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Immune checkpoint blockade (ICB) has markedly improved outcomes across a range of tumours, including metastatic melanoma (MM). However, peripheral biomarkers of response remain lacking and underlying mechanisms of action incompletely described. A number of studies have demonstrated the value of T cell receptor (TCR) repertoire analysis in determining associations with response, however identifying key groups of T cells based on their TCR usage has remained elusive. Here we performed deep sequencing of the TCR of CD8+T cells isolated from peripheral blood of patients receiving ICB for MM (n=91) at multiple time points, along with healthy control samples (n=42) and resected tumour specimens (from n=7 patients). Using the GLIPH2 algorithm to cluster TCR based on putative shared antigen specificity, we describe groups of TCR which expand post-ICB in responding patients which we term ‘Emergent Responder’ (ER) clones. We find that these ER clones are typically large and of a memory phenotype, with increased expression of genes encoding cytotoxic proteins. Analysis of tumours resected in advance of ICB demonstrates ER clones are enriched and expanded within the tumour compared to the periphery at pre-treatment. Significantly, we note the proportion of the peripheral repertoire occupied by ER clones strongly correlates with long-term clinical response. Clinical outcome further associated with HLA type and, crucially, can be validated across replication and independent datasets. This work provides the first-in-kind description of TCR-defined CD8+T cells that mediate the response to ICB in MM, demonstrating the prognostic utility of the peripheral immune repertoire with potential widespread therapeutic and prognostic applications.

Background Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed. Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P P = 2.8 × 10−6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.

Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8+ T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.

The antitumor action of immune checkpoint blockade (ICB) is primarily mediated by CD8(+) T cells. How sensitivity to ICB varies across CD8(+) T cell subsets and clonotypes and the relationship of these with clinical outcome is unclear. To explore this, we used single-cell V(D)J and RNA-sequencing to track gene expression changes elicited by ICB across individual peripheral CD8(+) T cell clones, identify baseline markers of CD8(+) T cell clonal sensitivity, and chart how CD8(+) T cell transcriptional changes vary according to phenotypic subset and clonal size. We identified seven subsets of CD8(+) T cells with divergent reactivity to ICB and found that the cytotoxic effector subset showed the greatest number of differentially expressed genes while remaining stable in clonal size after ICB. At the level of CD8(+) T cell clonotypes, we found a relationship between transcriptional changes and clone size, with large clones showing a greater number of differentially regulated genes enriched for pathways including T cell receptor (TCR) signaling. Cytotoxic CD8(+) effector clones were more likely to persist following ICB and were more likely to correspond with public tumor-infiltrating lymphocyte clonotypes. Last, we demonstrated that individuals whose CD8(+) T cell pretreatment showed low cytotoxicity and had fewer expanded clones typically had worse outcomes after ICB treatment. This work further advances understanding of the molecular determinants of ICB response, assisting in the search for peripheral prognostic biomarkers and highlighting the importance of the baseline CD8(+) immune landscape in determining ICB response in metastatic melanoma.

Immune checkpoint blockade (ICB) of PD-1 and CTLA-4 to treat metastatic melanoma (MM) has variable therapeutic benefit. To explore this in peripheral samples, we characterized CD8+ T cell gene expression across a cohort of patients with MM receiving anti-PD-1 alone (sICB) or in combination with anti-CTLA-4 (cICB). Whereas CD8+ transcriptional responses to sICB and cICB involve a shared gene set, the magnitude of cICB response is over fourfold greater, with preferential induction of mitosis- and interferon-related genes. Early samples from patients with durable clinical benefit demonstrated overexpression of T cell receptor–encoding genes. By mapping T cell receptor clonality, we find that responding patients have more large clones (those occupying >0.5% of repertoire) post-treatment than non-responding patients or controls, and this correlates with effector memory T cell percentage. Single-cell RNA-sequencing of eight post-treatment samples demonstrates that large clones overexpress genes implicated in cytotoxicity and characteristic of effector memory T cells, including CCL4, GNLY and NKG7. The 6-month clinical response to ICB in patients with MM is associated with the large CD8+ T cell clone count 21 d after treatment and agnostic to clonal specificity, suggesting that post-ICB peripheral CD8+ clonality can provide information regarding long-term treatment response and, potentially, facilitate treatment stratification. Transcriptomic analysis of peripheral CD8+ T cells in a cohort of patients with metastatic melanoma receiving checkpoint inhibitors shows that the number of large clones early post-treatment is strongly associated with six-month clinical outcome.

IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide. In monocytes, both surface IL7R and sIL7R expression strongly associate with allelic carriage of rs6897932, a disease-associated IL7R polymorphism. Monocytes produce more sIL7R than CD4 + T cells, and the amount is additionally correlated with the expression of DDX39A, encoding a splicing factor. Synovial fluid-derived monocytes from patients with spondyloarthritis are enriched for IL7R+ cells with a unique transcriptional profile that overlaps with IL-7-induced gene sets. Our data thus suggest a previously unappreciated function for monocytes in IL-7 biology and IL7R-associated diseases., Interleukin-7 (IL-7) is a central cytokine in T cell homeostasis. Here the authors show that allelic variation at rs6897932, an autoimmune GWAS risk allele at IL7R, regulates surface and soluble IL-7R in stimulated monocytes, indicating a function of monocytes in IL-7-related autoimmunity.

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Despite their role in cancer surveillance, adoptive immunotherapy using γδ T-cells has achieved limited efficacy. To enhance trafficking to bone marrow, circulating γδ T-cells were expanded in serum-free medium containing TGF-β1 and IL-2 (γδ[T2] cells).Unexpectedly, the yield and viability of γδ[T2] cells were also increased by TGF-β1,when compared to γδ[2] controls (IL-2 alone). γδ[T2] cells were less differentiated and yet displayed increased cytolytic activity, cytokine release and anti-tumor activity in several leukemic and solid tumor models. Efficacy was further enhanced by cancer cell sensitization using amino bisphosphonates or cytarabine, or by CAR re-programming. A number of contributory effects of TGF-β1 were identified, including prostaglandinE2 receptor downmodulation, upregulation of CD103 and enhanced IL-9 production by γδ[T2] cells. Biological relevance is supported by the identification of a favorable γδ[T2] signature in acute myeloid leukemia. Given their enhanced therapeutic activity and compatibility with allogeneic use, γδ[T2] cells warrant evaluation in cancer immunotherapy.

NP105–113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105–113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105–113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105–113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105–113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design. Peng et al. find that immunodominant cytotoxic T lymphocytes (CTLs) specific for NP105–113-B*07:02 are associated with reduced COVID-19 severity. Mechanistically, NP105–113-B*07:02-specific CTLs show potent antiviral functionality and may represent rational T cell vaccine targets.

1Abstract1.1BackgroundImmune checkpoint blockers (ICBs) activate CD8+ T cells to elicit anti-cancer activity but frequently lead to immune-related adverse events (irAEs). The relationship of irAE with baseline parameters and clinical outcome is unclear. We investigated associations between irAE development, CD8+ T cell receptor diversity and expression and clinical outcome in a non-trial setting.1.2MethodsPatients ≥18 years old with metastatic melanoma (MM) receiving combination ICB (ipilimumab plus nivolumab – cICB, n=60) or single-agent ICB (nivolumab/pembrolizumab – sICB, n=78) were prospectively recruited. We retrospectively evaluated the impact of irAEs on survival. This analysis was repeated in an independent cohort of MM patients treated at a separate institution (n=210, cICB:74, sICB:136). We performed RNA sequencing of CD8+ T cells isolated from patients prior to treatment, analysing T cell receptor clonality differential transcript expression according to irAE development.1.3Results48.6% of patients experienced treatment-related irAEs within the first 5 cycles of treatment. Development of irAE prior to the 5th cycle of ICB was associated with longer progression-free and overall survival (PFS, OS) in the primary cohort (log-rank test, PFS: P=0.00034; OS: PP=0.00064). Across cohorts median survival for those patients not experiencing irAE was 14.4 (95% CI:9.6-19.5) months vs not-reached (95% CI:28.9 - Inf), P=3.0×10−7. Pre-treatment performance status and neutrophil count, but not BMI, were additional predictors of clinical outcome. Analysis of CD8+ T cells from 128 patients demonstrated irAE development was associated with increased T cell receptor diversity post-treatment (P=4.3×10−5). Development of irAE in sICB recipients was additionally associated with baseline differential expression of 224 transcripts (FDRCYP4F3 and PTGS2.1.4ConclusionsEarly irAE development post-ICB is strongly associated with favourable survival in MM and increased diversity of peripheral CD8+ T cell receptors after treatment. irAE post-sICB is associated with pre-treatment upregulation of inflammatory pathways, indicating irAE development may reflect baseline immune activation states.Key messageImmune-related adverse events (irAEs) commonly occur in patients with metastatic melanoma treated with immune checkpoint blockade (ICB) therapy. In real world setting we find development of early irAEs post-ICB treatment is associated with survival benefit, indicative of a shared mechanism with anti-tumour efficacy. CD8+ T cells from patients who develop irAE show increased receptor diversity, and pre-treatment samples from patients who develop irAE post single-agent anti-PD1 show over-expression of inflammatory pathways, indicating baseline immune state can determine irAE development.

Summary Despite its role in cancer surveillance, adoptive immunotherapy using γδ T cells has achieved limited efficacy. To enhance trafficking to bone marrow, circulating Vγ9Vδ2 T cells are expanded in serum-free medium containing TGF-β1 and IL-2 (γδ[T2] cells) or medium containing IL-2 alone (γδ[2] cells, as the control). Unexpectedly, the yield and viability of γδ[T2] cells are also increased by TGF-β1, when compared to γδ[2] controls. γδ[T2] cells are less differentiated and yet display increased cytolytic activity, cytokine release, and antitumor activity in several leukemic and solid tumor models. Efficacy is further enhanced by cancer cell sensitization using aminobisphosphonates or Ara-C. A number of contributory effects of TGF-β are described, including prostaglandin E2 receptor downmodulation, TGF-β insensitivity, and upregulated integrin activity. Biological relevance is supported by the identification of a favorable γδ[T2] signature in acute myeloid leukemia (AML). Given their enhanced therapeutic activity and compatibility with allogeneic use, γδ[T2] cells warrant evaluation in cancer immunotherapy., Graphical abstract, Highlights • TGF-β enhances the yield and viability of expanded γδ T cells (γδ[T2] cells) • γδ[T2] cells achieve more efficient tumor cell killing and cytokine release • γδ[T2] cells traffic to bone marrow and resist suppression by TGF-β or PGE2 • γδ[T2] cells mediate enhanced antitumor and antileukemic activity, γδ T cells mediate immune surveillance and represent an attractive option for cancer immunotherapy. Here, Beatson et al. show that when circulating γδ T cells are expanded in the presence of TGF-β, they achieve enhanced bone marrow trafficking, tumoricidal activity, and cytokine release, enabling greater efficacy in leukemic and solid tumor models.

To investigate whether sub-Saharan African countries have succeeded in reducing wealth-related inequalities in the coverage of reproductive, maternal, newborn and child health interventions.We analysed survey data from 36 countries, grouped into Central, East, Southern and West Africa subregions, in which at least two surveys had been conducted since 1995. We calculated the composite coverage index, a function of essential maternal and child health intervention parameters. We adopted the wealth index, divided into quintiles from poorest to wealthiest, to investigate wealth-related inequalities in coverage. We quantified trends with time by calculating average annual change in index using a least-squares weighted regression. We calculated population attributable risk to measure the contribution of wealth to the coverage index.We noted large differences between the four regions, with a median composite coverage index ranging from 50.8% for West Africa to 75.3% for Southern Africa. Wealth-related inequalities were prevalent in all subregions, and were highest for West Africa and lowest for Southern Africa. Absolute income was not a predictor of coverage, as we observed a higher coverage in Southern (around 70%) compared with Central and West (around 40%) subregions for the same income. Wealth-related inequalities in coverage were reduced by the greatest amount in Southern Africa, and we found no evidence of inequality reduction in Central Africa.Our data show that most countries in sub-Saharan Africa have succeeded in reducing wealth-related inequalities in the coverage of essential health services, even in the presence of conflict, economic hardship or political instability.Déterminer si les pays d'Afrique subsaharienne sont parvenus à réduire l'impact des inégalités de richesse sur la prise en charge des interventions de santé reproductives, maternelles et infantiles.Nous avons analysé des données d'enquêtes menées dans 36 pays regroupé en sous-régions (Afrique centrale, Afrique de l'Est, Afrique australe et Afrique de l'Ouest). Au moins deux enquêtes devaient dater d'après 1995. Nous avons calculé l'indice de prise en charge composite en fonction de plusieurs paramètres essentiels d'interventions de santé maternelle et infantile. Nous avons également adopté l'indice de richesse divisé en quintiles, du plus pauvre au plus nanti, afin d'étudier l'impact des inégalités de richesse dans cette prise en charge. Nous avons quantifié les tendances par rapport au temps, en calculant l'évolution annuelle moyenne de l'indice à l'aide de la régression des moindres carrés pondérés. Enfin, nous avons évalué le risque attribuable à la population pour mesurer la contribution de la richesse à l'indice de prise en charge.Nous avons remarqué des différences considérables entre les quatre régions, avec un indice médian de prise en charge composite allant de 50,8% en Afrique de l'Ouest à 75,3% en Afrique australe. Les inégalités liées à la richesse étaient très répandues dans toutes les sous-régions; les plus fortes ont été observées en Afrique de l'Ouest, les plus faibles en Afrique australe. Le revenu absolu n'est pas un indicateur valable car nous avons constaté une meilleure prise en charge dans la sous-région d'Afrique australe (environ 70%) que dans celles d'Afrique centrale et d'Afrique de l'Ouest (environ 40%) pour des revenus équivalents. La majorité des inégalités de prise en charge liées à la richesse ont diminué en Afrique australe, et nous n'avons trouvé aucune preuve de réduction des inégalités en Afrique centrale.Nos données montrent que la plupart des pays d'Afrique subsaharienne ont réussi à atténuer les inégalités de prise en charge liées à la richesse pour les services de santé essentiels, même en cas de conflit, de difficultés économiques ou d'instabilité politique.Investigar si los países del África subsahariana han logrado reducir las desigualdades relacionadas con la riqueza en la cobertura de las intervenciones sanitarias relativas a la salud reproductiva, materna, neonatal e infantil.Se analizaron los datos de las encuestas de 36 países, agrupados en las subregiones de África central, oriental, meridional y occidental, en los que se habían realizado por lo menos dos encuestas desde 1995. Se calculó el índice compuesto de cobertura, en función de los parámetros esenciales de las intervenciones sanitarias relativas a la salud maternoinfantil. Se adoptó el índice de riqueza, dividido en quintiles de más pobres a más ricos, para investigar las desigualdades de cobertura relacionadas con la riqueza. Se cuantificaron las tendencias con el tiempo al calcular el cambio anual medio del índice por medio de una regresión por mínimos cuadrados ponderados. También se calculó el riesgo atribuible a la población para medir la contribución de la riqueza al índice de cobertura.Se observaron grandes diferencias entre las cuatro regiones, con un índice compuesto medio de cobertura que oscilaba entre el 50,8 % para el África occidental y el 75,3 % para el África meridional. Las desigualdades relacionadas con la riqueza prevalecían en todas las subregiones y eran mayores en el África occidental y menores en el África meridional. Los ingresos absolutos no eran un factor de predicción de la cobertura, ya que se observó una mayor cobertura en las subregiones del sur (alrededor del 70 %) en comparación con las subregiones central y occidental (alrededor del 40 %) para los mismos ingresos. Las desigualdades de cobertura relacionadas con la riqueza se redujeron en mayor medida en el África meridional, y no encontramos pruebas de reducción de la desigualdad en el África central.Estos datos muestran que la mayoría de los países del África subsahariana han logrado reducir las desigualdades relacionadas con la riqueza en la cobertura de los servicios sanitarios esenciales, incluso en presencia de conflictos, dificultades económicas o inestabilidad política.الغرض التحقق مما إذا كانت الدول الأفريقية في جنوب الصحراء الكبرى قد نجحت في الحد من حالات عدم المساواة المتعلقة بالثروة في تغطية التدخلات الصحية المتعلقة بالصحة الإنجابية، وصحة الأم، وصحة المواليد، وصحة الأطفال. الطريقة قمنا بتحليل بيانات المسح من 36 دولة، ثم تجميعها في مناطق وسط وشرق وجنوب وغرب إفريقيا الفرعية، والتي تم فيها إجراء مسحين على الأقل منذ عام 1995. وقمنا بحساب مؤشر التغطية المركبة، وهي وظيفة لمعاملات التدخل الصحي الأساسية للأم والطفل. قمنا بانتهاج مؤشر الثروة، وقسمناه إلى الفئات الخمسية من الأشد فقراً إلى الأكثر غنى، للتحقيق في حالات عدم المساواة المتعلقة بالثروة في التغطية. وقمنا بقياس الاتجاهات مع مرور الوقت عن طريق حساب متوسط ​​التغيير السنوي في المؤشر باستخدام انحدار المربعات الصغرى المرجح. قمنا بحساب المخاطر التي تعزى إلى السكان لقياس مساهمة الثروة في مؤشر التغطية. النتائج لاحظنا وجود اختلافات كبيرة بين المناطق الأربع، مع متوسط ​​للمؤشر المركب للتغطية من 50.8% في غرب إفريقيا إلى 75.3% في جنوب أفريقيا. كانت حالات عدم المساواة المتعلقة بالثروة سائدة في كل المناطق الفرعية، وكانت في أعلى درجاتها في غرب أفريقيا، وأدنى درجاتها في جنوب أفريقيا. لم يكن الدخل المطلق عاملاً للتنبؤ بالتغطية، حيث لاحظنا تغطية أعلى في المناطق الجنوبية (حوالي 70%) مقارنة بالمناطق الفرعية الوسطى والغربية (حوالي 40%) لنفس الدخل. تقلصت حالات عدم المساواة في التغطية المتعلقة بالثروة، بأكبر قدر ممكن في جنوب أفريقيا، بينما لم نجد دليلاً على الحد من عدم المساواة في وسط أفريقيا.تُظهر بياناتنا أن معظم الدول الأفريقية في جنوب الصحراء الكبرى قد نجحت في الحد من حالات عدم المساواة المتعلقة بالثروة في تغطية الخدمات الصحية الأساسية، حتى في وجود الصراع، أو الصعوبات الاقتصادية، أو عدم الاستقرار السياسي旨在调查撒哈拉以南的非洲国家是否成功减少了在生育、孕产妇、新生儿和儿童健康干预措施覆盖方面呈现出的与财富有关的不平等现象。.我们分析了来自中非、东非、南非和西非地区的 36 个国家的调查数据，这些国家自 1995 年以来已至少进行了两次调查。我们计算了综合覆盖指数，这是一种妇幼健康干预基本参数函数。我们采用财富指数，从最贫困到最富有共划分了五个等级，以调查在覆盖范围方面与财富相关的不平等现象。我们使用最小二乘加权回归法计算指数的年平均变化，从而量化其随时间的变化趋势。我们计算了人群归因风险度来衡量财富对覆盖指数的贡献。.我们发现这四个地区之间存在巨大差异，综合覆盖指数中位数从西非的 50.8%，到南非的 75.3%。与财富有关的不平等现象普遍存在于非洲各个次区域，其中西非的不平等程度最高，南非的不平等程度最低。我们观察到，在相同的收入水平下，南部地区（约 70%）的覆盖率高于中部和西部地区（约 40%），因此绝对收入并非覆盖率的预测指标。与财富相关的不平等现象在非洲南部减少最多，而在中非，我们没有发现不平等现象减少的迹象。.我们的数据显示，即使存在冲突、经济困难或政治动荡问题，大多数撒哈拉以南的非洲国家在基本卫生服务覆盖方面成功地减少了与财富相关的不平等现象。.Изучить, удалось ли странам Африки, расположенным южнее Сахары, успешно сократить неравенство в охвате мероприятиями по охране репродуктивного здоровья, материнства, здоровья новорожденных и детского здравоохранения, связанное с уровнем доходов.Авторы проанализировали данные опросов в 36 странах, сгруппированных в субрегионы Восточной, Западной, Центральной и Южной Африки, в которых в период с 1995 года было проведено по меньшей мере два опроса. Авторы рассчитали составной индекс охвата как функцию существенных параметров мероприятий по охране здоровья матери и ребенка. За основу был взят показатель благосостояния, разбитый на квинтили от самых бедных до самых богатых, позволяющий изучить неравенство в охвате мероприятиями, связанное с различиями в уровне доходов. Авторы выполнили количественную оценку тенденций по времени посредством расчета среднегодового изменения показателя с использованием средневзвешенной регрессии по методу наименьших квадратов. Авторы рассчитали популяционный риск, чтобы измерить зависимость показателя охвата мероприятиями от уровня дохода.Было отмечено значительное различие между четырьмя регионами: средний составной индекс охвата составил от 50,8% в Западной Африке до 75,3% в Южной Африке. Неравенство, связанное с уровнем доходов, присутствовало во всех субрегионах и было сильнее всего выражено в странах Западной Африки и слабее всего выражено в странах Южной Африки. Абсолютный доход не позволял прогнозировать уровень охвата мероприятиями по охране здоровья, поскольку авторы наблюдали более высокий уровень охвата (около 70%) в Южной Африке по сравнению с уровнем охвата в Центральном и Западном субрегионах (около 40%) при том же уровне дохода. Неравенство, связанное с различиями в уровне дохода, значительно уменьшилось в Южной Африке, тогда как в Центральной Африке снижения неравенства не отмечается.Данные показывают, что большинству стран Африки, расположенных южнее Сахары, удалось сократить неравенство в охвате основными видами медицинских услуг, связанное с уровнем доходов, несмотря на наличие конфликтов, тяжелой экономической ситуации или политической нестабильности.

Subnational inequalities have received limited attention in the monitoring of progress towards national and global health targets during the past two decades. Yet, such data are often a critical basis for health planning and monitoring in countries, in support of efforts to reach all with essential interventions. Household surveys provide a rich basis for interventions coverage indicators on reproductive, maternal, newborn and child health (RMNCH) at the country first administrative level (regions or provinces). In this paper, we show the large subnational inequalities that exist in RMNCH coverage within 39 countries in sub-Saharan Africa, using a composite coverage index which has been used extensively by Countdown to 2030 for Women’s, Children’s and Adolescent’s Health. The analyses show the wide range of subnational inequality patterns such as low overall national coverage with very large top inequality involving the capital city, intermediate national coverage with bottom inequality in disadvantaged regions, and high coverage in all regions with little inequality. Even though nearly half of the 34 countries with surveys around 2004 and again around 2015 appear to have been successful in reducing subnational inequalities in RMNCH coverage, the general picture shows persistence of large inequalities between subnational units within many countries. Poor governance and conflict settings were identified as potential contributing factors. Major efforts to reduce within-country inequalities are required to reach all women and children with essential interventions.

Background Immune Checkpoint blockade for the treatment of metastatic melanoma is associated with highly variable clinical outcomes between individuals in terms of both oncological benefit and immune-related adverse events. Early markers of response are urgently sought. Whereas numerous intra-tumoural determinants of sensitivity to immunotherapy are known, the identification of peripheral predictors of response is limited. We aimed to characterize the CD8+ T-cell transcriptomic and clonal changes to treatment across a large cohort of patients in an effort to gain further insight into the peripheral markers of response. Methods We performed paired-end 75bp read RNA-sequencing to assay the peripheral CD8+ response at baseline and across multiple cycles of treatment (n = 105 patients, 69 controls, 315 separate transcriptomes). We validated identified clonal subsets indicative of response using 10X Chromium single cell sequencing (16 samples, 8 patients), flow-cytometry and targeted PCR. Results After adjusting for multiple testing, we identify >5,800 transcripts induced by treatment. These fall into discrete gene modules, with several markedly diverging between combination immunotherapy and anti-PD1 alone. Patients demonstrating a durable radiological response to checkpoint immunotherapy (absence of progression at 6 months) have significantly increased numbers of large peripheral CD8+ circulating clones by day 21 after treatment, compared to non-responders and controls. We replicate this observation in a separately recruited cohort. Large peripheral clones have a distinct gene expression profile, characterized by high expression of CCL5, BCL2L1and NKG7 amongst other genes. Conclusions We identify robust and reproducible predictors of 6 month clinical and radiological responses to immune checkpoint blockade in the transcriptomes of peripheral circulating CD8+ T-cells from metastic melanoma patients after 21 days of treatment. These observations can be used to further our understanding of determinants of patient response, and may provide a mechanism for early treatment stratification of patients with a non-favourable peripheral profile. Legal entity responsible for the study Oxford Radcliffe Biobank. Funding Wellcome Trust, Oxford NIHR Biomedical Research Centre, Cancer Research UK. Disclosure All authors have declared no conflicts of interest.

This study examines catch-up immunisation for people of refugee-like background in Victoria, exploring effective models of service delivery to complete catch-up vaccinations. The analysis is based on: (i) review of the medical literature, Commonwealth and Victorian government immunisation policy and immunisation patient information; (ii) review of vaccination coverage and service delivery data; and (iii) stakeholder interviews completed in 2014 with 45 people from 34 agencies, including 9 local government areas in Victoria. Although refugees and asylum seekers all need catch-up vaccinations on arrival, they face significant barriers to completing immunisation in Australia. Analysis suggests missed opportunities by service providers and perceptions that catch-up vaccination is time-consuming, difficult and resource-intensive. Service delivery is fragmented across primary care and local government, and pathways depend on age, location and healthcare access. There are strengths, but also limitations in all current service delivery models. Gaps in vaccine funding for refugee-like populations have now been addressed through Commonwealth initiatives, however migration is still not well considered in immunisation policy, and existing systems for notification payments do not capture catch-up vaccination for these groups. Providers identify areas for improvement in professional development and support, patient information, patient-held records and immunisation surveillance data.

Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAF(V600)-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAF(V600)-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies. SIGNIFICANCE: The use of RAF inhibitors for BRAF(V600)-mutant metastatic melanoma improves patient outcomes, but most patients demonstrate early or acquired resistance to this targeted therapy. We reveal the genetic landscape of clinical resistance mechanisms to RAF inhibitors from patients using whole-exome sequencing, and experimentally assess new observed mechanisms to define potential subsequent treatment strategies. (C)2013 AACR.

Plants in the genus Monarda produce complex essential oils that contain antifungal compounds. The objectives of this research were to identify selections of monarda that reduce Rhizoctonia damping-off of tomato, and to determine relationships between essential oil composition of 13 monarda herbages (dried and ground leaves) and disease suppression. Herbages were grouped into five chemotypes, based on essential oil composition and effective concentrations for reducing growth by 50% for Rhizoctonia solani. Replicated and repeated disease control assays were conducted with monarda herbages in greenhouse medium, with or without Rhizoctonia. Percent survival, seedling height, and stem diameter were evaluated at 8 weeks. Survival, seedling height, and stem diameter in herbage-only treatments were not different from the control (no-herbage, no-pathogen) for most herbage treatments. In the pathogen control (no-herbage + Rhizoctonia), seedling survival was 10% that of the control. In pathogen-infested media, seedling survival ranged from 65 to 80% for treatments with thymol chemotypes and 55 to 65% for carvacrol chemotypes. Effective control of Rhizoctonia damping-off was correlated with phenolic monoterpenes; herbages classified as carvacrol chemotypes effectively protected tomato seedlings from Rhizoctonia damping-off disease without phytotoxicity. This study provides evidence that monarda herbages have potential as growing media amendments for control of Rhizoctonia damping-off disease.