Socioeconomic Disparities and COVID-19 Vaccination Acceptance: Experience from Israel

COVID-19 vaccination acceptance has a key role in mitigating the pandemic. Concern has been raised that vaccination rates will be limited in demographically defined areas of lower income. Israels rapid vaccination campaign may allow to assess these assumptions in real-world and to devise tools for effectively focusing the vaccination efforts. We analyzed the correlation between COVID-19 vaccination rates, socioeconomic status (SES) and active COVID-19 disease burden. We carried out a nationwide study, based on data provided by Ministry of Health of COVID-19 vaccination rates in all municipalities in Israel up to January 12th, 2021. Municipal Vaccination rates of population older than 60 significantly correlated with the socioeconomic status (r=0.83, 95% confidence interval [0.79 to 0.87]). Finally, we established a novel metric for focusing the vaccination efforts based on % vaccinations and active disease burden. In Israel, a case-model country for COVD-19 vaccinations, vaccination rates were strongly correlated with SES. The study findings demonstrate the need to directly target vaccination acceptance to socio-economically disadvantaged populations and suggest potential tools for policymakers to focus their efforts.

Clinical evaluation of a dressing with poly absorbent fibres and a silver matrix for managing chronic wounds at risk of infection: a non comparative trial.

OBJECTIVE: To assess the efficacy, safety and acceptability of a new silver poly absorbent dressing (UrgoCleanAg) in the local management of exudative chronic wounds at risk of infection, with inflammatory signs suggesting heavy bacterial load. METHOD: This prospective, multicentre, non-comparative clinical trial was conducted in French hospital wards (dermatology and vascular medicine) or specialised private-practice physicians. Patients were considered at high-risk of infection when presenting with at least three of five selected inflammatory clinical signs, suggesting a heavy bacterial load (pain between two dressing changes, erythema, oedema, malodorous wound and presence of a heavy exudate). They were treated for a maximum period of four weeks, and followed by the physician on a weekly basis, including a clinical examination, area tracings and photographs. The primary efficacy criterion of the trial was the relative wound surface area reduction at the end of the four weeks of treatment. Acceptability was documented by the nursing staff at each dressing change between the weekly evaluations. RESULTS: We recruited 37 patients with chronic wounds. Wound surface area, mostly covered by sloughy tissue, was reduced by 32.5% at the end of the treatment (median value), while the clinical score (maximum value of 5, based on inflammatory clinical signs) decreased from 4.0 to 2.0. Effective debridement properties were documented (62.5% relative reduction of sloughy tissue at week 4; 58.8% of debrided wounds at week 4) and improvement of the periwound skin status was noted (healthy for 28.6% of the patients at week 4 versus 2.7% at baseline). In addition, the tested wound dressing presented a good safety profile associated to a high level of acceptability, noted by both patients and nursing staff. CONCLUSION: These clinical data support that the tested dressing is a credible therapeutic alternative for the management of chronic wounds at risk of infection with inflammatory signs suggesting heavy bacterial load.

The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate abatacept therapy in patients with non-life-threatening systemic lupus erythematosus (SLE) and polyarthritis, discoid lesions, or pleuritis and/or pericarditis. METHODS: In a 12-month, multicenter, exploratory, phase IIb randomized, double-blind, placebo-controlled trial, SLE patients with polyarthritis, discoid lesions, or pleuritis and/or pericarditis were randomized at a ratio of 2:1 to receive abatacept (∼10 mg/kg of body weight) or placebo. Prednisone (30 mg/day or equivalent) was given for 1 month, and then the dosage was tapered. The primary end point was the proportion of patients with new flare (adjudicated) according to a score of A/B on the British Isles Lupus Assessment Group (BILAG) index after the start of the steroid taper. RESULTS: A total of 118 patients were randomized to receive abatacept and 57 to receive placebo. The baseline characteristics were similar in the 2 groups. The proportion of new BILAG A/B flares over 12 months was 79.7% (95% confidence interval [95% CI] 72.4, 86.9) in the abatacept group and 82.5% (95% CI 72.6, 92.3) in the placebo group (treatment difference -3.5 [95% CI -15.3, 8.3]). Other prespecified flare end points were not met. In post hoc analyses, the proportions of abatacept-treated and placebo-treated patients with a BILAG A flare were 40.7% (95% CI 31.8, 49.5) versus 54.4% (95% CI 41.5, 67.3), and the proportions with physician-assessed flare were 63.6% (95% CI 54.9, 72.2) and 82.5% (95% CI 72.6, 92.3), respectively; treatment differences were greatest in the polyarthritis group. Prespecified exploratory patient-reported outcomes (Short Form 36 health survey, sleep problems, fatigue) demonstrated a treatment effect with abatacept. The frequency of adverse events (AEs) was comparable in the abatacept and placebo groups (90.9% versus 91.5%), but serious AEs (SAEs) were higher in the abatacept group (19.8 versus 6.8%). Most SAEs were single, disease-related events occurring during the first 6 months of the study (including the steroid taper period). CONCLUSION: Although the primary/secondary end points were not met in this study, improvements in certain exploratory measures suggest some abatacept efficacy in patients with non-life-threatening manifestations of SLE. The increased rate of SAEs requires further assessment.

Rheumatic fever.

Rheumatic fever is a multisystem inflammatory disease that occurs as a delayed sequel to group A streptococcal pharyngitis. It is less common than it was 50 years ago but is still a major cause of heart disease in developing areas of the world. The relationship between the site of infection, the type of causative organism, and susceptibility of the host is essential in the development of the disease. Its major clinical manifestations include carditis, migratory polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. It can manifest as an acute febrile illness consisting of migratory polyarthritis involving the large joints, as carditis and valvulitis, or as Sydenham's chorea with involvement of the central nervous system. The disorder in its milder form resolves itself without sequelae. Carditis is the condition most associated with increased mortality and morbidity and may be fatal in its severe forms. Penicillin is the most appropriate primary and secondary prophylaxis. Anti- inflammatory agents provide symptomatic relief but do not prevent rheumatic heart disease.

Use of serum immune complexes in a new test that accurately confirms early Lyme disease and active infection with Borrelia burgdorferi.

The present recommendation for serologic confirmation of Lyme disease (LD) calls for immunoblotting in support of positive or equivocal ELISA. Borrelia burgdorferi releases large quantities of proteins, suggesting that specific antibodies in serum might be trapped in immune complexes (ICs), rendering the antibodies undetectable by standard assays using unmodified serum. Production of ICs requires ongoing antigen production, so persistence of IC might be a marker of ongoing or persisting infection. We developed an immunoglobulin M (IgM) capture assay (EMIBA) measuring IC-derived IgM antibodies and tested it using three well-defined LD populations (from an academic LD referral center, a well-described Centers for Disease Control and Prevention (CDC) serum bank, and a group of erythema migrans patients from whose skin lesions B. burgdorferi was grown) and controls (non-Lyme arthritis inflammatory joint disease, syphilis, multiple sclerosis, and nondisease subjects from a region where LD is endemic, perhaps the most relevant comparison group of all). Previous studies demonstrated that specific antigen-antibody complexes in the sera of patients with LD could be precipitated by polyethylene glycol and could then be disrupted with maintenance of the immunoreactivity of the released antibodies, that specific anti-B. burgdorferi IgM was concentrated in ICs, and that occasionally IgM to specific B. burgdorferi antigens was found in the IC but not in unprocessed serum. EMIBA compared favorably with commercial and CDC flagellin-enhanced enzyme-linked immunosorbent assays and other assays in confirming the diagnosis of LD. EMIBA confirmed early B. burgdorferi infection more accurately than the comparator assays. In addition, EMIBA more accurately differentiated seropositivity in patients with active ongoing infection from seroreactivity persisting long after clinically successful antibiotic therapy; i.e., EMIBA identified seroreactivity indicating a clinical circumstance requiring antibiotic therapy. Thus, EMIBA is a promising new assay for accurate serologic confirmation of early and/or active LD.

A molecular beacon strategy for the thermodynamic characterization of triplex DNA: triplex formation at the promoter region of cyclin D1.

We studied the formation of triplex DNA in the purine-pyrimidine-rich promoter site sequence of cyclin D1, located at -116 to -99 from the transcription initiation site, with a molecular beacon comprised of a G-rich 18-mer triplex forming oligodeoxyribonucleotide. Formation of triplex DNA was monitored by enhanced fluorescence of the beacon, due to the weakening of fluorescence energy transfer, upon its binding to the target duplex. Electrophoretic mobility shift assay confirmed triplex DNA formation by these oligonucleotides. In low salt buffer (10 mM Na(+)), triplex DNA formation was not observed in the absence of a ligand such as spermine. At room temperature (22 degrees C), the equilibrium association constant (K(a)) calculated in the presence of 1 microM spermine and 10 mM Na(+) was 3.2 x 10(8) M(-1). The K(a) value was 1.0 x 10(9) M(-1) in the presence of 150 mM Na(+), and it increased by 10-fold by the addition of 1 mM spermine. Delta H, Delta S, and Delta G of triplex DNA formation, calculated from the temperature dependence of K(a) in the range of 20--45 degrees C, were -35.9 kcal/mol, -77 cal/(mol.K), and -13 kcal/mol, respectively, in the presence of 150 mM NaCl. The corresponding values were -52.9 kcal/mol, -132.5 cal/(mol.K), and -13.4 kcal/mol in the presence of 150 mM NaCl and 1 mM spermine. Structurally related polyamines exerted different degrees of triplex DNA stabilization, as determined by binding constant measurements. Comparison of spermine versus hexamine showed a 17-fold increase in the equilibrium association constant, whereas bis(ethyl) derivatization lead to a 4-fold decrease of this value. In the absence of added duplex and polyamines, the molecular beacon dissociated with a melting temperature of 67 degrees C. Thermodynamic parameters of beacon melting were calculated from the melting curve, and the Delta H, Delta S, and Delta G values were 37.8 kcal/mol, 112 cal/(mol.K), and 4.4 kcal/mol, respectively. These results demonstrate that molecular beacons can be used for the direct determination of the equilibrium association constants and thermodynamic parameters of triplex DNA formation in the presence of ligands such as polyamines.

Lyme disease: a clinical update.

With adequate attention to specifics and details, the diagnosis and management of Lyme disease are usually relatively straight-forward. Still, there can be subtleties--for instance, in determining precisely what pathogen a tick bite transmitted, whether a patient's arthralgia is truly Lyme arthritis, or whether "positive" serologies represent refractory Lyme disease.

Replication of the human hepatitis delta virus genome Is initiated in mouse hepatocytes following intravenous injection of naked DNA or RNA sequences.

As early as 5 days after DNA copies of the hepatitis delta virus (HDV) genome or even in vitro-transcribed HDV RNA sequences were injected into the mouse tail vein using the hydrodynamics-based transfection procedure of F. Liu et al. (Gene Ther. 6:1258-1266, 1999), it was possible to detect in the liver by Northern analyses of RNA, immunoblots of protein, and immunostaining of liver sections what were considered typical features of HDV genome replication. This transfection strategy should have valuable applications for in vivo studies of HDV replication and pathogenesis and may also be useful for studies of other hepatotropic viruses.

H9724, a monoclonal antibody to Borrelia burgdorferi's flagellin, binds to heat shock protein 60 (HSP60) within live neuroblastoma cells: a potential role for HSP60 in peptide hormone signaling and in an autoimmune pathogenesis of the neuropathy of Lyme disease.

Although Borrelia burgdorferi, the causative agent of Lyme disease, is found at the site of many disease manifestations, local infection may not explain all its features. B. burgdorferi's flagellin cross-reacts with a component of human peripheral nerve axon, previously identified as heat shock protein 60 (HSP60). The cross-reacting epitopes are bound by a monoclonal antibody to B. burgdorferi's flagellin, H9724. Addition of H9724 to neuroblastoma cell cultures blocks in vitro spontaneous and peptide growth-factor-stimulated neuritogenesis. Withdrawal of H9724 allows return to normal growth and differentiation. Using electron microscopy, immunoprecipitation and immunoblotting, and FACS analysis we sought to identify the site of binding of H9724, with the starting hypotheses that the binding was intracellular and not identical to the binding site of II-13, a monoclonal anti-HSP60 antibody. The current studies show that H9724 binds to an intracellular target in cultured cells with negligible, if any, surface binding. We previously showed that sera from patients with neurological manifestations of Lyme disease bound to human axons in a pattern identical to H9724's binding; these same sera also bind to an intracellular neuroblastoma cell target. II-13 binds to a different HSP60 epitope than H9724: II-13 does not modify cellular function in vitro. As predicted, II-13 bound to mitochondria, in a pattern of cellular binding very different from H9724, which bound in a scattered cytoplasmic, nonorganelle-related pattern. H9724's effect is the first evidence that HSP60 may play a role in peptide-hormone-receptor function and demonstrates the modulatory potential of a monoclonal antibody on living cells.

Molecular biology and immunology for clinicians, 14: Antigen presenting cells--Class II.

Pivotal to immunity and auto-immunity is the ability of the human immune response to make antigen-specific responses, both cellular and humoral. T- and B-cells contain within themselves the ability to recognize and react to specific antigens, but they must be made aware of the presence of their target in the surrounding environment to respond. Turns out this part of the education of T-cells (not B-cells, which are activated by specific antigens in a different manner) is provided by a large number of cells, all coming under the umbrella term: antigen-presenting cells. Understanding how these cells take up molecules from the environment or acquire protein molecules from the intracellular milieu, manipulate them, and then offer the modified material to engage potentially responding cells in an immunological educational conversation is crucial to understanding normal immune function and, of course, auto-immunity and other forms of immune dysregulation. In the broadest of terms, there are two sources of proteins: endogenous (produced within the cell) and exogenous (produced outside of the cell), and there are two not entirely mutually exclusive pathways involved in antigen processing and presentation. To decrease confusion between these two separate pathways antigens, I will proceed with a description of the latter in this paper and cover the former in the next paper in this series. So, now on to antigen processing and presentation of proteins.

Molecular biology and immunology for clinicians 15: Antigen presenting cells--class I.

Class I-bearing antigen presenting cells (APCs) monitor intracellular proteins which are cellular proteins made on a routine basis, endogenous proteins made by stressed cells, proteins made by infected or transformed cells, or proteins made by intracellular pathogens, e.g., viruses, chlamydiae, mycoplasma, Listeria, and some Enterobacteriaceae. The mechanisms by which peptides interact with and are expressed by class I complexes on the surface of APCs is described and contrasted with the circumstances of class II antigen presentation.

Update on Lyme Carditis.

Lyme carditis is an uncommon manifestation of infection with Borrelia bugdorferi. It is easily treated with standard antibiotic regimens and prognosis is excellent, especially if treatment is prompt. For symptomatic or higher degrees of block, patients may require hospitalization for monitoring and occasionally temporary external pacing. Intravenous antibiotics are warranted for such patients. For less severe conduction disturbances, oral therapy suffices.

The role of catastrophizing in the pain and depression of women with fibromyalgia syndrome.

OBJECTIVE: Although 2 recent studies have found associations between catastrophizing and poor medical outcomes in patients with fibromyalgia syndrome (FMS), neither assessed these findings in comparison with a similar group of patients with chronic pain. Our study examined the complex relationships between depression, catastrophizing, and the multidimensional aspects of pain in women with FMS and compared these relationships with those in women with rheumatoid arthritis (RA). METHODS: Sixty-four FMS patients and 30 RA patients completed the Coping Strategies Questionnaire (CSQ), the Beck Depression Inventory II (BDI-II), and the McGill Pain Questionnaire. RESULTS: Compared with subjects with RA, FMS subjects scored significantly higher on the catastrophizing subscale of the CSQ. FMS patients also earned higher scores on overall depression and on the cognitive subscale of the BDI-II. Furthermore, the relationship between catastrophizing and depression was significant in the FMS group only. Regression analyses revealed that in FMS, catastrophizing as a measure of coping predicted patients' perception of pain better than demographic variables such as age, duration of illness, and education. CONCLUSION: Cognitive factors, such as catastrophizing and depressive self-statements, have a more pronounced role in the self-reported pain of patients with FMS than in patients with RA. Clinically, this indicates that treating pain and depression in FMS by adding cognitive therapy and coping skills components to a comprehensive treatment program may improve the outcomes obtained with pharmacologic interventions.

Bone marrow-derived antigen-presenting cells are required for the generation of cytotoxic T lymphocyte responses to viruses and use transporter associated with antigen presentation (TAP)-dependent and -independent pathways of antigen presentation.

Bone marrow (BM)-derived professional antigen-presenting cells (pAPCs) are required for the generation of cytotoxic T lymphocyte (CTL) responses to vaccinia virus and poliovirus. Furthermore, these BM-derived pAPCs require a functional transporter associated with antigen presentation (TAP). In this report we analyze the requirements for BM-derived pAPCs and TAP in the initiation of CTL responses to lymphocytic choriomeningitis virus (LCMV) and influenza virus (Flu). Our results indicate a requirement for BM-derived pAPCs for the CTL responses to these viruses. However, we found that the generation of CTLs to one LCMV epitope (LCMV nucleoprotein 396-404) was dependent on BM-derived pAPCs but, surprisingly, TAP independent. The study of the CTL response to Flu confirmed the existence of this BM-derived pAPC-dependent/TAP-independent CTL response and indicated that the TAP-independent pathway is approximately 10-300-fold less efficient than the TAP-dependent pathway.

Immune complexes from serum of patients with lyme disease contain Borrelia burgdorferi antigen and antigen-specific antibodies: potential use for improved testing.

We report sequestration of specific IgM anti-Borrelia burgdorferi (Bb) and Bb antigens within immune complexes (ICs) isolated from serum of patients with Lyme disease (LD). The relative enrichment in specific IgM measured by ELISA was apparent, even after correcting for differences in total IgM concentration in serum versus ICs. Immunoblot demonstrated that ICs contained antibodies against specific Bb proteins, whereas reactivity was absent or significantly lessened in unprocessed serum. This is the first study to show ICs containing Bb antigen identified by immunoblot with anti-Bb monoclonal antibody. ICs may be a useful source of antigen and antibody for development of more-accurate testing for LD.