Assessment of socio-clinical profile of neonates admitted in sick neonatal care unit of tertiary care hospital: Odisha

Background: Neonatal mortality rate of 29 and early neonatal mortality rate is 20 which contributes 53% of IMR. India targets to achieve single digit under 5 and neonatal death by 2030. Early identification and management of common morbidities among neonates is desirable for improving the survival. Therefore, this study was conducted with the aim of assessing socio-clinical profile of neonates admitted to SNCU and its impact on morbidities of newborn from different strata.Methods: A cross sectional study was conducted in SNCU of MKCG medical college from January 2016 to December 2016. Convenient sampling was done. Data was collected using pre-designed semi structured questionnaire.Results: Total 752 study subjects were taken. Most common cause of admission was sepsis (47.4%) followed by prematurity (27.8%), birth asphyxia (13.9%) and IUGR (7.5%). Majority of out born neonates were admitted for sepsis (87.9%) while in born neonates for birth asphyxia (81.9%). All the morbidities were significantly higher among early neonates, babies born to illiterate mother and those with inadequate antenatal check-up.Conclusions: Majority of babies were out born, may be due to delay and lack of quality new born care in the referring facilities. Sepsis was most common preventable morbidity by simple intervention of clean delivery practices which should be promoted. Birth asphyxia can be reduced by adequate skill development training of the staffs and minimising the 3 delays maternal care

Determinants of uptake of post-partum intra-uterine contraceptive device among women delivering in a tertiary hospital, Odisha, India

Background: IUCDs are used by only two percent of the contraceptive users in India. There is a need for identifying the factors which influence the uptake of PPIUCD, so as to plan ways for increasing its usage. To determine the uptake and factors influencing the uptake of PPIUCD among the women delivering in a tertiary care hospital of OdishaMethods: This was a case control study conducted at the Obstetrics Department of M.K.C.G Medical College, Berhampur. All those who had agreed for and had undergone PPIUCD insertion were included in cases and those who did not undergo PPIUCD insertion were pooled into controls.Results: 94 cases and 188 controls were recruited. Significantly higher proportions of cases belonged to nuclear families, had one or more male child, did not want any future pregnancies, had heard about it prior to pregnancy and also had received counselling for the same during the antenatal period. The adjusted odds of uptake of PPIUCD in women having at least one male child is 10 (4.3-22.6) times that of mothers with no male children. The most common reasons told by controls for not taking up PPIUCD was disapproval from family members (42.6%), followed by fear of complication (33%) and preference for other methods of contraception (20.2%).Conclusions: In present study, we found that counselling in the antenatal period was a key point in increasing acceptance of post-partum IUCD. Desire for male child also influenced uptake of postpartum IUCD

Lactate-Mediated Epigenetic Reprogramming Regulates Formation of Human Pancreatic Cancer-Associated Fibroblasts

Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including CXCR4. Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CXCR4. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the demethylase TET enzyme led to decreased cytosine methylation and increased hydroxymethylation during de novo differentiation of MSCs to CAF. Co-injection of neoplastic cells with TET-deficient MSCs inhibited tumor growth in vivo. Thus, in PDAC, a tumor-mediated lactate flux is associated with widespread epigenomic reprogramming that is seen during CAF formation

Study of efficacy and longevity of immune response to third and fourth doses of COVID-19 vaccines in patients with cancer: A single arm clinical trial

Background: Cancer patients show increased morbidity with COVID-19 and need effective immunization strategies. Many healthcare regulatory agencies recommend administering ‘booster’ doses of COVID-19 vaccines beyond the standard two-dose series, for this group of patients. Therefore, studying the efficacy of these additional vaccine doses against SARS-CoV-2 and variants of concern is of utmost importance in this immunocompromised patient population Methods: We conducted a prospective single arm clinical trial enrolling patients with cancer that had received two doses of mRNA or one dose of AD26.CoV2.S vaccine and administered a third dose of mRNA vaccine. We further enrolled patients that had no or low responses to three mRNA COVID vaccines and assessed the efficacy of a fourth dose of mRNA vaccine. Efficacy was assessed by changes in anti-spike antibody, T-cell activity, and neutralization activity, which were again assessed at baseline and 4 weeks. Results: We demonstrate that a third dose of COVID-19 vaccine leads to seroconversion in 57% of patients that were seronegative after primary vaccination series. The immune response is durable as assessed by anti-SARS-CoV-2 (anti-S) antibody titers, T-cell activity, and neutralization activity against wild-type (WT) SARS-CoV2 and BA1.1.529 at 6 months of follow-up. A subset of severely immunocompromised hematologic malignancy patients that were unable to mount an adequate immune response (titer <1000 AU/mL) after the third dose and were treated with a fourth dose in a prospective clinical trial which led to adequate immune boost in 67% of patients. Low baseline IgM levels and CD19 counts were associated with inadequate seroconversion. Booster doses induced limited neutralization activity against the Omicron variant. Conclusions: These results indicate that third dose of COVID vaccine induces durable immunity in cancer patients and an additional dose can further stimulate immunity in a subset of patients with inadequate response. Funding: Leukemia Lymphoma Society, National Cancer Institute. Clinical trial number: NCT05016622

Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations

Background: Mutations in the SF3B1 splicing factor are commonly seen in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), yet the specific oncogenic pathways activated by mis-splicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in the pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood. Methods: RNA-seq data from SF3B1 mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 (IRAK4) isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in preclinical models of MDS/AML. Results: RNA-seq splicing analysis of SF3B1 mutant MDS samples revealed retention of full-length exon 6 of IRAK4, a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteasomal degradation. Expression of IRAK4-long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models. Conclusions: SF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models.</p

High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.7%; 17 out of 255; odds ratio, 3.14; 95% confidence interval, 1.64-6.03; P = 0.0006) after controlling for age, sex and race/ethnicity. The frequency of somatic mutations in WTC-exposed first responders showed an age-related increase and predominantly affected DNMT3A, TET2 and other CH-associated genes. Exposure of lymphoblastoid cells to WTC particulate matter led to dysregulation of DNA replication at common fragile sites in vitro. Moreover, mice treated with WTC particulate matter developed an increased burden of mutations in hematopoietic stem and progenitor cell compartments. In summary, the high burden of CH in WTC-exposed first responders provides a rationale for enhanced screening and preventative efforts in this population