Slow release is a fundamental feature of long-acting injectable (LAI) antipsychotics. This property allows continuous drug exposure between dosing intervals. However, there can be a significant delay between giving the first LAI dose and achievement of efficacious plasma concentrations. This time period requires additional pharmacologic intervention. Until now, this delay was addressed with one of two strategies: 1) continuing with supplemental oral antipsychotic, or 2) giving more LAI up front (e.g. loading dose). A third strategy has now been developed to reduce the time needed for oral supplementation when starting the LAI aripiprazole lauroxil (AL) from 21days to 1day. A nano-crystalline milled dispersion of AL (ALNCD; brand name ARISTADA INITIO™) was formulated by reducing the AL particle diameter from micron-size particles to nanometer- sized particles. ALNCD has faster dissolution and a shorter half-life than AL and is designed to be used as a single injection along with a single oral aripiprazole dose of 30mg as a 1-day alternative to the 21days of oral aripiprazole supplementation. Here we provide an overview of the new 1-day initiation regimen for starting AL treatment, and demonstrate the relative contributions of each of its components.

A blinded, randomized, phase 1, pharmacokinetic (PK), and safety study compared the 1-day initiation regimen with the 21-day oral aripiprazole regimen. A combination of observed data, and population pharmacokinetic model–based simulations were used to plot plasma aripiprazole concentrations of single doses of ALNCD, 30mg oral aripiprazole, and AL, individually, and all three combined.

The PK profiles of the 1-day and 21-day initiation regimens (both in conjunction with either 441mg or 882mg doses of AL) were comparable, with therapeutically relevant aripiprazole levels achieved within 4days of treatment initiation. The safety profile of the 1-day initiation regimen was similar to the 21-day initiation regimen, and consistent with that of AL. Aripiprazole concentration–time profiles demonstrated that each component delivered aripiprazole to the systemic circulation at different time periods, with the 30mg dose of oral aripiprazole predominant in the first week, followed by ALNCD, and then AL.

The 1-day initiation regimen is well-tolerated and a suitable alternative to 21days of oral aripiprazole supplementation for starting AL. Each component of the 1-day initiation regimen, together with AL, is necessary to provide continuous coverage from treatment initiation until the next regularly scheduled AL injection.

Funding Acknowledgements: This study was funded by Alkermes Inc.

Medication nonadherence is a public health concern and can impact clinical trial data quality. Traditional compliance collection (pill counts, diaries) can be unreliable in central nervous system trials. As such, strategies such as adherence technologies may play a key role in trial outcomes. AiCure, a computer vision-assisted dosing mobile application (app), collects dosing data and connects patients to sites for dosing support. Phone-based computer vision algorithms confirm dosing and transfer videos for artificial intelligence and human review. Boehringer Ingelheim is partnering with AiCure on pilot trials using AiCure adherence data to improve patient retention and clinical trial data quality. Here we report initial findings.

This pilot used data from two Phase II trials on the efficacy and safety of BI 409306 in people with schizophrenia (NCT03351244) or Attenuated Psychosis Syndrome (NCT03230097). The AiCure mobile app alerted participants to dosing protocols. The dose event was visually confirmed, providing sites a real-time view of adherence and allowing for targeted outreach and intervention. Adherence data from the first 2 weeks generated quantitative, machine-learning models to predict the individual adherence over the trial. Predictive modeling explored different monitoring periods (7-, 10-, and 14-day) and adherence cutoff points (0.8, 0.7, 0.6).

Initial AiCure assessment identified 43% of participants in NCT03351244 as ≤80% compliant (definition of compliance >80% compliant). Variance in adherence rates between electronic case report forms (eCRF; 78%) and AiCure (26%) data was also observed in the highly compliant/adherent group in NCT03230097. Using the first 2 weeks of adherence data (both studies combined), a participant’s adherence predicted their average adherence for the remainder of the trial. Observation of a participant’s adherence for the latest 4 weeks predicted the probability of premature dropout from the trial. There were further correlations of lower predicted adherence with actual disposition-based dropouts.

The early adherence predictive model (0.6 adherence cutoff) identified 22%, 20%, and 19% of patients for trial NCT03351244 (total n=235) as high-risk patients (low-adherence prediction) across 7-, 10-, and 14-day monitoring periods, respectively. Of those high-risk patients, 81%, 90%, and 96%, respectively, were truly nonadherent based on actual adherence data. The 14-day monitoring period model provided the lowest false omission rate, indicative of a better performing model.

AiCure data provided insights into patient behavior and adherence patterns which would not be available via CRF. Predictive models developed with AiCure adherence data can identify and predict future poor adherers. This creates opportunities to plan interventions and mitigation strategies to improve patient adherence during trials, thereby providing test drugs the best opportunity at proving efficacy.

Boehringer Ingelheim International GmbH (NCT03351244/1289-0049 and NCT03230097/1289-0032)

This review discusses the potential negative consequences of untreated insomnia in correctional settings.

A literature review was conducted on the association between insomnia and negative health outcomes, the best practices for treating insomnia with and without medications, and common practices that prohibit the treatment of insomnia in correctional settings.

Untreated insomnia was associated with increased psychiatric distress, increased risk for suicide, and increased all-cause mortality. Common practices in many correctional institutions impose restrictions on treating insomnia. These practices lead to an increased likelihood for negative health outcomes, including suicide and an increase in all-cause death.

Practices that prohibit the treatment of sleep in correctional settings increase the risk of death by suicide and other adverse health outcomes. The practices are often put in place due to pressure from the security staff who have trouble controlling the black-market trade of prescribed medications and other contraband within jails and prisons. Healthcare professionals in the correctional setting must advocate for the importance of treating sleep problems in jails and prisons and work with security staff on ways to overcome the problems of pill diversion and the trade of contraband in order to provide quality healthcare to this protected population.

Major depressive disorder (MDD) has been ranked among the top causes worldwide of years lived with disability. In this study we assessed meaningful change for the PHQ-9 and the SDS and determined the meaningful change threshold (MCT) using anchor-based methods, which could be used to compare meaningful differences in patients within different treatment arms.

TRANSFORM-1 (NCT02417064) and -2 (NCT0241858) were Phase 3 trials that evaluated the efficacy and safety of fixed and flexible doses of esketamine nasal spray (56 mg or 84 mg) in combination with newly initiated oral antidepressant (ESK+AD) vs oral antidepressant + placebo nasal spray (AD+PBO) in TRD patients. Patient Reported Outcomes (PROs) were integrated into these trials to evaluate the patient perspective of treatment using instruments capturing concepts of importance to patients. The 9-item Patient Health Questionnaire (PHQ-9) is a PRO instrument used to assess self-reported depression symptoms and the Sheehan Disability Scale (SDS) is a PRO for self-reported function and disability. Blinded trial data (combined treatment groups) from TRANSFORM-1 was used for the anchor-based analysis. The Clinical Global Impression - Severity (CGI-S) was used as an anchor and patients were classified into response groups depending on their level of change over the course of the study. Patients were classified among all possible change categories (15 levels, ranging from -7 to 7 where negative change scores indicate improvement). Cumulative Distribution Function (CDF) curves of change from baseline to day 28 were generated using unblinded data from TRANSFORM-2 to visualize the range of responses demonstrated in the respective treatment groups for the PHQ-9 and SDS. MCT values were used to as thresholds to evaluate percentage of responders in each treatment group.

In anchor-based analyses using TRANSFORM-1 combined treatment groups, the correlation between change on the CGI-S and change on the PHQ-9 at Day 28 was high (> 0.60) with anchor-based MCTs ranging from 5 to 8 points. The magnitude of change (standardized effect size estimate within-subject change) for patients improving was exceptionally high (> 0.80). Similar results were observed on the SDS: high correlation of CGI-S and SDS at Day 28 (0.75), moderate SES (0.66), with suggested MCT ranging from 3 to 7 with an MCT value of 5 pts. CDF curves from TRANSFORM-2 showed clear separation between the ESK+AD vs AD+PBO across a number of responder definitions inclusive of those identified with the anchor-based analyses.

The current study is the first to derive an MCT on the PHQ-9 and SDS in TRD to measure meaningful change from the perspective of the patient using regulatory-preferred psychometric anchor-based methodology. These analyses assist with interpretation of meaningfulness of esketamine phase 3 clinical trial results from the patient perspective.

Study was funded by Janssen Global Services, LLC.

Objectives for this survey are to determine similarities or differences in treatment goals reported by psychiatrists, patients with schizophrenia (SCZ) and caregivers in the US, as well as whether goals differed by patients currently on an oral antipsychotic (OAP) or long-acting injectable (LAI), and whether goals differed by age.

This was a real-world, cross-sectional survey of US psychiatrists, patients =18 years old diagnosed with SCZ, and caregivers. Data was collected using the Disease Specific Programme (DSP) methodology. Psychiatrists (n=120) completed detailed record forms for next 8 outpatients and 2 inpatients matching inclusion criteria. The same patients and their caregivers, if present, were invited by their psychiatrist to voluntarily complete a separate survey.

Responses on treatment goals were collected from psychiatrists for all patients included in the analysis (n=1161), patients (n= 542) and caregivers (n=130). Among 3 top goals, psychiatrists, patients and caregivers concurred that “decrease in disease symptoms” is most important (63%, 64%, 68% respectively). For psychiatrists and caregivers, second was “decrease in hospitalization for relapse” (41%, and 38% respectively), whereas for patients, it was “thinking clearly” (47%). Of the 3 least important goals, psychiatrists, patients and caregivers agreed with “sexual problems” (59%, 43%, 44%, respectively) and “weight gain” (38%, 44%, 38%, respectively).

When asked which goals were met by current medication, patients responded “decrease in disease symptoms” (68%) and “thinking clearly” (39%). However, caregivers responded “thinking clearly” (30%) was not met by current medication. Caregivers most important goals, “decrease in disease symptom” (70%) and “decrease in hospitalization for relapse” (41%), were met. Additional analyses of patients on OAPs and LAIs, did not show differences in goals. However, “decrease in disease symptoms” was numerically more important for patients on LAIs vs OAPs according to psychiatrists (68% vs 62%) and caregivers (77% vs 70% respectively). Caregivers responded “decrease in hospitalization for relapse” was met for 63% patients currently on an LAI and 35% OAP. No major differences in treatment goals were observed by patient age (18–35 vs 36–65 vs >65 years).

There is consensus among US psychiatrists, patients and caregivers on the most important treatment goal “decrease in disease symptoms”, regardless of patients’ current medication or age. For patients, “thinking more clearly” was second, compared with “decrease in hospitalization due to relapse”, for psychiatrists and caregivers. All agreed that least important treatment goals, related to AEs, were “weight gain” and “sexual problems”. More caregivers agreed “decrease in hospitalization for relapse” was met by patients on LAIs vs OAPs. These findings may help with discussions between psychiatrists, patients and caregivers.

Lundbeck LLC and Otsuka Pharmaceutical Development & Commercialization, Inc.

Ekbom’s delusion as a prelude to Cotard’s syndrome, has not heretofore been described.

Case study: A 45-year-old woman with a past diagnosis of bipolar disorder with psychotic features was admitted, having been up all night conversing with spirits, proclaiming that she had made a deal with Satan. Convinced that her grandmother was possessed by the devil, she smashed her grandmother’s head with a two-by-four. Results: Mental Status Examination: self conversing with her eyes darting around the room. Poor hygiene. Behavior: guarded and withdrawn. Oriented x2. Speech: hyperverbal. Insight and judgment: poor. Mood: hostile, aggressive, and angry. Thought process disorganized, incongruent, and tangentiality. She was convinced she was infested with little black bugs crawling around her insides which had been placed there by the devil. After two days of olanzapine she reported the bugs were no longer present, but rather that she herself was dead and that her organs were decomposing, which persisted through the remainder of the hospitalization.

Neuroimaging abnormalities in Ekbom’s syndrome involve the striatum, basal ganglia (putamen and caudate nucleus), insular and cingulate cortices, cortex (prefrontal, right parietal, and temporal lobes), right lingual and orbitofrontal gyri, and thalamus. In Cotard’s syndrome, abnormalities have been identified in the striatum, frontal and temporal lobes, and right-sided and bilateral hemispheres. An overlap between the delusions exists in the striatum, inferior parietal, and temporal lobes. A single lesion in the nondominant inferior parietal lobe may cause both syndromes, due to its substantial interconnection with the temporo-limbic areas. Since the parietal lobe is also involved in somatosensory processing, peradventure distorted sensory perception with associated sensation of formication may have been the nidus for the delusional infestation as well as a nidus for the perception of thanatos habitus. Such misperception may have then been amplified into a delusion because of a hyperconnection between the parietal lobe and the limbic system. This may represent a variant of the two-factor hypothesis of delusions whereby a distorted sensory perception is then misrepresented in a delusion. Dysfunction of the right hemisphere, which normally acts to censor the left, allows the delusion to manifest. A single lesion of the inferior parietal lobule may be sufficient for both sensory distortions and loss of inhibition of delusional interpretation of distorted sensation by the frontal lobe, yclept the sensorialist hypothesis.

In those with monothematic delusions, the search for transient fluctuation in delusional states may be revealing.

No Funding

CerefolinNAC (CFLN-NAC) contains L-methylfolate (6 mg), methylcobalamin (2 mg), and N-acetylcysteine [NAC] (600 mg) [Pamlab 2017]. Dizziness and lightheadedness have not heretofore been described with use of CFLN-NAC.

Case Study: A 64 year old right-handed female was started on CFLN-NAC for smell and taste issues. Over a three day period, she experienced a gradual increase in dizziness. This was a non-vertiginous lightheadedness, so severe that she was unable to walk, and would lie down the entire day to alleviate the dizziness. It was associated with nausea, but without any vomiting or falls. The dizziness would come and go, last for several hours, and was 9/10 in severity.

She admits to a past history of epochs of vertigo. The vertigo occurred three times with nausea and vomiting 13 years, 11 years, and 4 years prior to presentation. She also developed a constant, bilateral, high-pitched tinnitus 14 years prior to presentation, which obstructs her hearing. It is level 3/10 in intensity during the night and in the quiet. There were no alleviating or aggravating factors. Acupuncture was without effect, and she denies any ear pain. After ceasing CFLN-NAC for three days, a gradual reduction of dizziness to baseline ensued.

Abnormalities in Physical Examination: General: Decreased blink frequency and hypokinesia. Cranial Nerve III, IV, VI: Saccadization of horizontal eye movements. Motor Examination: Tone: 1+ cogwheel rigidity in both upper extremities, left more than right. Drift Test: Bilateral Abductor Digiti Minimi sign with cerebellar spooning. Reflexes: Absent quadriceps femoris and Achilles bilaterally. Positive Hoffman reflex bilaterally. Neuropsychiatric Testing: Go-No-Go Test: 6/6 (normal). Animal Fluency Test: 19 (normal). Reliable Digit Span: 10 (normal). Clock Drawing Test: 4 (normal). Center for Neurologic Study Lability Scale: 10 (normal). Other: Audiometry and Fiberoptic Endoscopy: normal. MRI of the brain with and without contrast was normal.

None of the individual components in CFLN-NAC have been reported to precipitate dizziness [Pamlab 2017]. The non-vertiginous nature of the dizziness makes it unlikely to be due to vestibular involvement, raising the spectre of this drug having an impact on the autonomic nervous system. While a nocebo effect could be in action, this is unlikely since dizziness was not presented as a potential side effect on initiation of the medication. In addition, methylcobalamin can cause hyperviscosity syndrome, but due to an absence of visual disturbances and altered mental status, it is also improbable. The relatively rapid onset with initiation and resolution upon discontinuation of this medication strongly suggests that it is not a coincidence, rather an origin for the dizziness. Those who are treated with CFLN-NAC should be queried as to new onset dizziness. For those already dizzy, one should consider other treatment options.

Smell and Taste Treatment and Research Foundation

Meningitis causes inflammation of the meninges and when bacteria are not the cause may be considered aseptic. Drug-induced aseptic meningitis (DIAM) can arise from the use of certain medications. The pathophysiology of DIAM is not well understood. Within the antiepileptic medication class, only lamotrigine, carbamazepine, and levetiracetam have been associated with DIAM via documented cases. Common presentation of DIAM involves fever, headache, meningismus, and mental status changes (abnormal consciousness and focal neurological deficits). Other clinical features may include neck stiffness, photophobia, nausea, vomiting, abdominal pain, bone pain, hypotension, edema (facial and optic nerve), rash, and seizures. Case reports of DIAM with varying or limited symptomology exist. Therefore, the presentation alone will not allow for a DIAM diagnosis, prompting further analysis and diagnostic exclusion.

A middle-aged male presented with a 48-hour history of confusion, disorientation, unresponsiveness, and hypersomnolence. Past medical history included hypertension, hyperlipidemia, type-2 diabetes, and seizures. Home medication included chlorthalidone, levetiracetam, lisinopril, metformin, potassium chloride, rosuvastatin with no medication allergies reported. Upon admission, the patient denied fever, headache, nausea, neck pain, vomiting, and rash. Somnolence, dysarthria, and obtundation were noted during the physical evaluation. Hospital medications included home medications along with enoxaparin, correctional dose insulin lispro, and IV lactated ringers. Vitals and labs were unremarkable. On hospital day (HD) 1 the MRI scan was unremarkable, ruling out a demyelinating process. Serology tests (ie, ANA and dsANA) were negative. Neurology was consulted, and a lumbar puncture was performed. On HD-2 AEIM was suspected, prompting levetiracetam discontinuation and lacosamide initiation (50 mg by mouth twice daily). The CSF analysis was notable for pleocytosis (lymphocytic predominance at 96%), elevated protein (100 mg/dL), and slightly elevated glucose (79 mg/dL). The CSF VDRL was negative, ruling out neurosyphilis. Bacterial meningitis was ruled out based on the CSF analysis (WBC 144 × 103 and glucose) and the lack of bacterial growth on gram stain. Inasmuch, antibiotic therapy was not initiated. Empiric acyclovir 1000 mg IV every 8 hours was initiated as viral meningitis had not been eliminated, due to the lack of viral meningeal PCR testing. By HD-3, the CSF culture resulted without growth and the patient was alert and oriented. By HD-4 the patient was discharged, having received 6 doses of IV acyclovir, with 7 more days of oral therapy.

In 2018, McDonald et al documented the first case of probable levetiracetam-related antiepileptic induced meningitis (AEIM). The mainstay of treatment is discontinuing the offending agent. Resolution of symptoms is typically 2 to 3 days after drug discontinuation as seen in this patient case report. Symptomatic resolution within days of stopping the suspected offending drug has been observed in all reported cases of AEIM where 1 to 2 weeks is generally seen with viral meningitis. Applying the Naranjo Scale yields a score of 4, which indicates possible levetiracetam-induced meningitis in this adult patient. Providers should be cognizant when prescribing antiepileptics to assess and monitor for aseptic meningitis that may appear with atypical symptoms.

No funding

Anxiety disorder is one of the common mental health problems in college students, which hurts their study, work, and life. Comprehensive psychological crisis intervention is a complete psychological treatment method expected to be essential in treating anxiety disorders in college students.

One hundred college students with anxiety disorder were selected as research subjects and randomly divided into two groups. The experimental group received comprehensive psychological crisis intervention treatment and comprehensive intervention measures such as psychological assistance, cognitive behavioral therapy, and intimate relationship training. The control group received traditional psychotherapy, including counseling and medication. The Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), and other assessment tools were used to carry out psychological measurements of the two groups of patients before, after, and at the follow-up point, respectively. The collected information was statistically analyzed by SPSS23.0 software.

After the comprehensive psychological crisis intervention treatment, the anxiety and depression levels of the experimental group were significantly reduced (P<0.001), and life satisfaction was significantly increased (P<0.001). Compared with the control group, the experimental group showed obvious advantages in curative effect.

Comprehensive psychological crisis intervention has shown remarkable efficacy in college students with anxiety disorders, can effectively reduce anxiety and depression, and improves the life satisfaction of patients. This approach may become an essential option for treating anxiety disorders in college students.

2021 Humanities and Social Sciences Research Project for Basic Research Business Expenses of Provincial Undergraduate Universities in Heilongjiang Province. No. 2021- kyywf-0384.

The psychological problems of college students are the focus of social concern and hot discussions. Influenced by the epidemic, college students’ study, life and employment have been affected to a certain extent. Schools should strengthen mental health education to improve college students’ ability to resist pressure and help students improve their ability to adapt to society. Positive psychology can help students improve their mental health by guiding their mental activities and tapping their own strengths. In the process of using positive psychological knowledge to intervene with college students, self-help incentive training and personality cultivation can help students understand their own mental health problems. Therefore, in the psychological health education of colleges and universities, we can consider taking these two methods to carry out psychological intervention on college students, so as to improve the students’ ability to withstand pressure.

In the experiment, 360 college students who meet the requirements were randomly selected in colleges and universities through a questionnaire survey as the research objects of mental health problems. There are 187 boys and 173 girls, with an average age of (20 ± 2) years. The 360 college students were randomly divided into the intervention group and the control group, 180 in each. The intervention group used positive psychological thinking for psychological intervention, while the control group did not take any psychological intervention measures. The Perceived Stress Scale (PSS) was selected as the test scale of college students’ compressive capacity, and SPSS23.0 was used to analyze the score results.

The score of the PSS scale is shown in Table 1. It can be seen from the table that after the intervention group received the psychological intervention, their problem-solving and rationalization abilities were significantly improved (P < 0.05), and their withdrawal emotions were significantly reduced (P < 0.05).Table 1.

PSS score

The results show that after the intervention of positive psychology, the psychological pressure resistance of college students has been significantly improved, which helps to improve the level of mental health of college students, so as to better solve many psychological problems caused by the epidemic.

Postpartum depression (PPD), now referred to as perinatal depression, is a prevalent and debilitating mood disorder that reduces health-related quality of life (HRQoL) and psychosocial functioning. Esketamine, which is efficacious in adults with treatment-resistant depression and individuals with depression and suicidality, is also analgesic in pain management during childbirth labour. Herein, we investigate the efficacy of prophylactic esketamine in reducing the incidence of PPD.

We performed a systematic review (i.e., PubMed, Scopus, and Ovid databases; inception to January 22, 2024) of randomized controlled trials that investigated the use of esketamine for PPD. We delimited our search to studies that prespecified the prevention of PPD with esketamine as the primary outcome. A meta-analysis was performed on PPD incidence rates using a random effects model.

Our analysis consisted of seven studies that met our eligibility criteria. We found that esketamine was significantly associated with a decreased incidence of PPD diagnosis within one week of childbirth (OR = 0.30, 95% CI = [0.15, 0.60], p = 0.0047). We also observed that esketamine was significantly associated with a decreased incidence of PPD diagnosis between 4 to 6 weeks post-delivery (OR = 0.33, 95% CI = [0.18, 0.59], p = 0.0034).

Our results indicate that esketamine may have preventive antidepressant effects during the postpartum period. The aforementioned points have both mechanistic and clinically meaningful implications for the treatment of PPD.

Deutetrabenazine is FDA approved for tardive dyskinesia (TD) based on two 12-week, placebo-controlled studies evaluating safety and efficacy in patients with baseline Abnormal Involuntary Movement Scale (AIMS) score ≥6. Deutetrabenazine reduced overall AIMS scores compared with placebo in ARM-TD (–3.0 vs –1.6, P=0.019) and AIM-TD (24 mg/day, –3.2 vs –1.4, P=0.003; 36 mg/day, –3.3 vs –1.4, P=0.001). This analysis assessed Minimal Clinically Important Difference (MCID) in AIMS score in patients with TD treated with deutetrabenazine.

MCID is the smallest change from baseline in AIMS score that is meaningful for patients. MCID analyses were performed based on Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC) as anchors described by Hauser et al., where MCID is the difference between patients treated with deutetrabenazine who were minimally improved and patients treated with placebo who were unchanged. Additional MCID definitions were explored: difference between patients who demonstrated treatment improvement versus those who did not (Method 2); difference between patients who demonstrated treatment success versus those who did not (Method 3).

295 patients were analyzed. Based on PGIC, the suggested MCID was –2.8. Results were similar for Method 2 (75% of patients had treatment improvement; MCID = –2.8) and Method 3 (38% of patients had treatment success; MCID = –2.6). Based on CGIC, the suggested MCID was –2.6. Results were similar for Method 2 (76% of patients had treatment improvement; MCID = –2.8) and Method 3 (41% of patients had treatment success; MCID = –3.0). Therefore, the suggested MCID for deutetrabenazine is –3.

The MCID for change in AIMS score based on PGIC and CGIC for deutetrabenazine was –3 regardless of the analytical method. Findings suggest an AIMS score reduction of ~3 is associated with clinically meaningful improvement in TD symptoms.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel