Elimination of Chlamydia muridarum from the female reproductive tract is IL-12p40 dependent, but independent of Th1 and Th2 cells.

Chlamydia vaccine approaches aspire to induce Th1 cells for optimal protection, despite the fact that there is no direct evidence demonstrating Th1-mediated Chlamydia clearance from the female reproductive tract (FRT). We recently reported that T-bet-deficient mice can resolve primary Chlamydia infection normally, undermining the potentially protective role of Th1 cells in Chlamydia immunity. Here, we show that T-bet-deficient mice develop robust Th17 responses and that mice deficient in Th17 cells exhibit delayed bacterial clearance, demonstrating that Chlamydia-specific Th17 cells represent an underappreciated protective population. Additionally, Th2-deficient mice competently clear cervicovaginal infection. Furthermore, we show that sensing of IFN-γ by non-hematopoietic cells is essential for Chlamydia immunity, yet bacterial clearance in the FRT does not require IFN-γ secretion by CD4 T cells. Despite the fact that Th1 cells are not necessary for Chlamydia clearance, protective immunity to Chlamydia is still dependent on MHC class-II-restricted CD4 T cells and IL-12p40. Together, these data point to IL-12p40-dependent CD4 effector maturation as essential for Chlamydia immunity, and Th17 cells to a lesser extent, yet neither Th1 nor Th2 cell development is critical. Future Chlamydia vaccination efforts will be more effective if they focus on induction of this protective CD4 T cell population.

Advancing Global Palliative Care Over Two Decades: Health System Integration, Access to Essential Medicines, and Pediatrics.

CONTEXT: Between 2000 and 2020 Open Society Foundations was one of very few funders that supported global palliative care development and advocacy. OBJECTIVES: To describe progress made in three priority areas-the integration of palliative care into public health systems, access to controlled medicines, and pediatric palliative care-during those 20 years. METHODS: Activities and developments between 2000 and 2020 on global integration of palliative care into health systems, access to and availability of controlled medicines, and pediatric palliative care are described and analyzed. RESULTS: Major progress has been made in each area. Whereas in 2000, integration of palliative care into public healthcare systems was on the agenda in just a few pioneering countries, by 2020 a global consensus had emerged that palliative care should be integral to all health systems including in universal health coverage and countries were increasingly taking steps to integrate it into national health systems. While limited availability of these medicines was barely recognized as a public health or drug control issue in 2000, it had become an important priority in global drug policy debates by 2020 and numerous countries had taken steps to improve access to these medicines. Pediatric palliative care, available mostly in a small number of wealthy countries in the 1990s, has seen rapid growth, especially in low- and middle-income countries, and now has a solid foothold in all world regions. CONCLUSION: Despite this progress, significant challenges remain as funding for palliative care advocacy is limited, the overdose crisis in the US has recently had a chilling effect on efforts to improve availability of opioid analgesics, and economic crises related to the COVID-19 pandemic create uncertainty over the future of universal health coverage.

Palliative care and catastrophic costs in Malawi after a diagnosis of advanced cancer: a prospective cohort study.

BACKGROUND: Inclusive universal health coverage requires access to quality health care without financial barriers. Receipt of palliative care after advanced cancer diagnosis might reduce household poverty, but evidence from low-income and middle-income settings is sparse. METHODS: In this prospective study, the primary objective was to investigate total household costs of cancer-related health care after a diagnosis of advanced cancer, with and without the receipt of palliative care. Households comprising patients and their unpaid family caregiver were recruited into a cohort study at Queen Elizabeth Central Hospital in Malawi, between Jan 16 and July 31, 2019. Costs of cancer-related health-care use (including palliative care) and health-related quality-of-life were recorded over 6 months. Regression analysis explored associations between receipt of palliative care and total household costs on health care as a proportion of household income. Catastrophic costs, defined as 20% or more of total household income, sale of assets and loans taken out (dissaving), and their association with palliative care were computed. FINDINGS: We recruited 150 households. At 6 months, data from 89 (59%) of 150 households were available, comprising 89 patients (median age 50 years, 79% female) and 64 caregivers (median age 40 years, 73% female). Patients in 55 (37%) of the 150 households died and six (4%) were lost to follow-up. 19 (21%) of 89 households received palliative care. Catastrophic costs were experienced by nine (47%) of 19 households who received palliative care versus 48 (69%) of 70 households who did not (relative risk 0·69, 95% CI 0·42 to 1·14, p=0·109). Palliative care was associated with substantially reduced dissaving (median US$11, IQR 0 to 30 vs $34, 14 to 75; p=0·005). The mean difference in total household costs on cancer-related health care with receipt of palliative care was -36% (95% CI -94 to 594; p=0·707). INTERPRETATION: Vulnerable households in low-income countries are subject to catastrophic health-related costs following a diagnosis of advanced cancer. Palliative care might result in reduced dissaving in these households. Further consideration of the economic benefits of palliative care is justified. FUNDING: Wellcome Trust; National Institute for Health Research; and EMMS International.

Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.

The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.

A global update on the development of palliative care services.

On World Hospice and Palliative Care Day-8 October 2011-the Worldwide Palliative Care Alliance (WPCA) launched a global update highlighting the progress that has been made in hospice and palliative care over the past 5 years (Lynch et al, 2011; WPCA 2011). Encouragingly, the study shows that there has been a marked increase in the number of countries providing one or more hospice and palliative care services-from 49% of countries in 2006 to 58% in 2011. Here we explore some of the key factors behind this progress, focusing particularly on advocacy and policy.