Digitally strengthened, midwife-led intervention to reach the unreached mothers across ten conflict-prone provinces of Afghanistan during humanitarian crisis

Background: Coronavirus disease 2019 (COVID-19) pandemic had significant negative impact on sexual and reproductive health (SRH) with devastating impact on pregnant women in resource constrain humanitarian settings. This paper provides detailed account of a community midwife-led intervention in ten humanitarian settings of Afghanistan using world health organization (WHO) emergency disaster risk management (EDRM) framework.Objectives: The project is aimed at increasing access to Integrated Package of Essential SRH Services and Minimal Initial Service Package (MISP) with a specific focus on prevention of Postpartum Haemorrhage (PPH) and screening and management of preeclampsia and eclampsia.Methods: The project was implemented through 150 Community outreach midwives (COMs). Each midwife served 300 households; mentored by gynaecologists and supervisors. Midwives were trained through a digitally enabled, simulation based training and equipped with a set of off-the shelf devices and kits.Results: During COVID-19 pandemic and in absence of health care services during crisis, this intervention has played as a lifesaving intervention for the community in Afghanistan. Variable digital literacy, sociocultural barriers, reluctance in adapting to digital platforms, security and uncertainties were some of the challenges faced. Adaptation of outreach methods integrated high impactful digital technologies has been the most appropriate strategy "to reach the unreached".Conclusion: Through this model, national and global stakeholders were engaged even during the crisis in Afghanistan. It also provided vital inputs for the donors, governments, civil society organizations and other stakeholders for sustaining and advancing the delivery of quality SRH services in humanitarian settings

Therapeutic relevance of the protein phosphatase 2A in cancer

Chromosomal Instability (CIN) is regarded as a unifying feature of heterogeneous tumor populations, driving intratumoral heterogeneity. Polo-Like Kinase 1 (PLK1), a serine-threonine kinase that is often overexpressed across multiple tumor types, is one of the key regulators of CIN and is considered as a potential therapeutic target. However, targeting PLK1 has remained a challenge due to the off-target effects caused by the inhibition of other members of the polo-like family. Here we use synthetic dosage lethality (SDL), where the overexpression of PLK1 is lethal only when another, normally non-lethal, mutation or deletion is present. Rather than directly inhibiting PLK1, we found that inhibition of PP2A causes selective lethality to PLK1-overexpressing breast, pancreatic, ovarian, glioblastoma, and prostate cancer cells. As PP2A is widely regarded as a tumor suppressor, we resorted to gene expression datasets from cancer patients to functionally dissect its therapeutic relevance. We identified two major classes of PP2A subunits that negatively correlated with each other. Interestingly, most mitotic regulators, including PLK1, exhibited SDL interactions with only one class of PP2A subunits (PPP2R1A, PPP2R2D, PPP2R3B, PPP2R5B and PPP2R5D). Validation studies and other functional cell-based assays showed that inhibition of PPP2R5D affects both levels of phospho-Rb as well as sister chromatid cohesion in PLK1-overexpressing cells. Finally, analysis of clinical data revealed that patients with high expression of mitotic regulators and low expression of Class I subunits of PP2A improved survival. Overall, these observations point to a context-dependent role of PP2A that warrants further exploration for therapeutic benefits.status: publishe

Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T-cell activation

Mycobacterium tuberculosis (Mtb) establishes a persistent infection, despite inducing antigen-specific T-cell responses. Although T cells arrive at the site of infection, they do not provide sterilizing immunity. The molecular basis of how Mtb impairs T-cell function is not clear. Mtb has been reported to block major histocompatibility complex class II (MHC-II) antigen presentation; however, no bacterial effector or host-cell target mediating this effect has been identified. We recently found that Mtb EsxH, which is secreted by the Esx-3 type VII secretion system, directly inhibits the endosomal sorting complex required for transport (ESCRT) machinery. Here, we showed that ESCRT is required for optimal antigen processing; correspondingly, overexpression and loss-of-function studies demonstrated that EsxH inhibited the ability of macrophages and dendritic cells to activate Mtb antigen-specific CD4+ T cells. Compared with the wild-type strain, the esxH-deficient strain induced fivefold more antigen-specific CD4+ T-cell proliferation in the mediastinal lymph nodes of mice. We also found that EsxH undermined the ability of effector CD4+ T cells to recognize infected macrophages and clear Mtb. These results provide a molecular explanation for how Mtb impairs the adaptive immune response