Associations of psychosocial factors, knowledge, attitudes and practices with hospitalizations in internal medicine divisions in different population groups in Israel.

BACKGROUND: Inequalities in healthcare utilization exist across ethnic groups; however, the contributions of health-related knowledge and psychosocial factors to these inequalities remain unclear. We examined associations of social determinants of health, psychological factors, knowledge, attitudes and health practices, with hospitalizations in internal medicine divisions, among Israeli adults, Jews and Arabs, with non-communicable diseases, in a setting of universal health insurance. METHODS: A retrospective study was undertaken among 520 Jews and Arabs aged 40 years or older with non-communicable diseases, members of a large health maintenance organization. Hospitalization (at least once during 2008) in an internal medicine division was determined based on documentation in electronic health records. Participants were randomly selected in strata of sex, population-group and hospitalization status (yes/no). Data were collected from medical records and via face-to-face interviews using a structured questionnaire. Main independent variables included comorbidity burden, health behaviors, mental health wellbeing and self-rated health. Scales measuring health knowledge and attitudes/beliefs were constructed using factor analysis. RESULTS: Comorbidity burden (OR 1.41 [95% CI 1.24-1.61]) and self-rated health (not good vs. good) (OR 1.88 [95% CI 1.13-3.12]) were positively associated with hospitalizations in an internal medicine division, while an inverse association was found with better mental health wellbeing (OR 0.98 [95% CI 0.96-0.99, for each 1-point score increase). Among Jewish participants, positive associations were found of the number of offspring, comorbidity burden and perceived difficulty, with hospitalizations. No significant associations were found with hospitalizations of other sociodemographics, health behaviors, knowledge and attitudes/beliefs. CONCLUSIONS: Comorbidity burden was the main risk factor of hospitalizations in internal medicine divisions. Psychosocial factors, such as self-rated health, a complex variable affected by social capital, mental wellbeing, the number of offspring, and perceived burden and difficulty, seem also to contribute. These findings suggest the involvement of broad family and social factors, beyond individual level characteristics and medical needs, in hospitalizations in internal medicine divisions. Interventions to reduce hospitalizations should be comprehensive and integrate aspects of mental health wellbeing; they should build on familial characteristics (e.g., number of offspring), factors related to social capital such as self-rated health, and perceived burden and difficulty.

Non-random length distribution of individual telomeres in immunodeficiency, centromeric instability and facial anomalies syndrome, type I.

Mutations in the de novo DNA methyltransferase DNMT3B lead to Immunodeficiency, Centromeric Instability and Facial anomalies (ICF) syndrome, type I. This syndrome is characterized, among other hypomethylated genomic loci, by severe subtelomeric hypomethylation that is associated with abnormally short telomere length. While it was demonstrated that the mean telomere length is significantly shorter in ICF type I cells, it is unknown whether all telomeres are equally vulnerable to shortening. To study this question we determined by combined telomere-FISH and spectral karyotyping the relative length of each individual telomere in lymphoblastoid cell lines (LCLs) generated from multiple ICF syndrome patients and control individuals. Here we confirm the short telomere lengths, and demonstrate that telomere length variance in the ICF patient group is much larger than in the control group, suggesting that not all telomeres shorten in a uniform manner. We identified a subgroup of telomeres whose relatively short lengths can distinguish with a high degree of certainty between a control and an ICF metaphase, proposing that in ICF syndrome cells, certain individual telomeres are consistently at greater risk to shorten than others. The majority of these telomeres display high sequence identity at the distal 2 kb of their subtelomeres, suggesting that the attenuation in DNMT3B methylation capacity affects individual telomeres to different degrees based, at least in part, on the adjacent subtelomeric sequence composition.

Induced pluripotent stem cells as a model for telomeric abnormalities in ICF type I syndrome.

Human telomeric regions are packaged as constitutive heterochromatin, characterized by extensive subtelomeric DNA methylation and specific histone modifications. ICF (immunodeficiency, centromeric instability, facial anomalies) type I patients carry mutations in DNA methyltransferase 3B (DNMT3B) that methylates de novo repetitive sequences during early embryonic development. ICF type I patient fibroblasts display hypomethylated subtelomeres, abnormally short telomeres and premature senescence. In order to study the molecular mechanism by which the failure to de novo methylate subtelomeres results in accelerated telomere shortening, we generated induced pluripotent stem cells (iPSCs) from 3 ICF type I patients. Telomeres were elongated in ICF-iPSCs during reprogramming, and the senescence phenotype was abolished despite sustained subtelomeric hypomethylation and high TERRA levels. Fibroblast-like cells (FLs) isolated from differentiated ICF-iPSCs maintained abnormally high TERRA levels, and telomeres in these cells shortened at an accelerated rate, leading to early senescence, thus recapitulating the telomeric phenotype of the parental fibroblasts. These findings demonstrate that the abnormal telomere phenotype associated with subtelomeric hypomethylation is overridden in cells expressing telomerase, therefore excluding telomerase inhibition by TERRA as a central mechanism responsible for telomere shortening in ICF syndrome. The data in the current study lend support to the use of ICF-iPSCs for modeling of phenotypic and molecular defects in ICF syndrome and for unraveling the mechanism whereby subtelomeric hypomethylation is linked to accelerated telomeric loss in this syndrome.

[MARY LYON (1925-2014) AND THE RANDOM INACTIVATION OF CHROMOSOME X].

Since the beginning of the last century, genetic research has been preoccupied with the dosage compensation question: What mechanism controls equal expression of chromosome X genes between females and males? In the 1950s, many discoveries occurred in the field of cytogenetics related to the sex chromatin of female mammals. Concomitantly, genetic information accumulated with regard to expression patterns of X-linked genes in female mice and the expression effect of translocations between chromosome X and autosomes. In addition, many case reports were published about families with sex-linked diseases. The lately deceased scientist Mary F. Lyon suggested a unifying theory of these findings. In her articles "Gene action in the X-chromosome of the mouse (Mus musculus L.T in 1961, and "Sex chromatin and gene action in the mammalian X-chromosome" in 1962, she suggested that: (1) the heteropyknotic chromosome X was genetically inactivated, (2) the inactivated chromosome X could be either paternal or maternal in origin in different cells of the same animal, and (3) the inactivation occurred early in embryonic development. This theory led to an immediate breakthrough in understanding the basic mechanisms responsible for X-linked diseases and solved many unexplained case studies. Moreover, the inquiry of the mechanism of the phenomenon promoted scientific understanding of a wide range of areas in molecular biology such as DNA methylation, the silencing mechanism by XIST, histone modifications, DNA replication timing and more. The current article deals with some biographical details about Mary F. Lyon, the background of her theory, her historical articles and the development of the field since.

[Short-and long-term effects of cannabinoids on memory, cognition and mental illness].

Marijuana is considered the most commonly used drug in the world, with estimated millions of users. There is dissent in the medical world about the positive and negative effects of marijuana, and recently, a large research effort has been directed to that domain. The main influencing drug ingredient is THC, which acts on the cannabinoid system and binds to the CB1 receptor. The discovery of the receptor led to the finding of an endogenous ligand, anandamide, and another receptor-CB2. The researchers also discovered that cannabinoids have extensive biological activity, and its short and long-term effects may cause cognitive and emotional deficiencies. Findings show that the short-term effects, such as shortterm memory and verbal Learning, are reversible. However, despite the accumulation of evidence about long-term cognitive damage due to cannabis use, it is difficult to find unequivocal results, arising from the existence of many variables such as large differences between cannabis users, frequency of use, dosage and endogenous brain compensation. Apart from cognitive damage, current studies investigate how marijuana affects mental illness: a high correlation between cannabis use and schizophrenia was found and a high risk to undergo a psychotic attack. Furthermore, patients with schizophrenia who used cannabis showed a selective neuro-psychological disruption, and similar cognitive deficiencies and brain morphological changes were found among healthy cannabis users and schizophrenia patients. In contrast to the negative effects of marijuana including addiction, there are the medical uses: reducing pain, anxiety and nausea, increasing appetite and an anti-inflammatory activity. Medicalization of marijuana encourages frequent use, which may elevate depression.

Early death after a diagnosis of metastatic solid cancer-raising awareness and identifying risk factors from the SEER database.

BACKGROUND: Cancer death rates are declining, in part due to smoking cessation, better detection and new treatments; nevertheless, a large fraction of metastatic cancer patients die soon after diagnosis. Few studies and interventions focus on these patients. Our study aims to characterize early mortality in a wide range of metastatic solid tumors. METHODS: We retrieved data on adult patients diagnosed with pathologically confirmed de- novo metastatic solid tumors between the years 2004-2016 from the Surveillance, Epidemiology, and End Results database (SEER). Our primary outcome was cancer specific early death rate (defined as death within two months of diagnosis). Additional data extracted included socio-demographical data, tumor primary, sites of metastases, and cause of death. RESULTS: 109,207 (20.8%) patients died of de-novo metastatic cancer within two months of diagnosis. The highest rates of early death were found in hepatic (36%), pancreato-biliary (31%) and lung (25%) primaries. Factors associated with early death included primary site, liver, and brain metastases, increasing age, and lower income. Cancer was the cause of death in 92.1% of all early deaths. Two-month mortality rates have moderately improved during the study period (from 22.4% in 2004 to 18.8% in 2016). CONCLUSION: A fifth of de-novo metastatic cancer patients die soon after diagnosis, with little improvement over the last decade. Further research is required to better classify and identify patients at risk for early mortality, which patients might benefit from faster diagnostic tracks, and which might avoid invasive and futile diagnostic procedures.

RCC Real-World Data: Prognostic Factors and Risk Stratification in the Immunotherapy Era.

Immunotherapy has transformed the landscape of treatment in metastatic renal cell carcinoma (mRCC) in the last decade. Currently, prognostic risk stratification is based on the model developed in the era of vascular endothelial growth factor receptor inhibitors (VEGFRi) by Heng in 2009. Our study aims to find the most relevant risk criteria for mRCC patients treated with checkpoint inhibitors (CPI). In a retrospective cohort study, laboratory, pathology, demographic, and clinical data were retrieved from electronic medical records of consecutive mRCC patients treated with CPI in a tertiary center between 2015 and 2020. An unbiased multivariate analysis was performed to define predictive variables with a bootstrap validation step. We analyzed data on 127 patients with a median follow-up of 60 months. The median overall survival (OS) since the diagnosis of metastatic disease was 57 months. The response rate for CPI was 39%. Five risk factors were correlated with worse OS: intact primary kidney tumor (HR 2.33, p = 0.012), liver metastasis (HR 3.33, p = 0.001),

Immune-Related Thyroiditis as a Predictor for Survival in Metastatic Renal Cell Carcinoma.

Immune checkpoint inhibitors (CPI) are indicated for metastatic renal cell carcinoma (mRCC). Immune-related thyroiditis (irT), an immune-related adverse event (irAE), affects up to 30% of patients. We aimed to determine whether irT is associated with overall survival in mRCC. A retrospective cohort study of 123 consecutive patients treated with CPI for mRCC in a single center between 2015 and 2020 was conducted. Disease risk stratification was assessed by two methods: Heng criteria and a novel dichotomic stratification system to "Low risk" versus "High risk" adding number of metastatic sites. Thirty-eight percent of patients developed irT. In the general cohort, irT was not associated with a survival benefit. However, irT was associated with better survival in the poor risk group per Heng criteria (n = 17, HR = 0.25, p = 0.04) and in the novel "High risk" group (HR = 0.28, n = 42, p = 0.01), including after accounting for covariates in multivariate analysis (HR = 0.27, p = 0.003). Having any irAE was associated with improved survival in the whole cohort, with no significant correlation of any specific irAE, in either the whole cohort or the "High risk" group. We conclude that irT is an early and prevalent irAE, associated with prolonged survival in patients with poor/"High" risk mRCC.

Real-world evidence for immunotherapy in the first line setting in small cell lung cancer.

OBJECTIVE: Despite major progress over the past decade in the field of lung cancer care, only mild advances have occurred in Small Cell Lung Cancer (SCLC), with prognosis remaining poor. Based on two randomized clinical trials (RCTs), two checkpoint-inhibitors have recently been approved in extensive-SCLC with moderate improvements in median overall survival (OS). However, only limited data exist regarding the impact of immunotherapy in real-world SCLC patients. This study reports the efficacy of immunotherapy in the first-line treatment of extensive-stage SCLC patients in a real-world setting. METHODS: a retrospective cohort study of all patients treated for extensive-SCLC with chemotherapy with or without immunotherapy, at a single center in Israel between October-2017 and July-2021. Patient characteristics, adverse-events and survival analyses were conducted. RESULTS: Of 102 patients identified, 54 patients (53%) received immunotherapy in addition to chemotherapy. 34.7% of patients had a performance status (PS) of 2-4. Patients that received only chemotherapy were older, had more liver metastasis and a poorer PS. In the whole cohort, patients receiving immunotherapy had a significantly longer median OS (353 days vs 194 days, HR = 0.40p < 0.0001). After stratification by PS groups, survival analysis remained significantly longer in the PS 0-1 group (HR 0.43, p = 0.0036), with a trend for better survival in the PS 2-3 group. Multivariate analysis validated an OS advantage with immunotherapy (HR = 0.46, p = 0.004). CONCLUSION: We present evidence for the efficacy of immunotherapy in SCLC in a real-world setting. Although treatment groups differ in their baseline characteristics, it appears that even some patients not included in RCTs, such as poor PS, may benefit from the addition of immunotherapy to their treatment protocol.

Correlates of hospitalizations in internal medicine divisions among Israeli adults of different ethnic groups with hypertension, diabetes and cardiovascular diseases.

BACKGROUND: Disparities in non-communicable diseases (NCDs) may affect health care utilization. We compared the correlates of hospitalizations in internal medicine divisions, of adults with NCDs, between the main population groups in Israel. METHODS: A cross-sectional study was conducted among Jews (N = 17,952) and Arabs (N = 10,441) aged ≥40 years with diabetes, hypertension or cardiovascular diseases, utilizing the computerized database of the largest health maintenance organization in Israel. Information was retrieved on sociodemographics, background diseases, hospitalizations and utilizations of other health services. Multivariable log binomial regression models were performed. RESULTS: Overall, 3516 (12.4%) patients were hospitalized at least once during a one-year period (2008). Hospitalization in internal medicine divisions was more common among Arab than Jewish patients; prevalence ratio 1.24 (95% CI 1.14-1.35), and increased with age (P<0.001). An inverse association was found between residential socioeconomic status and hospitalization among Jewish patients, but not among Arab, who lived mostly in low socioeconomic status communities. In both population groups, congestive heart failure, arrhythmias, heart surgery, cardiac catheterization, kidney disease, asthma, neurodegenerative diseases, mental illnesses, smoking (in men) and disability were positively related to hospitalization in internal medicine divisions, which was more common also in patients who consulted any specialist and a specialist in cardiology. Emergency room visits, consulting with an ophthalmologist and performing cancer screening tests were inversely related to hospitalizations among Jewish patients only (P = 0.009 and P = 0.067 for interaction, respectively). CONCLUSIONS: In a country with universal health insurance, the correlates of hospitalizations included sociodemographics, multi-morbidity, health behaviors and health services use patterns. Socioeconomic disparities might account for ethnic differences in hospitalizations. Individuals with several NCDs, rather than one specific disease, disability and smoking should be targeted to reduce healthcare costs related to hospitalizations.

Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids.

DNA:RNA hybrids, nucleic acid structures with diverse physiological functions, can disrupt genome integrity when dysregulated. Human telomeres were shown to form hybrids with the lncRNA TERRA, yet the formation and distribution of these hybrids among telomeres, their regulation and their cellular effects remain elusive. Here we predict and confirm in several human cell types that DNA:RNA hybrids form at many subtelomeric and telomeric regions. We demonstrate that ICF syndrome cells, which exhibit short telomeres and elevated TERRA levels, are enriched for hybrids at telomeric regions throughout the cell cycle. Telomeric hybrids are associated with high levels of DNA damage at chromosome ends in ICF cells, which are significantly reduced with overexpression of RNase H1. Our findings suggest that abnormally high TERRA levels in ICF syndrome lead to accumulation of telomeric hybrids that, in turn, can result in telomeric dysfunction.

Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects.

The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1-STN1-TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients' phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach.

Characterization and rescue of telomeric abnormalities in ICF syndrome type I fibroblasts.

Mutations in the human DNA methyltransferase 3B (DNMT3B) gene lead to ICF (immunodeficiency, centromeric region instability, and facial anomalies) syndrome type I. We have previously described a telomere-related phenotype in cells from these patients, involving severe hypomethylation of subtelomeric regions, abnormally short telomeres and high levels of telomeric-repeat-containing RNA (TERRA). Here we demonstrate that ICF-patient fibroblasts carry abnormally short telomeres at a low population doubling (PD) and enter senescence prematurely. Accordingly, we attempted to rescue the senescence phenotype by ectopic expression of human telomerase, which led to elongated telomeres with hypomethylated subtelomeres. The senescence phenotype was overcome under these conditions, thus dissociating subtelomeric-DNA hypomethylation per se from the senescence phenotype. In addition, we examined whether the subtelomeric methylation could be restored by expression of a normal copy of full length DNMT3B1 in ICF fibroblasts. Ectopic expression of DNMT3B1 failed to rescue the abnormal hypomethylation at subtelomeres. However, partial rescue of subtelomeric-hypomethylation was achieved by co-expression of DNMT3B1 together with DNA methyltransferase 3-like (DNMT3L), encoding a protein that functions as a stimulator of DNMT3A and DNMT3B. DNMT3B1 and DNMT3L are predominantly expressed during early embryonic development, suggesting that de novo subtelomeric DNA methylation during crucial stages of human embryonic development may be necessary for setting and maintaining normal telomere length.

Why can seizures remain intractable? Clinical vignettes from the life experience of a pediatric epileptologist.

Most childhood seizures can be controlled by the appropriate antiepileptic drugs. When seizures remain intractable in a normally developing child with an intact neurologic examination, it is usually possible to identify a clear reason, and the physician, like a detective, needs to investigate and reveal it. In this article we will describe cases that were encountered during a lifetime at a pediatric epilepsy clinic, which will illustrate the different reasons seizures remain intractable in patients who do not have structural abnormalities or resistant epileptic syndromes.

Medex test, a novel modality for liver disease diagnosis: a pilot study.

BACKGROUND AND AIMS: Liver diseases are associated with significant morbidity and health- related expenditure. Although cost-effective treatments are available, the disease is often asymptomatic until late in its course. "Medex Test," is the noninvasive detection of liver abnormalities by the measurement of changes in electrical impedance of dermal zones. This method is based on neuroreflexology, a branch of complementary medicine. This study addressed 2 questions: can Medex Test detect liver disease, and can it measure the severity of a known liver disease. METHODS: This blinded case-control study included 2 parts. First, 113 patients with a known liver disease (hepatitis C, hepatitis B, and nonalcoholic fatty liver disease) and 85 controls with no known liver disease were evaluated by the Medex Test device. Second, necroinflammatory grading of biopsy results of 60 patients with chronic hepatitis C were compared with grade determined by Medex Test. RESULTS: Medex Test detected with high sensitivity (85%) and specificity (94.1%) the presence of liver disorders. The high rates were similar for the different disorders and were independent of age and sex. Additionally, Medex Test matched the biopsy pathologic grading of necroinflammation in 78% of patients. Positive predictive value was not affected by age and sex and was better for higher degree of necroinflammation. CONCLUSIONS: This pilot study demonstrated that Medex Test detects with high accuracy the presence of liver disorders and the necroinflammatory grade. This noninvasive, low cost test may in the future become an important tool in the diagnosis and management of liver disorders. We believe the further study of this novel method is warranted.

Acute hepatitis C in Israel: a predominantly iatrogenic disease?

BACKGROUND AND AIMS: Acute hepatitis C virus infection in the era of universal screening of blood products has not disappeared, and is thought to be transmitted primarily via injecting drug use. A growing body of evidence supports iatrogenic transmission as an important mode of transmission. The aim of this study was to examine transmission routes and clinical characteristics in a group of patients with acute hepatitis C in Israel. METHODS: A retrospective chart review was conducted in three different liver clinics in Israel, of all new hepatitis C patients. Patients identified as possible acute hepatitis C were re-interviewed and all other sources such as blood bank records and pre-employment check-ups reviewed in order to establish the diagnosis of acute hepatitis C infection and to identify the transmission route. RESULTS: Twenty-nine patients were found to have acute hepatitis C, representing 0.75% of all new referrals for hepatitis C. The most frequent (65%) mode of transmission was iatrogenic involving several, often minimal, procedures and clinical settings. The group in which iatrogenic transmission was suspected was older and the patients more often in monogamous relationship compared with other transmission routes groups. Injecting drug use was the second most common route of infection. Spontaneous seroconversion has occurred in approximately one third of the patients. CONCLUSIONS: Acute hepatitis C in the post universal blood products screening era was found to be predominantly an iatrogenic disease in the investigated localities. This finding should direct attention and resources towards the development and implementation of preventive measures.

Re-evaluation of serum alanine aminotransferase upper normal limit and its modulating factors in a large-scale population study.

BACKGROUND: The upper normal limit (ULN) of serum alanine-aminotrasferase (ALT) normal range was recently challenged, because patients diagnosed with liver diseases may have 'normal' or near-'normal' ALT levels, and because possible modulators are often ignored in determining normal range. AIM: To estimate the ULN for serum ALT and to identify factors modulating it. SUBJECTS AND METHODS: We reviewed medical records of subjects aged 15-90, who underwent standard panels of laboratory tests, including serum ALT, over 6 months at a central laboratory. Three groups were defined: Group 1, comprised total study population (N=272 273). Group 2 (N=87 020) comprised total study population, excluding those receiving potentially hepatotoxic drugs, or diagnosed with liver disease, or had any abnormal laboratory test results other than for triglycerides, cholesterol, glucose, or HbA1c. Group 3 (N=17 496) the 'healthy' population, from whose ALT values we established the new ULN, comprised Group 2 subjects with normal triglycerides, cholesterol, glucose, and HbA1c levels. RESULTS: The 95th percentile ALT values, corresponding to the ULN, in groups 1, 2, and 3 were 50.1, 40, and 37.5 U/l, respectively. 6.2% (16 943/273 273) of subjects whose ALT was below ULN listed by the test manufacturer (52 U/l), had ALT level above our new ULN. Linear and logistic-regression analyses showed that ALT levels were significantly modified by gender, age, glucose, cholesterol, triglycerides, and overweight/obesity diagnosis. Significant interaction was found between gender, glucose and cholesterol levels. CONCLUSIONS: In this first large-scale study of 'healthy' population, serum ALT ULN was far lower than currently accepted value. Age and gender may be considered when determining the ULN for ALT.