populations, and the biological mechanism should be explored.

Dyskinesias in patients with Parkinson's disease: effect of the leucine-rich repeat kinase 2 (LRRK2) G2019S mutation.

BACKGROUND: While Parkinson's disease (PD) phenotype in leucine-rich repeat kinase 2 gene (LRRK2)-associated and sporadic PD seems similar, there is paucity of data on the possible effect of mutations in LRRK2 on response to and complications of dopaminergic therapy. OBJECTIVE: To assess the impact of the LRRK2 Gly2019Ser (G2019S) carrier status on the time to the onset of levodopa-induced dyskinesias (LID). METHODS: Consecutive PD patients treated with levodopa were genotyped for the LRRK2 G2019S mutation. The relationship between mutation carrier status and the time to LID onset was explored after matching carriers to non-carriers for age at PD onset, gender, and time from PD diagnosis to levodopa initiation, using Kaplan-Meier curves and the Cox proportional hazards model, using LID onset as an end-point. RESULTS: Overall, 349 Israeli PD patients [222 Ashkenazi-Jewish (AJ), 60.5% males, mean age at diagnosis: 60.6 ± 13.2 years] participated in the study. Of these, 33 patients (9.5%, 30 AJ) carried the LRRK2 G2019S mutation. The prevalence of LID was non-significantly higher among carriers (22/33, 66.7%) than non-carriers (168/316, 53.2%, p = 0.15). The mean duration of therapy from levodopa initiation to the development of LID or last follow-up (in cases who were LID-free) was 5.1 ± 5.4 years for carriers and 4.4 ± 4.0 years in non-carriers (p = 0.47) and the survival curves in carriers and matched non-carriers were not significantly different (Cox proportional hazards test and log-rank test; p = 0.79). CONCLUSIONS: The LRRK2 G2019S mutation status has no discernable effect on the prevalence of LID or on LID latency in Israeli levodopa-treated PD patients.