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\"البحث الأميركي عن السلام بين العرب وإسرائيل\"، أعطى الكاتب هذا العنوان العريض لكتابه هذا، ليحكي كل الحكايا حول المفاوضات العربية الإسرائيلية، وليفضي بكل ما كان يحصل وراء كواليسها من أحداث، ولبعرض آراء وتوجهات المعنيين فيها من الرؤساء السابقين لأميركا، ووزراء خارجيتها السابقين، إلى القادة السياسيين العرب والإسرائيليين، من خلال المقابلات التي أجريت معهم. فمن موقعه كمستشار لعدد من الرؤساء الأميركيين ووزراء الخارجية ومستشاري الأمن القومي، وكأحد المفاوضين المشاركين المباشرين في عملية السلام بين العرب وإسرائيل، أستطاع الكاتب وهوالمؤرخ والمحلل السياسي، من الوصول إلى وجهة نظر فريدة تجاه هذه المعضلة المستمرة. بأسلوب روائي شيق ومثير للفضول، ومن منظار شامل وحس نقدي، يفصل الكاتب السياسة الأميركية تجاه الشرق الأوسط، ويعطي صفاتا موجزة وذات دلالات سياسية وتاريخية لرجال أميركا الذين عملوا على هذه المفاوضات وعايشوها، فهنري كيسنجر \"صاحب الاستراتيجيات\"، وجيمي كارتر \"التبشيري\"، وجيمس بيكر \"المفاوض\"، وبيل كلنتون\"الرجل اللطيف\" الذي أفرط في حبه للعرب والإسرائيليين، وجورج دبليو بوش \"المتملص\". لا يبخل الكاتب بالإدلاء بمجموعة من الوقائع والحقائق ويطلق على أثرها الاستنتاجات، فيقول مثلا : \"كل من يعتقد أن الإسرائيليين والفلسطينيين قد اقتربوا من الاتفاق في أي من مفاوضاتهم الأخيرة\" \"فلا بد من أنه قد أمضى وقتا طويلا في عالم الخيال\". ويتساءل في القسم الأخير \"هل يمكن تحقيق السلام العربي-الإسرائيلي، وما الذي يمكن لأميركا أن تفعله من أجله ؟\"، ويجيب فيما يجيبه :\"لسنا قادرين على دفع القطار إلى الأمام بالدرجة التي كنت أتصورها\"، أما \"تحقيق ذلك فيستحق كل ما يتطلب من جهود..\".

The prevalence of many chronic diseases has increased over the last decades. It has been postulated that dysbiosis driven by environmental factors such as antibiotic use is shifting the microbiome in ways that increase inflammation and the onset of chronic disease. Dysbiosis can be defined through the loss or gain of bacteria that either promote health or disease, respectively. Here we use multiple independent datasets to determine the nature of dysbiosis for a cluster of chronic diseases that includes urinary stone disease (USD), obesity, diabetes, cardiovascular disease, and kidney disease, which often exist as co-morbidities. For all disease states, individuals exhibited a statistically significant association with antibiotics in the last year compared to healthy counterparts. There was also a statistically significant association between antibiotic use and gut microbiota composition. Furthermore, each disease state was associated with a loss of microbial diversity in the gut. Three genera, Bacteroides, Prevotella , and Ruminococcus , were the most common dysbiotic taxa in terms of being enriched or depleted in disease populations and was driven in part by the diversity of operational taxonomic units (OTUs) within these genera. Results of the cross-sectional analysis suggest that antibiotic-driven loss of microbial diversity may increase the risk for chronic disease. However, longitudinal studies are needed to confirm the causative effect of diversity loss for chronic disease risk.

Understanding the circumstances under which arboviruses emerge is critical for the development of targeted control and prevention strategies. This is highlighted by the emergence of chikungunya and Zika viruses in the New World. However, to comprehensively understand the ways in which viruses emerge and persist, factors influencing reductions in virus activity must also be understood. Western equine encephalitis virus (WEEV), which declined during the late 20th century in apparent enzootic circulation as well as equine and human disease incidence, provides a unique case study on how reductions in virus activity can be understood by studying evolutionary trends and mechanisms. Previously, we showed using phylogenetics that during this period of decline, six amino acid residues appeared to be positively selected. To assess more directly the effect of these mutations, we utilized reverse genetics and competition fitness assays in the enzootic host and vector (house sparrows and Culex tarsalis mosquitoes). We observed that the mutations contemporary with reductions in WEEV circulation and disease that were non-conserved with respect to amino acid properties had a positive effect on enzootic fitness. We also assessed the effects of these mutations on virulence in the Syrian-Golden hamster model in relation to a general trend of increased virulence in older isolates. However, no change effect on virulence was observed based on these mutations. Thus, while WEEV apparently underwent positive selection for infection of enzootic hosts, residues associated with mammalian virulence were likely eliminated from the population by genetic drift or negative selection. These findings suggest that ecologic factors rather than fitness for natural transmission likely caused decreased levels of enzootic WEEV circulation during the late 20th century.

During March and April 2024, we studied dairy cattle specimens from a single farm in Texas, USA, using multiple molecular, cell culture, and next-generation sequencing pathogen detection techniques. Here, we report evidence that highly pathogenic avian influenza A(H5N1) virus strains of clade 2.3.4.4b were the sole cause of this epizootic.

The prevalence of urinary stone disease (USD) is rapidly rising. However, the factors driving this increase are unknown. Recent microbiome studies suggest that dysbiosis may in part contribute to the increasing prevalence. The objective of the current study was to determine the nature and location of dysbiosis associated with USD. We conducted microbiome analysis from the gastrointestinal and urinary tracts, along with a metabolomic analysis of the urinary metabolome, from subjects with an active episode of USD or no history of the disease. Higher rates of antibiotic use among USD patients along with integrated microbiome and metabolomic results support the hypothesis that USD is associated with an antibiotic-driven shift in the microbiome from one that protects against USD to one that promotes the disease. Specifically, our study implicates urinary tract Lactobacillus and Enterobacteriaceae in protective and pathogenic roles for USD, respectively, which conventional, culture-based methods of bacterial analysis from urine and kidney stones would not necessarily detect. Results suggest that antibiotics produce a long-term shift in the microbiome that may increase the risk for USD, with the urinary tract microbiome holding more relevance for USD than the gut microbiome.

Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing–remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis. This international, randomised, double-blind, placebo-controlled, phase 3 study enrolled adults aged 18–55 years with relapsing multiple sclerosis, one or more relapse in the previous 12 months or two or more in the previous 24 months but no relapse in the previous 30 days, and an Expanded Disability Status Scale (EDSS) score of 5·5 points or less. Patients were recruited from 189 sites in 26 countries and randomly assigned (1:1:1) to once-daily placebo, teriflunomide 7 mg, or teriflunomide 14 mg via an interactive voice recognition system. Treatment duration was variable, ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate (number of relapses per patient-year) and the key secondary endpoint was time to sustained accumulation of disability (an EDSS score increase of at least 1 EDSS point sustained for a minimum of 12 weeks), both analysed in the modified intention-to-treat population (all patients who received at least one dose of assigned study medication). This study is registered with ClinicalTrials.gov, number NCT00751881. Between Sept 17, 2008, and Feb 17, 2011, 1169 patients were randomly assigned to a treatment group, of whom 388, 407, and 370 patients received at least one dose of placebo, teriflunomide 7 mg, or teriflunomide 14 mg, respectively. By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0·50 [95% CI 0·43–0·58]) than in those assigned to teriflunomide 14 mg (0·32 [0·27–0·38]; p=0·0001) or teriflunomide 7 mg (0·39 [0·33–0·46]; p=0·0183). Compared with placebo, teriflunomide 14 mg reduced the risk of sustained accumulation of disability (hazard ratio [HR] 0·68 [95% CI 0·47–1·00]; log-rank p=0·0442); however, teriflunomide 7 mg had no effect on sustained accumulation of disability (HR 0·95 [0·68–1·35]; log-rank p=0·7620). The most common adverse events were alanine aminotransferase increases (32 [8%] of 385 patients in the placebo group vs 46 [11%] of 409 patients in the teriflunomide 7 mg group vs 52 [14%] of 371 patients in the teriflunomide 14 mg group), hair thinning (17 [4%] vs 42 [10%] vs 50 [13%]), and headache (42 [11%] vs 60 [15%] vs 46 [12%]). Incidence of serious adverse events was similar in all treatment groups (47 [12%] vs 52 [13%] vs 44 [12%]). Four deaths occurred, none of which was considered to be related to study drug (respiratory infection in the placebo group, traffic accident in the teriflunomide 7 mg group, and suicide and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy in the teriflunomide 14 mg group). Teriflunomide 14 mg was associated with a lower relapse rate and less disability accumulation compared with placebo, with a similar safety and tolerability profile to that reported in previous studies. These results confirm the dose effect reported in previous trials and support the use of teriflunomide 14 mg in patients with relapsing multiple sclerosis. Genzyme, a Sanofi company.

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

CD4 + T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8 + T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8 + T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-specific CD4 + T cells is less well understood. We have characterized the murine CD4 + T cell response against a validated NeoAg (CLTC H129>Q ) expressed by the MHC-II-deficient squamous cell carcinoma tumor model (SCC VII) at the level of single T cell receptor (TCR) clonotypes and in the setting of adoptive immunotherapy. We find that the natural CLTC H129>Q -specific repertoire is diverse and contains TCRs with distinct avidities as measured by tetramer-binding assays and CD4 dependence. Despite these differences, CD4 + T cells expressing high or moderate avidity TCRs undergo comparable in vivo proliferation to cross-presented antigen from growing tumors and drive similar levels of therapeutic immunity that is dependent on CD8 + T cells and CD40L signaling. Adoptive cellular therapy (ACT) with NeoAg-specific CD4 + T cells is most effective when TCR-engineered cells are differentiated ex vivo with IL-7 and IL-15 rather than IL-2 and this was associated with both increased expansion as well as the acquisition and stable maintenance of a T stem cell memory (T SCM )-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with T SCM -like CD4 + T cells results in lower PD-1 expression by CD8 + T cells in the tumor microenvironment and an increased frequency of PD-1 + CD8 + T cells in tdLNs. These findings illuminate the role of NeoAg-specific CD4 + T cells in mediating antitumor immunity via providing help to CD8 + T cells and highlight their therapeutic potential in ACT. In cancer, neoantigen (NeoAg)-specific CD8 +  T cells capable of direct tumor recognition have been extensively studied but little is known of the role of NeoAg-specific CD4 +  T cells. Here Schoenberger and colleagues analyze an oligoclonal CD4 +  T cell response to a naturally arising murine tumor NeoAg at the level of TCR usage and functionality.

Secondary progressive multiple sclerosis (MS) is typically defined as deterioration independent of relapses for ≥ 6 months following an initial relapsing–remitting course; however, this definition is not always easily applied in clinical practice and the declaration of the change in clinical phenotype is often delayed. To identify the length of time required to re-classify relapsing–remitting MS (RRMS) patients whom have clinically transitioned to secondary progressive MS (SPMS) in clinical practice. We reviewed 123 patients with long-term follow-up and identified a sub-group whom transitioned from RRMS to SPMS, then characterized this transition period. There were 14/20 patients who transitioned during the follow-up period that had visits with uncertainty related to the clinical phenotype characterized by possible, but not definitive progression. The mean duration of this period of uncertainty was 2.9 ± 0.8 years. A period of diagnostic uncertainty regarding the transition from RRMS to SPMS existed in many of our patients. Potential reasons included the subtle nature of early progressive disease and caution in applying a progressive label, in light of the lack of evidence-based treatments as well as third-party payer concerns. Delay in definitive identification of an SPMS phenotype has a variety of implications related to patient care and research.

Abstract Background Injection drug use (IDU) and IDU-related infections have increased dramatically. However, the incidence of IDU-related infections may be underreported because drug use is not recorded in diagnostic records where associated infections are identified. Our goal was to estimate a more accurate incidence of IDU-related infections by including IDU-related infections not recorded at the time infections are diagnosed. Methods We performed a retrospective cohort study using inpatient and emergency department visits from the Healthcare Cost and Utilization Project for California, Florida, and New York. We identified all patients diagnosed with bacteremia or sepsis, endocarditis, osteomyelitis or septic arthritis, and skin or soft tissue infection. We estimated the incidence of IDU-related infections by identifying cases where drug use was recorded at the time of an infection and cases where drug use was not recorded at the time of infection but within 6 months before or after the infection diagnosis. We also analyzed factors associated with unrecorded IDU. Results There has been an increasing trend in the number of IDU-related infections. The annual number of IDU-related infections increased between 105% and 218% after incorporating infections in which drug use was unrecorded. Factors associated with drug use being unrecorded included emergency department diagnosis, the level of hospital experience treating drug use, age <18 years, and having Medicare as the primary payer. Conclusions More than half of all IDU-related infections may be unrecorded in existing surveillance estimates. There may be many missed opportunities to record, diagnose, or treat underlying drug abuse among patients presenting with IDU-related infections. Injection drug use (IDU)–related infections may be missed if drug use is not diagnosed or recorded when an infection is identified. We find that more than half of all IDU-related infections may be unrecorded in existing surveillance estimates.