Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.

Recurrent Guillain-Barré Syndrome: Clinical Profile and Outcome.

OBJECTIVES: To compare clinical, neurological, treatment and outcome of recurrent Guillian-Barré Syndrome (GBS) with non-recurrent GBS. Also, to compare different episodes of recurrent GBS. METHODS: The patient's case records were retrieved retrospectively from the electronic database and case record files. Clinical profile, nerve conduction study, treatment, and outcome details of children with a diagnosis of GBS admitted in Pediatric Intensive Care Unit (PICU) from 2010 to March 2022 were screened. Recurrent GBS cases, as defined by the National Institute of Neurological and Communicative Diseases and Strokes (NINCDS) criteria, were analysed separately. The comparison was made between the first episode of recurrent GBS with non-recurrent GBS, and predictors of recurrence were identified. A comparison of course and outcome was also done between different episodes of GBS in recurrent cases. RESULTS: Recurrent GBS was observed in 11 (4.7%) out of 234 cases during the study period. The presence of respiratory (p 0.015) and gastrointestinal illness (p 0.007) as preceding illnesses were associated with recurrence. No difference was noted between the first episode of recurrent GBS and non-recurrent GBS. The first and second episodes of GBS in 11 recurrent cases were similar in course and outcome. CONCLUSIONS: Recurrent GBS is underreported but a known entity. No difference was seen between the two episodes of recurrent GBS. However, more data is required to find the features of recurrent GBS so that limited PICU resources can be used judiciously and intervention planned accordingly.

Antibiotic resistance determinants among carbapenemase producing bacteria isolated from wastewaters of Kathmandu, Nepal.

The emergence of carbapenem resistant bacteria (CRB) possesses a remarkable threat to the health of humans. CRB and carbapenem resistance genes (CRGs) have frequently been reported in clinical isolates from hospitals, however, their occurrence and distribution in wastewaters from various sources and river water have not been emphasized in Nepal. So, this study aimed to detect carbapenem resistant bacterial isolates and their resistance determinants in river water and different types of wastewaters. River water and both untreated and treated wastewater samples from hospitals, pharmaceutical industries, and municipal sewage were collected in summer and winter seasons. From 68 grab wastewater samples, CRB were detected only in 16 samples, which included eight hospital wastewater, and four each from untreated municipal sewage and river water. A total of 25 CRB isolates were detected with dominance of E. coli (44.0%) and K. pneumoniae (24.0%). The majority of the isolates harbored blaNDM-1 (76.0%), followed by blaOXA (36.0%) and blaKPC (20.0%) genes. Hospital wastewater majorly contributed to the presence of blaNDM-1, blaKPC, and blaOXA along with intI1 genes compared to river water and untreated municipal sewage, especially during the winter season. However, CRB were not detected in treated effluents of hospitals and municipal sewage, and both influents and effluents from pharmaceutical industries. The combined presence of each blaNDM-1 & blaOXA and blaKPC & blaOXA occurred in 16.0% of the bacterial isolates. The increased minimum inhibitory concentration (MIC) of meropenem was significantly associated with the presence of CRGs. The results of this study highlight the significance of carbapenem resistance in bacteria isolated from wastewater and river water, and underscore the necessity for efficient monitoring and control strategies to prevent the dispersion of carbapenem resistance in the environment and its potential consequences on human health.

Furosemide Stress Test and Renal Resistive Index for Prediction of Severity of Acute Kidney Injury in Sepsis.

Introduction The furosemide stress test (FST) predicts the severity and the need for renal replacement therapy (RRT) in patients with sepsis-associated acute kidney injury (S-AKI). The renal resistive index (RRI) indicates renal vascular resistance. Objectives The primary objective was to find the correlation between FST and RRI in S-AKI. The secondary objectives were to evaluate the role of FST and RRI on the progression of S-AKI. Methods A total of 154 consenting adult patients with S-AKI were administered FST. Renal echography was performed within the first 12 hours of admission, and RRI was calculated. The patients were grouped either into progressors or non-progressors to AKI-KDIGO stage 3. Results Of the patients who had RRI at Day 1 less than 0.73, 60% recovered, 34.3% needed RRT, and 35.5% died, whereas in those who had RRI at Day 1 greater than 0.73, only 22% recovered, 46.6% required RRT, and 51.6% died. RRI value of 0.73 predicted the need for RRT with a sensitivity of 35.1%, specificity of 80.4% and accuracy of 69.1%. The highest number of patients of KDIGO stage 3 (50%), followed by stage 2 (28.1%) and stage 1 (21.9%), presented technical difficulties in measuring the RRI. Conclusion FST is an economical and easily administered test to assess renal tubular function and can predict the occurrence and progression of S-AKI. RRI is a modest marker for predicting the need for RRT or persistent AKI.

Combined atrial fibrillation ablation and left atrial appendage occlusion procedure in the United States: a propensity score matched analysis from 2016-2019 national readmission database.

AIMS: The safety and feasibility of combining percutaneous catheter ablation (CA) for atrial fibrillation with left atrial appendage occlusion (LAAO) as a single procedure in the USA have not been investigated. We analyzed the US National Readmission Database (NRD) to investigate the incidence of combined LAAO + CA and compare major adverse cardiovascular events (MACEs) with matched LAAO-only and CA-only patients. METHODS AND RESULTS: In this retrospective study from NRD data, we identified patients undergoing combined LAAO and CA procedures on the same day in the USA from 2016 to 2019. A 1:1 propensity score match was performed to identify patients undergoing LAAO-only and CA-only procedures. The number of LAAO + CA procedures increased from 28 (2016) to 119 (2019). LAAO + CA patients (n = 375, mean age 74 ± 9.2 years, 53.4% were males) had non-significant higher MACE (8.1%) when compared with LAAO-only (n = 407, 5.3%) or CA-only patients (n = 406, 7.4%), which was primarily driven by higher rate of pericardial effusion (4.3%). All-cause 30-day readmission rates among LAAO + CA patients (10.7%) were similar when compared with LAAO-only (12.7%) or CA-only (17.5%) patients. The most frequent primary reason for readmissions among LAAO + CA and LAAO-only cohorts was heart failure (24.6 and 31.5%, respectively), while among the CA-only cohort, it was paroxysmal atrial fibrillation (25.7%). CONCLUSION: We report an 63% annual growth (from 28 procedures) in combined LAAO and CA procedures in the USA. There were no significant difference in MACE and all-cause 30-day readmission rates among LAAO + CA patients compared with matched LAAO-only or CA-only patients.

Severe dengue associated with Staphylococcus aureus sepsis in pediatric patients: a case series.

BACKGROUND: Staphylococcus aureus co-infection is seldom reported in children with severe dengue. METHODOLOGY: In this retrospective study, we reported five children with severe dengue and S. aureus co-infection admitted to pediatric intensive care unit (PICU) during July-December 2021. RESULTS: All children had prolonged fever, persistence of bilateral pleural effusion beyond the critical phase, thrombocytopenia and raised inflammatory markers [C-reactive protein (CRP) and procalcitonin]. S. aureus was isolated from pleural fluid (n = 2, 40%), blood (n = 2, 40%) and endotracheal aspirate (n = 1, 20%). Four children (80%) grew methicillin-sensitive S. aureus, while 1 (20%) had methicillin-resistant S. aureus. Two children (40%) had septic thromboemboli in skin, and 1 (20%) had limb cellulitis. One child required anterior thoracotomy, pericardiectomy and bilateral pleural decortication, while all other children required intercostal chest tube drainage. All children required prolonged targeted antibiotics, invasive mechanical ventilation and had prolong stay in PICU and all of them survived. CONCLUSION: In children with severe dengue, persistence of fever, persistence of pleural effusion beyond critical phase and raised CRP and procalcitonin should raise suspicion of bacterial/S. aureus co-infection.

Mycobacterium tuberculosis exploits MPT64 to generate myeloid-derived suppressor cells to evade the immune system.

Mycobacterium tuberculosis (Mtb) is a smart and successful pathogen since it can persist in the intimidating environment of the host by taming and tuning the immune system. Mtb releases MPT64 (Rv1980c) protein in high amounts in patients with active tuberculosis (TB). Consequently, we were curious to decipher the role of MPT64 on the differentiating dendritic cells (DCs) and its relation to evading the immune system. We observed that pre-exposure of differentiating DCs to MPT64 (DCMPT64) transformed them into a phenotype of myeloid-derived suppressor cells (MDSCs). DCMPT64 expressed a high level of immunosuppressive molecules PD-L1, TIM-3, nitric oxide (NO), arginase 1, IDO-1, IL-10 and TGF-ß, but inhibited the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-12. DCMPT64 chemotaxis function was diminished due to the reduced expression of CCR7. DCMPT64 promoted the generation of regulatory T cells (Tregs) but inhibited the differentiation of Th1 cells and Th17 cells. Further, high lipid and methylglyoxal content, and reduced glucose consumption by DCMPT64, rendered them metabolically quiescent and consequently, reduced DCMPT64 ability to phagocytose Mtb and provided a safer shelter for the intracellular survival of the mycobacterium. The mechanism identified in impairing the function of DCMPT64 was through the increased production and accumulation of methylglyoxal. Hence, for the first time, we demonstrate the novel role of MPT64 in promoting the generation of MDSCs to favor Mtb survival and escape its destruction by the immune system.

Impact of Active and Historical Cancers on the Management and Outcomes of Acute Myocardial Infarction Complicating Cardiogenic Shock.

BACKGROUND: There are limited data on the outcomes of acute myocardial infarction-cardiogenic shock (AMI-CS) in patients with concomitant cancer. METHODS: A retrospective cohort of adult AMI-CS admissions was identified from the National Inpatient Sample (2000-2017) and stratified by active cancer, historical cancer, and no cancer. Outcomes of interest included in-hospital mortality, use of coronary angiography, use of percutaneous coronary intervention, do-not-resuscitate status, palliative care use, hospitalization costs, and hospital length of stay. RESULTS: Of the 557,974 AMI-CS admissions during this 18-year period, active and historical cancers were noted in 14,826 (2.6%) and 27,073 (4.8%), respectively. From 2000 to 2017, there was a decline in active cancers (adjusted odds ratio, 0.70 [95% CI, 0.63-0.79]; P < .001) and an increase in historical cancer (adjusted odds ratio, 2.06 [95% CI, 1.89-2.25]; P < .001). Compared with patients with no cancer, patients with active and historical cancer received less-frequent coronary angiography (57%, 67%, and 70%, respectively) and percutaneous coronary intervention (40%, 47%, and 49%%, respectively) and had higher do-not-resuscitate status (13%, 15%, 7%%, respectively) and palliative care use (12%, 10%, 6%%, respectively) (P < .001). Compared with those without cancer, higher in-hospital mortality was found in admissions with active cancer (45.9% vs 37.0%; adjusted odds ratio, 1.29 [95% CI, 1.24-1.34]; P < .001) but not historical cancer (40.1% vs 37.0%; adjusted odds ratio, 1.01 [95% CI, 0.98-1.04]; P = .39). AMI-CS admissions with cancer had a shorter hospitalization duration and lower costs (all P < .001). CONCLUSION: Concomitant cancer was associated with less use of guideline-directed procedures. Active, but not historical, cancer was associated with higher mortality in patients with AMI-CS.

Usefulness of Urinary Neutrophil Gelatinase-associated Lipocalin as a Predictor of Acute Kidney Injury in Critically Ill Children.

Background: Acute kidney injury (AKI) is common among critically ill children. The current definitions of AKI rely on serum creatinine and urine output, which may not be deranged until late in the course of the illness. There has been a lot of work in search of novel biomarkers to define and predict AKI, and urinary neutrophil gelatinase-associated lipocalin (NGAL) is a promising one. We planned to study the usefulness of urinary NGAL in predicting AKI. Patients and methods: Children in the age group of 1 month to 18 years admitted to the pediatric intensive care unit (PICU) from September 2016 to December 2017 were enrolled. Children with preexisting kidney disease, urinary tract infection (UTI), postsurgical patients, or children with expected duration of stay <48 hours were excluded. Data regarding demographics, clinical features, and laboratory parameters were collected. Urinary NGAL was sent within 6 hours of admission. Children were classified to have AKI based upon the Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease (pRIFLE) criteria. Using receiver operating characteristic (ROC) curves, sensitivity, specificity, and area under the curve (AUC) for admission creatinine and urinary NGAL to predict AKI were deduced. Results: One hundred and thirty children were included. Out of 130 children, 59 (45.4%) developed AKI. Urinary NGAL at admission to the PICU >88.5 ng/mL had a sensitivity of 81.4% and specificity of 83.6% in detecting AKI while its AUC to detect AKI was 0.842 (95% confidence interval (CI) 0.765-0.918). Urinary NGAL predicted AKI in 17 (28.8%) of 59 patients at least 24 hours earlier than serum creatinine. Mortality rates in patients with and without AKI were 18.6 and 2.8%, respectively. Conclusion: Urinary NGAL has good sensitivity and specificity in detecting AKI and predicts AKI earlier than creatinine in a significant number of patients. How to cite this article: Kapalavai SK, Ramachandran B, Krupanandan R, Sadasivam K. Usefulness of Urinary Neutrophil Gelatinase-associated Lipocalin as a Predictor of Acute Kidney Injury in Critically Ill Children. Indian J Crit Care Med 2022;26(5):634-638.

Oral Application of Colostrum and Mother's Own Milk in Preterm Infants-A Randomized, Controlled Trial.

OBJECTIVES: To evaluate the effects of oral application of mother's own milk (OMOM) on clinical outcomes in preterm infants of 260/7-306/7 wk gestation. METHODS: In this placebo-controlled randomized trial, subjects received either OMOM or sterile water, beginning at 24-72 h of life, until the infant reached 32 wk postmenstrual age or spoon-feeds were initiated, whichever was earlier. The primary outcome was a composite adverse health outcome, defined as the occurrence of either mortality, late-onset sepsis (LOS), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), or retinopathy of prematurity (ROP). Antibiotic usage and time to full enteral feed were secondary outcomes. Salivary IgA (sIgA) levels at baseline and after 7 d of application in a subset of infants were also compared. RESULTS: A total of 133 neonates (66 colostrum and 67 placebo) were analyzed for the primary outcome. OMOM group had lower incidence of composite adverse health outcome (43.9% vs. 61.2%, RR: 0.70; 95% CI: 0.50-0.99, p = 0.046) and LOS (22.7% vs. 43.3%, RR: 0.73; 95% CI: 0.57-0.93; p = 0.012). There were no significant differences in mortality, NEC, IVH, BPD, ROP, and time to full feeds. The effects were more pronounced in the 290/7-306/7 wk subgroup, in whom the colostrum group also achieved full feeds earlier. There were no differences in the change of sIgA levels from baseline to the seventh day of the application. No adverse effects related to the OMOM application were found. CONCLUSIONS: OMOM decreases the incidence of late-onset sepsis in preterm neonates (260/7-306/7 wk) and is safe. TRIAL REGISTRATION: Clinical Trials Registry-India CTRI/2017/03/008031.

Outcomes and predictors of readmission after implantation of a percutaneous left atrial appendage occlusion device in the United States: A propensity score-matched analysis from The National Readmission Database.

BACKGROUND: Left atrial appendage occlusion (LAAO) devices have become a favorable alternative option among nonvalvular atrial fibrillation (AF) patients with long-term contraindication to anticoagulation. Real-world experience with postprocedural readmission rates and predictors of readmission in LAAO patients is limited. OBJECTIVE: To assess all-cause 30-day readmission rate and predictors of readmission after LAAO procedure in the United States. METHOD: This retrospective observational study included all AF patients undergoing percutaneous LAAO procedures in the United States from January 1, 2016, and December 31, 2017, in the National Readmission Database. The primary outcome measure was all-cause 30-day readmission. A propensity score-matched analysis compared outcomes with a non-LAAO AF cohort. RESULT: Among 14 024 LAAO procedures (age: 76 ± 8 years; 60.5% males), 9.4% were readmitted within 30-days and, 0.2% died during their index hospitalization. The most frequent primary diagnosis during readmission among LAAO was gastrointestinal bleeding (12%). The incidence of LAAO procedures increased by 102%. In the multivariate model, gender and CHA2 DS2 -VASc failed to predict readmission. Age 55-64 years had lower odds (adjusted odds ratios [aOR]: 0.41; 95% confidence interval [CI]: 0.18-0.94), while drug abuse (aOR: 4.1; 95% CI: 1.34-12.54), and deficiency anemia (aOR: 1.88; 95% CI: 1.12-3.18) had higher odds of readmission. In propensity-matched cohort, compared to non-LAAO AF, LAAO patients had lower 30-day readmission (9.4% vs. 10.98%, p = .002) and all-cause in-hospital mortality (0.19% vs. 0.57%, p < .001). CONCLUSION: The readmission rate following the LAAO procedure is substantial (approximately 10%), and largely attributable to gastrointestinal bleeding. Factors such as drug abuse and anemia must be explored further to minimize readmission risk.

A Child with Unilateral Pulmonary Edema due to Mitral Valve Rupture Following Blunt Trauma.

A 7-year-old boy was admitted with a history of cough and tachypnea for 1 day. There was a history of a fall from a motorcycle with some abrasions over the left arm. The child was found to have tachypnea and tachycardia and was started on noninvasive ventilation. Auscultation revealed a pansystolic murmur over the precordium. Chest X-ray revealed unilateral pulmonary edema on the right side. Echocardiography showed severe mitral regurgitation (MR) with the tear of the anterior leaflet. The child improved with diuretics and supportive care. After 3 months, he underwent surgical repair of the mitral valve. Traumatic mitral valve tear is quite rare in children. Unilateral pulmonary edema is a feature of MR with eccentric jet and is frequently misinterpreted. How to cite this article: Mukherjee S, Ravikumar K, Kapalavai SK, Ramachandran B. A Child with Unilateral Pulmonary Edema due to Mitral Valve Rupture Following Blunt Trauma. Indian J Crit Care Med 2021; 25(6):729-731.

Overall survival based on oncologist density in the United States: A retrospective cohort study.

Medically underserved areas (MUA) or health professional shortage areas (HPSA) designations are based on primary care health services availability. These designations are used in recruiting international medical graduates (IMGs) trained in primary care or subspecialty (e.g., oncology) to areas of need. Whether the MUA/HPSA designation correlates with Oncologist Density (OD) and supports IMG oncologists' recruitment to areas of need is unknown. We evaluated the concordance of OD with the designation of MUAs/HPSAs and evaluated the impact of OD and MUA/HPSA status on overall survival. We conducted a retrospective cohort study of patients diagnosed with hematological malignancies or metastatic solid tumors in 2011 from the Surveillance Epidemiology and End Results (SEER) database. SEER was linked to the American Medical Association Masterfile to calculate OD, defined as the number of oncologists per 100,000 population at the county level. We calculated the proportion of counties with MUA or HPSA designation for each OD category. Overall survival was estimated using the Kaplan-Meier method and compared between the OD category using a log-rank test. We identified 68,699 adult patients with hematologic malignancies or metastatic solid cancers in 609 counties. The proportion of MUA/HPSA designation was similar across counties categorized by OD (93.2%, 95.4%, 90.3%, and 91.7% in counties with <2.9, 2.9-6.5, 6.5-8.4 and >8.4 oncologists per 100K population, p = 0.7). Patients' median survival in counties with the lowest OD was significantly lower compared to counties with the highest OD (8 vs. 11 months, p<0.0001). The difference remained statistically significant in multivariate and subgroup analysis. MUA/HPSA status was not associated with survival (HR 1.03, 95%CI 0.97-1.09, p = 0.3). MUA/HPSA designation based on primary care services is not concordant with OD. Patients in counties with lower OD correlated with inferior survival. Federal programs designed to recruit physicians in high-need areas should consider the availability of health care services beyond primary care.

Gut Dysbiosis Thwarts the Efficacy of Vaccine Against Mycobacterium tuberculosis.

The generation of enduring protective immunity by vaccines is of utmost importance. Intriguingly, there is considerable variation in the efficacy of vaccines amongst individuals. Various studies have shown that normal flora of gastrointestinal tract plays a vital role in maintaining host homeostasis and immunity. Since gut microbiome is also extremely variable between individuals, we speculate that it might impact individual's response to vaccines. Consequently, we administered broad spectrum antibiotics cocktail to induce gut dysbiosis and monitored its impact on the generation of long-lasting memory T cells and thereby BCG vaccine efficacy. Interestingly, gut dysbiosis significantly decreased the activation of CD4+ T cells and CD8+ T cells. Further, there was decline in the frequency of memory CD4+ T cells and CD8+ T cells in lungs and secondary lymphoid organs of the vaccinated animals. Moreover, it dampened the IFN-γ and TNF-α secretion and proliferation of Mtb-specific T cells. Most importantly, dysbiosis hampered Mtb clearance in vaccinated animals, as evidenced by increase in the colony forming units (CFUs) in lungs and spleen. Our findings indicate that gut dysbiosis can be one of the major factors responsible for variable efficacy of TB vaccines across the world.