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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.)

Suicide constitutes a public health issue of major concern. Ongoing progress in the field of artificial intelligence, particularly in the domain of large language models, has played a significant role in the detection, risk assessment, and prevention of suicide. The purpose of this review was to explore the use of LLM tools in various aspects of suicide prevention. PubMed, Embase, Web of Science, Scopus, APA PsycNet, Cochrane Library, and IEEE Xplore-for studies published were systematically searched for articles published between January 1, 2018, until April 2024. The 29 reviewed studies utilized LLMs such as GPT, Llama, and BERT. We categorized the studies into three main tasks: detecting suicidal ideation or behaviors, assessing the risk of suicidal ideation, and preventing suicide by predicting attempts. Most of the studies demonstrated that these models are highly efficient, often outperforming mental health professionals in early detection and prediction capabilities. Large language models demonstrate significant potential for identifying and detecting suicidal behaviors and for saving lives. Nevertheless, ethical problems still need to be examined and cooperation with skilled professionals is essential., Competing Interests: Declarations. Ethics Approval: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

The "l-Doubling" phenomenon emanates from the coupling between molecular rotations and perpendicular vibrations (bending modes) in polyatomic molecules. This elusive phenomenon has been largely discarded in laser-induced molecular alignment. Here we explore and unveil the ramifications of l-Doubling on the coherent rotational dynamics of linear triatomic molecules at ambient temperatures and above. The observed l-Doubling dynamics may be wrongly considered as collisional decay throughout the first few hundreds of picoseconds past excitation, highlighting the importance of correct assimilation of l-Doubling in current research of dissipative rotational dynamics and in coherent rotational dynamics in general.

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.)

This qualitative study examined the experiences of school counsellors facing loss of colleagues, an unexplored area in educational settings. Twenty-one school counsellors who had lost their colleagues within the past five years participated in the semi-structured interviews. The findings revealed a wide spectrum of experiences among school counsellors who face colleague loss. Reactions range from initial shock to immediate action and are influenced by the nature of previous relationships with the deceased. Counsellors experience conflict between professional responsibilities and personal emotions and often struggle with blurred professional boundaries. They provide immediate emotional support to staff and students while simultaneously needing ongoing support, which is not always possible. Counsellors have developed diverse coping mechanisms, including peer support groups. These results highlight the need for formal support systems for counsellors dealing with colleague loss, emphasizing the complex interplay between personal grief and professional duties in a unique school environment., 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.

Background: Underdiagnosis of relevant risk factors has contributed to the increasing stroke incidence in young adults. Blood pressure cut-off values for adolescents are neither sex specific nor based on cardiovascular outcomes., Methods: This nationwide, population-based, retrospective cohort study included all Israeli adolescents 16-19 years of age who were medically evaluated before compulsory military service from 1985 to 2013, including routine blood pressure measurements. The primary outcome was the first occurrence of a stroke (ischemic or hemorrhagic) at a young age (≤52 years), as documented in the Israeli National Stroke Registry. Cox proportional hazard models were stratified by sex and adjusted for birth year, sociodemographic variables, and adolescent body mass index., Results: The cohort comprised 1,897,048 adolescents (42.4% women). During 11,355,476 person-years of follow-up, there were 1470 first stroke events at a young age. In men, an adolescent diastolic blood pressure value of ≥80 mmHg, compared with the reference group (diastolic blood pressure value of <70 mmHg), was associated with an increased risk of stroke (adjusted hazard ratio 1.28; 95% confidence interval [CI], 1.04 to 1.58), while a diastolic blood pressure value of 70-79 mmHg was not associated with an increased risk of stroke (adjusted hazard ratio 1.11; 95% CI 0.90 to 1.34). Among women, an adolescent diastolic blood pressure value of ≥80 mmHg, compared with the reference group (diastolic blood pressure value of <70 mmHg) was associated with an increased risk of stroke at a young age (adjusted hazard ratio 1.38; 95% CI 1.03 to 1.88), as was a diastolic blood pressure value of 70-79 mmHg (adjusted hazard ratio 1.41; 95% CI 1.09 to 1.81). Elevated adolescent systolic blood pressure values (≥120 mmHg) were not associated with an increased risk of stroke., Conclusions: Diastolic blood pressure values of ≥80 mmHg in adolescence were associated with an increased risk of stroke at a young age in both men and women. No similar association was observed for elevated systolic blood pressure.

Recent neuroimaging and eye-tracking studies have suggested that children with autism exhibit more variable and idiosyncratic brain responses and eye movements than typically developing (TD) children. Here, we extended this research to pupillometry recordings. We successfully acquired pupillometry recordings from 111 children (74 with autism), 4.5-years-old on average, who viewed three 90 s movies, twice. We extracted their pupillary time-course for each movie, capturing their stimulus evoked pupillary responses. We then computed the correlation between the time-course of each child and those of all others in their group as well as between each autistic child and all children in the TD group. This yielded an average inter-subject correlation value per child, representing how similar their pupillary responses were to all others in their group or the comparison group. Children with autism exhibited significantly weaker inter-subject correlations than TD children in all comparisons. These differences were independent of previously reported differences in gaze inter-subject correlations and were largest in responses to a naturalistic movie containing footage of a social interaction between two TD children. The results demonstrate the utility of measuring the idiosyncrasy of pupil regulation, which can be performed with passive viewing of movies even by young children with co-occurring intellectual disability. These findings reveal that a considerable number of children with autism have significantly less stable, idiosyncratic pupil regulation than TD children, indicative of more variable, weakly regulated, underlying neural activity., (© 2024 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Background: Management of cancer patients presenting with an acute coronary syndrome (ACS) may be challenging. In this study, we sought to examine whether and how a concomitant diagnosis of active cancer affects patients' management and outcomes following an event of ACS., Methods: We used a retrospective cohort data analysis of patients from the Acute Coronary Syndrome Israeli Survey (ACSIS) carried out between the years 2016-2021 to compare patients with and without a concomitant diagnosis of active cancer., Results: Of 4913 patients who presented with an ACS, 90 (1.8%) patients had a concomitant active cancer. Cancer patients were older, with a higher prevalence of hypertension and chronic renal failure. The rate of ST-elevation myocardial infarction (STEMI) was similar (40%) between both groups. Cancer patients were less likely to undergo coronary angiography during hospitalization; but once it was performed, the rate of percutaneous coronary intervention was similar. The presence of cancer during an ACS was associated with an increased short- and long-term mortality. In a multivariate analysis, the risk for 1-year mortality remained significantly higher in cancer patient (HR 2.72, 95% CI 1.74-4.24, p < 0.001), and was most prominent in patients presenting with STEMI (HR 5.00, 95% CI 2.40-10.39, p < 0.001). Short- and long-term death rates were also higher in cancer patients after a propensity score matching and adjustment for comorbidities other than cancer., Conclusion: Despite significant advances in oncologic and cardiac care, the presence of active cancer in patients with an ACS is still associated with significantly increased risk for 1-year mortality., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

In 2014, the International Myeloma Working Group (IMWG) updated the criteria for diagnosing myeloma and added three additional criteria to the traditional Calcium elevation, Renal impairment, Anemia, Bone disease (CRAB) criteria, called the Sixty % marrow plama cells, Light chain ratio >60, Mri demonstates lytic lesions (SLiM) criteria (clonal bone marrow plasma cells ≥60%, involved to uninvolved free light chain ratio (FLCr) ≥100 and >1 focal lesion on magnetic resonance imaging (MRI)). We report on the outcomes of 30 patients who underwent autologous stem cell transplantation (ASCT) where therapy was initiated solely based on SLiM criteria and compared them to a matched cohort of 60 patients whose myeloma-defining event was CRAB. The SLiM cohort had a shorter median time to neutrophil (15 vs. 16 days, p = 0.049) and platelet (15 vs. 17 days, p = 0.0004) engraftment. The 36-month overall survival (OS) was 100% in the SLiM group and 93.27% in the control group (95% CI 83.06%-97.42%), with a trend towards longer OS in the SLiM cohort (p = 0.065). The 36-month progression-free survival (PFS) was 91.61% in the SLiM (95% CI 69.93%-97.87%) and 65.95% in the control group (95% CI 52.31%-76.53%). There was no difference in the PFS between the cohorts (p = 0.414). ASCT is efficacious and safe in MM patients transplanted only due to SLIM criteria. Early intervention in this asymptomatic cohort did not appear to result in deeper responses or better PFS compared to outcomes in symptomatic patients., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

It has long been established that axions could have been produced within the nascent proto-neutron star formed following the type II supernova SN1987A, escaped the star due to their weak interactions, and then converted to gamma rays in the Galactic magnetic fields; the nonobservation of a gamma-ray flash coincident with the neutrino burst leads to strong constraints on the axion-photon coupling for axion masses m&#95;{a}≲10^{-10}  eV. In this Letter, we use SN1987A to constrain higher mass axions, all the way to m&#95;{a}∼10^{-3}  eV, by accounting for axion production from the Primakoff process, nucleon bremsstrahlung, and pion conversion along with axion-photon conversion on the still-intact magnetic fields of the progenitor star. Moreover, we show that gamma-ray observations of the next Galactic supernova, leveraging the magnetic fields of the progenitor star, could detect quantum chromodynamics axions for masses above roughly 50  μeV, depending on the supernova. We propose a new full-sky gamma-ray satellite constellation that we call the GALactic AXion Instrument for Supernova (GALAXIS) to search for such future signals along with related signals from extragalactic neutron star mergers.

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.)

Microorganisms use toxins to kill competing microorganisms or eukaryotic cells. Polymorphic toxins are proteins that encode carboxy-terminal toxin domains. Here we developed a computational approach to identify previously undiscovered, conserved toxin domains of polymorphic toxins within 105,438 microbial genomes. We validated nine short toxins, showing that they cause cell death upon heterologous expression in either Escherichia coli or Saccharomyces cerevisiae. Five cognate immunity genes that neutralize the toxins were also discovered. The toxins are encoded by 2.2% of sequenced bacteria. A subset of the toxins exhibited potent antifungal activity against various pathogenic fungi but not against two invertebrate model organisms or macrophages. Experimental validation suggested that these toxins probably target the cell membrane or DNA or inhibit cell division. Further characterization and structural analysis of two toxin-immunity protein complexes confirmed DNase activity. These findings expand our knowledge of microbial toxins involved in inter-microbial competition that may have the potential for clinical and biotechnological applications., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Objective: Depression is a substantial public health issue, with global ramifications. While initial literature reviews explored the intersection between artificial intelligence (AI) and mental health, they have not yet critically assessed the specific contributions of Large Language Models (LLMs) in this domain. The objective of this systematic review was to examine the usefulness of LLMs in diagnosing and managing depression, as well as to investigate their incorporation into clinical practice., Methods: This review was based on a thorough search of the PubMed, Embase, Web of Science, and Scopus databases for the period January 2018 through March 2024. The search used PROSPERO and adhered to PRISMA guidelines. Original research articles, preprints, and conference papers were included, while non-English and non-research publications were excluded. Data extraction was standardized, and the risk of bias was evaluated using the ROBINS-I, QUADAS-2, and PROBAST tools., Results: Our review included 34 studies that focused on the application of LLMs in detecting and classifying depression through clinical data and social media texts. LLMs such as RoBERTa and BERT demonstrated high effectiveness, particularly in early detection and symptom classification. Nevertheless, the integration of LLMs into clinical practice is in its nascent stage, with ongoing concerns about data privacy and ethical implications., Conclusion: LLMs exhibit significant potential for transforming strategies for diagnosing and treating depression. Nonetheless, full integration of LLMs into clinical practice requires rigorous testing, ethical considerations, and enhanced privacy measures to ensure their safe and effective use., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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).)

We present the investigation of a Burkholderia pseudomallei strain isolated from the urine of a 56-year-old male returning from a recreational trip to Thailand. The patient initially presented with fever and chills, and lobar as well as bladder and prostate involvement was demonstrated on imaging. Treatment first involved trimethoprim-sulfamethoxazole, the backbone of melioidosis therapy, but was discontinued upon the discovery of resistance to the drug through antimicrobial sensitivity testing via broth microdilution. Further analysis included genomic sequencing, immunotyping, and phenotypic assessment, including virulence testing in an animal model. Results indicated that this strain is a distinct, novel variant with antigenic similarity to other Thai strains displaying high virulence, with a significantly low murine intranasal lethal dose 50% inoculum. The emergence of such a strain, particularly if prevalent in tourist destinations in Thailand, could pose a substantial public health risk, highlighting the need for ongoing vigilance among infectious disease specialists and clinical microbiologists.

This study aimed to investigate the acute changes in proximal aortic distensibility, a measure of aortic stiffness, induced by acute exercise in participants with and without heart failure (HF). Participants with HF (n = 24) and without HF (n = 26) underwent cardiovascular magnetic resonance (CMR) (1.5 T) imaging at rest and after submaximal supine bicycle ergometry. The participants were further categorized into HF with reduced ejection fraction (HFrEF) (n = 14) and HF with preserved ejection fraction (n = 10) based on the left ventricular ejection fraction. At rest and immediately after exercise, cine CMR images of the cross-sectional ascending and descending aorta at the pulmonary artery bifurcation level were obtained to determine aortic distensibility (AoD), with lower AoD indicating greater aortic stiffness. Differences in means of values at rest and before and after exercise were compared using the nonparametric Wilcoxon sign test. There was no significant difference in AoD at rest between subjects with HF and controls. However, immediately after exercise, participants with HF but not controls exhibited a significant reduction in AoD, indicating higher aortic stiffness related to exercise (median [interquartile range] for the ascending aorta: 3.16 (1.26) × 10 -3 mm Hg -1 to 2.39 (1.57) × 10 -3 mm Hg -1 and the descending aorta: 4.19 (2.58) × 10 -3 mm Hg -1 to 2.96 (1.79) × 10 -3 mm Hg -1 ) (both p = 0.023). This decrease was particularly observed in participants with HFrEF but not in those with HF with preserved ejection fraction. Exercise-induced aortic stiffness, detectable by noninvasive CMR, may contribute to unfavorable ventricular-vascular interactions during exercise in participants with HF, especially HFrEF., Competing Interests: Declaration of competing interest The authors have no competing interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)