Lirentelimab for severe and chronic forms of allergic conjunctivitis.

BACKGROUND: Allergic conjunctivitis (AC) is an ocular inflammatory disease with symptoms driven by eosinophils and mast cells. Allergic comorbidities are common. Current treatments are often ineffective in severe AC and limited by potential side effects. Lirentelimab is an anti-sialic acid-binding immunoglobulin-like lectin-8 mAb that depletes eosinophils and inhibits mast cells. OBJECTIVE: We sought to determine safety and preliminary efficacy of lirentelimab in an open-label, phase 1b study. METHODS: Patients with chronic, severely symptomatic atopic keratoconjunctivitis, vernal keratoconjunctivitis, and perennial AC, and who had history of topical or systemic corticosteroid use, were enrolled to receive up to 6 monthly lirentelimab infusions (dose 1: 0.3 mg/kg, dose 2: 1 mg/kg, subsequent doses: 1 or 3 mg/kg). Changes from baseline in peripheral blood eosinophils, changes in patient-reported symptoms (measured by daily Allergic Conjunctivitis Symptom Questionnaire, including atopic comorbidities), changes in investigator-reported ocular signs and symptoms (Ocular Symptom Scores), changes in quality of life, and changes in tear cytokine and chemokine levels were assessed. RESULTS: Thirty patients were enrolled (atopic keratoconjunctivitis n = 13, vernal keratoconjunctivitis n = 1, perennial AC n = 16), 87% of whom had atopic comorbidities. After lirentelimab treatment, mean improvement was observed in Allergic Conjunctivitis Symptom Questionnaire score (-61%; 95% CI, -75% to -48%) and Ocular Symptom Scores (-53%; 95% CI, -76% to -31%), consistent across atopic keratoconjunctivitis, vernal keratoconjunctivitis, and perennial AC groups. There was substantial improvement in atopic comorbidities, with -55% (95% CI, -78% to -31%), -50% (95% CI, -82% to -19%), and -63% (95% CI, -87% and -38%) reduction in symptoms of atopic dermatitis, asthma, and rhinitis, respectively. Levels of key mediators of inflammation were reduced in patient tears after lirentelimab treatment. The most common adverse effects were mild to moderate infusion-related reactions. CONCLUSIONS: Lirentelimab was well tolerated, improved severe AC and concomitant atopic symptoms, and reduced inflammatory mediators in patient tears.

Amyloid fibril polymorphism: a challenge for molecular imaging and therapy.

The accumulation of misfolded proteins (MPs), both unique and common, for different diseases is central for many chronic degenerative diseases. In certain patients, MP accumulation is systemic (e.g. TTR amyloid), and in others, this is localized to a specific cell type (e.g. Alzheimer's disease). In neurodegenerative diseases, NDs, it is noticeable that the accumulation of MP progressively spreads throughout the nervous system. Our main hypothesis of this article is that MPs are not only markers but also active carriers of pathogenicity. Here, we discuss studies from comprehensive molecular approaches aimed at understanding MP conformational variations (polymorphism) and their bearing on spreading of MPs, MP toxicity, as well as MP targeting in imaging and therapy. Neurodegenerative disease (ND) represents a major and growing societal challenge, with millions of people worldwide suffering from Alzheimer's or Parkinson's diseases alone. For all NDs, current treatment is palliative without addressing the primary cause and is not curative. Over recent years, particularly the shape-shifting properties of misfolded proteins and their spreading pathways have been intensively researched. The difficulty in addressing ND has prompted most major pharma companies to severely downsize their nervous system disorder research. Increased academic research is pivotal for filling this void and to translate basic research into tools for medical professionals. Recent discoveries of targeting drug design against MPs and improved model systems to study structure, pathology spreading and toxicity strongly encourage future studies along these lines to provide an opportunity for selective imaging, prognostic diagnosis and therapy.

Body mass index and infectious disease mortality in midlife in a cohort of 2.3 million adolescents.

BACKGROUND: Obesity was linked to altered immunity, but also to favorable outcomes among patients with infectious disease (ID) in some settings. We assessed the association between adolescent body mass index (BMI) and ID mortality. METHODS: BMI of 2 294 139 Israeli adolescents (60% men; age 17.4±0.3 years) was measured between 1967 and 2010. The outcome, obtained by linkage with official national records, was death due to ID as the underlying cause. Multivariable Cox proportional hazards models were applied. RESULTS: During 42 297 007 person-years of follow-up (median 18.4 years), there were 689 deaths from ID (mean age 44.1±10.5 years). Adjusted hazard ratios (HR) were 1.039 (1.011-1.068) and 1.146 (1.099-1.194) among men and women, respectively, per unit increment in BMI (P for sex interaction=4.4 × 10-5). Adjusted hazard ratios among men were 1.2 (1.0-1.5), 1.9 (1.4-2.5) and 2.5 (1.5-4.2) for those with high-normal BMI (22.0-24.9 kg m-2), overweight and obese, respectively, compared with the 18.5⩽BMI<22 kg m-2 reference group, and 1.7 (1.1-2.6), 2.6 (1.6-4.3) and 6.6 (3.3-13.1) among women, respectively. The increased risk among underweight (<18.5 kg m-2) boys was attenuated when the study sample was restricted to those with unimpaired health at baseline. A multivariable spline model indicated a minimum risk for total ID mortality at 20.7 and 18.0 kg m-2 for men and women, respectively, with significantly increased risk seen above adolescent BMI values of 23.6 and 24.0 kg m-2, respectively. The association with BMI was particularly evident for bacterial infections (predominantly sepsis), airways and central nervous system infections (63% of the ID deaths). CONCLUSIONS: Adolescent overweight and obesity were strongly associated with ID mortality, especially of bacterial origin and among women.

Connecting the Sequence-Space of Bacterial Signaling Proteins to Phenotypes Using Coevolutionary Landscapes.

Two-component signaling (TCS) is the primary means by which bacteria sense and respond to the environment. TCS involves two partner proteins working in tandem, which interact to perform cellular functions whereas limiting interactions with non-partners (i.e., cross-talk). We construct a Potts model for TCS that can quantitatively predict how mutating amino acid identities affect the interaction between TCS partners and non-partners. The parameters of this model are inferred directly from protein sequence data. This approach drastically reduces the computational complexity of exploring the sequence-space of TCS proteins. As a stringent test, we compare its predictions to a recent comprehensive mutational study, which characterized the functionality of 204 mutational variants of the PhoQ kinase in Escherichia coli We find that our best predictions accurately reproduce the amino acid combinations found in experiment, which enable functional signaling with its partner PhoP. These predictions demonstrate the evolutionary pressure to preserve the interaction between TCS partners as well as prevent unwanted cross-talk. Further, we calculate the mutational change in the binding affinity between PhoQ and PhoP, providing an estimate to the amount of destabilization needed to disrupt TCS.

Molecular characterization and antibiotic resistance of group G streptococci in Israel: comparison of invasive, non-invasive and carriage isolates.

Beta-hemolytic group G streptococci (GGS) are increasingly recognized as a source of substantial morbidity, causing mild to severe sporadic infections as well as outbreaks. The purpose of this study was to determine the genetic diversity and antibiotic resistance of GGS in Israel in order to aid in prevention and control. A total of 325 GGS isolates were collected in Israel between 2007 and 2011 from three determined settings: (1) carriage (n = 60), an observational longitudinal carriage study in the IF, (2) non-invasive (n = 166), clinical sporadic and epidemic non-invasive cases in the IDF, and (3) invasive (n = 99) cases of bacteremia collected during this period in Israel from a similar age group, at the national Streptococcal Reference Center. All isolates were characterized genetically and by their antibiotic-resistance profile. emm typing revealed 35 distinct types and subtypes among 228 S. dysgalactiae subsp. equisimilis (SDSE) isolates, with high genetic diversity. An additional 97 GGS were identified as Streptococcus anginosus (SAG). The proportion of SDSE was higher in the invasive (100 %) and non-invasive (63.8 %) isolates compared to the carriage ones (38.3 %). Clindamycin, erythromycin, azithromycin and tetracycline resistance was detected in 6.6 %, 8.6 %, 9.7 % and 37.6 % of isolates, respectively. Overall, the most resistant isolates were in the invasive group and the fewest were in the SAG group. Considerable genetic diversity and common antibiotic resistance were revealed among GGS strains which differed according to the epidemiologic settings. Further clinical, epidemiological and basic research of GGS as a pathogen is warranted.

Smoking initiation among Israeli adolescents: a 24-year time-to-event analysis.

INTRODUCTION: Preventing smoking initiation will protect future generations from smoking-attributable death and disease. This study examines the correlates and patterns of initiation among Israeli youth using time-to-event analysis and other methods. METHODS: Twenty-four consecutive representative samples (1986-2009) of new military recruits (N=50,254) were analyzed. Cox regression and Kaplan-Meier analysis were used to identify factors associated with smoking initiation, and logistic regression was used to identify factors associated with smoking status. RESULTS: The most hazardous age for smoking initiation was seventeen, subsequent to the mean age of smoking initiation (males: 15.7, females: 16.0). Age of initiation and age of greatest hazard for initiation declined among recruits between the years 1986 and 2009. Earlier smoking initiation among boys and girls was significantly associated with low education levels (<12years) (males: HR=2.98, CI: [2.79, 3.18]; females: HR=3.35, CI: [2.96, 3.80]), low paternal education levels, Russian birthplace, and religion. Earlier initiation in boys was associated with high fitness levels and low/medium socio-economic status. Earlier initiation in girls was associated with being Western-born and ever-use of contraception. CONCLUSIONS: Smoking initiation among Israeli youth recruited to the armed forces is associated with individual and family characteristics, particularly low education levels. Time-to-event analysis complements traditional means of understanding smoking initiation by identifying ages at which initiation hazard is high.

Secular and seasonal trends of infectious mononucleosis among young adults in Israel: 1978-2009.

Recent evidence that infectious mononucleosis (IM) may be sexually transmitted prompted the present analysis. Infectious mononucleosis is a notifiable disease in the Israel Defense Forces (IDF). For the present study, the archives of the IDF were reviewed for all cases of IM from January 1, 1978 to December 31, 2009, and the rates were calculated. Annual rates decreased from 2.99 cases per 1,000 in 1979 to a low of 0.38 cases per 1,000 young adults in 1987. Between 2002 and 2009, the average annual rate was 0.88 cases per 1,000, just half the average rate of 1.69 observed between 1989 and 2001. Average monthly rates varied from a low of 0.90 cases per 10,000 in February to a high of 1.50 cases per 10,000 in August. The difference in the average rates between winter (1.02 cases per 10,000 soldiers) and summer (1.29 cases per 10,000 soldiers) was significant (p < 0.01). Analysis of the long-term epidemiology of IM shows that the infection rate has varied over time, and that the disease is more prevalent in the warmer months. This seasonality trend was also observed in several STD, raising the possibility of considering this mode of transmission in IM.

Transmission of Streptococcus pneumoniae in adults may occur through saliva.

Of 742 army recruits tested for pneumococcal nasopharyngeal/oropharyngeal carriage, 6·6% were positive. Frequent sharing of a drinking glass/bottle was a common, strong and independent risk factor for pneumococcal carriage. Our findings strongly suggest, for the first time, that in young adults, transmission of pneumococci may occur via saliva and this should be considered when conducting an outbreak investigation and carriage studies.

Quantum optimization of maximum independent set using Rydberg atom arrays.

Realizing quantum speedup for practically relevant, computationally hard problems is a central challenge in quantum information science. Using Rydberg atom arrays with up to 289 qubits in two spatial dimensions, we experimentally investigate quantum algorithms for solving the maximum independent set problem. We use a hardware-efficient encoding associated with Rydberg blockade, realize closed-loop optimization to test several variational algorithms, and subsequently apply them to systematically explore a class of graphs with programmable connectivity. We find that the problem hardness is controlled by the solution degeneracy and number of local minima, and we experimentally benchmark the quantum algorithm's performance against classical simulated annealing. On the hardest graphs, we observe a superlinear quantum speedup in finding exact solutions in the deep circuit regime and analyze its origins.

Controlling quantum many-body dynamics in driven Rydberg atom arrays.

The control of nonequilibrium quantum dynamics in many-body systems is challenging because interactions typically lead to thermalization and a chaotic spreading throughout Hilbert space. We investigate nonequilibrium dynamics after rapid quenches in a many-body system composed of 3 to 200 strongly interacting qubits in one and two spatial dimensions. Using a programmable quantum simulator based on Rydberg atom arrays, we show that coherent revivals associated with so-called quantum many-body scars can be stabilized by periodic driving, which generates a robust subharmonic response akin to discrete time-crystalline order. We map Hilbert space dynamics, geometry dependence, phase diagrams, and system-size dependence of this emergent phenomenon, demonstrating new ways to steer complex dynamics in many-body systems and enabling potential applications in quantum information science.

Probing topological spin liquids on a programmable quantum simulator.

Quantum spin liquids, exotic phases of matter with topological order, have been a major focus in physics for the past several decades. Such phases feature long-range quantum entanglement that can potentially be exploited to realize robust quantum computation. We used a 219-atom programmable quantum simulator to probe quantum spin liquid states. In our approach, arrays of atoms were placed on the links of a kagome lattice, and evolution under Rydberg blockade created frustrated quantum states with no local order. The onset of a quantum spin liquid phase of the paradigmatic toric code type was detected by using topological string operators that provide direct signatures of topological order and quantum correlations. Our observations enable the controlled experimental exploration of topological matter and protected quantum information processing.

Antigen recognition and antibody specificity. Carrier specificity and genetic control of anti-dinitrophenyl-oligolysine antibody.

The exact specifiicity of anti-DNP antibody produced by Hartley guinea pigs immunized with a series of defined alpha,DNP and epsilon,DNP-oligolysines was studied by fluorescence quenching. All responder animals made anti-DNP antibody which recognized the precise chain length, +/- 1 lysyl residue, of the DNP-oligolysines used to induce the immune response as measured by an increase in binding energy (-DeltaF degrees ) for that antigen. The ability of the immune system to detect the smallest possible change in oligolysine chain length suggests that the anti-hapten antibody-forming cell possesses a highly specific recognition system for carrier conformation. When DNP-oligolysines are incorporated in an adjuvant containing M. tuberculosis H37Rv, both responder and nonresponder produce anti-DNP antibody, but only the responder develops delayed skin sensitivity. In addition to their failure to develop delayed hypersensitivity, nonresponders produced anti-DNP oligolysine antibody which did not show the increase in -DeltaF degrees for the immunizing antigen characteristic of responder antibody. These observations support a local environment hypothesis for antigen recognition at the level of the anti-hapten antibody-forming cell and suggest that the polylysine gene exerts its control at the same cell.

Antibody-dependent cellular cytotoxicity by allosensitized human T cells.

Peripheral human T cells, isolated by sheep erythrocyte-rosette formation and density centrifugation, were highly cytotoxic to both Ab-coated autologous lymphocytes and antibody (Ab)-coated chicken erythrocytes when stimulated in mixed lymphocyte culture, but were not lytic when freshly purified, or when unstimulated in 6-day culture. Allosensitized T cells were shown to effect this activity by a specific effector-target cell interaction dependent on Ab, as indicated by: (a) induction of killing by Ab to target cells not lysed in the absence of Ab. (b) inhibition of Ab-dependent killing by aggregated Ig. The mechanism by which allosensitized T cells effect antibody-dependent cellular cytotoxicity is discussed.

Expression of interleukin 2 receptors and binding of interleukin 2 by gamma interferon-induced human leukemic and normal monocytic cells.

Gamma interferon induced surface expression of interleukin 2 (IL-2) receptors on normal human monocytes and the monocytoid cell lines U937 and HL60. These receptors were detected by anti-IL-2 receptor monoclonal antibodies, and U937 IL-2 receptors were indistinguishable from T lymphocyte IL-2 receptors by immunoprecipitation. Also, U937 IL-2 receptors bound biologically active IL-2. These results suggest a role for monocyte IL-2 receptors in T cell/monocyte interaction during an immune response.

Functional consequences of interleukin 2 receptor expression on resting human lymphocytes. Identification of a novel natural killer cell subset with high affinity receptors.

In this study, we have used radiolabeled IL-2 binding assays, Northern blot analysis, immunofluorescent flow cytometry and cell sorting, as well as proliferation and cytotoxicity assays to perform an extensive phenotypic and functional characterization of the IL-2 receptor in normal resting human peripheral blood lymphocytes. Our results indicate that almost all T cells (greater than 98%) express neither the high affinity IL-2 receptor nor the functional intermediate affinity p75 chain of the IL-2 receptor without prior activation. In contrast, most NK cells constitutively express the isolated intermediate affinity p75 IL-2 receptor. In addition, a subpopulation of NK cells, distinguished by high density expression of the NKH1 antigen, constitutively express the high affinity IL-2 receptor, in addition to an excess of the isolated intermediate affinity p75 IL-2 receptor. These NKH1bright+ cells exhibit a brisk proliferative response to IL-2, similar to that seen with antigen-activated T cells, yet do so in the absence of any known antigenic stimuli. No other resting peripheral blood lymphocyte population, including CD4+, CD8+, and CD20 cells, exhibits this property. The intermediate affinity p75 IL-2 receptor, as it exists in its isolated form on resting NK cells, does not transduce a growth signal equivalent to that seen in NK cells expressing the high affinity IL-2 receptor, despite doses of IL-2 that are known to fully saturate the isolated p75 chain. This strongly suggests that additional structural or functional components are involved in generating the proliferative response following the binding of IL-2 to the high affinity heterodimeric form of the IL-2 receptor. The constitutive expression of this functional high affinity IL-2 receptor on a small population of resting NK cells provides further evidence in support of a role for these cells in the host's early defense against viral infection or malignant transformation, before the more delayed but specific T cell response.

Developmental regulation of a mucinlike glycoprotein selectively expressed on natural killer cells.

Natural killer (NK) cells are CD3:TCR-, CD16+, CD56+ large granular lymphocytes capable of recognizing and eliminating a variety of virus-infected, malignant, and antibody-coated target cells. Two functionally distinct populations of peripheral blood NK cells can be differentiated by their surface expression of an isoform of the neural cell adhesion molecule (CD56). CD56bright NK cells have the attributes of an undifferentiated cell, in that they proliferate in response to exogenous cytokines, but exert poor cytolytic activity. CD56dim NK cells have the attributes of a more differentiated cell, in that they proliferate poorly in response to exogenous cytokines, but are potent cytolytic effector cells. Here we describe the molecular characterization of a NK cell restricted epitope (PEN5) that is selectively expressed on the functionally differentiated CD56dim NK cells. PEN5+ NK cells proliferate poorly in response to interleukin 2 (IL-2), but are potent cytolytic effectors, whereas PEN5- NK cells proliferate in response to IL-2, but are poor cytolytic effectors. Biochemical and immunochemical analyses reveal the PEN5 epitope to be an unusual sulfated poly-N-lactosamine carbohydrate related to keratan sulfate glycosaminoglycans. Immunoprecipitates prepared using a monoclonal antibody reactive with PEN5 include two polydisperse membrane-bound glycoproteins, PEN5 alpha (120-170 kD) and PEN5 beta (210-245 kD). Enzymatic deglycosylation reduces the apparent molecular weight of both PEN5 isoforms by 80-90%, and classifies PEN5 beta as a mucinlike glycoprotein. The surface expression of the PEN5 epitope is downmodulated by stimuli that induce NK cell proliferation, and it is absent from leukemic NK cells of patients with granular lymphocyte proliferative disorder. Taken together, these results indicate that PEN5 is a developmentally regulated poly-N-lactosamine epitope associated with a mucin-type glycoprotein, whose expression is restricted to the population of nonproliferative NK cells fully committed to cytolytic effector function.

Expression of the NKTa clonotype in a series of human natural killer clones with identical cytotoxic specificity.

Over a period of 3 yr, a series of ten NK clones that express a unique clonotypic T cell receptor-like structure, termed NKTa, has been generated from a single individual. These clones were derived from either peripheral blood nonadherent cell fractions (JT9, JT10, JT11), NKH2-purified cells (CNK8, CNK9), or NKTa-purified cells (CNK11, CNK12, CNK13, CNK14, CNK15). Flow cytometric analysis of peripheral blood mononuclear cells from this individual showed that NKTa+ cells occur with a frequency of approximately 0.15%. The existence of NKTa+ cells in peripheral blood was confirmed by use of immunorosette enrichment techniques, flow cytometric purification, and subsequent clonal expansion of NKTa+ cells. Phenotypic analysis of NKTa+ clones showed that all expressed NKH1 as well as T3, T8, T11, T12, and Mo1 antigens. Only five of ten clones expressed NKH2 antigen. All NKTa+ clones had broad cytolytic activity against a series of seven different target cells that was similar to that of other NK clones. In addition, cytotoxicity of each clone could be inhibited by preincubation of effector cells with monoclonal anti-NKTa or by preincubation of target cells with monoclonal anti-TNKTAR. Although half of the NKTa+ clones appeared phenotypically different from the other half with regard to the expression of NKH2 antigen, analysis of T cell receptor gene rearrangements indicated that all NKTa+ clones contained identical gene rearrangements of C beta 2.

Secular trends of gonorrhea in young adults in Israel: three decades of follow-up.

Recent reports of increased rates of gonorrhea initiated an analysis of secular trends of gonorrhea in a young adult population. Gonorrhea is a notifiable disease in the Israel Defense Forces. The diagnosis is based on the typical clinical presentation, relevant epidemiologic data, and positive bacteriological culture. For the present study, the archives of the Epidemiology Department were reviewed for all documented cases of gonorrhea from January 1, 1978 to December 31, 2008, and the annual and seasonal incidence rates were calculated. Annual gonorrhea rates decreased from 2.3 cases per 1,000 soldiers in 1978 to an all-time low of 0.07 cases per 1,000 soldiers in 2008, representing a 97% decline. Multi-year average monthly rates varied from a low of 5.83 cases per 100,000 population in February to a high of 8.97 cases per 100,000 in August. The difference in the person-time incidence (PTI) rates for winter (5.9 cases per 100,000 person-years) and summer (6.8 cases per 100,000 person-years) was statistically significant (p < 0.01). Analyzing the long-term epidemiology of gonorrhea has shown that the infection rate is continuously decreasing and that it appears to be more prevalent in the warmer months.

Post exposure prophylaxis of tick-borne relapsing fever.

Tick-borne relapsing fever (TBRF) is endemic to Israel. Since 2004, the Israel Defence Forces (IDF) has mandated the prophylaxis of tick-bitten subjects with a five-day doxycycline course. We examined the safety and effectiveness of this policy in preventing TBRF. We analyzed the records from January 2004 to January 2007, and identified all reported events of tick bites or TBRF cases. Data were available on 27 events in which 816 soldiers have undergone physical examination following exposure, and seven TBRF cases were recorded in this group-an attack rate of 0.86% compared with the expected rate of 5.34% from previous army data (relative risk [RR] = 0.16). Of those screened, 128 (15.7%) had tick-bite and were intended for prophylaxis, of which four TBRF cases occurred-3.13% attack rate compared with an expected rate of 38.4% in these bitten individuals without prophylaxis (RR = 0.08, number needed to treat = 3). In all cases in which screening and prophylaxis were provided within 48 h of tick bite, complete prevention of TBRF was achieved. No cases of Jarisch-Herxheimer reaction (JHR) was recorded. Tick-bite screening and prophylactic treatment with doxycycline in endemic areas is a practical, safe, and highly effective policy for preventing TBRF.