Paediatric oncologists' perspectives on Strategic solutions to develop Integrated Cancer Palliative Care: feedback intervention theory as an explanatory Framework.

BACKGROUND: Globally, children with cancer often experience delays in palliative care referral or are infrequently referred. Therefore, we conducted a qualitative study to gain insight from paediatric oncologists into what enables or deters palliative care referral. Strategic solutions to develop integrated palliative care was a critical study theme. In this paper, we have explained and interpreted these strategic solutions through the lens of feedback intervention theory. METHODOLOGY: The study findings were interpreted using Kumar's six-step approach that enabled systematic evaluation of a theory's appropriateness and alignment with the researcher's paradigm, methodology, and study findings. It also explained how theory informed analysis and elucidated challenges or the development of new models. The feedback intervention theory appraises the discrepancy between actual and desired goals and provides feedback to improve it. RESULTS: Strategic solutions generated from the study findings were coherent with the aspects elucidated in theory, like coping mechanisms, levels of feedback hierarchy, and factors determining the effect of the feedback intervention on performance. Paediatric oncologists suggested integrating palliative care providers in the team innocuously, improving communication between teams, relabelling palliative care as symptom control, and working with a skilled and accessible palliative care team. The paper proposes an infinite loop model developed from the study, which has the potential to foster integrated palliative care through excellent collaboration and continuous feedback. CONCLUSION: Applying feedback intervention theory can bridge the gap between actual and desired practice for integrated cancer palliative care in paediatric oncology.

Palliative and end-of-life care practices for critically ill patients and their families in a peri-intensive care setting: A protocol for an umbrella review.

OBJECTIVES: This umbrella review will summarize palliative and end-of-life care practices in peri-intensive care settings by reviewing systematic reviews in intensive care unit (ICU) settings. Evidence suggests that integrating palliative care into ICU management, initiating conversations about care goals, and providing psychological and emotional support can significantly enhance patient and family outcomes. METHODS: The Joanna Briggs Institute (JBI) methodology for umbrella reviews will be followed. The search will be carried out from inception until 30 September 2023 in the following databases: Cochrane Library, SCOPUS, Web of Science, CINAHL Complete, Medline, EMBASE, and PsycINFO. Two reviewers will independently conduct screening, data extraction, and quality assessment, and to resolve conflicts, adding a third reviewer will facilitate the consensus-building process. The quality assessment will be carried out using the JBI Critical Appraisal Checklist. The review findings will be reported per the guidelines outlined in the Preferred Reporting Items for Overviews of Reviews statement. RESULTS: This umbrella review seeks to inform future research and practice in critical care medicine, helping to ensure that end-of-life care interventions are optimized to meet the needs of critically ill patients and their families.

Utility of Clinical Variables for Deciding Palliative Care in Paraquat Poisoning: A Retrospective Study.

Background: Patients with paraquat poisoning (PP) have a mortality rate comparable to that of advanced malignancies, yet palliative care is seldom considered in these patients. This audit aimed to identify triggers for early palliative care referral in critically ill patients with PP. Methods: Medical records of patients with PP were audited. Predictors of mortality within 48 hours of hospitalization and 24 hours of intensive care unit (ICU) admission were considered as triggers for palliative care referral. Results: Among 108 patients, 84 complete records were analyzed, and 53 out of 84 (63.1%) expired. Within 48 hours after hospitalization, the lowest oxygen partial pressure in arterial blood to a fraction of inspired oxygen [the ratio of partial pressure of oxygen in arterial blood (PaO2) to the fraction of inspiratory oxygen concentration (FiO2) (PaO2/FiO2)] was the independent predictor of mortality, cut-off ≤ 197; the area under the curve (AUC), 0.924; sensitivity, 97%; specificity, 78%; p <0.001; and 95% confidence interval (CI): 0.878-0.978. Kaplan-Meier survival plot showed that the mean survival time of patients with the lowest PaO2/FiO2, ≤197, was 4.64 days vs 17.20 days with PaO2/FiO2 >197 (log-rank p < 0.001). Sequential organ failure assessment (SOFA) score within 24 hours of ICU admission had a cut-off ≥9; AUC, 0.980; p < 0.001; 95% CI: 0.955-1.000; 91% sensitivity; and 90% specificity for mortality prediction. Out of the total of 84 patients with PP analyzed, there were 11 patients admitted to the high dependency units (13.1%) and 73 patients admitted to the ICU (86.9%). Out of the total of 84 patients of PP in whom data was analyzed, 53 (63.1%) patients required ventilator support. All the 53 patients who required ventilator support due to worsening hypoxemia, eventually expired. Conclusion: The lowest PaO2/FiO2 ≤ 197 within 48 hours of hospitalization, SOFA score ≥9 within 24 hours of ICU admission or need for mechanical ventilation are predictors of mortality in PP patients, who might benefit from early palliative care. How to cite this article: Rao S, Maddani SS, Chaudhuri S, Bhatt MT, Karanth S, Damani A, et al. Utility of Clinical Variables for Deciding Palliative Care in Paraquat Poisoning: A Retrospective Study. Indian J Crit Care Med 2024;28(5):453-460.

Amycolatopsis from Desert Specialist Fungus-Growing Ants Suppresses Contaminant Fungi Using the Antibiotic ECO-0501.

Symbiotic Actinobacteria help fungus-growing ants suppress fungal pathogens through the production of antifungal compounds. Trachymyrmex ants of the southwest desert of the United States inhabit a unique niche far from the tropical rainforests in which most fungus-growing ant species are found. These ants may not encounter the specialist fungal pathogen Escovopsis known to threaten colonies of other fungus-growing ants. It is unknown whether Actinobacteria associated with these ants antagonize contaminant fungi and, if so, what the chemical basis of such antagonism is. We find that Pseudonocardia and Amycolatopsis strains isolated from three desert specialist Trachymyrmex species do antagonize diverse contaminant fungi isolated from field-collected ant colonies. We did not isolate the specialist fungal pathogen Escovopsis in our sampling. We trace strong antifungal activity from Amycolatopsis isolates to the molecule ECO-0501, an antibiotic that was previously under preclinical development as an antibacterial agent. In addition to suppression of contaminant fungi, we find that this molecule has strong activity against ant-associated Actinobacteria and may also play a role in bacterial competition in this niche. By studying interspecies interactions in a previously unexplored niche, we have uncovered novel bioactivity for a structurally unique antibiotic. IMPORTANCE Animal hosts often benefit from chemical defenses provided by microbes. These molecular defenses are a potential source of novel antibiotics and offer opportunities for understanding how antibiotics are used in ecological contexts with defined interspecies interactions. Here, we recover contaminant fungi from nests of Trachymyrmex fungus-growing ants of the southwest desert of the United States and find that they are suppressed by Actinobacteria isolated from these ants. The antibiotic ECO-0501 is an antifungal agent used by some of these Amycolatopsis bacterial isolates. This antibiotic was previously investigated in preclinical studies and known only for antibacterial activity.

CTGF-D4 Amplifies LRP6 Signaling to Promote Grafts of Adult Epicardial-derived Cells That Improve Cardiac Function After Myocardial Infarction.

Transplantation of stem/progenitor cells holds promise for cardiac regeneration in patients with myocardial infarction (MI). Currently, however, low cell survival and engraftment after transplantation present a major barrier to many forms of cell therapy. One issue is that ligands, receptors, and signaling pathways that promote graft success remain poorly understood. Here, we prospectively isolate uncommitted epicardial cells from the adult heart surface by CD104 (ß-4 integrin) and demonstrate that C-terminal peptide from connective tissue growth factor (CTGF-D4), when combined with insulin, effectively primes epicardial-derived cells (EPDC) for cardiac engraftment after MI. Similar to native epicardial derivatives that arise from epicardial EMT at the heart surface, the grafted cells migrated into injured myocardial tissue in a rat model of MI with reperfusion. By echocardiography, at 1 month after MI, we observed significant improvement in cardiac function for animals that received epicardial cells primed with CTGF-D4/insulin compared with those that received vehicle-primed (control) cells. In the presence of insulin, CTGF-D4 treatment significantly increased the phosphorylation of Wnt co-receptor LRP6 on EPDC. Competitive engraftment assays and neutralizing/blocking studies showed that LRP6 was required for EPDC engraftment after transplantation. Our results identify LRP6 as a key target for increasing EPDC engraftment after MI and suggest amplification of LRP6 signaling with CTGF-D4/insulin, or by other means, may provide an effective approach for achieving successful cellular grafts in regenerative medicine.

Kannada Translation and Validation of the ESAS-r Renal for Symptom Burden Survey in Patients with End-Stage Kidney Disease.

Objectives: End-stage kidney disease (ESKD) is a life-limiting illness that leads to significant health-related suffering for the patients and their caregivers. Moreover, disease-directed options such as dialysis and renal transplant might not be universally accessible. Inadequate assessment and management of symptoms often lead to diminished quality of life. For evaluating symptoms and their associated distress, various tools have been identified. However, these are not available for the native Kannada-speaking population for assessing ESKD symptom burden. In this study, we determined the reliability and validity of the Edmonton Symptom Assessment System Revised Renal (ESAS-r: Renal) in Kannada-speaking ESKD patients. Materials and Methods: ESAS-r: Renal English version was translated into Kannada using the forward and backward method. The translated version was endorsed by Nephrology, Palliative care, Dialysis technology and Nursing experts. As a pilot study, 12 ESKD patients evaluated the content of the questionnaires for appropriateness and relevance. The ESAS-r: Renal Kannada version was validated by administering this tool to 45 patients twice a fortnight. Result: The translated ESAS-r: Renal Kannada version questionnaire had an acceptable face and content validity. Experts' opinion was assessed by content validity ratio (CVR), and the value of CVR of ESAS-r: Renal Kannada version was-'1'-. Internal consistency of the tool was assessed among Kannada-speaking ESKD patients; its Cronbach's α was 0.785, and test-retest validity was 0.896. Conclusion: The validated Kannada version of ESAS-r: Renal was reliable and valid for assessing symptom burden in ESKD patients.

COVID-19 Palliative and End-of-Life Care Plan: Development and Audit of Outcomes.

Objectives: Palliative care (PC) referral in serious and critical COVID-19 improves decision-making, health resource utilisation, end-of-life symptom management and family support. In this study, we explored developing a systematic decision-making matrix for PC referral in COVID-19 and audited its outcomes. Materials and Methods: A team of interdisciplinary experts developed a hospital COVID-19 PC plan. PC referral and outcomes of PC referral in hospitalised COVID-19 patients were audited. Results: Out of 1575 inpatients, 1066 (67.7%) had mild and 509 (32.3%) had serious and critical COVID-19 illness. Among 50 (3.1%) referred to PC, 5 (0.4%) had mild and 45 (8.8%) had serious and critical COVID-19 illness. Out of 45 serious and critical COVID-19 patients referred to PC, 38 (84%) received end-of-life care (EOLC), 4 (9%) self-discharged against medical advice and 3 (7%) recovered. Forty-seven (94%) were referred for goals-of-care discussion. About 78% received opioids, 70% benzodiazepines and 42% haloperidol for symptom management. Among 45 serious and critical COVID-19 patients referred to PC, foregoing life-sustaining treatment was documented in 43 (96%) but implemented only in 23 (53%). Out of 38 who received EOLC, ICU was the place of death in 31 (82%) and ward in 7 (18%). Conclusion: Despite interdisciplinary experts developing a hospital COVID-19 PC, low referral of serious and critical COVID-19 patients to PC was observed. PC referral enabled access to management of end-of-life symptoms and facilitated limitation of life-sustaining treatment in some COVID-19 patients with serious illness. Educating critical care physicians about the scope of PC in the COVID-19 setting might improve PC referral.

Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration.

Zebrafish regenerate cardiac tissue through proliferation of pre-existing cardiomyocytes and neovascularization. Secreted growth factors such as FGFs, IGF, PDGFs and Neuregulin play essential roles in stimulating cardiomyocyte proliferation. These factors activate the Ras/MAPK pathway, which is tightly controlled by the feedback attenuator Dual specificity phosphatase 6 (Dusp6), an ERK phosphatase. Here, we show that suppressing Dusp6 function enhances cardiac regeneration. Inactivation of Dusp6 by small molecules or by gene inactivation increased cardiomyocyte proliferation, coronary angiogenesis, and reduced fibrosis after ventricular resection. Inhibition of Erbb or PDGF receptor signaling suppressed cardiac regeneration in wild-type zebrafish, but had a milder effect on regeneration in dusp6 mutants. Moreover, in rat primary cardiomyocytes, NRG1-stimulated proliferation can be enhanced upon chemical inhibition of Dusp6 with BCI. Our results suggest that Dusp6 attenuates Ras/MAPK signaling during regeneration and that suppressing Dusp6 can enhance cardiac repair.

FSTL-1 Attenuation Causes Spontaneous Smoke-Resistant Pulmonary Emphysema.

Rationale: The role of FSTL-1 (follistatin-like 1) in lung homeostasis is unknown.Objectives: We aimed to define the impact of FSTL-1 attenuation on lung structure and function and to identify FSTL-1-regulated transcriptional pathways in the lung. Further, we aimed to analyze the association of FSTL-1 SNPs with lung disease.Methods: FSTL-1 hypomorphic (FSTL-1 Hypo) mice underwent lung morphometry, pulmonary function testing, and micro-computed tomography. Fstl1 expression was determined in wild-type lung cell populations from three independent research groups. RNA sequencing of wild-type and FSTL-1 Hypo mice identified FSTL-1-regulated gene expression, followed by validation and mechanistic in vitro examination. FSTL1 SNP analysis was performed in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort.Measurements and Main Results: FSTL-1 Hypo mice developed spontaneous emphysema, independent of smoke exposure. Fstl1 is highly expressed in the lung by mesenchymal and endothelial cells but not immune cells. RNA sequencing of whole lung identified 33 FSTL-1-regulated genes, including Nr4a1, an orphan nuclear hormone receptor that negatively regulates NF-κB (nuclear factor-κB) signaling. In vitro, recombinant FSTL-1 treatment of macrophages attenuated NF-κB p65 phosphorylation in an Nr4a1-dependent manner. Within the COPDGene cohort, several SNPs in the FSTL1 region corresponded to chronic obstructive pulmonary disease and lung function.Conclusions: This work identifies a novel role for FSTL-1 protecting against emphysema development independent of smoke exposure. This FSTL-1-deficient emphysema implicates regulation of immune tolerance in lung macrophages through Nr4a1. Further study of the mechanisms involving FSTL-1 in lung homeostasis, immune regulation, and NF-κB signaling may provide additional insight into the pathophysiology of emphysema and inflammatory lung diseases.

Maggots in the Intercostal Drain: Case Report of a Rare Presentation with a Brief Review of Literature.

Maggots are dipterous larvae of flies. Infestation of vertebrate animals (including humans) by maggots is termed as Myiasis. Warm and Humid climate, low socio-economic status, lack of knowledge and poor living conditions, malignant wounds predispose the cancer patients to maggot infestation in India. Apart from infestation in the wounds; oral, ophthalmic, nasal, aural, enteric, urogenital, trachea-pulmonary and rectal myiasis have been reported. Maggot infestation of the Intercostal drain (ICD) container without associated pleural myiasis is an extremely rare entity. We describe a rare case report of maggots in the ICD in a patient with metastatic chondrosarcoma femur with ICD in situ for malignant pleural effusion. Early detection and management are the keys to prevent the catastrophic complication of pleural myiasis.

Decision-making around Commencing Dialysis.

The decision regarding dialysis initiation is complex. Awareness that renal replacement therapy should not be regarded as default therapy for every patient with advanced renal failure is necessary. Decision to initiate dialysis and modality should be individualized in a shared decision-making process involving the treating nephrologist and the patient. Patients should receive predialysis education early in the course of chronic kidney disease so as to help prepare them well in advance for this eventuality. Withholding dialysis may be a reasonable option in a certain subset of patients, especially elderly patient with multiple co-morbid illnesses. Comprehensive conservation care should be offered in all patients where the decision to not dialyze is taken.

Evaluating the Need for Integrated Pediatric Palliative Care Services in a Pediatric Oncology Setting: A Retrospective Audit.

OBJECTIVES: Early integrated palliative care has shown to improve the quality of life in patients with cancer. During the past decade, pediatric palliative care has become an established area of medical expertise, however due to scant information available regarding the triggers for referral and referral practice very few children receive a formal palliative care consult. MATERIALS AND METHODS: A retrospective audit of medical case records of pediatric oncology patients over a period of 1 year from September 30, 2019, to September 30, 2020, was conducted. Demographic details, diagnosis, staging, clinical parameters, reason for referral, and palliative care plan were captured in a predesigned pro forma. RESULTS: Among 126 children with cancer, 27 (21.4%) patients were referred to palliative care. Majority 21 (77%) referrals were inpatient consults. Symptom management 17 (44.7%) was the most common trigger for referral followed by referrals for psychosocial support 12 (14.4%). Children with solid tumors 16 (59%) were more often referred than hematological malignancies. Among those needing end of life care, 8 (88.8%) out of 9 families preferred home than hospital. CONCLUSION: Low incidence of palliative care referral and presence of symptoms as a trigger for palliative care referral suggests gaps in the integrated approach. The study findings prompt a review of palliative care referral criteria and referral practice in a pediatric oncology setting.

Myoglobin promotes nitrite-dependent mitochondrial S-nitrosation to mediate cytoprotection after hypoxia/reoxygenation.

It is well established that myoglobin supports mitochondrial respiration through the storage and transport of oxygen as well as through the scavenging of nitric oxide. However, during ischemia/reperfusion (I/R), myoglobin and mitochondria both propagate myocardial injury through the production of oxidants. Nitrite, an endogenous signaling molecule and dietary constituent, mediates potent cardioprotection after I/R and this effect relies on its interaction with both myoglobin and mitochondria. While independent mechanistic studies have demonstrated that nitrite-mediated cardioprotection requires the presence of myoglobin and the post-translational S-nitrosation of critical cysteine residues on mitochondrial complex I, it is unclear whether myoglobin directly catalyzes the S-nitrosation of complex I or whether mitochondrial-dependent nitrite reductase activity contributes to S-nitrosation. Herein, using purified myoglobin and isolated mitochondria, we characterize and directly compare the nitrite reductase activities of mitochondria and myoglobin and assess their contribution to mitochondrial S-nitrosation. We demonstrate that myoglobin is a significantly more efficient nitrite reductase than isolated mitochondria. Further, deoxygenated myoglobin catalyzes the nitrite-dependent S-nitrosation of mitochondrial proteins. This reaction is enhanced in the presence of oxidized (Fe3+) myoglobin and not significantly affected by inhibitors of mitochondrial respiration. Using a Chinese Hamster Ovary cell model stably transfected with human myoglobin, we show that both myoglobin and mitochondrial complex I expression are required for nitrite-dependent attenuation of cell death after anoxia/reoxygenation. These data expand the understanding of myoglobin's role both as a nitrite reductase to a mediator of S-nitrosation and as a regulator of mitochondrial function, and have implications for nitrite-mediated cardioprotection after I/R.

Thiopeptide Defense by an Ant's Bacterial Symbiont.

Fungus-growing ants and their microbial symbionts have emerged as a model system for understanding antibiotic deployment in an ecological context. Here we establish that bacterial symbionts of the ant Trachymyrmex septentrionalis antagonize their most likely competitors, other strains of ant-associated bacteria, using the thiopeptide antibiotic GE37468. Genomic analysis suggests that these symbionts acquired the GE37468 gene cluster from soil bacteria. This antibiotic, with known activity against human pathogens, was previously identified in a biochemical screen but had no known ecological role. GE37468's host-associated defense role in this insect niche intriguingly parallels the function of similar thiopeptides in the human microbiome.

Palliative Care in Coronavirus Disease 2019 Pandemic: Position Statement of the Indian Association of Palliative Care.

The global pandemic involving severe acute respiratory syndrome-coronavirus-2 has brought new challenges to clinical practice and care in the provision of palliative care. This position statement of the Indian Association of Palliative Care (IAPC) represents the collective opinion of the experts chosen by the society and reports on the current situation based on recent scientific evidence. It purports to guide all health-care professionals caring for coronavirus disease 2019 (COVID-19) patients and recommends palliative care principles into government decisions and policies. The statement provides recommendations for palliative care for both adults and children with severe COVID-19 illness, cancer, and chronic end-stage organ impairment in the hospital, hospice, and home setting. Holistic care incorporating physical, psychological, social, and spiritual support for patients and their families together with recommendations on the rational use of personal protective equipment has been discussed in brief. Detailed information can be accessed freely from the website of the IAPC http://www.palliativecare.in/. We hope that this position statement will serve as a guiding light in these uncertain times.

Priming with ligands secreted by human stromal progenitor cells promotes grafts of cardiac stem/progenitor cells after myocardial infarction.

Transplantation of culture-expanded adult stem/progenitor cells often results in poor cellular engraftment, survival, and migration into sites of tissue injury. Mesenchymal cells including fibroblasts and stromal cells secrete factors that protect injured tissues, promote tissue repair, and support many types of stem/progenitor cells in culture. We hypothesized that secreted factors in conditioned medium (CdM) from adult bone marrow-derived multipotent stromal cells (MSCs) could be used to prime adult cardiac stem/progenitor cells (CSCs/CPCs) and improve graft success after myocardial infarction (MI). Incubation of adult rat CPCs in CdM from human MSCs isolated by plastic adherence or by magnetic sorting against CD271 (a.k.a., p75 low-affinity nerve growth factor receptor; p75MSCs) induced phosphorylation of STAT3 and Akt in CPCs, supporting their proliferation under normoxic conditions and survival under hypoxic conditions (1% oxygen). Priming CSCs with 30× p75MSC CdM for 30 minutes prior to transplantation into subepicardial tissue 1 day after MI markedly increased engraftment compared with vehicle priming. Screening CdM with neutralizing/blocking antibodies identified connective tissue growth factor (CTGF) and Insulin as key factors in p75MSC CdM that protected CPCs. Human CTGF peptide (CTGF-D4) and Insulin synergistically promoted CPC survival during hypoxia in culture. Similar to CdM priming, priming of CSCs with CTGF-D4 and Insulin for 30 minutes prior to transplantation promoted robust engraftment, survival, and migration of CSC derivatives at 1 week and 1 month after MI. Our results indicate that short-term priming of human CSCs with CTGF-D4 and Insulin may improve graft success and cardiac regeneration in patients with MI.

Myoglobin Inhibits Breast Cancer Cell Fatty Acid Oxidation and Migration via Heme-dependent Oxidant Production and Not Fatty Acid Binding.

The monomeric heme protein myoglobin (Mb), traditionally thought to be expressed exclusively in cardiac and skeletal muscle, is now known to be expressed in approximately 40% of breast tumors. While Mb expression is associated with better patient prognosis, the molecular mechanisms by which Mb limits cancer progression are unclear. In muscle, Mb's predominant function is oxygen storage and delivery, which is dependent on the protein's heme moiety. However, prior studies demonstrate that the low levels of Mb expressed in cancer cells preclude this function. Recent studies propose a novel fatty acid binding function for Mb via a lysine residue (K46) in the heme pocket. Given that cancer cells can upregulate fatty acid oxidation (FAO) to maintain energy production for cytoskeletal remodeling during cell migration, we tested whether Mb-mediated fatty acid binding modulates FAO to decrease breast cancer cell migration. We demonstrate that the stable expression of human Mb in MDA-MB-231 breast cancer cells decreases cell migration and FAO. Site-directed mutagenesis of Mb to disrupt Mb fatty acid binding did not reverse Mb-mediated attenuation of FAO or cell migration in these cells. In contrast, cells expressing Apo-Mb, in which heme incorporation was disrupted, showed a reversal of Mb-mediated attenuation of FAO and cell migration, suggesting that Mb attenuates FAO and migration via a heme-dependent mechanism rather than through fatty acid binding. To this end, we show that Mb's heme-dependent oxidant generation propagates dysregulated gene expression of migratory genes, and this is reversed by catalase treatment. Collectively, these data demonstrate that Mb decreases breast cancer cell migration, and this effect is due to heme-mediated oxidant production rather than fatty acid binding. The implication of these results will be discussed in the context of therapeutic strategies to modulate oxidant production and Mb in tumors. Highlights: Myoglobin (Mb) expression in MDA-MB-231 breast cancer cells slows migration.Mb expression decreases mitochondrial respiration and fatty acid oxidation.Mb-dependent fatty acid binding does not regulate cell migration or respiration.Mb-dependent oxidant generation decreases mitochondrial metabolism and migration.Mb-derived oxidants dysregulate migratory gene expression.