Search

Abstract Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive phenotypic continuum of microphthalmia, anophthalmia and ocular coloboma, with no apparent coding-region disease-causing mutation. Homozygosity mapping of several affected Jewish Iranian families, combined with whole genome sequence analysis, identified a 0.5 Mb disease-associated chromosome 2q35 locus (maximal LOD score 6.8) harboring an intronic founder variant in NHEJ1, not predicted to affect NHEJ1. The human NHEJ1 intronic variant lies within a known specifically limb-development enhancer of a neighboring gene, Indian hedgehog (Ihh), known to be involved in eye development in mice and chickens. Through mouse and chicken molecular development studies, we demonstrated that this variant is within an Ihh enhancer that drives gene expression in the developing eye and that the identified variant affects this eye-specific enhancer activity. We thus delineate an Ihh enhancer active in mammalian eye development whose variant causes human microphthalmia, anophthalmia and ocular coloboma. The findings highlight disease causation by an intronic variant affecting the expression of a neighboring gene, delineating molecular pathways of eye development.

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E−12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

Perineal urethrostomy in cats is indicated for urethral pathologies located distal to the bulbourethral glands. The description of the bulbourethral glands as the cranial landmark when performing a PU is based on the increased urethral diameter at this location, rather than on an anatomical limitation. This suggests that urethral pathologies cranial to the bulbourethral glands could potentially be treated with PU. At present, the extent to which the pelvic urethra can be mobilized is unknown. Characterization and quantification of the effect of PU on the pelvic urethra is required prior to attempting to define the location of the pelvic urethra, cranial to the bulbourethral glands, which can be exteriorized when performing a PU. Our aim was to characterize and quantify the effect of performing a PU on the location and length of the pelvic urethra. Methods: Ten male feline cadavers were used, and four markers were placed on the pelvic urethra via a ventral approach to the peritoneal and pelvic cavities. Two orthogonal radiographic views were acquired prior and subsequent to performing a PU. The distance of each marker to a predefined landmark/origin and the distances of the markers relative to each other were measured on all radiographs. Results: PU resulted in significant caudal translation of the markers relative to the predefined landmark on all radiographic views; however, PU did not result in a significant change in the distances between the markers. Conclusions: Performing a PU results in caudal translation and minimal stretching of the mobilized pelvic urethra.

Propagation of membrane tension mediates mechanical signal transduction along surfaces of live cells and sets the time scale of mechanical equilibration of cell membranes. Recent studies in several cell types and under different conditions revealed a strikingly wide variation range of the tension propagation speeds including extremely low ones. The latter suggests a possibility of long-living inhomogeneities of membrane tension crucially affecting mechano-sensitive membrane processes. Here, we propose, analyze theoretically, and support experimentally a mechanism of tension propagation in membranes crumpled by the contractile cortical cytoskeleton. The tension spreading is mediated by the membrane flow between the crumples. We predict the pace of the tension propagation to be controlled by the intra-cellular pressure and the degree of the membrane crumpling. We provide experimental support for the suggested mechanism by monitoring the rate of tension propagation in cells exposed to external media of different osmolarities., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: We report the use of intra-operative endoscopy, termed here 'surgically-assisted endoscopy'. The procedure spares a gastrotomy, therefore, shortening anaesthetic time, minimising potential complications and resulting in a quicker and less painful recovery., Methods: Four dogs and one cat requiring surgical celiotomy for various conditions were treated. In all animals, a gastrointestinal foreign body (FB) was located at surgery. During the surgery, with the patient still in dorsal recumbency and the abdomen still open, in lieu of gastrotomy, the animals had their FBs removed via endoscopy, sparing a gastrotomy procedure and its potential complications., Results: In all five cases, a gastrotomy was avoided and the FBs were successfully extracted using the endoscope. Only one minor complication was seen intra-operatively and none at short-term follow-up., Clinical Significance: Although prognosis after gastrotomy is considered excellent, potential complications still exist and include haemorrhage, intra-operative spillage, peritonitis and post-operative dehiscence. Alternatively, endoscopy negates many of those possible complications and shortens anaesthesia time. In many cases of gastric FBs, or where intestinal FBs can be safely manipulated into the stomach, surgically assisted endoscopy could be considered a viable and potentially preferred option to gastrotomy., (© 2024 The Author(s). Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Objective: Anxiety is prevalent in childhood but often remains undiagnosed due to its physical manifestations and significant comorbidity. Despite the availability of effective treatments, including medication and psychotherapy, research indicates that physicians struggle to identify childhood anxiety, particularly in complex and challenging cases. This study aims to explore the potential effectiveness of artificial intelligence (AI) language models in diagnosing childhood anxiety compared to general practitioners (GPs)., Methods: During February 2024, we evaluated the ability of several large language models (LLMs; ChatGPT-3.5 and ChatGPT-4, Claude.AI, Gemini) to identify cases childhood anxiety disorder, compared with reports of GPs., Results: AI tools exhibited significantly higher rates of identifying anxiety than GPs. Each AI tool accurately identified anxiety in at least one case: Claude.AI and Gemini identified at least four cases, ChatGPT-3 identified three cases, and ChatGPT-4 identified one or two cases. Additionally, 40% of GPs preferred to manage the cases within their practice, often with the help of a practice nurse, whereas AI tools generally recommended referral to specialized mental or somatic health services., Conclusion: Preliminary findings indicate that LLMs, specifically Claude.AI and Gemini, exhibit notable diagnostic capabilities in identifying child anxiety, demonstrating a comparative advantage over GPs., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Cutaneous squamous cell carcinoma (cSCC) is characterized by a high tumor mutational burden due to solar damage and a favorable response to anti-PD-1 immunotherapy. Yet, we encounter tumors arising in areas with minimal sun exposure, such as cSCC that develops in chronically inflamed skin, also known as Marjolin's Ulcer (MU). The response of MU-SCC to immunotherapy remains unknown., Methods: We performed a retrospective analysis of patients diagnosed with cSCC and treated with cemiplimab or pembrolizumab in a single tertiary medical center. Patients lost to follow up were excluded., Results: Of the 84 eligible patients, 9 (11%) had MU-SCC. Of these, 2 (22%) reached partial response (PR), and none reached complete response (CR). In contrast, of the 75 patients with solar damage-related cSCC, 40 had PR (53%), and 20 had CR (26%). The difference between the two subtypes was significant (P < .001). Interestingly, 3 patients with MU-SCC received a second-line chemo-immunotherapy and experienced a partial response that continued for 5 to 21 months. Patients with MU-SCC had a significantly shorter median time to progression (TTP) (1.6 vs 51.6 months, P < .001) and progression-free survival (PFS) (1.6 vs 15.4 months, P < .001). Overall survival (OS) was not significantly shorter (17.4 vs 36.7 months, P = .096). Multivariate analysis confirmed that MU-SCC is an independent risk factor for shorter TTP (HR 5.5, 95% CI 2.2-14.0, P < .001) and PFS (HR 3.5, 95% CI 1.5-8.1, P = .003)., Conclusions: This study suggests that immunotherapy is less beneficial in SCC-MU. More work is needed to verify our findings and explore other treatment options., (© The Author(s) 2024. Published by Oxford University Press.)

The development and application of human TCR-like (TCRL) antibodies recognizing disease-specific MHC-peptide complexes may prove as an important tool for basic research and therapeutic applications. Multiple sclerosis is characterized by aberrant CD4 T-cell response to self-antigens presented by MHC class II molecules. This led us to select a panel of TCRL Abs targeting the immunodominant autoantigenic epitope MOG 35-55 derived from myelin oligodendrocyte glycoprotein (MOG) presented on HLA-DR2, which is associated with multiple sclerosis (MS). We demonstrate that these TCRL Abs bind with high specificity to human HLA-DR2/MOG 35-55 -derived MHC class II molecules and can detect APCs that naturally present the MS-associated autoantigen in the humanized EAE transgenic mouse model. The TCRL Abs can block ex vivo and in vivo CD4 T-cell proliferation in response to MOG 35-55 stimulation in an antigen-specific manner. Most significantly, administration of TCRL Abs to MOG 35-55 -induced EAE model in HLA-DR2 transgenic mice both prevents and regresses established EAE. TCRL function was associated with a reduction in autoreactive pathogenic T-cell infiltration into the CNS, along with modulation of activated CD11b+ macrophages/microglial APCs. Collectively, these findings demonstrate the combined action of TCRL Abs in blocking TCR-MHC interactions and modulating APC presentation and activation, leading to a profound antigen-specific inhibitory effect on the neuroinflammatory process, resulting in regression of EAE. Our study constitutes an in vivo proof of concept for the utility of TCR-like antibodies as antigen-specific immunomodulators for CD4-mediated autoimmune diseases such as MS, validating the importance of the TCR-MHC axis as a therapeutic target for various autoimmune and inflammatory diseases., (© 2024 Goor et al.)

Background: On October 7, 2023, Hamas carried out an unprecedented attack on the State of Israel and kidnapped 251 people into captivity to the Gaza Strip. Several months later, as part of a humanitarian exchange deal, 105 hostages were released in five phases and admitted to one of six hospitals throughout the country for treatment. Shamir Medical Center (SMC) was one of these facilities. This study aims to describe the structure, process and outcomes of establishing a comprehensive, multi-step, operational protocol for receiving hostages returning from captivity., Method: The process of preparing SMC as a receiving center, the establishment of procedures for implementation of the medical protocol, and the assessment of multi-disciplinary team preparedness and implementation and outcomes in an institutional protocol are described., Results: 24 returning hostages were received at SMC. Social workers, dietitians and translators were used by 100% of the majority group of returning hostages from the same country of origin and the sole individual from the other country of origin utilized a dietitian, social worker, ENT consultations, and a hearing test. Among the majority group, orthopedic and dermatological consultations were utilized by 17.4% and 13% received an ENT consultation. Of the administered imaging, 13% received a chest X-ray, 8.7% received a limb X-ray, 17.4% received a head CT scan, and 4.3% received an abdominal CT. In addition, 21.7% were provided antibiotic therapy. Protocol efficacy was measured by assessing time to various operational aspects of protocol implementation and medical procedures such as mean hours to room assignment, primary physician evaluation and social worker session. No correlation between age and operational variables was found., Conclusion: This novel operational protocol was successfully implemented and may serve as a framework for managing similar unpredictable sensitive events in the case of future need., (© 2024. The Author(s).)

Background: Diabetes mellitus (DM) is associated with premature atherosclerotic disease, coronary artery disease (CAD) and chronic heart failure (HF), leading to increased morbidity and mortality. Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2i) exhibit cardioprotective benefits beyond glucose lowering, reducing the risk of major cardiovascular events (MACE) and HF hospitalizations in patients with DM and CAD. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in vascular repair, mobilized in response to vascular injury. The number and function of circulating EPCs (cEPCs) are negatively affected by cardiovascular risk factors, including DM. This study aimed to examine the response of cEPCs to SGLT2i treatment in DM patients with stable CAD., Methods: A prospective single-center study included patients with DM and stable CAD who were started on an SGLT2i (empagliflozin). Peripheral blood samples were collected at baseline, 1 month, and 3 months to evaluate cEPC levels and function by flow cytometry, immunohistochemistry and MTT assays., Results: Eighteen patients were included in the study (median age 73, (IQR 69, 77) years, 67% male). After 1 month of treatment with empagliflozin, there was no significant change in cEPCs level or function. However, following 3 months of treatment, a significant increase was observed both in cell levels (CD34(+)/VEGFR-2(+): from 0.49% (IQR 0.32, 0.64) to 1.58% (IQR 0.93, 1.82), p = 0.0006; CD133(+)/VEGFR-2(+): from 0.38% (IQR 0.27, 0.6) to 0.82% (IQR 0.7, 1.95), p = 0.0001) and in cell function (from 0.25 CFUs (IQR 0, 0.5) at baseline, to 2 CFUs (IQR 1, 2) at 3 months, p = 0.0012)., Conclusions: Empagliflozin treatment in patients with DM and stable CAD increases cEPC levels and function, implying a cardioprotective mechanism. These findings highlight the potential of SGLT2i in treating cardiovascular diseases, warranting further research to explore these effects and their long-term implications., (© 2024. The Author(s).)

Continuous monitoring of high-risk neonates is essential for the timely management of medical conditions. However, the current reliance on wearable or contact sensor technologies for vital sign monitoring often leads to complications including discomfort, skin damage, and infections which can impede medical management, nursing care, and parental bonding. Moreover, the dependence on multiple devices is problematic since they are not interconnected or time-synchronized, use a variety of different wires and probes/sensors, and are designed based on adult specifications. Therefore, there is an urgent unmet need to enable development of wireless, non- or minimal-contact, and non-adhesive technologies capable of integrating multiple signals into a single platform, specifically designed for neonates. This paper summarizes the limitations of existing wearable devices for neonates, discusses advancements in non-contact sensor technologies, and proposes directions for future research and development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Krbec, Zhang, Chityat, Brady-Mine, Linton, Copeland, Anthony, Edelman and Davis.)

Autism spectrum disorder (ASD) is characterized by social and neurocognitive impairments, with mutations of the SHANK3 gene being prominent in patients with monogenic ASD. Using the InsG3680 mouse model with a Shank3 mutation seen in humans, we revealed an unknown role for Shank3 in postsynaptic oligodendrocyte (OL) features, similar to its role in neurons. This was shown by impaired molecular and physiological glutamatergic traits of InsG3680-derived primary OL cultures. In vivo, InsG3680 mice exhibit significant reductions in the expression of key myelination-related transcripts and proteins, along with deficits in myelin ultrastructure, white matter, axonal conductivity, and motor skills. Last, we observed significant impairments, with clinical relevance, in induced pluripotent stem cell-derived OLs from a patient with the InsG3680 mutation. Together, our study provides insight into Shank3's role in OLs and reveals a mechanism of the crucial connection of myelination to ASD pathology.

Objective: This article uses the framework of Schwartz's values theory to examine whether the embedded values-like profile within large language models (LLMs) impact ethical decision-making dilemmas faced by primary care. It specifically aims to evaluate whether each LLM exhibits a distinct values-like profile, assess its alignment with general population values, and determine whether latent values influence clinical recommendations., Methods: The Portrait Values Questionnaire-Revised (PVQ-RR) was submitted to each LLM (Claude, Bard, GPT-3.5, and GPT-4) 20 times to ensure reliable and valid responses. Their responses were compared to a benchmark derived from a diverse international sample consisting of over 53,000 culturally diverse respondents who completed the PVQ-RR. Four vignettes depicting prototypical professional quandaries involving conflicts between competing values were presented to the LLMs. The option selected by each LLM and the strength of its recommendation were evaluated to determine if underlying values-like impact output., Results: Each LLM demonstrated a unique values-like profile. Universalism and self-direction were prioritized, while power and tradition were assigned less importance than population benchmarks, suggesting potential Western-centric biases. Four clinical vignettes involving value conflicts were presented to the LLMs. Preliminary indications suggested that embedded values-like influence recommendations. Significant variances in confidence strength regarding chosen recommendations materialized between models, proposing that further vetting is required before the LLMs can be relied on as judgment aids. However, the overall selection of preferences aligned with intrinsic value hierarchies., Conclusion: The distinct intrinsic values-like embedded within LLMs shape ethical decision-making, which carries implications for their integration in primary care settings serving diverse populations. For context-appropriate, equitable delivery of AI-assisted healthcare globally it is essential that LLMs are tailored to align with cultural outlooks., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2024 The Authors. Published by Elsevier Ltd.)

Significance: Rapid acquisition of large imaging volumes with microscopic resolution is an essential unmet need in biological research, especially for monitoring rapid dynamical processes such as fast activity in distributed neural systems., Aim: We present a multifocal strategy for fast, volumetric, diffraction-limited resolution imaging over relatively large and scalable fields of view (FOV) using single-camera exposures., Approach: Our multifocal microscopy approach leverages diffraction to image multiple focal depths simultaneously. It is based on a custom-designed diffractive optical element suited to low magnification and large FOV applications and customized prisms for chromatic correction, allowing for wide bandwidth fluorescence imaging. We integrate this system within a conventional microscope and demonstrate that our design can be used flexibly with a variety of magnification/numerical aperture (NA) objectives., Results: We first experimentally and numerically validate this system for large FOV microscope imaging (three orders-of-magnitude larger volumes than previously shown) at resolutions compatible with cellular imaging. We then demonstrate the utility of this approach by visualizing high resolution three-dimensional (3D) distributed neural network at volume rates up to 100 Hz. These demonstrations use genetically encoded Ca 2 + indicators to measure functional neural imaging both in vitro and in vivo. Finally, we explore its potential in other important applications, including blood flow visualization and real-time, microscopic, volumetric rendering., Conclusions: Our study demonstrates the advantage of diffraction-based multifocal imaging techniques for 3D imaging of mm-scale objects from a single-camera exposure, with important applications in functional neural imaging and other areas benefiting from volumetric imaging., (© 2024 The Authors.)

Background: It has long been of interest to characterize the components of the motor abnormality in the arm after stroke. One approach has been to decompose the hemiparesis phenotype into negative signs, such as weakness, and positive signs, such as intrusion of synergies. We sought to identify the contributions of weakness and flexor synergy to motor deficits in sub-acute stroke., Methods: Thirty-three sub-acute post-stroke participants and 16 healthy controls performed two functional arm movements; one within flexor synergy (shoulder and elbow flexion), and the other outside flexor synergy (shoulder flexion and elbow extension). We analyzed upper limb 3D kinematics to assess both overall task performance and intrusion of pathological synergies. Weakness and spasticity were also measured., Results: Both tasks produced similar impairments compared to controls. Analysis of elbow and shoulder multi-joint coordination patterns revealed intrusion of synergies in the out-of-synergy reaching task based on the time spent within a flexion-flexion pattern and the correlation between shoulder and elbow angles. Regression analysis indicated that both weakness and synergy intrusion contributed to motor impairment in the out-of-synergy reaching task. Notably, the Fugl-Meyer Assessment (FMA) was abnormal even when only weakness caused the impairment, cautioning that it is not a pure synergy scale., Conclusions: Weakness and synergy intrusion contribute to motor deficits in the sub-acute post-stroke period. An abnormal FMA score cannot be assumed to be due to synergy intrusion. Careful kinematic analysis of naturalistic movements is required to better characterize the contribution of negative and positive signs to upper limb impairment after stroke., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Extracellular vesicles (EVs) are important mediators of communication between cells. Here, we reveal a new mode of intercellular communication by melanosomes, large EVs secreted by melanocytes for melanin transport. Unlike small EVs, which are disintegrated within the receiver cell, melanosomes stay intact within them, gain a unique protein signature, and can then be further transferred to another cell as "second-hand" EVs. We show that melanoma-secreted melanosomes passaged through epidermal keratinocytes or dermal fibroblasts can be further engulfed by resident macrophages. This process leads to macrophage polarization into pro-tumor or pro-immune cell infiltration phenotypes. Melanosomes that are transferred through fibroblasts can carry AKT1, which induces VEGF secretion from macrophages in an mTOR-dependent manner, promoting angiogenesis and metastasis in vivo. In melanoma patients, macrophages that are co-localized with AKT1 are correlated with disease aggressiveness, and immunotherapy non-responders are enriched in macrophages containing melanosome markers. Our findings suggest that interactions mediated by second-hand extracellular vesicles contribute to the formation of the metastatic niche, and that blocking the melanosome cues of macrophage diversification could be helpful in halting melanoma progression., (© 2024. The Author(s).)

Introduction: Variations in the left atrial appendage (LAA) morphology are associated with different embolic risk in patients with atrial fibrillation (AF). Data are scarce regarding the association between LAA morphology and Embolic stroke of undetermined source (ESUS)., Patients and Methods: Using cardiac computed tomography (CCT) scans, LAA morphology was categorized as either chicken wing (CW), cactus, windsock, or cauliflower. Furthermore, we examined the presence of large secondary lobes arising from the main lobe, considering their existence as indicative of a complex LAA morphology. LAA morphologies were compared between ESUS ( n  = 134) and AF patients ( n  = 120); and between ESUS patients with ( n  = 24) and without ( n  = 110) subsequent AF diagnosis during long-term follow-up., Results: ESUS patients had a significantly higher prevalence of cauliflower morphology compared to AF group (52% vs 34%, respectively, p  = 0.01); however, no significant difference was found between the groups when categorizing LAA morphology to either CW or non-CW. ESUS patients had significantly higher prevalence of large secondary lobes compared with AF patients (50% vs 29%, respectively, p  = 0.001). When comparing ESUS patients with and without AF diagnosis during follow-up (20-48 months of follow-up, median 31 months), there were no significant differences in the prevalence of the "classical" morphologies, but large secondary lobes were significantly more prevalent among those without subsequent AF diagnosis., Conclusion: ESUS patients have a high prevalence of complex LAA morphology, which might be associated with an increased risk for thrombus formation even in the absence of AF., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas (CRISPR-associated proteins) systems provide acquired heritable protection to bacteria and archaea against selfish DNA elements, such as viruses. These systems must be tightly regulated because they can capture DNA fragments from foreign selfish elements, and also occasionally from self-chromosomes, resulting in autoimmunity. Most known species from the halophilic archaeal genus Haloferax contain type I-B CRISPR-Cas systems, and the strongest hotspot for self-spacer acquisition by H. mediterranei was a locus that contained a putative transposable element, as well as the gene HFX&#95;2341 , which was a very frequent target for self-targeting spacers. To test whether this gene is CRISPR-associated, we investigated it using bioinformatics, deletion, over-expression, and comparative transcriptomics. We show that HFX&#95;2341 is a global transcriptional regulator that can repress diverse genes, since its deletion results in significantly higher expression of multiple genes, especially those involved in nutrient transport. When over-expressed, HFX&#95;2341 strongly repressed the transcript production of all cas genes tested, both those involved in spacer acquisition ( cas1 , 2 and 4 ) and those required for destroying selfish genetic elements ( cas3 and 5-8 ). Considering that HFX&#95;2341 is highly conserved in haloarchaea, with homologs that are present in species that do not encode the CRISPR-Cas system, we conclude that it is a global regulator that is also involved in cas gene regulation, either directly or indirectly.

Introduction: Depression can exacerbate diabetes by impairing self-care behaviors and increasing the risk of complication; however, the underlying mechanism is still unclear. Given the suggested associations between walking activity, depression status, and blood glucose levels this study explores the intricate relationship between depression and blood glucose (BG) control, with a focus on walking activity as a behavioral mediator. The purpose of this study is to examine walking activity's mediating role in depression's impact on BG levels, investigating and validating the non-linear association between BG levels and walking activity. This retrospective real-world study demonstrates the potential of regular walking activity as a simple and accessible intervention to mitigate the negative effects of depression on BG levels in T2D and prediabetes., Methods: A cohort of 989 users with T2D and prediabetes, who regularly tracked their steps levels and BG levels for 12 months using the Dario digital health platform was evaluated. The mediating role of the monthly average number of steps on the relationship between the self-reported depression status and lagged monthly average BG was assessed. Additionally, the association between monthly walking activity and monthly average BG was tested using a piecewise linear mixed effects model., Results: Users with self-reported depression demonstrated increased BG levels compared to users without depression (B=8.00, P=.01). The association between depression and monthly average number of steps was significant (B=-.27, P<.005) and monthly average number of steps significantly predicted the following months' average BG (B=-.81, P=.001), adjusting for depression. The monthly average number of steps significantly mediated the effect of self-reported depression on the following month's average BG (M=.22, P<.005). Further sensitivity analysis demonstrated model robustness over various periods. Finally, non-linear dynamics of walking activity over time was validated using unseen data showing a decrease in monthly average BG for users with over an average of 400 steps per day (B=-1.87, P<.01)., Discussion: This study shows how regular walking may reduce the negative impact of depression on BG levels in people with T2D. Our findings advocate for the integration of walking activity into treatment protocols as a cost-effective, accessible intervention strategy to improve glycemic management and depressive symptoms in this population., Competing Interests: YF-H, IB, and OM are employees at Dario Health. MR and DH serve as Dario Health scientific advisory board members. PG has received a consulting fee to assist with analyses but otherwise has no conflict of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fundoiano-Hershcovitz, Breuer Asher, Kantor, Rahmon, Ritholz, Horwitz, Manejwala and Goldstein.)

Living organisms are constructed from proteins that assemble into biomolecular complexes, each with a unique shape and function. Our knowledge about the structure-activity relationship of these complexes is still limited, mainly because of their small size, complex structure, fast processes, and changing environment. Furthermore, the constraints of current microscopic tools and the difficulty in applying molecular dynamic simulations to capture the dynamic response of biomolecular complexes and long-term phenomena call for new supplementary tools and approaches that can help bridge this gap. In this paper, we present an approach to comparing biomolecular and origami hierarchical structures and apply it to comparing bacterial microcompartments (BMCs) with spiral-based origami models. Our first analysis compares proteins that assemble the BMC with an origami model called "flasher", which is the unit cell of an assembled origami model. Then, the BMC structure is compared with the assembled origami model and based on the similarity, a physical scaled-up origami model, which is analogous to the BMC, is constructed. The origami model is translated into a computer-aided design model and manufactured via 3D-printing technology. Finite element analysis and physical experiments of the origami model and 3D-printed parts reveal trends in the mechanical response of the icosahedron, which is constructed from tiled-chiral elements. The chiral elements rotate as the icosahedron expands and we deduce that it allows the BMC to open gates for transmembrane passage of materials.

Background: Non-suicidal self-injury (NSSI) involves the deliberate harm of one's body without the intent to commit suicide and is particularly concerning among adolescents. Teachers play a critical role as gatekeepers in identifying and addressing self-harm, underscoring the importance of their knowledge and response strategies in this area. This study explored how teachers' knowledge, attitudes towards NSSI, perceived roles, and workplace barriers affect their responses to students exhibiting NSSI behaviors., Methods: A cross-sectional survey was conducted among 203 middle and high school teachers in Israel. Data were collected during July and August 2023 using six validated questionnaires., Results: Higher levels of teacher knowledge, positive attitudes, and strong role perceptions correlated with more effective responses to NSSI, whereas increased workplace barriers tended to diminish response efficacy. Positive correlations emerged between role perception and both knowledge and attitudes, whereas negative correlations emerged between workplace barriers, attitudes, and role perceptions. Teaching experience moderated the impact of role perception and workplace barriers on responses. Significant differences were observed between regular and special education settings, although no differences were noted in referral rates or years of seniority., Conclusions: These findings suggest that enhancing teacher knowledge and attitudes towards NSSI, while addressing workplace barriers, can improve response efficacy in educational settings.

Rodents continuously move their heads and whiskers in a coordinated manner while perceiving objects through whisker-touch. Studies in head-fixed rodents showed that the ventroposterior medial (VPM) and posterior medial (POm) thalamic nuclei code for whisker kinematics, with POm involvement reduced in awake animals. To examine VPM and POm involvement in coding head and whisker kinematics in awake, head-free conditions, we recorded thalamic neuronal activity and tracked head and whisker movements in male mice exploring an open arena. Using optogenetic tagging, we found that in freely moving mice, both nuclei equally coded whisker kinematics and robustly coded head kinematics. The fraction of neurons coding head kinematics increased after whisker trimming, ruling out whisker-mediated coding. Optogenetic activation of thalamic neurons evoked overt kinematic changes and increased the fraction of neurons leading changes in head kinematics. Our data suggest that VPM and POm integrate head and whisker information and can influence head kinematics during tactile perception., (© 2024. The Author(s).)

Large variability exists in people's responses to foods. However, the efficacy of personalized dietary advice for health remains understudied. We compared a personalized dietary program (PDP) versus general advice (control) on cardiometabolic health using a randomized clinical trial. The PDP used food characteristics, individual postprandial glucose and triglyceride (TG) responses to foods, microbiomes and health history, to produce personalized food scores in an 18-week app-based program. The control group received standard care dietary advice (US Department of Agriculture Guidelines for Americans, 2020-2025) using online resources, check-ins, video lessons and a leaflet. Primary outcomes were serum low-density lipoprotein cholesterol and TG concentrations at baseline and at 18 weeks. Participants (n = 347), aged 41-70 years and generally representative of the average US population, were randomized to the PDP (n = 177) or control (n = 170). Intention-to-treat analysis (n = 347) between groups showed significant reduction in TGs (mean difference = -0.13 mmol l -1 ; log-transformed 95% confidence interval = -0.07 to -0.01, P = 0.016). Changes in low-density lipoprotein cholesterol were not significant. There were improvements in secondary outcomes, including body weight, waist circumference, HbA1c, diet quality and microbiome (beta-diversity) (P < 0.05), particularly in highly adherent PDP participants. However, blood pressure, insulin, glucose, C-peptide, apolipoprotein A1 and B, and postprandial TGs did not differ between groups. No serious intervention-related adverse events were reported. Following a personalized diet led to some improvements in cardiometabolic health compared to standard dietary advice. ClinicalTrials.gov registration: NCT05273268 ., (© 2024. The Author(s).)

Introduction: Seasonality in the incidence of stroke has been examined in numerous studies, yet data on whether it differs with age are limited. To fill this gap, we utilized a largescale dataset from Israel., Patients and Methods: We retrieved data of all hospitalizations for ischemic stroke (IS), transient ischemic attack (TIA) and intra cerebral hemorrhage (ICH) from 2000 to 2020. We maintained separate datasets for IS/TIA and ICH, divided into five age groups: 18-49, 50-59, 60-69, 70-79, and 80+. We modeled the monthly incidence using a generalized additive model. The seasonal effect was defined by the rate ratio (RR) of each month compared to the annual mean., Results: The analysis included 317,586 and 23,789 events of IS/TIA and ICH respectively. We found an interaction between age and seasonality, accounting for a phase shift with age in the seasonal pattern of IS/TIA incidence. For cases under 70 years, the peak was during summertime and the RRs increased with decreasing age, reaching 1.11 (95% CI 1.09-1.13) at the youngest age group. In contrast, among the elderly, a winter peak was observed and the RRs increased with age to 1.07 (95% CI 1.06-1.08) at the oldest age group. For ICH, a winter/autumn peak was identified and the RRs increased with age to 1.20 (95% CI 1.16-1.24)., Conclusions: Our finding of age-dependent seasonal patterns in the occurrence of stroke, suggests closer monitoring of cardiovascular risk factors during wintertime among elderly individuals. The mechanism governing the seasonal phase shift with age in IS/TIA incidence, requires further investigation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Lipid droplets (LDs) comprise a triglyceride core surrounded by a lipid monolayer enriched with proteins, many of which function in LD homeostasis. How proteins are targeted to the growing LD is still unclear. Rab1b, a GTPase regulating secretory transport, was recently associated with targeting proteins to LDs in a Drosophila RNAi screen. LD formation was prevented in human hepatoma cells overexpressing dominant-negative Rab1b. We thus hypothesized that Rab1b recruits lipid-synthesizing enzymes, facilitating LD growth. Here, FRET between diacylglycerol acyltransferase 2 (DGAT2) and Rab1b and activity mutants of the latter demonstrated that Rab1b promotes DGAT2 ER to the LD surface redistribution. Last, alterations in LD metabolism and DGAT2 redistribution, consistent with Rab1b activity, were caused by mutations in the Rab1b-GTPase activating protein TBC1D20 in Warburg Micro syndrome (WARBM) model mice fibroblasts. These data contribute to our understanding of the mechanism of Rab1b in LD homeostasis and WARBM, a devastating autosomal-recessive disorder caused by mutations in TBC1D20.

Growing concerns over gambling problems across age groups have sparked research in public health and psychology. During emerging adulthood, individuals are more susceptible to mental health problems and more likely to develop gambling problems than in other age groups. This study explored the potential differences between emerging adults and adults aged 30+ in terms of problem gambling severity (PGS), gambling-related harm (GRH), depression and anxiety, and the mediating role of depression and anxiety in the association between age, PGS, and GRH. A representative online sample of 3244 Israelis aged 18 and over was divided into two groups: 740 emerging adults aged 18-29 and 2504 adults aged 30+. Gambling behaviors, the Problem Gambling Severity Index, the Short Gambling Harm Screen, and the Patient Health Questionnaire-4 assessing depression and anxiety were administered. Emerging adults had significantly higher levels of GRH, PGS, and depression-anxiety than their older counterparts, above and beyond gender and education. Depression-anxiety fully mediated the associations between age and gambling-related outcomes. These findings underscore the importance of considering psychological well-being in efforts to address problem gambling and gambling-related harms, especially in emerging adults.

The aim of this study was to evaluate the effectiveness of ChatGPT-3.5 and ChatGPT-4 in incorporating critical risk factors, namely history of depression and access to weapons, into suicide risk assessments. Both models assessed suicide risk using scenarios that featured individuals with and without a history of depression and access to weapons. The models estimated the likelihood of suicidal thoughts, suicide attempts, serious suicide attempts, and suicide-related mortality on a Likert scale. A multivariate three-way ANOVA analysis with Bonferroni post hoc tests was conducted to examine the impact of the forementioned independent factors (history of depression and access to weapons) on these outcome variables. Both models identified history of depression as a significant suicide risk factor. ChatGPT-4 demonstrated a more nuanced understanding of the relationship between depression, access to weapons, and suicide risk. In contrast, ChatGPT-3.5 displayed limited insight into this complex relationship. ChatGPT-4 consistently assigned higher severity ratings to suicide-related variables than did ChatGPT-3.5. The study highlights the potential of these two models, particularly ChatGPT-4, to enhance suicide risk assessment by considering complex risk factors., Competing Interests: The authors declare that they have no competing interests., (© 2024 Shinan-Altman et al.)

This study examines mental health service providers who provided care to evacuees during the Israel-Hamas conflict. Utilizing a phenomenological qualitative method, the research delves into the psychological impact on the participants' lived experiences. The sample included 25 mental health providers (13 female, age range 28-63, mean 42.4, SD 7.3; 15 psychologists and 10 social worker, average seniority 10.8 years, SD 5.2, range 2-18 years). Data were collected through semi-structured interviews conducted between December 2023 and March 2024. The data analysis revealed a dual narrative: Participants paid a major personal price and experienced secondary traumatization manifesting in emotional detachment, physical symptoms, and heightened arousal. They also derived a profound sense of meaning and fulfillment from their work, contributing to personal and professional growth. These findings underscore the complexity of their experiences, which were marked by the challenges of secondary trauma and the resilience fostered through their work. This study emphasizes the importance of support systems, including social and familial networks and professional supervision, in navigating these challenges. This study has several limitations, including small sample size and the use of virtual interviews, suggesting the need for further research with a broader participant base and in different contexts.

Objective: Burkholderia pseudomallei, the etiological cause of melioidosis, is a soil saprophyte endemic in South-East Asia, where it constitutes a public health concern of high-priority. Melioidosis cases are sporadically identified in nonendemic areas, usually associated with travelers or import of goods from endemic regions. Due to extensive intercontinental traveling and the anticipated climate change-associated alterations of the soil bacterial flora, there is an increasing concern for inadvertent establishment of novel endemic areas, which may expand the global burden of melioidosis. Rapid diagnosis, isolation and characterization of B. pseudomallei isolates is therefore of utmost importance particularly in non-endemic locations., Data Description: We report the genome sequences of two novel clinical isolates (MWH2021 and MST2022) of B. pseudomallei identified in distinct acute cases of melioidosis diagnosed in two individuals arriving to Israel from India and Thailand, respectively. The data includes preliminary genetic analysis of the genomes determining their phylogenetic classification in rapport to the genomes of 131 B. pseudomallei strains documented in the NCBI database. Inspection of the genomic data revealed the presence or absence of loci encoding for several documented virulence determinants involved in the molecular pathogenesis of melioidosis. Virulence analysis in murine models of acute or chronic melioidosis established that both strains belong to the highly virulent class of B. pseudomalleii., (© 2024. The Author(s).)

Unlabelled: This paper explores a significant shift in the field of mental health in general and psychotherapy in particular following generative artificial intelligence's new capabilities in processing and generating humanlike language. Following Freud, this lingo-technological development is conceptualized as the "fourth narcissistic blow" that science inflicts on humanity. We argue that this narcissistic blow has a potentially dramatic influence on perceptions of human society, interrelationships, and the self. We should, accordingly, expect dramatic changes in perceptions of the therapeutic act following the emergence of what we term the artificial third in the field of psychotherapy. The introduction of an artificial third marks a critical juncture, prompting us to ask the following important core questions that address two basic elements of critical thinking, namely, transparency and autonomy: (1) What is this new artificial presence in therapy relationships? (2) How does it reshape our perception of ourselves and our interpersonal dynamics? and (3) What remains of the irreplaceable human elements at the core of therapy? Given the ethical implications that arise from these questions, this paper proposes that the artificial third can be a valuable asset when applied with insight and ethical consideration, enhancing but not replacing the human touch in therapy., (© Yuval Haber, Inbar Levkovich, Dorit Hadar-Shoval, Zohar Elyoseph. Originally published in JMIR Mental Health (https://mental.jmir.org).)

Introduction: Hyperbaric oxygen has been used as a medical treatment tool in hyperbaric chambers and is an integral part of professional and combat divers' activity. In extreme cases, exposure to hyperbaric oxygen can develop central nervous system oxygen toxicity (CNS-OT), which leads to seizures and eventually death. CNS-OT is caused by neuronal hyperactivity due to high oxygen levels, potentially damaging brain cells including the blood-brain barrier (BBB). However, the effect of hyperbaric oxygen levels on the healthy BBB has not been characterized directly yet., Methods: Six or three different groups of ~ eight rats or mice, respectively, were exposed to increasing levels of partial pressure of oxygen (0.21 to 5 ATA) in a hyperbaric chamber, followed by MRI scanning with gadolinium. Statistical significance (adjusted p-value ≤ 0.05) was assessed using linear regression and ordinary one-way (rats) or two-way (mice) ANOVA with correction of multiple comparison tests. In rats, the effect of 100% oxygen at 5 ATA was independently validated using FITC-Dextran (5 kDa). Statistical significance (p-value ≤ 0.05) was assessed using Welch's t-test and effect size was calculated by Cohen's D., Results: In rats, analyzed MRI scans showed a significant trend of increase in the % gadolinium in brain tissues as a result of hyperbaric oxygen pressures (p-value = 0.0079). The most significant increase was measured at 4 ATA compared to air (adjusted p-value = 0.0461). Significant increased FITC-Dextran levels were measured in the rats' brains under 100% oxygen at 5 ATA versus air (p-value = 0.0327; Effect size = 2.0). In mice, a significant increase in gadolinium penetration into the hippocampus and frontal cortex was measured over time (adjusted p-value < 0.05) under 100% oxygen at 3 and 5 ATA versus air, and between the treatments (adjusted p-value < 0.0001)., Conclusions: The BBB is increasingly disrupted due to higher levels of hyperbaric oxygen in rodents, indicating a direct relation between hyperbaric oxygen and BBB dysregulation for the first time. We suggest considering this risk in different diving activities, and protocols using a hyperbaric chamber. On the other hand, this study highlights the potential therapeutic usage of hyperbaric oxygen for controlled drug delivery through the BBB into brain tissues in different brain-related diseases., (© 2024. The Author(s).)

Methionine biosynthesis relies on the sequential catalysis of multiple enzymes. Escherichia coli , the main bacteria used in research and industry for protein production and engineering, utilizes the three-step trans-sulfurylation pathway catalyzed by L-homoserine O-succinyl transferase, cystathionine gamma synthase and cystathionine beta lyase to convert L-homoserine to L-homocysteine. However, most bacteria employ the two-step direct-sulfurylation pathway involving L-homoserine O-acetyltransferases and O-acetyl homoserine sulfhydrylase. We previously showed that a methionine-auxotroph Escherichia coli strain (MG1655) with deletion of metA , encoding for L-homoserine O-succinyl transferase, and metB , encoding for cystathionine gamma synthase, could be complemented by introducing the genes metX , encoding for L-homoserine O-acetyltransferases and metY , encoding for O-acetyl homoserine sulfhydrylase, from various sources, thus altering the Escherichia coli methionine biosynthesis metabolic pathway to direct-sulfurylation. However, introducing metX and metY from Corynebacterium glutamicum failed to complement methionine auxotrophy. Herein, we generated a randomized genetic library based on the metX and metY of Corynebacterium glutamicum and transformed it into a methionine-auxotrophic Escherichia coli strain lacking the metA and metB genes. Through multiple enrichment cycles, we successfully isolated active clones capable of growing in M9 minimal media. The dominant metX mutations in the evolved methionine-autotrophs Escherichia coli were L315P and H46R. Interestingly, we found that a metY gene encoding only the N-terminus 106 out of 438 amino acids of the wild-type MetY enzyme is functional and supports the growth of the methionine auxotroph. Recloning the new genes into the original plasmid and transforming them to methionine auxotroph Escherichia coli validated their functionality. These results show that directed enzyme-evolution enables fast and simultaneous engineering of new active variants within the Escherichia coli methionine direct-sulfurylation pathway, leading to efficient complementation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (© 2024 The Authors.)

For breast cancer survivors, returning to work is an important step for their personal, financial, and psycho-social recovery. Returning to work as a school counselor can be particularly challenging because of the demands of their job and stress at work. This qualitative study examines return to work among school counselors who are breast cancer survivors. In-depth, semi-structured interviews were conducted with 28 survivors of breast cancer stages I-III between the ages of 32 and 55, and up to ten years after the completion of chemotherapy. Interviews focused on the discovery of the illness, treatment period, ramifications of the diagnosis on various aspects of life, and implications for work. Using thematic analysis of the data collected, analysis of the findings revealed three key themes: 1) "Everyone is replaceable": The significance of disruptions in work continuity for school counselors who are breast cancer survivors. 2) "From Zero to a Hundred": Challenges Faced by Counselors in Returning to Work after Breast Cancer Recovery.3) "It's hard to listen to counselees' problems when I am immersed in my own crisis": How surviving breast cancer affects return to work among school counselors. Findings highlight the unique needs of these counselors and the challenges they face upon returning to work. The study discusses recommendations for school principals including training, advocacy, and awareness to support survivors and improve their return to work., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Levkovich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: The number of cancer survivors living with and beyond cancer treatment is rising globally. It is fundamental to understand the extent and type of psychosocial care services offered worldwide. We evaluated models of cancer survivorship care, psychosocial care practices in the post-treatment survivorship phase, and barriers/facilitators to delivery of psychosocial care services, including in low- and middle-income countries (LMICs)., Methods: The International Psycho-Oncology Society (IPOS) Survivorship Special Interest Group led a cross-sectional online survey between March and November 2022. Health care professionals and researchers in psycho-oncology were invited through the IPOS global membership, social media, and snowballing. The survey was administered to individuals but included questions related to practices in their country at a national level., Results: Two hundred eighty-three respondents from 37 countries participated (40% from LMICs), with a median of 12 years of experience (IQR, 6-20) in the psycho-oncology field. Participants reported that the most common elements of routine survivorship care were related to the prevention/management of recurrences/new cancers (74%), physical late effects (59%), and chronic medical conditions (53%), whereas surveillance/management of psychosocial late effects (27%) and psychosocial/supportive care (25%) were least common. Service availability was more commonly reported in high-income countries (HICs) than LMICs related to reproductive health (29% v 17%), genetic counseling/support (40% v 20%), and identifying/managing distress (39% v 26%) and pain (66% v 48%). Key barriers included providers focusing on treatment not survivorship (57%), medical not psychosocial care (60%), and a lack of allied health providers to deliver psychosocial care (59%)., Conclusion: The psychosocial needs of people living with cancer are not adequately available and/or provided in post-treatment survivorship even in HICs, because of barriers at patient, provider, and system levels.

Background: Sports and physical activity are known risk factors for pelvic floor dysfunction (PFD). The aim of this study is to examine the impact of amateur running on PFD, quality of life (QoL), and sexual function., Methods: Amateur runners were contacted through social media. Their PFD, sexual function, and QoL were evaluated by self-reporting validated questionnaires (PFDI-20, PISQ-12, IIQ-7). They were divided by degree of effort into two categories, 'High effort' and 'Moderate effort'. The differences between the two groups were examined by a Mann-Whitney U Test, T-Test, and Chi-square test., Results: 180 women were included. A high incidence of PFD was found among 'High effort' runners in comparison to 'Moderate effort' runners. In addition, women who scored above the median in the PFDI-20 showed significantly greater impairment in QoL and sexual function. Interestingly, the 'High effort' group reported experiencing higher intensity orgasms compared with women in the 'Moderate effort' group. A correlation was also found between the weekly running distance and the intensity of orgasm experienced (P value = 0.004)., Conclusion: 'High effort' runners present a higher incidence of PFD in comparison to 'Moderate effort' runners. Professional pelvic floor muscle training counselling should be considered even for amateur runners. Future interventional physical therapy studies should be carried out in order to investigate preventative strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mutations in the human AAA-ATPase VPS4 isoform, VPS4A, cause severe neurodevelopmental defects and congenital dyserythropoietic anemia (CDA). VPS4 is a crucial component of the endosomal sorting complex required for transport (ESCRT) system, which drives membrane remodeling in numerous cellular processes, including receptor degradation, cell division, and neural pruning. Notably, while most organisms encode for a single VPS4 gene, human cells have 2 VPS4 paralogs, namely VPS4A and VPS4B, but the functional differences between these paralogs is mostly unknown. Here, we set out to investigate the role of the human VPS4 paralogs in cytokinetic abscission using a series of knockout cell lines. We found that VPS4A and VPS4B hold both overlapping and distinct roles in abscission. VPS4A depletion resulted in a more severe abscission delay than VPS4B and was found to be involved in earlier stages of abscission. Moreover, VPS4A and a monomeric-locked VPS4A mutant bound the abscission checkpoint proteins CHMP4C and ANCHR, while VPS4B did not, indicating a regulatory role for the VPS4A isoform in abscission. Depletion of VTA1, a co-factor of VPS4, disrupted VPS4A-ANCHR interactions and accelerated abscission, suggesting that VTA1 is also involved in the abscission regulation. Our findings reveal a dual role for VPS4A in abscission, one that is canonical and can be compensated by VPS4B, and another that is regulatory and may be delivered by its monomeric form. These observations provide a potential mechanistic explanation for the neurodevelopmental defects and other related disorders reported in VPS4A-mutated patients with a fully functional VPS4B paralog., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dvilansky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Medical cannabis treatment for autistic children has recently become popular, and studies have focused on examining the treatment's effects on children's symptom presentation, reported side effects, and dropout rates. However, no previous study has investigated the factors influencing adherence and dropout rates in cannabis treatment., Method: This explanatory sequential mixed-methods study explored these factors by examining the characteristics of 87 autistic children and their families and deepening parents' perspectives and experiences of the 6-month CBD-rich cannabis treatment's benefits and barriers., Results: We found this treatment to have a high (75%) adherence rate, relatively mild side effects, and substantial reported benefits for the children and families. However, this treatment was not free of barriers; the intake regime, some side effects, and in some cases, unrealistic parental expectations made adherence difficult for some families., Conclusion: Our results highlight the importance of providing professional guidance and knowledge to parents of autistic children, enhancing their understanding of the impact of CBD-rich cannabis treatment on their children and expected related challenges, and coordinating realistic treatment expectations. We hope that addressing these important aspects will influence parents' ability to adhere to and enjoy the benefits of cannabis treatment for their autistic children., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The diagnosis of Q fever is challenging due to nonspecific symptoms and negative standard blood culture results. Serological testing through immunofluorescence assay (IFA) is the most commonly used method for diagnosing this disease. Polymerase chain reaction (PCR) tests can also be used to detect bacterial DNA if taken at an appropriate time. Once the presence of bacteria is confirmed in a sample, an enrichment step is required before characterizing it through sequencing. Cultivating C. burnetii is challenging as it can only be isolated by inoculation into cell culture, embryonated eggs, or animals. In this article, we describe the isolation of C. burnetii from a valve specimen in Vero cells. We conducted genome sequencing and taxonomy profiling of this isolate and were able to determine its taxonomic affiliation. Furthermore, Multispacer sequence typing (MST) analysis suggests that the infection originated from a local strain of C. burnetii found around northern Israel and Lebanon. This novel strain belongs to a previously described genotype MST6, harboring the QpRS plasmid, never reported in Israel., Competing Interests: None declared, (© 2024 The Authors.)

Background: The aim of this study was to determine whether genetic variants are associated with idiopathic intracranial hypertension (IIH) in a unique village where many of the IIH patients have familial ties, a homogenous population and a high prevalence of consanguinity. Several autosomal recessive disorders are common in this village and its population is considered at a high risk for genetic disorders., Methods: The samples were genotyped by the Ilumina OmniExpress-24 Kit, and analyzed by the Eagle V2.4 and DASH software package to cluster haplotypes shared between our cohort. Subsequently, we searched for specific haplotypes that were significantly associated with the patient groups., Results: Fourteen patients and 30 controls were included. Samples from 22 female participants (11 patients and 11 controls) were evaluated for haplotype clustering and genome-wide association studies (GWAS). A total of 710,000 single nucleotide polymorphisms (SNPs) were evaluated. Candidate areas positively associated with IIH included genes located on chromosomes 16, 8 (including the CA5A and BANP genes, p < 0.01), and negatively associated with genes located on chromosomes 1 and 6 (including PBX1, LMX1A, ESR1 genes, p < 0.01)., Conclusions: We discovered new loci possibly associated with IIH by employing a GWAS technique to estimate the associations with haplotypes instead of specific SNPs. This method can in all probability be used in cases where there is a limited amount of samples but strong familial connections. Several loci were identified that might be strong candidates for follow-up studies in other well-phenotypes cohorts., (© 2024. The Author(s).)

Background: Stress is an emotional response caused by external triggers and is a high-prevalence global problem affecting mental and physical health. Several different digital therapeutic solutions are effective for stress management. However, there is limited understanding of the association between relaxation components and stress levels when using a digital app., Objective: This study investigated the contribution of relaxation tools to stress levels over time. We hypothesized that participation in breathing exercises and cognitive behavioral therapy-based video sessions would be associated with a reduction in stress levels. We also hypothesized a significant reduction specifically in participants' perceived sense of burden and lack of productivity when engaged with breathing exercises and video sessions., Methods: Stress levels were evaluated in a real-world data cohort using a behavioral health app for digital intervention and monitoring change. This retrospective real-world analysis of users on a mobile platform-based treatment followed users (N=490) who started with moderate and above levels of stress and completed at least 2 stress assessments. The levels of stress were tracked throughout the first 10 weeks. A piecewise mixed effects model was applied to model the trajectories of weekly stress mean scores in 2 time segments (1-6 weeks and 6-10 weeks). Next, a simple slope analysis was used for interpreting interactions probing the moderators: breathing exercises and video sessions. Piecewise mixed-effects models were also used to model the trajectories of specific perceived stress item rates in the stress questionnaire in the 2 segments (1-6 weeks and 6-10 weeks) and whether they are moderated by the relaxation engagements. Simple slope analysis was also used here for the interpretation of the interactions., Results: Analysis revealed a significant decrease in stress symptoms (β=-.25; 95% CI -0.32 to -0.17; P<.001) during the period of 1-6 weeks of app use that was maintained during the period of 6-10 weeks. Breathing exercises significantly moderated the reduction in stress symptoms during the period of 1-6 weeks (β=-.07; 95% CI -0.13 to -0.01; P=.03), while engagement in digital video sessions did not moderate stress scores. Engagement in digital video sessions, as well as breathing exercises, significantly moderated the reduction in perceived sense of burden and lack of productivity during weeks 1-6 and remained stable during weeks 6-10 on both items., Conclusions: This study sheds light on the association between stress level reduction and specific components of engagement in a digital health app, breathing exercises, and cognitive behavioral therapy-based video sessions. Our findings provide a basis for further investigation of current and moderating factors that contribute to the personalization of digital intervention. In addition, results may aid in developing a more comprehensive understanding of how digital intervention tools work for mental health and for whom they are most effective., (©Inbar Breuer-Asher, Marilyn D Ritholz, David L Horwitz, Omar Manejwala, Ephraim Behar, Yifat Fundoiano-Hershcovitz. Originally published in JMIR Formative Research (https://formative.jmir.org), 19.03.2024.)

Background: The current paradigm in mental health care focuses on clinical recovery and symptom remission. This model's efficacy is influenced by therapist trust in patient recovery potential and the depth of the therapeutic relationship. Schizophrenia is a chronic illness with severe symptoms where the possibility of recovery is a matter of debate. As artificial intelligence (AI) becomes integrated into the health care field, it is important to examine its ability to assess recovery potential in major psychiatric disorders such as schizophrenia., Objective: This study aimed to evaluate the ability of large language models (LLMs) in comparison to mental health professionals to assess the prognosis of schizophrenia with and without professional treatment and the long-term positive and negative outcomes., Methods: Vignettes were inputted into LLMs interfaces and assessed 10 times by 4 AI platforms: ChatGPT-3.5, ChatGPT-4, Google Bard, and Claude. A total of 80 evaluations were collected and benchmarked against existing norms to analyze what mental health professionals (general practitioners, psychiatrists, clinical psychologists, and mental health nurses) and the general public think about schizophrenia prognosis with and without professional treatment and the positive and negative long-term outcomes of schizophrenia interventions., Results: For the prognosis of schizophrenia with professional treatment, ChatGPT-3.5 was notably pessimistic, whereas ChatGPT-4, Claude, and Bard aligned with professional views but differed from the general public. All LLMs believed untreated schizophrenia would remain static or worsen without professional treatment. For long-term outcomes, ChatGPT-4 and Claude predicted more negative outcomes than Bard and ChatGPT-3.5. For positive outcomes, ChatGPT-3.5 and Claude were more pessimistic than Bard and ChatGPT-4., Conclusions: The finding that 3 out of the 4 LLMs aligned closely with the predictions of mental health professionals when considering the "with treatment" condition is a demonstration of the potential of this technology in providing professional clinical prognosis. The pessimistic assessment of ChatGPT-3.5 is a disturbing finding since it may reduce the motivation of patients to start or persist with treatment for schizophrenia. Overall, although LLMs hold promise in augmenting health care, their application necessitates rigorous validation and a harmonious blend with human expertise., (© Zohar Elyoseph, Inbar Levkovich. Originally published in JMIR Mental Health (https://mental.jmir.org).)

Control over the joint spectral amplitude of a photon pair has proved highly desirable for many quantum applications, since it contains the spectral quantum correlations, and has crucial effects on the indistinguishability of photons, as well as promising emerging applications involving complex quantum functions and frequency encoding of qudits. Until today, this has been achieved by engineering a single degree of freedom, either by custom poling nonlinear crystal or by shaping the pump pulse. We present a combined approach where two degrees of freedom, the phase-matching function, and the pump spectrum, are controlled. This approach enables the two-dimensional control of the joint spectral amplitude, generating a variety of spectrally encoded quantum states - including frequency uncorrelated states, frequency-bin Bell states, and biphoton qudit states. In addition, the joint spectral amplitude is controlled by photon bunching and anti-bunching, reflecting the symmetry of the phase-matching function.

The COVID-19 pandemic has led to high global demand for vaccines to safeguard public health. To that end, our institute has developed a recombinant viral vector vaccine utilizing a modified vesicular stomatitis virus (VSV) construct, wherein the G protein of VSV is replaced with the spike protein of SARS-CoV-2 (rVSV-ΔG-spike). Previous studies have demonstrated the production of a VSV-based vaccine in Vero cells adsorbed on Cytodex 1 microcarriers or in suspension. However, the titers were limited by both the carrier surface area and shear forces. Here, we describe the development of a bioprocess for rVSV-ΔG-spike production in serum-free Vero cells using porous Fibra-Cel ® macrocarriers in fixed-bed BioBLU ® 320 5p bioreactors, leading to high-end titers. We identified core factors that significantly improved virus production, such as the kinetics of virus production, the use of macrospargers for oxygen supply, and medium replenishment. Implementing these parameters, among others, in a series of GMP production processes improved the titer yields by at least two orders of magnitude (2e9 PFU/mL) over previously reported values. The developed process was highly effective, repeatable, and robust, creating potent and genetically stable vaccine viruses and introducing new opportunities for application in other viral vaccine platforms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cohen, Simon, Hazan, Tal, Tzadok, Levin, Girshengorn, Mimran, Natan, Baruhi, David, Rosen, Shmaya, Borni, Cohen, Lupu, Kedmi, Zilberman, Jayson, Monash, Dor, Diamant, Goldvaser, Cohen-Gihon, Israeli, Lazar, Shifman, Beth-Din, Zvi, Oren, Makovitzki, Lerer, Mimran, Toister, Zichel, Adar and Epstein.)

Background: Breast cancer is a common cause for central nervous system (CNS) metastasis, resulting in a significant reduction in overall survival. Germline pathogenic variants (PVs) in BRCA1/2 are the most common genetic risk factor for breast cancer, associated with poor prognostic factors. This study sought to explore the patterns and outcome of CNS metastases in breast cancer patients with germline PVs in BRCA1/2 genes., Methods: A retrospective cohort of 75 breast cancer patients with known BRCA1/2 mutation status, who were diagnosed with CNS metastases in 2006-2021. Histopathology, characteristics of CNS disease, treatments, and survival were compared between BRCA1/2 carriers (n = 25) and non-carriers (n = 50), using propensity score matching (1:2 ratio) to control for the possible influence of tumor receptor status (ER, PR, HER2) and patient age. Pearson chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses., Results: Patients with PVs in BRCA1/2 had more high-grade tumors (88% vs. 68%, P = 0.060), were younger at CNS disease diagnosis (median 46.69 vs. 55.02 years, P = 0.003) and had better ECOG performance status (ECOG PS 0 in 20% vs. 2%, P = 0.033), but without significant differences in systemic or CNS-directed treatment approaches. BRCA1/2 mutation was associated with a higher rate of temporal lobe involvement (52% vs. 26%, P = 0.026) and leptomeningeal spread (40% vs. 20%, P = 0.020). Survival after diagnosis of CNS disease was shorter (median 8.03 vs. 28.36 months, P < 0.0001), with no significant differences in time to development of CNS metastases or overall-survival., Conclusion: Patients with CNS metastatic breast cancer and PVs in BRCA1/2 showed a higher rate of leptomeningeal and temporal lobe involvement, and a shorter survival with CNS disease. To the best of our knowledge, this is the first study suggesting an exclusive impact of germline BRCA1/2 mutations in CNS metastatic breast cancer., (© 2024. The Author(s).)