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Post-traumatic stress disorder (PTSD) is a protracted and debilitating consequence of traumatic events. Identifying early predictors of PTSD can inform the disorder's risk stratification and prevention. We used advanced computational models to evaluate the contribution of early neurocognitive performance measures to the accuracy of predicting chronic PTSD from demographics and early clinical features. We consecutively enrolled adult trauma survivors seen in a general hospital emergency department (ED) to a 14-month long prospective panel study. Extreme Gradient Boosting algorithm evaluated the incremental contribution to 14 months PTSD risk of demographic variables, 1-month clinical variables, and concurrent neurocognitive performance. The main outcome variable was PTSD diagnosis, 14 months after ED admission, obtained by trained clinicians using the Clinician-Administered PTSD Scale (CAPS). N = 138 trauma survivors (mean age = 34.25 ± 11.73, range = 18-64; n = 73 [53%] women) were evaluated 1 month after ED admission and followed for 14 months, at which time n = 33 (24%) met PTSD diagnosis. Demographics and clinical variables yielded a discriminatory accuracy of AUC = 0.68 in classifying PTSD diagnostic status. Adding neurocognitive functioning improved the discriminatory accuracy (AUC = 0.88); the largest contribution emanating from poorer cognitive flexibility, processing speed, motor coordination, controlled and sustained attention, emotional bias, and higher response inhibition, and recall memory. Impaired cognitive functioning 1-month after trauma exposure is a significant and independent risk factor for PTSD. Evaluating cognitive performance could improve early screening and prevention.

Various approaches exist to assess population differences in biological aging. Telomere length (TL) is one such measure, and is associated with disease, disability and early mortality. Yet, issues surrounding precision and reproducibility are a concern for TL measurement. An alternative method to estimate TL using DNA methylation (DNAmTL) was recently developed. Although DNAmTL has been characterized in adult and elderly cohorts, its utility in pediatric populations remains unknown. We examined the comparability of leukocyte TL measurements generated using qPCR (absolute TL; aTL) to those estimated using DNAmTL in a high-risk pediatric cohort (

A Meta-Nano Channel BioFET is demonstrated to decouple the electrostatics of the solution from the electrodynamics of the FET such that the Debye screening length can be electrostatically tuned to enhance the sensor output signal.

To investigate the effect of biologic treatments for psoriasis on the incidence of psoriatic arthritis (PsA).This retrospective cohort study was conducted using electronic medical records from a large health maintenance organization. Patients who received biologic treatment for psoriasis and were not diagnosed as having PsA before or at the time of biologic treatment initiation were included. Control psoriasis patients who did not receive biologic treatment were matched by age at time of diagnosis, sex, time from psoriasis diagnosis until treatment initiation, maximum body mass index, and smoking status. The groups were different in most characteristics. Therefore, propensity score matching was implemented. Log rank test and multivariable Cox proportional hazards regression were used to compare the groups.Overall, 1,326 patients were included, of whom 663 had received biologic treatment and 663 had not. The Kaplan-Meier curve for the propensity score-matched groups reflected a statistically significant increased risk for PsA among the control group compared to the biologic treatment group. The results of the multivariable Cox regression showed that the control group had a significantly higher risk for PsA compared to the biologic treatment group within 10 years of follow-up (adjusted hazard ratio 1.39 [95% confidence interval 1.03-1.87]).Our findings show a statistically and clinically significant decreased risk for developing PsA among patients with psoriasis who receive biologic treatments. The results suggest that biologic medications should be considered for patients who present with significant risk factors for PsA at an earlier stage of treatment.

The use of transcriptomes as reliable proxies for cellular proteomes is controversial. In the small intestine, enterocytes operate for 4 days as they migrate along villi, which are highly graded microenvironments. Spatial transcriptomics have demonstrated profound zonation in enterocyte gene expression, but how this variability translates to protein content is unclear. Here we show that enterocyte proteins and messenger RNAs along the villus axis are zonated, yet often spatially discordant. Using spatial sorting with zonated surface markers, together with a Bayesian approach to infer protein translation and degradation rates from the combined spatial profiles, we find that, while many genes exhibit proteins zonated toward the villus tip, mRNA is zonated toward the villus bottom. Finally, we demonstrate that space-independent protein synthesis delays can explain many of the mRNA-protein discordances. Our work provides a proteomic spatial blueprint of the intestinal epithelium, highlighting the importance of protein measurements for inferring cell states in tissues that operate outside of steady state.

Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81−/− mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection., Lactate is a by-product of glycolysis that can function via its G protein receptor GPR81. Here the authors show that LPS or Salmonella infection enhances glycolytic metabolism in bone marrow neutrophils, resulting in lactate production, which increases endothelial barrier permeability and mobilization of these neutrophils by targeting endothelial GPR81.

Background Maraviroc is an antiretroviral agent and C-C chemokine coreceptor 5 (CCR5) antagonist that is currently used to treat human immunodeficiency virus. CCR5/μ-opioid receptor heterodimerization suggests that maraviroc could be a treatment for oxycodone abuse. We treated rats with maraviroc to explore its effect on oxycodone-seeking and its interference with the analgesic effects of oxycodone. We used resting-state blood-oxygen-level-dependent functional connectivity to assess the effect of maraviroc on oxycodone-enhanced coupling in the reward circuitry and performed behavioural tests to evaluate the effect of maraviroc on oxycodone rewarding properties and on oxycodone-seeking after prolonged abstinence. Methods Two groups of rats were exposed to 8 consecutive days of oxycodone-conditioned place preference training and treatment with maraviroc or vehicle. Two additional groups were trained to self-administer oxycodone for 10 days and then tested for drug seeking after 14 days of abstinence with or without daily maraviroc treatment. We tested the effects of maraviroc on oxycodone analgesia using a tail-flick assay. We analyzed resting-state functional connectivity data using a rat 3-dimensional MRI atlas of 171 brain areas. Results Maraviroc significantly decreased conditioned place preference and attenuated oxycodone-seeking behaviour after prolonged abstinence. The analgesic effect of oxycodone was maintained after maraviroc treatment. Oxycodone increased functional coupling with the accumbens, ventral pallidum and olfactory tubercles, but this was reduced with maraviroc treatment. Limitations All experiments were performed in male rats only. Conclusion Maraviroc treatment attenuated oxycodone-seeking in abstinent rats and reduced functional coupling in the reward circuitry. The analgesic effects of oxycodone were not affected by maraviroc.

PURPOSE Relvar® (fluticasone furoate [FF]/vilanterol [VI]) is a once-daily inhaler with bronchodilator effect lasting 24 h. Our aim was to investigate the short- and long-term effects of FF/VI on exercise-induced asthma (EIA) in adolescents. METHODS Ninety-three adolescent asthmatics aged 12-18 years were referred for evaluation of EIA. Following a positive exercise challenge test (ECT), 22/44 were allocated to a single administration of salbutamol (400 μg) and 22/44 to FF/VI (92/22 μg) in a double-blind method. Thirty-five subjects were reassessed by repeat ECT 30-60 days of FF/VI. RESULTS Median FEV1 change post-ECT at baseline was -22.8% predicted (interquartile range [IQR] -26.1 and -18.0) for salbutamol and -21.0 (IQR -30.7 and -16.8) for FF/VI. Following bronchodilator, FEV1 improved similarly in both groups. Repeat ECT following 30-60 days of FF/VI resulted in negative ECT in 33/35 subjects; the median decrease in FEV1 of these 35 subjects was 22.6% predicted (IQR 29-18) before, and 4.6% predicted (IQR 8.7-2.5) after 30-60 days of FF/VI treatment (p

Aim: We describe PD-L1 testing patterns and first-line treatment for patients with metastatic non-small-cell lung cancer in a 2.3 million-member state-mandated health service in Israel. Materials & methods: Newly diagnosed stage IV non-small-cell lung cancer patients initiating systemic anticancer treatment from 1 January 2017 until 31 December 2018 were identified from the national cancer registry and Maccabi Healthcare Service database and followed until 30 June 2019. Results: The cohort consisted of 410 patients; 58% males, median age 68 years, 70% current/former smokers, 81% adenocarcinoma, 14% had brain metastases, and Eastern Cooperative Oncology Group performance status was 46/17/37% for 0–1/2–4/unknown, respectively. A total of 80% tested for PD-L1 expression, of which 47% had tumor proportion score (TPS) ≥ 50%. A total of 95% with TPS ≥ 50% and no known tumor aberrations (including EGFR mutations, and translocations in ALK and ROS1) received first-line PD-1/PD-L1-inhibitor monotherapy, and 80% of untested/TPS

Objectives: Mixed dopamine and serotonin receptor antagonists (DSRAs) are associated with significant weight gain and its complications. Our aim was to evaluate the effectiveness of metformin in re...

Bone-resorbing osteoclasts (OCLs) are multinucleated phagocytes, whose central roles in regulating bone formation and homeostasis are critical for normal health and development. OCLs are produced from precursor monocytes in a multistage process that includes initial differentiation, cell-cell fusion, and subsequent functional and morphological maturation; the molecular regulation of osteoclastogenesis is not fully understood. Here, we identify the receptor-type protein tyrosine phosphatase PTPRJ as an essential regulator specifically of OCL maturation. Monocytes from PTPRJ-deficient (JKO) mice differentiate and fuse normally, but their maturation into functional OCLs and their ability to degrade bone are severely inhibited. In agreement, mice lacking PTPRJ throughout their bodies or only in OCLs exhibit increased bone mass due to reduced OCL-mediated bone resorption. We further show that PTPRJ promotes OCL maturation by dephosphorylating the M-CSF receptor (M-CSFR) and Cbl, thus reducing the ubiquitination and degradation of the key osteoclastogenic transcription factor NFATc1. Loss of PTPRJ increases ubiquitination of NFATc1 and reduces its amounts at later stages of osteoclastogenesis, thereby inhibiting OCL maturation. PTPRJ thus fulfills an essential and cell-autonomous role in promoting OCL maturation by balancing between the pro- and anti-osteoclastogenic activities of the M-CSFR and maintaining NFATc1 expression during late osteoclastogenesis.

Purpose: Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance. Experimental Design: We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer. Results: ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased. Conclusions: Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.

Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access) PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Several studies have suggested that the incidence of infantile hypertrophic pyloric stenosis (IHPS) has decreased in recent decades. This decrement is controversial and not fully explained. Concurrently, there has been a major increase in folic acid consumption by pregnant women to prevent neural tube defects. We aimed to describe IHPS incidence in Israel in recent years and to assess its potential association with folic acid consumption.Using the electronic medical database of a 2.1 million member health organization in Israel, we identified all cases (n = 1899) of IHPS occurring between 1999 and 2015. Cases were individually matched with up to 5 controls (n = 7350) by birth date, sex, and region. Odds ratios and 95% confidence intervals by tertiles of cumulative dose of supplemented folic acid between three months prior to pregnancy and up to birth of index child were calculated using conditional logistic regression.During the study period IHPS incidence declined from 4.3 in 1999 to 2.1 per 1000 live births in 2015(p 0.0001). No significant (p = 0.81) association was observed between folic acid intake during pregnancy and risk of IHPS incidence. Preterm birth and infant's use of macrolides during first 3 postnatal months were significantly (p 0.01) associated with increased risk of IHPS.Similar to other countries, IHPS incidence in Israel has decreased in recent years. The decrement cannot be explained by increased use of folic acid.Case Control Study.Level III.Using linkage to a large electronic patient database, this study investigated the association between the decrease in infantile hypertrophic pyloric stenosis and maternal exposure to folic acid during pregnancy.

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results demonstrate that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.

Umbilical cord knot (UCK) is associated with increased risk of fetal death, but is usually diagnosed only after delivery. Our objective was to examine the accuracy of prenatal ultrasound in the diagnosis of UCK and the outcomes of these pregnancies.A prospective study was performed on 56 patients in which UCK was suspected during a routine level-II anatomical scan (study group). Data included demographics, pregnancy outcome, and short-term neonatal follow-up. The control group included pregnant women with normal pregnancy without UCK in a 4:1 ratio matched for gestational age at delivery.True knot was observed postnatally in 54 out of 56 fetuses (detection rate of 96.4 %). Gestational age at diagnosis of UCK was 22.1 ± 3.1 weeks. The female to male ratio was 1:1 in both groups. Maternal age and parity were significantly higher in pregnancies with UCK compared to controls. The mean gestational age at delivery was 37.1 weeks of gestation in the UCK group. There was no difference in the birthweight percentile. 47 patients (87 %) underwent induction of labor. There were no differences in the rate of cesarean section or Apgar scores. No neonate with UCK needed ventilation. None suffered from seizures and none needed brain imaging. There were no cases of fetal or neonatal death in the pregnancies with UCK.There is a high detection rate of UCK during targeted scan of the umbilical cord performed during the level-II anatomical scan. Careful pregnancy follow-up and early term delivery may result in excellent obstetrical outcomes.Der Nabelschnurknoten (UCK) ist mit einem erhöhten Risiko für intrauterinen Fruchttod verbunden, wird jedoch normalerweise erst nach Entbindung diagnostiziert. Unser Ziel war es, die Genauigkeit des pränatalen Ultraschalls bei der Diagnose des UCK und das Schwangerschafts-Outcome zu untersuchen.Eine prospektive Studie wurde an 56 Patienten durchgeführt, bei denen ein UCK während eines routinemäßigen anatomischen Scans der Stufe II (Studiengruppe) vermutet wurde. Die Daten umfassten demografische Daten, den Schwangerschaftsausgang und eine kurzfristige Nachbeobachtung von Neugeborenen. Die Kontrollgruppe umfasste schwangere Frauen mit normaler Schwangerschaft ohne UCK in einem Verhältnis von 4:1, mit Matching nach Schwangerschaftswoche bei Entbindung.Echte Knoten wurden postnatal bei 54 von 56 Föten beobachtet (Nachweisrate 96,4 %). Das Gestationsalter bei Diagnose des UCK betrug 22,1 ± 3,1 Wochen. Die Weiblich:Männlich-Ratio betrug in beiden Gruppen 1:1. Das mütterliche Alter und die Parität waren bei Schwangerschaften mit UCK im Vergleich zu den Kontrollen signifikant höher. Das mittlere Gestationsalter bei Entbindung betrug in der UCK-Gruppe 37,1 Schwangerschaftswochen. Bei der Perzentile des Geburtsgewichts gab es keinen Unterschied. Bei 47 Patienten (87 %) wurde die Geburt eingeleitet. Es gab keine Unterschiede in der Kaiserschnittrate oder bei den Apgar-Scores. Keines der Neugeborenen mit UCK musste beatmet werden. Keines litt unter Krampfanfällen, noch war eine Hirn-Bildgebung erforderlich. Bei den Schwangerschaften mit UCK gab es keine Fälle von fetalem oder neonatalem Tod.Es gibt eine hohe Detektionsrate von UCK bei der gezielten Untersuchung der Nabelschnur, die bei der anatomischen Level-II-Untersuchung durchgeführt wird. Eine sorgfältige Betreuung der Schwangerschaft und eine frühe Entbindung können zu einem hervorragenden geburtshilflichen Outcome führen.

Background Features of autism spectrum conditions (ASC) are normally distributed within the population, giving rise to the notion of the autism spectrum. One of the hallmark features of ASC is difficulties in social communication, which relies heavily on our ability to empathize with others. Empathy comprises of both cognitive (CE) and emotional (EE) components that, together, allow us to understand another’s emotions and be affected by them appropriately, while maintaining a self-other distinction. Although CE and EE depend on distinct neural and developmental trajectories, it was suggested that the two empathic capacities can influence, balance, and regulate each other. Previous findings regarding the role of emotional and cognitive empathy in ASC have been mixed. Therefore, our study aimed to investigate whether the intra-personal empathy imbalance between the cognitive and emotional components, a measure we termed empathic disequilibrium (ED), can be associated with autism traits at the neurotypical range. Methods Participants were 671 young-adults at the neurotypical range who self-reported their empathy, assessed using two highly validated questionnaires—the Interpersonal Reactivity Index and the Empathy Quotient, autism traits using the Autism-Spectrum Quotient, and the related traits, alexithymia, and systemizing. Results Controlling for the total empathy score, greater ED was found to be positively correlated with autism traits. Specifically, autism traits were found to be elevated in groups of individuals with relatively higher EE than CE, underscoring their imbalance. Conclusions Our study offers a novel perspective on the understanding of the social difficulties associated with autism tendencies in the general population and has potentially important clinical implications for understanding of ASC. We also propose a novel characterization of autism tendencies based on the imbalance between EE and CE, which we term ED, as opposed to examining EE and CE separately.

Annually, approximately 30 million patients are discharged from the emergency department (ED) after a traumatic event1. These patients are at substantial psychiatric risk, with approximately 10-20% developing one or more disorders, including anxiety, depression or post-traumatic stress disorder (PTSD)2-4. At present, no accurate method exists to predict the development of PTSD symptoms upon ED admission after trauma5. Accurate risk identification at the point of treatment by ED services is necessary to inform the targeted deployment of existing treatment6-9 to mitigate subsequent psychopathology in high-risk populations10,11. This work reports the development and validation of an algorithm for prediction of post-traumatic stress course over 12 months using two independently collected prospective cohorts of trauma survivors from two level 1 emergency trauma centers, which uses routinely collectible data from electronic medical records, along with brief clinical assessments of the patient's immediate stress reaction. Results demonstrate externally validated accuracy to discriminate PTSD risk with high precision. While the predictive algorithm yields useful reproducible results on two independent prospective cohorts of ED patients, future research should extend the generalizability to the broad, clinically heterogeneous ED population under conditions of routine medical care.

Objective The purpose of this study was to establish prognostic factors in fetuses diagnosed with periventricular pseudocysts (PVPCs) without known congenital infection, between 28 and 37 weeks of gestation. Methods This retrospective study included cases of fetal PVPC from 2008 to 2018. PVPCs were classified according to location, number, extension, morphology, and size. Additional findings, MRI and genetic studies were recorded. Pregnancy outcome, postnatal, or postmortem results were obtained. Images from patients with normal (Group 1) and abnormal postnatal development (Group 2) were compared for analysis of factors predictive of outcome. Results One-hundred and fifteen pseudocysts were observed in 59 patients. In 34 fetuses (57%), the PVPC was an isolated finding. Thirty-nine patients delivered live newborns, 27% opted for termination of pregnancy, and 4 patients were lost to follow-up. Eighty-four percent of the liveborns had normal development. When assessing for the influence of pseudocyst characteristics, a wide CSP, or large head circumference, neither of these affected the outcome. The presence of additional anomalies was the only positive predictor for abnormal development regradless of specific PVPC characteristics (P = .002). Conclusions In fetuses with PVPCs, the presence of additional anomalies was the only predictor for adverse postnatal outcome. No association between cystic characteristics and adverse outcome was observed.

Significance We present a method for virtual staining for morphological analysis of individual biological cells based on stain-free digital holography, allowing clinicians and biologists to visualize and analyze the cells as if they have been chemically stained. Our approach provides numerous advantages, as it 1) circumvents the possible toxicity of staining materials, 2) saves time and resources, 3) optimizes inter- and intralab variability, 4) allows concurrent staining of different types of cells with multiple virtual stains, and 5) provides ideal conditions for real-time analysis, such as rapid stain-free imaging flow cytometry. The proposed method is shown to be accurate, repeatable, and nonsubjective. Hence, it bears great potential to become a common tool in clinical settings and biological research., Many medical and biological protocols for analyzing individual biological cells involve morphological evaluation based on cell staining, designed to enhance imaging contrast and enable clinicians and biologists to differentiate between various cell organelles. However, cell staining is not always allowed in certain medical procedures. In other cases, staining may be time-consuming or expensive to implement. Staining protocols may be operator-sensitive, and hence may lead to varying analytical results, as well as cause artificial imaging artifacts or false heterogeneity. We present a deep-learning approach, called HoloStain, which converts images of isolated biological cells acquired without staining by holographic microscopy to their virtually stained images. We demonstrate this approach for human sperm cells, as there is a well-established protocol and global standardization for characterizing the morphology of stained human sperm cells for fertility evaluation, but, on the other hand, staining might be cytotoxic and thus is not allowed during human in vitro fertilization (IVF). After a training process, the deep neural network can take images of unseen sperm cells retrieved from holograms acquired without staining and convert them to their stainlike images. We obtained a fivefold recall improvement in the analysis results, demonstrating the advantage of using virtual staining for sperm cell analysis. With the introduction of simple holographic imaging methods in clinical settings, the proposed method has a great potential to become a common practice in human IVF procedures, as well as to significantly simplify and radically change other cell analyses and techniques such as imaging flow cytometry.

Objective: The aim of this retrospective cohort study was to examine whether adherence to metformin treatment may be associated with lower onset of rheumatoid arthritis (RA).Method: Using the compu...

Background Studies on the prevalence of sleep disorders have found great variability due to different data collection methods and case definitions. We aimed at assessing the prevalence of sleep disorders in a large, unselected population using validated clinical patient records. To the best of our knowledge, this is the first large clinically based study on sleep disorders. Methods This retrospective study used the computerized data of 2.3 million members of Maccabi Healthcare Services (MHS) public mandated health provider. Among enrolled MHS members alive in June 2018, electronic medical records were searched from January 2010 for sleep disorders using diagnosis codes, sleep medications, and recorded sleep studies. Results A total of 195,201 patients (9% of the total MHS population) were identified. Patients were 48.3% men and the average age at diagnosis was 50.4 years (SD = 20.9). Prevalence increased with age; 3.2% in children under 10 years, 5.2% in young adults, and 22.3% among seniors aged 75 or older. The two most prevalent disorders were insomnia (7.4%), and sleep-related breathing disorders (2%). Less prevalent disorders included central disorders of hypersomnolence (100 per 100,000), circadian rhythm sleep–wake disorders (49 per 100,000), parasomnias (140 per 100,000), and sleep-related movement disorders (20 per 100,000). Conclusions The overall prevalence of sleep disorders including insomnia and sleep related breathing disorders in Israel were similar to other western countries despite stressful life events of ongoing war and terrorism. The large sample size allowed us to calculate the prevalence of more rare sleep disorders, which have been generally less known.

BACKGROUND: Low hippocampal volume could serve as an early risk factor for Post-traumatic Stress Disorder (PTSD) in interaction with other brain anomalies of developmental origin. One such anomaly may well be a presence of large Cavum Septum Pellucidum (CSP), which has been loosely associated with PTSD. Here, we performed a longitudinal prospective study of recent trauma survivors. We hypothesized that at one-month after trauma exposure, the relation between hippocampal volume and PTSD symptom severity will be moderated by CSP volume, and that this early interaction will account for persistent PTSD symptoms at subsequent time-points. METHODS: 171 adults (87 females, average age=34.22, range=18–65) admitted to a general hospital’s emergency department following a traumatic event, underwent clinical assessment and structural MRI within one-month after trauma. Follow-up clinical evaluations were conducted at six (n=97) and fourteen (n=78) months after trauma. Hippocampus and CSP volumes were measured automatically by FreeSurfer software and verified manually by a neuroradiologist. RESULTS: At one-month following trauma, CSP volume significantly moderated the relation between hippocampal volume and PTSD severity (p=0.026), and this interaction further predicted symptom severity at fourteen months post-trauma (p=0.018). Specifically, individuals with smaller hippocampus and larger CSP at one-month post-trauma, showed more severe symptoms at one- and fourteen months following trauma exposure. CONCLUSIONS: Our study provides evidence for an early neuroanatomical risk factors for PTSD, which could also predict the progression of the disorder in the year following trauma exposure. Such a simple-to-acquire neuroanatomical signature for PTSD could guide early management, as well as long-term monitoring. TRIAL REGISTRATION: Neurobehavioral Moderators of Post-traumatic Disease Trajectories. ClinicalTrials.gov registration: NCT03756545. https://clinicaltrials.gov/ct2/show/NCT03756545

Telomeres are the protective DNA-protein sequences appearing at the ends of chromosomes; they shorten with each cell division and are considered a biomarker of aging. Shorter telomere length and greater erosion have been associated with compromised physical and mental health and are hypothesized to be affected by early life stress. In the latter case, most work has relied on retrospective measures of early life stressors. The Dutch research (n = 193) presented herein tested 3 hypotheses prospectively regarding effects of sensitive-insensitive parenting during the first 2.5 years on telomere length at age 6, when first measured, and change over the following 4 years. It was predicted that (1) less sensitive parenting would predict shorter telomeres and greater erosion and that such effects would be most pronounced in children (2) exposed to prenatal stress and/or (3) who were highly negatively emotional as infants. Results revealed, only, that prenatal stress amplified parenting effects on telomere change-in a differential-susceptibility-related manner: Prenatally stressed children displayed more erosion when they experienced insensitive parenting and less erosion when they experienced sensitive parenting. Mechanisms that might initiate greater postnatal plasticity as a result of prenatal stress are highlighted and future work outlined. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Introduction Major depressive disorder (MDD) is one of the most common mental disorders worldwide, estimated to affect 10–15% of the population per year. Treatment resistant depression (TRD) is estimated to affect a third of these patients who show difficulties in social and occupational function, decline of physical health, suicidal thoughts and increased health care utilization. We describe the prevalence of MDD, TRD and associated healthcare resource utilization in Maccabi Healthcare Services (MHS), a 2.5 million-member state-mandated health service in Israel. Methods All MHS members with an MDD diagnosis were identified within the years 2017–2018 and prevalence assessed by age, sex and TRD. To assess the incidence of MDD, members aged 18–65 years at the start of any MDD episode were identified between 1st January 2016 and 31st May 2018 with at least one systemic first-line antidepressant treatment within three months before or after the initial episode. Treatment patterns, time on first-line treatment, and healthcare resource utilization were compared by TRD. Results A total of 4960 eligible MDD patients were identified (median age = 51 years, 65% female), representing a period prevalence of 0.218%, and of those, a high proportion of patients received drug treatment (92%). Among incident MDD cases (n = 2553), 24.4% had TRD. Factors associated with TRD included increasing age and personality disorder. Median time on treatment was 3.7 months (longer for those without TRD than those with) and 81.9% of patients purchased more than one month’s supply of therapy. In the year after index, patients with TRD had a significant increased number of visits to primary care physicians, psychiatrists, emergency room visits, general hospitalizations, and psychiatric hospitalizations. Conclusion Our study shows that prevalence of MDD in Israel is low compared to other countries, however once diagnosed, patients' are likely to receive drug treatment. Among patients diagnosed with MDD, the proportion of TRD is similar to other countries, increases with age and is associated with increased healthcare utilization, therefore should be a focus of continued research for finding effective long term treatment options.

Early life adversity (ELA) is a risk factor for early onset morbidities and mortality, a relationship that may be driven in part by immune system dysregulation. One mechanism of dysregulation that has yet to be fully examined in the context of ELA is alterations to immune cell dynamics in response to acute stress. Using a within-person between-group experimental design, we investigated stress-induced changes in immune cell populations, and how these changes may be altered in individuals with a history of ELA. Participants were young adults (N = 34, aged 18–25 years, 53% female, 47% with a history of ELA). Complete immune cell counts were measured at four time-points over a 5-hour window across two sessions (Trier Social Stress Test [TSST] vs. no-stress) separated by a week. Across all participants, total white blood cells increased over time (F(3,84)=38.97, p < .001) with a greater increase in response to the TSST compared to the no-stress condition at 240 minutes post-test (b = 0.43±.19; t(179)=2.22, p = .027). This pattern was mirrored by neutrophil counts. Lymphocyte counts were initially depressed by TSST exposure (b =−205±.67; t(184)=−3.07, p = .002) but recovered above baseline. ELA status was associated with higher stress-induced immune cell counts, a difference likely driven by increases in neutrophils (F(1,22)=4.45, p = .046). Overall, these results indicate differential immune cell dynamics in response to acute stress in individuals with a history of ELA. This points to altered immune system functioning in the context of stress, a finding that may be driving increased morbidity and mortality risk for ELA-exposed individuals.

Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence.

Real-world data on the epidemiology and economic burden of atopic dermatitis (AD) are limited. Here we describe the epidemiology and economic burden of AD using electronic healthcare data from Israel.A retrospective study was performed using the Maccabi Healthcare Services database. AD incidence in 2008-2017 and point prevalence (ADAD incidence was 7.0/1000 person-years; overall prevalence was 4.4% (female patients 4.5%, male patients 4.3%; age 0 to less than 6 months, 0.9%; 6 months to less than 12 years, 11.0%; 12 to less than 18 years, 5.8%; 18 years or older, 2.2%). Among ADAD epidemiology in Israel is comparable with other real-world database studies. AD imposes an economic burden that increases with disease severity.Occurrence and costs of atopic dermatitis in IsraelAtopic dermatitis is a disease that causes the skin to be inflamed and itchy. Atopic dermatitis is most common in children but can also occur in adolescents and adults. Using data from a large healthcare provider in Israel, this study aimed to describe how common atopic dermatitis is within the population. Costs related to the use of healthcare services (such as visits to dermatologists and creams to treat atopic dermatitis) in the year 2017 were compared between persons with versus without atopic dermatitis. For the years 2008 to 2017, approximately 7 out of 1000 people were newly diagnosed with atopic dermatitis each year (incidence). Among people alive on 31 December 2017, 4.4% had atopic dermatitis (prevalence), with 42.3% suggestive of moderate to severe disease. Patients with atopic dermatitis, particularly those with more severe disease, used healthcare services more frequently. Compared with people without atopic dermatitis, medical costs among patients with atopic dermatitis were 36% higher (corresponding to added costs of $126 per person per year). This study helps to better understand how many people have atopic dermatitis, and what healthcare resources are needed to manage this disease.

Background and Objectives: The success rates of surgical dental implant insertions are high. However, knowledge of patients’ recovery is still lacking. “Health-related quality of life” (HRQOL) questionnaires are gaining popularity in all fields of medicine. The present survey assessed the perception of recovery after the surgical placement of dental implants. Materials and Methods: Forty individuals (26 women and 14 men, mean age, 55 ± 12 years) filled a questionnaire evaluating patients’ perception of recovery for 7 consecutive days post-surgery. Confounding factors included age, gender, oral habits, smoking, bruxism, bone quality (tactile evaluation) and quantity, implant location, number of implants, implant type, length and diameter, one-stage vs. two-stage, and the need for bone grafting. Results: The most serious difficulties were found in swelling, which became minimal after 5 days, followed by eating everyday food, ability to enjoy everyday food, maximal pain and average pain (3 days), analgesics consumption (2.5 days), limitations in daily routine, mouth opening, and speech (2 days), swallowing and sleep (1.5 days), and, within 1 day, all other measures attained minimal levels. Gender, and implant location (anterior vs. posterior) were significant predictor variables exerting their different characteristic delayed recoveries. Conclusions: (1) Patients should expect, in general, recovery within 4 days after dental implant placement, (2) women will experience a delayed recovery, (3) implants placed in the intercanine area will result in postoperative eating difficulties for nearly one week, and (4) the number of implants placed during the same appointment has no effect on post treatment recovery.

BackgroundNon-Vitamin K antagonist oral anticoagulants (NOACs) emerged as an alternative with comparable or superior efficacy and safety to vitamin K antagonists (VKAs) for stroke prevention in patients with non-valvular atrial fibrillation (AF).ObjectivesThe aim of the current study was to investigate the patterns, predictors, timelines and temporal trends of shifting from VKAs to NOACs.MethodsIn this retrospective observational study, the computerized database of a large healthcare provider in Israel, Maccabi Healthcare Services, was searched to identify patients with AF for whom either a VKA or NOAC was prescribed between 2012 and 2015. Time from diagnosis to therapy initiation and to shifting between therapies was evaluated.ResultsOut of 6987 eligible AF incident patients, 2338 (33.4%) initiated treatment with a VKA and 2221 (31.7%) with a NOAC. In addition, 5259 prevalent patients were analyzed. During the study period, NOAC prescriptions proportion among the newly diagnosed cases increased from 32 to 68.4% (pfor trend 2and CHA2DS2-VASC score, non-smoking, and treatment with antiplatelets were associated with a greater likelihood for therapy shift. Shifting from a NOAC to a VKA decreased over time from 8 to 4.5% in 2012 to 0.5% and 0.7% in 2015 in the incident and prevalent groups,p ConclusionsShifting from VKA to NOAC occurred in 50% of the cases, more frequently among incident cases, and younger patients with greater stroke risk. Shifting from a NOAC to a VKA was much less frequent, yet it occurred more often in incident cases and decreased over time. A socially and economically sensitive program to optimize the initiation of OAC therapy upon diagnosis is warranted.

The intestine is lined with isolated lymphoid follicles (ILFs) that facilitate sampling of luminal antigens to elicit immune responses. Technical challenges related to the scarcity and small sizes of ILFs and their follicle-associated epithelium (FAE) impeded the characterization of their spatial gene expression programs. Here, we combined RNA sequencing of laser capture microdissected tissues with single-molecule transcript imaging to obtain a spatial gene expression map of the ILF and its associated FAE in the mouse small intestine. We identified zonated expression programs in both follicles and FAEs, with a decrease in enterocyte antimicrobial and absorption programs and a partial induction of expression programs normally observed at the villus tip. We further identified Lepr+ subepithelial telocytes at the FAE top, which are distinct from villus tip Lgr5+ telocytes. Our analysis exposes the epithelial and mesenchymal cell states associated with ILFs., The intestine is lined with isolated lymphoid follicles that facilitate sampling of luminal antigens to elicit immune responses. This study combines spatial transcriptomics and single molecule transcript imaging to identify spatially localized cellular states in intestinal follicles and their associated epithelium.

The intestinal epithelium is a structured organ composed of crypts harboring Lgr5+ stem cells, and villi harboring differentiated cells. Spatial transcriptomics have demonstrated profound zonation of epithelial gene expression along the villus axis, but the mechanisms shaping this spatial variability are unknown. Here, we combine laser capture micro-dissection and single cell RNA sequencing to uncover spatially zonated populations of mesenchymal cells along the crypt-villus axis. These include villus tip telocytes (VTTs) that express Lgr5, a gene previously considered a specific crypt epithelial stem cell marker. VTTs are elongated cells that line the villus tip epithelium and signal through Bmp morphogens and the non-canonical Wnt5a ligand. Their ablation is associated with perturbed zonation of enterocyte genes induced at the villus tip. Our study provides a spatially-resolved cell atlas of the small intestinal stroma and exposes Lgr5+ villus tip telocytes as regulators of the epithelial spatial expression programs along the villus axis., Nature Communications, 11 (1), ISSN:2041-1723