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In this study, we evaluated the contribution of the putative genetic factors into the established associations between selected circulating adipokine levels, body composition measurements, and low-back-pain-related disability scores (LBP_DS). A total of 1078 individuals from 98 nuclear families (with 1 to 11 siblings per family) were examined. A detailed self-report questionnaire was used to collect LBP disability data; body composition (fat, skeletal muscle mass, and extracellular water (ECW)) was assessed using the bioimpedance method; plasma levels of adipokines were measured by ELISA. Pedigree-based statistical analysis methods were used, including family-based variance component analysis (VCA) and principal phenotype analysis (PPA), to estimate the contribution of potential genetic and environmental factors. The VCA revealed a significant additive genetic component in LBP_DS and for the selected body composition phenotypes and adipokines. The study also revealed that both adipokines (GDF-15, chemerin, and follistatin) and body composition variables (BMI, fat mass/weight, waist circumference, and ECW) were genetically correlated with LBP_DS. Next, PPA generated two synthetic phenotypes: PPCT (combining cytokines) and PPBC (combining body composition variables). There was no significant correlation between the putative genetic factors underlying the created PPs. However, each of them displayed a significant genetic correlation with LBP_DS. These findings indicate that genetic factors that are assumingly common for several adipokine variations and several body composition measurements, respectively, presumably have a pleotropic genetic influence on the LBP_DS variation, independently from one another. This, in turn, suggests that the alleged genetic factors employing pleiotropic effects on LBP_DS have a complex and probably non-overlapping composition.

Background: Pediatric pain significantly affects children’s lives, leading to school absenteeism, impaired social interactions, and psychological distress. The perception of sensory signals as pain is influenced by the brain’s noradrenergic system, and recent evidence suggests that chronic pain may impact cognitive functioning and emotional regulation. Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with alterations in the dopaminergic/noradrenergic systems, which could affect pain perception. Pain-associated conditions and frequent analgesic use in childhood may be linked to ADHD development and could serve as early indicators, yet data on this potential association remain limited. Study Aim: This population-based case-control study in Israel aimed to assess the prevalence of pain-related diagnoses prior to ADHD diagnosis in children aged 5 to 18. The study included children registered with Leumit Health Services (LHS) between 1 January 2006, and 30 June 2021. Children diagnosed with ADHD were compared to matched controls, selected based on age, gender, socioeconomic status, and other sociodemographic factors, who were never diagnosed with ADHD during the study period. Results: Children with ADHD (N = 18,756) and controls (N = 37,512) were precisely matched for sociodemographic characteristics. Individuals with ADHD exhibited significantly higher frequencies of diverse pain conditions, including those associated with illness [headache, earaches, and throat pain (odds ratios [OR] = 1.156 [95%CI 1.085, 1.232], 1.295 [95%CI 1.217, 1.377], and 1.080 [95%CI 1.019, 1.145], respectively; p < 0.01)] and injury [sprains and strains (OR = 1.233 [95% CI 1.104,1.376)]. Analgesics were more frequently purchased by individuals with ADHD, particularly paracetamol (OR = 1.194 [95%CI 1.152, 1.237], p < 0.001) and ibuprofen (OR = 1.366 [95%CI 1.318, 1.416], p = 0.001). Conclusions: This study highlights a potential connection between ADHD and pediatric pain. The elevated rates of pain diagnoses and analgesic usage among children with ADHD underscore the need for further research.

The associations of cardiovascular disease (CVD) with comorbidities and biochemical and body composition measurements are repeatedly described but have not been studied simultaneously. In the present cross-sectional study, information on CVD and comorbidities [type 2 diabetes mellitus (T2DM), hypertension (HTN), and hyperlipidemia (HDL)], body composition, levels of soluble markers, and other measures were collected from 1079 individuals. When we examined the association of each comorbidity and CVD, controlling for other comorbidities, we observed a clear pattern of the comorbidity-related specific associations with tested covariates. For example, T2DM was significantly associated with GDF-15 levels and the leptin/adiponectin (L/A) ratio independently of two other comorbidities; HTN, similarly, was independently associated with extracellular water (ECW) levels, L/A ratio, and age; and HDL was independently related to age only. CVD showed very strong independent associations with each of the comorbidities, being associated most strongly with HTN (OR = 10.89, 6.46–18.38) but also with HDL (2.49, 1.43–4.33) and T2DM (1.93, 1.12–3.33). An additive Bayesian network analysis suggests that all three comorbidities, particularly HTN, GDF-15 levels, and ECW content, likely have a main role in the risk of CVD development. Other factors, L/A ratio, lymphocyte count, and the systemic inflammation response index, are likely indirectly related to CVD, acting through the comorbidities and ECW.

Urinary tract infections (UTIs) in childhood are common and are associated with considerable acute morbidity and long-term complications. The need for updated data to optimize empiric antibiotic therapy is crucial. We aimed to investigate the pathogens causing pediatric community acquired UTIs, their correlation with demographic characteristics, and trends in their antimicrobial resistance. This nationwide cross-sectional study included all 53,203 children (Escherichia coli (E. coli) (82.1%) was the most common uropathogen, followed by Enterobacter, Klebsiella, Proteus, Pseudomonas, and Enterococcus species. The bacterial distribution displayed statistically significant (p < 0.0001) gender- and sector-specific patterns with a higher relative prevalence of non-E. coli UTI in Jewish and males. The rate of extended-spectrum beta-lactamase-positive E. coli increased substantially and significantly (p < 0.001) from only 6.1% in 2007 to 25.4% in 2021. Most non-E. coli uropathogens exhibited resistance to commonly used empiric antibiotics for UTIs in children. These findings are significant in guiding optimal empiric antibiotic treatment for pediatric community acquired UTIs. The resistance of uropathogens to antimicrobials is region- and time-dependent. Therefore, the periodic and local assessment of antibiotic resistance trends is essential to update guidelines and provide the most appropriate antibacterial therapy for children with UTIs.

Background: The susceptibility to SARS-CoV-2 infection is complex and not yet fully elucidated, being related to many variables; these include human microbiome and immune status, which are both affected for a long period by antibiotic use. We therefore aimed to examine the association of previous antibiotic consumption and SARS-CoV-2 infection in a large-scale population-based study with control of known confounders. Methods: A matched case–control study was performed utilizing the electronic medical records of a large Health Maintenance Organization. Cases were subjects with confirmed SARS-CoV-2 infection (n = 31,260), matched individually (1:4 ratio) to controls without a positive SARS-CoV-2 test (n = 125,039). The possible association between previous antibiotic use and SARS-CoV-2 infection was determined by comparing antibiotic consumption in the previous 6 and 12 months between the cases and controls. For each antibiotic consumed we calculated the odds ratio (OR) for documented SARS-CoV-2 infection, 95% confidence interval (CI), and p-value using univariate and multivariate analyses. Results: The association between previous antibiotic consumption and SARS-CoV-2 infection was complex and bi-directional. In the multivariate analysis, phenoxymethylpenicillin was associated with increased rate of SARS-CoV-2 infection (OR 1.110, 95% CI: 1.036–1.191) while decreased rates were associated with previous consumption of trimethoprim-sulfonamides (OR 0.783, 95% CI: 0.632–0.971) and azithromycin (OR 0.882, 95% CI: 0.829–0.938). Fluroquinolones were associated with decreased rates (OR 0.923, 95% CI: 0.861–0.989) only in the univariate analysis. Previous consumption of other antibiotics had no significant association with SARS-CoV-2 infection. Conclusions: Previous consumption of certain antibiotic agents has an independent significant association with increased or decreased rates of SARS-CoV-2 infection. Plausible mechanisms, that should be further elucidated, are mainly antibiotic effects on the human microbiome and immune modulation.

Schizophrenia (SCZ) is a chronic neurodevelopmental psychotic disorder. The immune system and neuroinflammation seem to play a central role in the pathophysiology of SCZ. Clozapine is an effective atypical antipsychotic used for treatment-resistant SCZ. Life-threatening side effects, such as myocarditis, limit its use. We investigated the immunomodulatory effects of clozapine in an astroglial model of neuroinflammation. We thus assessed the effect of clozapine on the production of inflammatory mediators in human-derived astroglial (A172) cells, stimulated with a cytokine mix (TNFα, IL-1β, IFNγ). RT-PCR and ELISA analyses demonstrated that clozapine suppressed gene expression and production of TNFα, IL-1β and IL-8 and increased COX2 mRNA 24 h after stimulation. Clozapine inhibited Akt phosphorylation induced by the cytokine mix at 10 min and 40 min, as assessed by Western blot analysis with anti-pT308Akt antibody. Pretreatment with the Akt inhibitor MK-2206 increased COX2 gene expression in cytokine-stimulated cells, suggesting that Akt inhibition may be involved in COX2 gene expression upregulation. Clozapine may possess dual beneficial effects: inhibiting astroglial production of proinflammatory cytokines, thus attenuating neuroinflammation, and upregulating COX2 expression that may be relevant to improvement of neural functioning while accounting for some of its detrimental effects. Patients with TRS and neuroinflammatory markers may benefit particularly from clozapine treatment.

COVID-19 is a worldwide pandemic caused by SARS-CoV-2, to which adults are usually more susceptible than children. Growth hormone (GH) levels differ between children and adults and decrease with age. There is bidirectional crosstalk between the GH/insulin-like growth factor-1 (IGF-1) pathway and the immune system that plays a significant role in SARS-CoV-2 infection. We evaluated the association between somatotropin treatment (GH replacement therapy) and the risk for SARS-CoV-2 positivity (a marker for COVID-19 infection) in children with growth hormone issues (GHI): growth hormone deficiency (GHD) and idiopathic short stature (ISS). A population-based cross-sectional study in Leumit Health Services (LHS) was performed using the electronic health record (EHR) database. The rates of SARS-CoV-2 positivity were evaluated among children with GHI, treated or untreated with somatotropin. Higher rates of SARS-CoV-2 positivity were found in GHI children, influenced by the same confounders reported in the pediatric population. A lower prevalence of SARS-CoV-2 PCR positivity was found among the somatotropin-treated children. A multivariate analysis documented that somatotropin treatment was associated with a reduced risk of SARS-CoV-2 positivity (Odds Ratio (OR) = 0.47, Confidence Interval (CI) 0.24–0.94, p = 0.032). Thus, somatotropin might be a protective factor against SARS-CoV-2 infections, possibly related to its immunomodulatory activity.

We aimed to examine rates of COVID-19 vaccination to elucidate the need for targeted public health interventions. We retrospectively reviewed the electronic medical files of all adults registered in a central district in Israel from 1 January 2021 to 31 March 2022. The population was characterized by vaccination status against COVID-19 and the number of doses received. Univariate and multivariable analyses were used to identify predictors of low vaccination rates that required targeted interventions. Of the 246,543 subjects included in the study, 207,911 (84.3%) were vaccinated. The minority groups of ultra-Orthodox Jews and Arabs had lower vaccination rates than the non-ultra-Orthodox Jews (68.7%, 80.5% and 87.7%, respectively, p < 0.001). Adults of low socioeconomic status (SES) had lower vaccination rates compared to those of high SES (74.4% vs. 90.8%, p < 0.001). Adults aged 20–59 years had a lower vaccination rate than those ≥60 years (80.0% vs. 92.1%, p < 0.0001). Multivariate analysis identified five independent variables that were significantly (p < 0.001) associated with low vaccination rates: minority groups of the ultra-Orthodox sector and Arab population, and underlying conditions of asthma, smoking and diabetes mellitus (odds ratios: 0.484, 0.453, 0.843, 0.901 and 0.929, respectively). Specific targeted public health interventions towards these subpopulations with significantly lower rates of vaccination are suggested.

Shigella is the second most common cause of moderate to severe diarrhea among children worldwide and of diarrheal disease-associated mortality in young children in low-and middle-income countries. In spite of many years of attempts to develop Shigella vaccines, no licensed vaccines are yet available. Injectable conjugate vaccines made of the detoxified lipopolysaccharide (LPS) of S. flexneri 2a, S. sonnei, and S. dysenteriae type 1 covalently bound to protein carriers were developed in the early 1990s by John B. Robbins and Rachel Schneerson at the US National Institutes of Health. This approach was novel for a disease of the gut mucosa, at a time when live, rationally attenuated oral vaccine strains that intended to mimic Shigella infection and induce a protective local immune response were extensively investigated. Of keystone support to Shigella glycoconjugates development were the findings of a strong association between pre-existent serum IgG antibodies to S. sonnei or S. flexneri 2a LPS and a lower risk of infection with the homologous Shigella serotypes among Israeli soldiers serving in field units. In view of these findings and of the successful development of the pioneering Haemophilus influenzae type b conjugate vaccines, it was hypothesized that protective immunity may be conferred by serum IgG antibodies to the O-Specific Polysaccharide (O-SP) following parenteral delivery of the conjugates. S. sonnei and S. flexneri 2a glycoconjugates induced high levels of serum IgG against the homologous LPS in phase I and II studies in healthy volunteers. The protective efficacy of a S. sonnei detoxified LPS-conjugate was further demonstrated in field trials in young adults (74%) and in children older than three years of age (71%), but not in younger ones. The evaluation of the Shigella conjugates confirmed that IgG antibodies to Shigella LPS are correlates of protection and provided solid basis for the development of a new generation of glycoconjugates and other injectable LPS-based vaccines that are currently in advanced stages of clinical evaluation.

As of October 2021, SARS-CoV-2 infections were reported among 512,613 children and adolescents in Israel (~33% of all COVID-19 cases). The 5–11-year age group accounted for about 43% (223,850) of affected children and adolescents. In light of the availability of the Pfizer-BioNTech BNT162b2 vaccine against COVID-19 for children aged 5–11 years, we aimed to write a position paper for pediatricians, policymakers and families regarding the clinical aspects of COVID-19 and the vaccination of children against COVID-19. The first objective of this review was to describe the diverse facets of the burden of COVID-19 in children, including the direct effects of hospitalization during the acute phase of the disease, multisystem inflammatory syndrome in children, long COVID and the indirect effects of social isolation and interruption in education. In addition, we aimed to provide an update regarding the efficacy and safety of childhood mRNA COVID-19 vaccination and to instill confidence in pediatricians regarding the benefits of vaccinating children against COVID-19. We reviewed up-to-date Israeli and international epidemiological data and literature regarding COVID-19 morbidity and its sequelae in children, vaccine efficacy in reducing COVID-19-related morbidity and SARS-CoV-2 transmission and vaccine safety data. We conducted a risk–benefit analysis regarding the vaccination of children and adolescents. We concluded that vaccines are safe and effective and are recommended for all children aged 5 to 11 years to protect them from COVID-19 and its complications and to reduce community transmissions. Based on these data, after weighing the benefits of vaccination versus the harm, the Israeli Ministry of Health decided to recommend vaccination for children aged 5–11 years.

Sentinel lymph node (SLN) biopsy is an integral part of treatment planning for a variety of cancers as it evaluates whether a tumor has metastasized, an event that significantly reduces survival probability. However, this invasive procedure is associated with patient morbidity, and misses small metastatic deposits, resulting in the removal of additional nodes for tumors with high metastatic probability despite a negative SLN biopsy. To prevent this over-treatment and its associated morbidities for patients that were truly negative, we propose a tissue oxygen imaging method called Photoacoustic Lifetime Imaging (PALI) as an alternative or supplementary tool for SLN biopsy. As the hyper-metabolic state of cancer cells significantly depresses tissue oxygenation compared to normal tissue even for small metastatic deposits, we hypothesize that PALI can sensitively and specifically detect metastases. Before this hypothesis is tested, however, PALI’s maximum imaging depth must be evaluated to determine the cancer types for which it is best suited. To evaluate imaging depth, we developed and simulated a phantom composed of tubing in a tissue-mimicking, optically scattering liquid. Our simulation and experimental results both show that PALI’s maximum imaging depth is 16 mm. As most lymph nodes are deeper than 16 mm, ways to improve imaging depth, such as directly delivering light to the node using penetrating optical fibers, must be explored.

Human Norovirus is currently the main viral cause of acute gastroenteritis (AGEs) in most countries worldwide. Nearly 50 years after the discovery of the “Norwalk virus” by Kapikian and colleagues, the scientific and medical community continue to generate new knowledge on the full biological and disease spectrum of Norovirus infection. Nevertheless, several areas remain incompletely understood due to the serious constraints to effectively replicate and propagate the virus. Here, we present a narrated historic perspective and summarize our current knowledge, including insights and reflections on current points of interest for a broad medical community, including clinical and molecular epidemiology, viral–host–microbiota interactions, antivirals, and vaccine prototypes. We also include a reflection on the present and future impacts of the COVID-19 pandemic on Norovirus infection and disease.

It has recently been shown that children with early shigellosis are at increased risk of attention deficit/hyperactivity disorder (ADHD). This study aimed to evaluate the association between antibiotic treatment of shigellosis with long-term ADHD rates. A retrospective cohort study was conducted that included all the Leumit Health Services (LHS) enrollees aged 5–18 years between 2000–2018 with a documented Shigella-positive gastroenteritis before the age of 3 years. Of the 5176 children who were positive for Shigella gastroenteritis before the age of 3 years, 972 (18.8%) were treated with antibiotics early (

Political and public health leaders promoting COVID-19 vaccination should identify the most relevant criteria driving the vaccination decision. Social media is increasingly used as a source of vaccination data and as a powerful communication tool to increase vaccination. In December 2020, we performed a cross-sectional social media-based survey addressing personal sentiments toward COVID-19 vaccination in the USA. Our primary research objective is to identify socio-demographic characteristics and the reasons for the 1644 survey participants’ attitudes regarding vaccination. We present clear evidence that, contrary to the prevailing public perceptions, young audiences using social media have mostly a positive attitude towards COVID-19 vaccination (81.5%). These younger individuals want to protect their families and their relatives (96.7%); they see vaccination as an act of civic responsibility (91.9%) and express strong confidence in their healthcare providers (87.7%). Another critical factor is the younger population’s fear of personal COVID-19 infection (88.2%); moreover, the greater the number of children the participants have, the greater is their intent to get the COVID-19 vaccine. These results enable a practical public-messaging pathway to reinforce vaccination campaigns addressing the younger population.