Patterns and Outcomes in Pediatric Abdominal Tuberculosis: A Single Centre Cohort Study.

INTRODUCTION: Abdominal tuberculosis presents in a variety of ways. Different testing modalities must be applied in addition to having a high clinical suspicion to diagnose and initiate therapy. Medications have a good response; however, morbidity has been seen following surgical management of complicated presentations like intestinal obstruction and perforation. There is a paucity of studies in the pediatric age group which evaluate response to the different treatment regimen and identify factors associated with poorer outcomes in children with abdominal tuberculosis. METHODS: Patient records of 75 children with abdominal tuberculosis at a single center were evaluated using a questionnaire, covering a 14-year period from 2007 to 2021. Demographic features, presenting signs and symptoms, investigations and treatment details were studied. In- person or telephonic follow-up was conducted to identify treatment outcomes. RESULTS: Incidence of abdominal TB was 7%, of all TB children with a mean age of 10.1 years. Mesenteric lymph nodes were involved in 67% and small intestine in 33% cases. Surgery was required in 22 children. 85% children completed treatment. Small intestine involvement had higher probability of undergoing surgery. Of the 70 children with complete follow up, 64 were well and 6 children succumbed to the disease. Older age, small intestine involvement and surgery were independently associated with higher mortality. CONCLUSION: Intestinal involvement is associated with greater need for surgical intervention and greater mortality. Adolescents have poorer outcomes. Further studies are required focusing on these individual subgroups to understand the patterns of presentation, causes for mortality and prevention. LEVEL OF EVIDENCE: Level 5.

The Changing Face of Childhood Intussusception: A Refinement in the Technique of Saline Reduction and Outcome.

Aims: Intussusception is a common pediatric surgical emergency and an indicator for primary healthcare. We report our experience with childhood intussusception at a tertiary care hospital in the private sector in Central Kerala and add our refinement to the technique of hydrostatic saline reduction which had more desirable outcome. Settings and Design: Children presenting with the diagnosis of intussusception which were managed in our department of pediatric surgery at a private hospital in Kerala, India. Subjects and Methods: Eighty children, up to 15 years of age, (43 boys, 37 girls) confirmed to have intussusception on ultrasound and managed in our institution from October 2016 to July 2020 with hydrostatic saline reduction. Sixty-two (77%) of them were aged 3 months to 3 years (numbers <10 to be written in words); the age of idiopathic intussusception. Statistical Analysis Used: SPSS V25. Association between variables using Chi square test and independent t test. Results: A total of 80 children met the criteria out of that (n = 79) had successful nonoperative reduction. Hydrostatic saline enema 73, One Barium and five air enema. A child presented in shock was taken up for laparotomy and reduced operatively. Six recurred within 24 h (7% early recurrence) and a second attempt at nonoperative reduction succeeded in all six of them. (numbers <10 in words). Eleven children (14%) had a late recurrence, the attempt at saline hydrostatic reduction was successful in only 3 (27%) and 8 went on to have surgery. Six were successfully reduced operatively and 2 had resection anastomosis. Conclusions: After excluding those who need surgery on clinical grounds, we report a 98.7% success with nonoperative reduction for the first instance of intussusception, a 24 h recurrence of 7%, with successful repeat reductions in all. With the refinement in the technique, we could achieve a desirable outcome. At the first presentation, surgery was indicated in 1 of the 80 children. We report a late recurrence rate of 14%, with a 27% success rate for nonoperative reduction. No pathological lead points were identified even in this group. All the children had an uneventful and a faster recovery. In our series, we had 97.5% follow-up rate.

Assessing Radish Health during Space Cultivation by Gene Transcription.

During the Advanced Plant Habitat experiment 2, radish plants were grown in two successive grow-outs on the International Space Station (ISS) for 27 days each. On days 10, 18, and 24, leaf punch (LP) samples were collected and frozen. At harvest, bulb tissue was sampled with oligo-dT functionalized Solid Phase Gene Extraction (SPGE) probes. The space samples were compared with samples from ground controls (GC) grown at the Kennedy Space Center (KSC) under the same conditions as on the ISS, with notably elevated CO2 (about 2500 ppm), and from lab plants grown under atmospheric CO2 but with light and temperature conditions similar to the KSC control. Genes corresponding to peroxidase (RPP), glucosinolate biosynthesis (GIS), protein binding (CBP), myrosinase (RMA), napin (RSN), and ubiquitin (UBQ) were measured by qPCR. LP from day 24 and bulb samples collected at harvest were compared with RNA-seq data from material that was harvested, frozen, and analyzed after return to Earth. The results showed stable transcription in LP samples in GC but decreasing values in ISS samples during both grow-outs, possibly indicative of stress. SPGE results were similar between GC and ISS samples. However, the RNA-seq analyses showed different transcription profiles than SPGE or LP results, possibly related to localized sampling. RNA-seq of leaf samples showed greater variety than LP data, possibly because of different sampling times. RSN and RPP showed the lowest transcription regardless of method. Temporal analyses showed relatively small changes during plant development in space and in ground controls. This is the first study that compares developmental changes in space-grown plants with ground controls based on a comparison between RNA-seq and qPCR analyses.

Intranasal parainfluenza virus type 5 (PIV5)-vectored RSV vaccine is safe and immunogenic in healthy adults in a phase 1 clinical study.

Respiratory syncytial virus (RSV) can lead to serious disease in infants, and no approved RSV vaccine is available for infants. This first in-human clinical trial evaluated a single dose of BLB201, a PIV5-vectored RSV vaccine administrated via intranasal route, for safety and immunogenicity in RSV-seropositive healthy adults (33 to 75 years old). No severe adverse events (SAEs) were reported. Solicited local and systemic AEs were reported by <50% of participants and were mostly mild in intensity. Vaccine virus shedding was detected in 17% of participants. Nasal RSV-specific immunoglobulin A responses were detected in 48%, the highest level observed in adults among all intranasal RSV vaccines evaluated in humans. RSV-neutralizing antibodies titers in serum rose ≥1.5-fold. Peripheral blood RSV F-specific CD4+ and CD8+ T cells increased from ≤0.06% at baseline to ≥0.26 and 0.4% after vaccination, respectively, in >93% participants. The safety and immunogenicity profile of BLB201 in RSV-seropositive adults supports the further clinical development of BLB201.

The Management of Children and Youth With Pediatric Mental and Behavioral Health Emergencies.

Mental and behavioral health (MBH) emergencies in children and youth continue to increasingly affect not only the emergency department (ED), but the entire spectrum of emergency medical services for children, from prehospital services to the community. Inadequate community and institutional infrastructure to care for children and youth with MBH conditions makes the ED an essential part of the health care safety net for these patients. As a result, an increasing number of children and youth are referred to the ED for evaluation of a broad spectrum of MBH emergencies, from depression and suicidality to disruptive and aggressive behavior. However, challenges in providing optimal care to these patients include lack of personnel, capacity, and infrastructure, challenges with timely access to a mental health professional, the nature of a busy ED environment, and paucity of outpatient post-ED discharge resources. These factors contribute to prolonged ED stays and boarding, which negatively affects patient care and ED operations. Strategies to improve care for MBH emergencies, including systems level coordination of care, is therefore essential. The goal of this policy statement and its companion technical report is to highlight strategies, resources, and recommendations for improving emergency care delivery for pediatric MBH.

Hospitalisation outcomes in pneumococcal-vaccinated versus -unvaccinated patients with exacerbation of COPD: results from the HOPE COPD Study.

Background: Infectious exacerbations are crucial events that dictate the natural course of COPD patients. Pneumococcal vaccination has been shown to decrease incidence of community-acquired pneumonia in COPD patients. There is a paucity of data on outcomes of hospitalisation in pneumococcal-vaccinated COPD patients in comparison with unvaccinated subjects. The objectives of the present study were to evaluate the difference in hospitalisation outcomes in pneumococcal-vaccinated versus -unvaccinated COPD subjects hospitalised with acute exacerbation. Methods: This was a prospective analytical study on 120 subjects hospitalised with acute COPD exacerbation. 60 patients with prior pneumococcal vaccination and 60 unvaccinated patients were recruited. Outcomes of hospitalisation such as mortality rate, need for assisted ventilation, length of hospital stay, need for intensive care unit (ICU) care and length of ICU stay were collected and compared between two groups with appropriate statistical tools. Results: 60% of unvaccinated patients (36 out of 60) required assisted ventilation, whereas only 43.3% of vaccinated subjects (26 out of 60) needed assisted ventilation (p-value of 0.04). Most of the secondary outcomes were better in the vaccinated group. The mean±SD length of ICU stay in the vaccinated group was 0.67±1.11 days compared to 1.77±1.89 days in the unvaccinated group. The mean±SD length of hospital stay was 4.50±1.64 days and 5.47±2.03 days in the vaccinated and unvaccinated group, respectively (p-value of 0.005). Conclusions: COPD patients who have received prior pneumococcal vaccination have better outcomes when they are hospitalised for an acute exacerbation. Pneumococcal vaccination may be recommended for all patients with COPD who are at risk of hospitalisation with acute exacerbation.

The HAVEN study-hydroxychloroquine in ANCA vasculitis evaluation-a multicentre, randomised, double-blind, placebo-controlled trial: study protocol and statistical analysis plan.

BACKGROUND: Patients with non-severe ANCA-associated vasculitis (AAV) are often prescribed immunosuppressive medications that are associated with severe side effects and a reduced quality of life. There is an unmet need for safer effective treatments for these patients. Hydroxychloroquine is being explored due to its effect in similar autoimmune conditions such as systemic lupus erythematosus. METHODS: Double-blind, placebo-controlled multicentre trial recruiting 76 patients across 20 sites. Participants will be randomised 1:1 to hydroxychloroquine or placebo in addition to standard of care immunosuppressive therapies over the course of 52 weeks. A phase II selection design will be used to determine hdroxychloroquine's efficacy, using prednisolone dosage and Birmingham Vasculitis Activity Score as a measure of disease activity. Secondary outcomes will explore other elements of AAV progression, including disease flares and time to remission. DISCUSSION: This trial aims to explore Hydroxychloroquine as a treatment for patients with AAV. If effective, the need for immunosuppressive treatments such as prednisolone could be reduced. Hydroxychloroquine is safer, cheaper and has fewer adverse effects than conventional immunosuppressive treatments. This could improve patient outcomes while saving money for the NHS. TRIAL REGISTRATION: ISRCTN: ISRCTN79334891. Registered 07 June 2021. EudraCT: 2018-001268-40. Registered 13 September 2019. CLINICALTRIALS: gov: NCT04316494. Registered 20 March 2020.

Changes in endogenous abscisic acid and stomata of the resurrection fern, Pleopeltis polypodioides, in response to de- and rehydration.

PREMISE: While angiosperms respond uniformly to abscisic acid (ABA) by stomatal closure, the response of ferns to ABA is ambiguous. We evaluated the effect of endogenous ABA, hydrogen peroxide (H2 O2 ), nitric oxide (NO), and Ca2+ , low and high light intensities, and blue light (BL) on stomatal opening of Pleopeltis polypodioides. METHODS: Endogenous ABA was quantified using gas chromatography-mass spectrometry; microscopy results and stomatal responses to light and chemical treatments were analyzed with Image J. RESULTS: The ABA content increases during initial dehydration, peaks at 15 h and then decreases to one fourth of the ABA content of hydrated fronds. Following rehydration, ABA content increases within 24 h to the level of hydrated tissue. The stomatal aperture opens under BL and remains open even in the presence of ABA. Closure was strongly affected by BL, NO, and Ca2+ , regardless of ABA, H2 O2 effect was weak. CONCLUSIONS: The decrease in the ABA content during extended dehydration and insensitivity of the stomata to ABA suggests that the drought tolerance mechanism of Pleopeltis polypodioides is independent of ABA.

CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.

Alterations in cellular metabolism underpin macrophage activation, yet little is known regarding how key immunological molecules regulate metabolic programs in macrophages. Here we uncover a function for the antigen presenting molecule CD1d in the control of lipid metabolism. We show that CD1d-deficient macrophages exhibit a metabolic reprogramming, with a downregulation of lipid metabolic pathways and an increase in exogenous lipid import. This metabolic rewiring primes macrophages for enhanced responses to innate signals, as CD1d-KO cells show higher signalling and cytokine secretion upon Toll-like receptor stimulation. Mechanistically, CD1d modulates lipid import by controlling the internalization of the lipid transporter CD36, while blocking lipid uptake through CD36 restores metabolic and immune responses in macrophages. Thus, our data reveal CD1d as a key regulator of an inflammatory-metabolic circuit in macrophages, independent of its function in the control of T cell responses.

Half Disc Cartilage Tympanoplasty: A Newer Technique Versus Temporalis Fascia Tympanoplasty-Retrospective Analysis.

Tympanoplasty is a surgical procedure performed for the closure of tympanic membrane perforation. The present study was conducted to compare the outcomes of a newer technique of cartilage tympanoplasty which the author has named as half disc cartilage tympanoplasty and temporalis fascia tympanoplasty in the following areas-the improvement in hearing, frequency specific improvement in hearing, graft uptake rate. Retrospective study was conducted in the Department of Otorhinolaryngology Rajagiri Hospital from February 2018 to February 2020. 40 patients with moderate central, subtotal and anterior perforation were included in the study. 20 patients (group A) underwent tympanoplasty with temporalis fascia graft and 20 patients (group B) underwent tympanoplasty with temporalis fascia and cymba concha with perichondrium as the support in the anterior half. Both groups were compared for the improvement in hearing and frequency specific improvement in hearing. Follow up period for the study was 6 months. Chi square and t tests were used to assess association and as tests of significance. In our present study hearing improvement following half disc cartilage tympanoplasty was better than temporalis fascia tympanoplasty. In post half disc cartilage tympanoplasty and post temporalis fascia tympanoplasty hearing gain was maximum in low frequencies. Half disc cartilage tympanoplasty is superior to temporalis fascia tympanoplasty in terms of hearing gain. Low frequency hearing shows significant improvement following tympanoplasty.

Defective STAT5 Activation and Aberrant Expression of BCL6 in Naive CD4 T Cells Enhances Follicular Th Cell-like Differentiation in Patients with Granulomatosis with Polyangiitis.

Granulomatosis with polyangiitis (GPA) is a potentially fatal small vessel vasculitis of unknown etiology, characterized by anti-neutrophil cytoplasmic autoantibodies, chronic inflammation, and granulomatous tissue damage. T cell dysregulation, comprising decreased regulatory T cell function and increased circulating effector memory follicular Th cells (TFH), is strongly associated with disease pathogenesis, but the mechanisms driving these observations are unknown. We undertook transcriptomic and functional analysis of naive CD4 T cells from patients with GPA to identify underlying functional defects that could manifest in the pathogenic profiles observed in GPA. Gene expression studies revealed a dysregulation of the IL-2 receptor ß/JAK-STAT signaling pathway and higher expression of BCL6 and BCL6-regulated genes in GPA naive CD4 T cells. IL-2-induced STAT5 activation in GPA naive CD4 T cells was decreased, whereas STAT3 activation by IL-6 and IL-2 was unperturbed. Consistently, BCL6 expression was sustained following T cell activation of GPA naive CD4 T cells and in vitro TFH differentiation of these cells resulted in significant increases in the production TFH-related cytokines IL-21 and IL-6. Thus, naive CD4 T cells are dysregulated in patients with GPA, resulting from an imbalance in signaling equilibrium and transcriptional changes that drives the skewed pathogenic CD4 effector immune response in GPA.

Association of Accuracy, Conclusions, and Reporting Completeness With Acceptance by Radiology Conferences and Journals.

BACKGROUND: Preferential publication of studies with positive findings can lead to overestimation of diagnostic test accuracy (i.e. publication bias). Understanding the contribution of the editorial process to publication bias could inform interventions to optimize the evidence guiding clinical decisions. PURPOSE/HYPOTHESIS: To evaluate whether accuracy estimates, abstract conclusion positivity, and completeness of abstract reporting are associated with acceptance to radiology conferences and journals. STUDY TYPE: Meta-research. POPULATION: Abstracts submitted to radiology conferences (European Society of Gastrointestinal and Abdominal Radiology (ESGAR) and International Society for Magnetic Resonance in Medicine (ISMRM)) from 2008 to 2018 and manuscripts submitted to radiology journals (Radiology, Journal of Magnetic Resonance Imaging [JMRI]) from 2017 to 2018. Primary clinical studies evaluating sensitivity and specificity of a diagnostic imaging test in humans with available editorial decisions were included. ASSESSMENT: Primary variables (Youden's index [YI > 0.8 vs. <0.8], abstract conclusion positivity [positive vs. neutral/negative], number of reported items on the Standards for Reporting of Diagnostic Accuracy Studies [STARD] for Abstract guideline) and confounding variables (prospective vs. retrospective/unreported, sample size, study duration, interobserver agreement assessment, subspecialty, modality) were extracted. STATISTICAL TESTS: Multivariable logistic regression to obtain adjusted odds ratio (OR) as a measure of the association between the primary variables and acceptance by radiology conferences and journals; 95% confidence intervals (CIs) and P-values were obtained; the threshold for statistical significance was P < 0.05. RESULTS: A total of 1000 conference abstracts (500 ESGAR and 500 ISMRM) and 1000 journal manuscripts (505 Radiology and 495 JMRI) were included. Conference abstract acceptance was not significantly associated with YI (adjusted OR = 0.97 for YI > 0.8; CI = 0.70-1.35), conclusion positivity (OR = 1.21 for positive conclusions; CI = 0.75-1.90) or STARD for Abstracts adherence (OR = 0.96 per unit increase in reported items; CI = 0.82-1.18). Manuscripts with positive abstract conclusions were less likely to be accepted by radiology journals (OR = 0.45; CI = 0.24-0.86), while YI (OR = 0.85; CI = 0.56-1.29) and STARD for Abstracts adherence (OR = 1.06; CI = 0.87-1.30) showed no significant association. Positive conclusions were present in 86.7% of submitted conference abstracts and 90.2% of journal manuscripts. DATA CONCLUSION: Diagnostic test accuracy studies with positive findings were not preferentially accepted by the evaluated radiology conferences or journals. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Acceptance and results of therapy with omalizumab in real world Kerala setting: reports from the ARTWORK study, Kerala, South India.

OBJECTIVE: Despite the availability of effective medications, only a minority of asthma patients achieve guideline defined asthma control. Treatment success depends on patient concurrence to the prescribed drug and adherence to treatment. It is therefore crucial to identify the patient preferences as well as attitudes towards asthma medications. Omalizumab is recommended as a preferred option in step 5 of asthma therapy. There have been few studies to address patient perspectives on omalizumab therapy in India. METHODS: This was a retrospective study. Patients with inadequate asthma control were considered for the study. Systematic evaluation was done to identify and correct modifiable factors that can worsen asthma control. Patients with persisting poor asthma control who were deemed suitable to receive this agent were evaluated with their attitudes toward acceptance or refusal and the reasons for opting out were noted. The patients who received omalizumab were followed up to determine the results of treatment and duration of adherence to therapy. RESULTS: Thirty-five patients out of 51 patients chose to avoid this drug. The reasons for opting out included erroneous perception of optimal asthma control, cost of therapy, and concern about adverse effects. Patients took omalizumab for a median duration of 6 months. Improved asthma control and decreased frequency of exacerbation was noted in all patients which persisted during the 6-month follow-up. CONCLUSIONS: The majority of patients needing step 5 therapy opt out of omalizumab. Cost of drug, duration of therapy and erroneous perception of good asthma control account for refusing treatment. Omalizumab affords excellent clinical benefits to patients who receive it, and the benefits extend beyond the duration of therapy.

Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells.

The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.

Early discharge after nonoperative management of intussusception is both safe and cost-effective.

BACKGROUND/PURPOSE: We implemented a quality improvement (QI) initiative to safely reduce post-reduction monitoring for pediatric patients with ileocolic intussusception. We hypothesized that there would be decreased length of stay (LOS) and hospital costs, with no change in intussusception recurrence rates. METHODS: A retrospective cohort study was conducted of pediatric ileocolic intussusception patients who underwent successful enema reduction at a tertiary-care pediatric hospital from January 2015 through June 2020. In September 2017, an intussusception management protocol was implemented, which allowed discharge within four hours of reduction. Pre- and post-QI outcomes were compared for index encounters and any additional encounter beginning within 24 h of discharge. An economic evaluation was performed with hospital costs inflation-adjusted to 2020 United States Dollars ($). Cost differences between groups were assessed using multivariable regression, adjusting for Medicaid and transfer status, P < 0.05 significant. RESULTS: Of 90 patients, 37(41%) were pre-QI and 53(59%) were post-QI. Patients were similar by age, sex, race, insurance status, and transfer status. Pre-QI patients had a median LOS of 23.4 h (IQR: 16.1-34.6) versus 9.3 h (IQR 7.4-14.2) for post-QI patients, P < 0.001. Mean total costs per patient in the pre-QI group were $3,231 (95% CI, $2,442-$4,020) versus $1,861 (95% CI, $1,481-$2,240) in the post-QI group. The mean absolute cost difference was $1,370 less per patient in the post-QI group (95% CI, [-$2,251]-[-$490]). Five patients had an additional encounter within 24 h of discharge [pre-QI: 1 (3%) versus post-QI: 4 (8%), p = 0.7] with four having intussusception recurrence [pre-QI: 1 (3%) versus post-QI: 3 (6%), p = 0.6]. CONCLUSIONS: Implementation of a quality improvement initiative for the treatment of pediatric intussusception reduced hospital length of stay and costs without negatively affecting post-discharge encounters or recurrence rates. Similar protocols can easily be adopted at other institutions. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Retrospective comparative treatment study.

Delayed lung function testing after COVID-19 to detect persistent lung function abnormalities - The DELTA - COVID-19 lung function study.

Background: Coronavirus disease 2019 (COVID-19) has made its presence felt as the worst pandemic witnessed till date in the 21st century. The mortality and morbidity associated with COVID-19 does not end with the acute pneumonia and respiratory failure and consequences extend well into the subsequent weeks to months in a minority. After recovery from severe disease, symptoms, lung function abnormalities and radiological changes are known to persist for varying length of time in a small proportion of patients. Various studies report different incidences of lung function abnormalities post-COVID-19. The present study describes the occurrence, severity, pattern and risk factors for persistent lung function abnormalities post-COVID-19 patients. Aim: The present study was aimed to find out the occurrence of persistent lung function abnormalities in patients hospitalised with COVID-19 at three months of discharge who had normal previous lung function prior to COVID-19. In those with persisting abnormal lung function, the severity, pattern and risk factors for persistent lung function abnormalities were also studied. Methods: The present study was a retrospective study in patients hospitalised with COVID-19 who had radiological evidence of pneumonia at admission. Patients with prior abnormal lung function were excluded from the study. Lung function was analysed with spirometry, 6-min walk test and diffusion capacity between day 85 and 95 of hospital discharge and the occurrence, severity and pattern of impairment was described. Lung function impairment was correlated with baseline characteristics and univariate regression analysis was done to identify risk factors for persisting functional impairment. Results: 39 patients were included in the study. Spirometry at follow up showed a restrictive ventilatory defect in 26 out of 39 patients (64%) and a normal study was noted in 12 patients. One patient had an obstructive ventilatory defect. Diffusion impairment was present in 27 patients and normal transfer factor was seen in 12 patients. The degree of diffusion impairment was mild in 16 patients and moderate in 11 patients. Univariate regression analysis revealed that age, history of systemic hypertension, severe hypoxia at presentation, and extent of lung involvement by CT chest were associated with lung function impairment. Conclusion: Almost two-thirds of patients hospitalised with COVID-19 pneumonia have persistent lung function abnormalities at three months post-discharge. Advanced age, severe disease and medical comorbidities increase the risk of persistent functional abnormalities.

Improving the yield of diagnostic medical thoracoscopy for undiagnosed exudative pleural effusions using a rigid diagnostic algorithm.

Background: Establishing the etiology of exudative pleural effusions in the setting of an unrewarding pleural fluid analysis often requires biopsies from the parietal pleura. However, it may be noted that diagnosis such as pulmonary embolism and connective tissue diseases can result in an exudative pleural effusion where a pleural biopsy can yield nonspecific results. Medical thoracoscopy (MT) is a minimally invasive procedure performed under local anesthesia or moderate sedation with excellent yield and favorable safety profile. We analyzed the diagnostic yield of MT for exudative pleural effusions after employing a rigid diagnostic algorithm. The study was undertaken to ascertain the yield of MT in establishing the diagnosis in diagnosis of exudative pleural effusions, to find out the relative contribution of pleural tuberculosis (TB) as a cause of undiagnosed exudative pleural effusion, to describe the etiology of undiagnosed exudative pleural effusion in patients undergoing MT and to determine the correlation between pleural fluid adenosine deaminase (ADA) levels and TB pleuritis in patients undergoing MT. Methods: This was a retrospective study. Patients with undiagnosed exudative pleural effusion were included in the study. MT was performed with semirigid thoracoscope (Olympus LTF 160) under local anesthesia and conscious sedation. Gross appearance and ADA level of pleural fluid were noted. Pleural biopsy material was subjected to histopathology examination and culture for mycobacteria along with cartridge-based nucleic acid amplification test for TB. The yield of MT for establishing the etiology of pleural effusion and the relative contribution of tuberculous pleuritis as a cause of undiagnosed pleural effusion was ascertained. Correlation of pleural fluid ADA levels was done with a final diagnosis of TB pleuritis in patients undergoing MT. Results: Twenty-five patients with undiagnosed exudative pleural effusion underwent thoracoscopy of which 16 were male and 9 were female. MT was able to establish the diagnosis in all cases, providing a diagnostic yield of 100%. Histopathological examination of biopsy specimens yielded a diagnosis of malignant involvement of pleura in 10 patients and granulomatous pleuritis consistent with TB in 14 patients. Pleural TB contributed to 60% of undiagnosed pleural effusions in the present study. The mean ADA value among those who turned positive was 56.338 and 35.300 among those who turned negative using genexpert, which was found to be statistically significant. A value of 31 IU/L showed a sensitivity of 93.3% and specificity of 99.8% and hence can be taken as a cut off value for the diagnosis of pleural TB based on receiver-operating characteristic analysis. Conclusion: TB contributed to 60% of undiagnosed exudative pleural effusions in the present study. MT had 100% yield in the diagnosis of undiagnosed exudative effusions. Pleural fluid ADA levels may help in differentiating TB versus malignant effusion.

Immunogenomics of Colorectal Cancer Response to Checkpoint Blockade: Analysis of the KEYNOTE 177 Trial and Validation Cohorts.

BACKGROUND & AIMS: Colorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumor mutational burden (TMB). We conducted an integrated study of the cancer tissue and associated tumor microenvironment (TME) from patients treated with pembrolizumab (KEYNOTE 177 clinical trial) or nivolumab to dissect the cellular and molecular determinants of response to anti- programmed cell death 1 (PD1) immunotherapy. METHODS: We selected multiple regions per tumor showing variable T-cell infiltration for a total of 738 regions from 29 patients, divided into discovery and validation cohorts. We performed multiregional whole-exome and RNA sequencing of the tumor cells and integrated these with T-cell receptor sequencing, high-dimensional imaging mass cytometry, detection of programmed death-ligand 1 (PDL1) interaction in situ, multiplexed immunofluorescence, and computational spatial analysis of the TME. RESULTS: In hypermutated CRCs, response to anti-PD1 immunotherapy was not associated with TMB but with high clonality of immunogenic mutations, clonally expanded T cells, low activation of Wnt signaling, deregulation of the interferon gamma pathway, and active immune escape mechanisms. Responsive hypermutated CRCs were also rich in cytotoxic and proliferating PD1+CD8 T cells interacting with PDL1+ antigen-presenting macrophages. CONCLUSIONS: Our study clarified the limits of TMB as a predictor of response of CRC to anti-PD1 immunotherapy. It identified a population of antigen-presenting macrophages interacting with CD8 T cells that consistently segregate with response. We therefore concluded that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages to promote cytotoxic antitumor activity.

Incidence of cardiotoxicity and validation of the Heart Failure Association-International Cardio-Oncology Society risk stratification tool in patients treated with trastuzumab for HER2-positive early breast cancer.

PURPOSE: Trastuzumab improves survival in patients with HER2+ early breast cancer. However, cardiotoxicity remains a concern, particularly in the curative setting, and there are limited data on its incidence outside of clinical trials. We retrospectively evaluated the cardiotoxicity rates [left ventricular ejection fraction (LVEF) decline, congestive heart failure (CHF), cardiac death or trastuzumab discontinuation] and assessed the performance of a proposed model to predict cardiotoxicity in routine clinical practice. METHODS: Patients receiving curative trastuzumab between 2011 and 2018 were identified. Demographics, treatments, assessments and toxicities were recorded. Fisher's exact test, Chi-squared and logistic regression were used. RESULTS: 931 patients were included in the analysis. Median age was 54 years (range 24-83) and Charlson comorbidity index 0 (0-6), with 195 patients (20.9%) aged 65 or older. 228 (24.5%) were smokers. Anthracyclines were given in 608 (65.3%). Median number of trastuzumab doses was 18 (1-18). The HFA-ICOS cardiovascular risk was low in 401 patients (43.1%), medium in 454 (48.8%), high in 70 (7.5%) and very high in 6 (0.6%). Overall, 155 (16.6%) patients experienced cardiotoxicity: LVEF decline ≥ 10% in 141 (15.1%), falling below 50% in 55 (5.9%), CHF NYHA class II in 42 (4.5%) and class III-IV in 5 (0.5%) and discontinuation due to cardiac reasons in 35 (3.8%). No deaths were observed. Cardiotoxicity rates increased with HFA-ICOS score (14.0% low, 16.7% medium, 30.3% high/very high; p = 0.002). CONCLUSIONS: Cardiotoxicity was relatively common (16.6%), but symptomatic heart failure on trastuzumab was rare in our cohort. The HFA-ICOS score identifies patients at high risk of cardiotoxicity.