Post-traumatic stress trajectories of children and their parents over the year following intensive care discharge: A secondary analysis.

BACKGROUND: New research in the field of psychological trauma has emphasized (a) the heterogeneity of psychological reactions after traumatic events and (b) the existence of distinct symptom trajectories. AIMS: In this study, existing data on post-traumatic stress disorder (PTSD) symptoms in 66 parent-child dyads were re-examined in the light of this literature in order to establish whether a similar pattern of symptom trajectories also applies to this population. STUDY DESIGN: A prospective observational cohort study. Participants' PTSD symptoms were assessed 3 and 12 months after discharge from a paediatric intensive care unit (PICU), using a short form of the Davidson Trauma Scale with parents and the Child Revised Impact of Events Scale with children aged 7-17 years. RESULTS: Results confirmed that the majority of children (58%) and parents (46%) exhibited a 'Resilient' PTSD trajectory over the year, in the sense that their scores remained in the non-clinical range at both timepoints. Children displaying a 'Resilient' trajectory were more likely to have a parent who also displayed a 'Resilient' trajectory (p = .018). However, there was also evidence of a 'Recovery' trajectory in a significant minority in this sample and over 1 in 4 children and parents exhibited a 'Chronic' or 'Delayed' symptom trajectory. CONCLUSIONS: Although average PTSD scores reduced over time in this sample and 'Resilient' trajectories were common, a significant proportion of children and parents exhibited 'Chronic' and 'Delayed' symptom trajectories. RELEVANCE TO CLINICAL PRACTICE: These results suggest that, although the majority do well, a significant number of children and family members may develop chronic or delayed symptoms of PTSD in the year following PICU discharge. The monitoring of individual family members' symptoms beyond 3 months post-discharge may help to determine those who might most benefit from further support.

The impact of restrictions to visiting in paediatric intensive care during the COVID-19 pandemic.

BACKGROUND: Restrictions to hospital visiting were mandated during the COVID-19 pandemic, with variability in the degree of restriction imposed. At times, paediatric intensive care units (ICU) restricted visiting to one parent/carer. Views of parents/carers and ICU staff about changes in the visiting policy are not well understood. STUDY DESIGN: This is a Service evaluation involving questionnaire survey incorporating rating scales and free-text comments. Inner-city specialist children's hospital. Parents/carers of children on ICU between December 2020-March 2021 and staff who were working on ICU during May-June 2021. Parents and staff on ICU were invited to complete a questionnaire focusing on their experience of being or working on ICU. Quantitative data were analysed descriptively and free-text comments were thematically analysed. RESULTS: Completed questionnaires were received from 81/103 (79%) parents/carers and 217/550 (39%) staff. The majority of parents (n = 60;77%) and staff (n = 191;89%) understood the need for the one-parent visiting policy but acknowledged it was a source of considerable stress. More staff than parents agreed it was appropriate other relatives/friends visiting was not permitted (Z = 3.715;p < .001). There was no association between parents' satisfaction with their child's care and views about the visiting policy. However, staff were more likely to report an impact on their ability to deliver family centred care if they disagreed with the policy. CONCLUSION: The COVID-19 visiting policy had a clear impact on parents and staff. In the event of any future threat to open-access visiting to children in hospital, the potentially damaging effect on children, parents, and staff must be considered. RELEVANCE TO CLINICAL PRACTICE: Visiting policies need to take account of parents being partners in their child's care, rather than purely visitors to the unit where their child is being cared for. Visiting for two carers should always be facilitated, including during a crisis such as a pandemic.

Metagenomics and chemotherapy-induced nausea: A roadmap for future research.

Uncontrolled chemotherapy-induced nausea and vomiting can reduce patients' quality of life and may result in premature discontinuation of chemotherapy. Although nausea and vomiting are commonly grouped together, research has shown that antiemetics are clinically effective against chemotherapy-induced vomiting (CIV) but less so against chemotherapy-induced nausea (CIN). Nausea remains a problem for up to 68% of patients who are prescribed guideline-consistent antiemetics. Despite the high prevalence of CIN, relatively little is known regarding its etiology independent of CIV. This review summarizes a metagenomics approach to the study and treatment of CIN with the goal of encouraging future research. Metagenomics focuses on genetic risk factors and encompasses both human (ie, host) and gut microbial genetic variation. Little work to date has focused on metagenomics as a putative biological mechanism of CIN. Metagenomics has the potential to be a powerful tool in advancing scientific understanding of CIN by identifying new biological pathways and intervention targets. The investigation of metagenomics in the context of well-established demographic, clinical, and patient-reported risk factors may help to identify patients at risk and facilitate the prevention and management of CIN.

Efficacy and Safety of IV Sildenafil in the Treatment of Newborn Infants with, or at Risk of, Persistent Pulmonary Hypertension of the Newborn (PPHN): A Multicenter, Randomized, Placebo-Controlled Trial.

OBJECTIVE: To investigate the efficacy and safety of sildenafil added to inhaled nitric oxide (iNO) for newborn infants with persistent pulmonary hypertension of newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN. STUDY DESIGN: Part A of a multinational, randomized, double-blind, placebo-controlled trial. Infants ≤96 hours' old, >34 weeks of gestation, receiving iNO (10-20 ppm on ≥50% FiO2) for PPHN or HRF at risk of PPHN, and oxygen index >15 to <60, were randomized (1:1) to intravenous (IV) sildenafil (loading: 0.1 mg/kg, over 30 minutes; maintenance: 0.03 mg/kg/h) or placebo, for up to 14 days. Coprimary end points were treatment failure rate (day 14/discharge) and time on iNO without treatment failure. Secondary end points included time on ventilation and oxygenation measures. RESULTS: Of 87 infants screened, 29 were randomized to IV sildenafil and 30 to placebo; 13 discontinued treatment (sildenafil, n = 6; placebo: n = 7), including 3 deaths (sildenafil: n = 2; placebo: n = 1). Treatment failure rates did not differ with sildenafil (27.6%) vs placebo (20.0%; P = .4935). Mean time on iNO was not different with sildenafil (4.1 days) vs placebo (4.1 days; P = .9850). No differences were noted in secondary end points. Most common adverse events (AEs) with sildenafil (≥10% infants) were hypotension (n = 8/29), hypokalemia (n = 7/29), anemia, drug withdrawal syndrome (n = 4/29, each), and bradycardia (n = 3/29). One serious AE (hypotension) was considered treatment-related. CONCLUSIONS: IV sildenafil added to iNO was not superior to placebo in infants with PPHN or HRF at risk of PPHN. A review of AEs did not identify any pattern of events indicative of a safety concern with IV sildenafil. Infants will have developmental follow-up (Part B). TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01720524.

A Customized At-Home Stool Collection Protocol for Use in Microbiome Studies Conducted in Cancer Patient Populations.

Fecal specimen collection in the clinical setting is often unfeasible for large population studies, especially because cancer patients on immunotherapy often experience constipation. A method for constructing and using an at-home stool collection kit designed for epidemiological studies in cancer patients is presented. Participation and compliance rates of the collection kit among late-stage cancer patients from an ongoing, longitudinal study are also discussed. The kit includes three different media on which samples are introduced. Using one stool sample, patients collect specimens by smearing stool onto a fecal occult blood test (FOBT) card, containing three slides for collection. Additional specimens from the same stool sample are added to one tube containing 8 mL of RNAlater preservative and one tube containing 8 mL of 95% ethanol. Stool specimens are stored at room temperature and returned to researchers within 3 days of collection. The purpose of this kit is to yield stool specimens on a variety of media that can be preserved for extended periods of time at room temperature and are compatible with multi-omics approaches for specimen analysis. According to leading microbiome researchers and published literature, each collection method is considered optimal for use in large epidemiological studies. Moreover, the kit is comprised of various components that make stool collection easy, so as not to burden the patient and hence maximize overall compliance. Use of this kit in a study of late-stage lung cancer patients had a participation rate of 83% and baseline compliance rate of 58%.

Self-Reported Fatigue in Children Following Intensive Care Treatment.

OBJECTIVES: Adults report high levels of fatigue after intensive care, but little is known about pediatric survivors. This study aimed to explore rates of self-reported fatigue in children after critical illness. DESIGN: Prospective cohort study. SETTING: Tertiary children's hospital. PATIENTS: Ninety-seven children aged 7-17 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children completed the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale 3 months after discharge from PICU. Comparisons with normative data (n = 209) showed that PICU survivors reported similar mean (SD) total fatigue scores to their healthy peers (79.6 [16.3] vs 81.8 [12.5]; p = 0.239), but greater cognitive fatigue (77.4 [21.9] vs 82.4 [16.4]; p = 0.048). Also children who had sustained a traumatic brain injury reported "less" sleep/rest fatigue (84.6 [15.0] vs 76.8 [16.3]; p = 0.006). Baseline indices of severity of illness were not associated with fatigue. CONCLUSIONS: The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale appears to be a promising tool for use in outcomes research with PICU survivors. These results highlight the need to bear in mind the heterogeneity of PICU patients and the multidimensional nature of fatigue symptoms.

Feasibility and Acceptability of Methods to Collect Follow-Up Information From Parents 12 Months After Their Child's Emergency Admission to Pediatric Intensive Care.

OBJECTIVES: To evaluate the feasibility and acceptability of different methods of collecting follow-up data from parents 12 months after their child's emergency admission to a PICU. DESIGN: Mixed-methods explanatory sequential design. SETTING: One regional PICU transport service and three PICUs in England. PATIENTS: Children undergoing emergency transport to PICU recruited to an ongoing biomarker study whose parents consented to be contacted for follow-up 12 months after PICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Parents or guardians who consented were asked to complete three questionnaires about their child's functional status, quality of life, and behavior 12 months after PICU admission. Parents were given a choice about method of questionnaire completion: postal, online, or telephone interview and also asked for telephone feedback about the process and the reasons for their choice. Of 486 parents who consented to be contacted at 12 months, 232 were successfully contacted. Consent to receive questionnaires was obtained in 218 of 232 (94%). Of the 218 parents, 102 (47%) chose to complete questionnaires online (with 77% completion rate), 91 (42%) chose to complete postal questionnaires (48% completion rate), and 25 (11%) chose to complete questionnaires by telephone interview (44% completion rate). CONCLUSIONS: Parents expressed different preferences for follow-up questionnaire completion. Response rates varied by completion method. Understanding and catering for parental preferences is an important factor in maximizing response rates for follow-up studies in intensive care.

Impact of viral presence in tumor on gene expression in non-small cell lung cancer.

BACKGROUND: In our recent study, most non-small-lung cancer (NSCLC) tumor specimens harbored viral DNA but it was absent in non-neoplastic lung. However, their targets and roles in the tumor cells remain poorly understood. We analyzed gene expression microarrays to identify genes and pathways differentially altered between virus-infected and uninfected NSCLC tumors. METHODS: Gene expression microarrays of 30 primary and 9 metastatic NSCLC patients were preprocessed through a series of quality control analyses. Linear Models for Microarray Analysis and Gene Set Enrichment Analysis were used to assess differential expression. RESULTS: Various genes and gene sets had significantly altered expressions between virus-infected and uninfected NSCLC tumors. Notably, 22 genes on the viral carcinogenesis pathway were significantly overexpressed in virus-infected primary tumors, along with three oncogenic gene sets. A total of 12 genes, as well as seven oncogenic and 133 immunologic gene sets, were differentially altered in squamous cell carcinomas, depending on the virus. In adenocarcinoma, 14 differentially expressed genes (DEGs) were identified, but no oncogenic and immunogenic gene sets were significantly altered. In bronchioloalveolar carcinoma, several genes were highly overexpressed in virus-infected specimens, but not statistically significant. Only five of 69 DEGs (7.2%) from metastatic tumor analysis overlapped with 1527 DEGs from the primary tumor analysis, indicating differences in host cellular targets and the viral impact between primary and metastatic NSCLC. CONCLUSIONS: The differentially expressed genes and gene sets were distinctive among infected viral types, histological subtypes, and metastatic disease status of NSCLC. These results support the hypothesis that tumor viruses play a role in NSCLC by regulating host genes in tumor cells during NSCLC differentiation and progression.

Stress hormones and posttraumatic stress symptoms following paediatric critical illness: an exploratory study.

In this exploratory case-control study, we investigated basal cortisol regulation in 5-16-year-old children, 3-6 months following PICU (paediatric intensive care) admission. This was nested within a study of child psychological and cognitive function; 47 children were assessed alongside 56 healthy controls. Saliva samples were collected three times per day (immediately after waking, waking +30 min, and waking +12 h) over two consecutive weekdays. In addition, data on posttraumatic stress symptoms were ascertained from 33 PICU admitted children using the Impact of Events Scale-8 (IES-8). Primary analysis revealed no significant differences in basal cortisol concentrations between PICU discharged children and healthy controls (p > 0.05). Secondary analysis in the PICU group identified a significant positive association between posttraumatic stress symptoms and evening (waking +12 h) cortisol concentrations (p = 0.004). However, when subject to multivariate analysis, evening cortisol was a modest independent predictor of IES-8 scores, relative to the presence of septic illness and poor pre-morbid health. We conclude that paediatric critical illness does not appear to result in marked perturbations to basal cortisol at 3-6 month following discharge. There was evidence of a link between evening cortisol and symptoms of PTSD, but this was not a robust effect and requires further elucidation.

Bosentan as Adjunctive Therapy for Persistent Pulmonary Hypertension of the Newborn: Results of the Randomized Multicenter Placebo-Controlled Exploratory Trial.

OBJECTIVE: To evaluate the efficacy, safety, and pharmacokinetics of the endothelin receptor antagonist bosentan as adjunctive therapy for neonates with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: This was a phase 3, multicenter, randomized, placebo-controlled exploratory trial (FUTURE-4). Eligible patients were >34 weeks gestation, <7 days old, receiving inhaled nitric oxide (iNO) treatment (≥4 hours), and had persistent respiratory failure (oxygenation index [OI] ≥12). After 2:1 randomization, bosentan 2 mg/kg or placebo was given by nasogastric tube twice daily for ≥48 hours and up to 1 day after iNO weaning. RESULTS: Twenty-one neonates received a study drug (13 bosentan, 8 placebo). Compared with the placebo group, the group treated with bosentan had a higher median baseline OI and greater need for vasoactive agents. One treatment failure (need for extracorporeal membrane oxygenation) occurred in the group treated with bosentan. The time to weaning from iNO or mechanical ventilation was not different between the groups. Bosentan was well tolerated and did not adversely affect systemic blood pressure or hepatic transaminase levels. Anemia and edema were more frequent in patients receiving bosentan. Blood concentrations of bosentan were low and variable on day 1, and achieved steady state on day 5. CONCLUSION: Adjunctive bosentan was well tolerated, but did not improve oxygenation or other outcomes in our patients with PPHN. This effect may be related to delayed absorption of bosentan on treatment initiation in critically ill neonates or to more severe illness of the neonates who received bosentan. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01389856.

Persistence of Neuropsychological Deficits Following Pediatric Critical Illness.

OBJECTIVE: To study 12-month persistence of neuropsychological deficits in PICU survivors. DESIGN: Prospective follow-up study. SETTING: Two PICUs. PARTICIPANTS: Children 5-16 years old with neuropsychological deficits 3-6 months following PICU care for meningoencephalitis, sepsis, and other critical illnesses (excluding other primary neurological disorders). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Neuropsychological function was assessed using the Cambridge Neuropsychological Test Automated Battery, the Children's Memory Scale, and the Wechsler Abbreviated Scale of Intelligence or Wide Range Intelligence Test. Forty-seven of 88 PICU admitted children (53%) were identified as neuropsychologically impaired 3-6 months after discharge; of these, 23 provided 12-month follow-up data. In spite of significant improvements in measures of memory, there was little change in intelligence quotient and visual attention over the study period, and children's educational progress remained below expectation. CONCLUSIONS: We found persistently reduced neuropsychological function following PICU admission in the critical illnesses under study.

Mental and physical well-being following admission to pediatric intensive care.

OBJECTIVE: To assess mental and physical well-being in school-aged children following admission to pediatric intensive care and to examine risk factors for worse outcome. DESIGN: A prospective cohort study. SETTING: Two PICUs. SUBJECTS: A consecutive sample of 88 patients 5-16 years old (median age, 10.00 yr; interquartile range, 6.00-13.00 yr) admitted to PICU from 2007 to 2010 with septic illness, meningoencephalitis, or other critical illnesses were assessed a median of 5 months following discharge and outcomes compared with 100 healthy controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Parents completed questionnaires documenting child mental and physical well-being, including the Strengths and Difficulties Questionnaires, Chalder Fatigue Scale, and Child Sleep Habits Questionnaire. Children over 8 years completed the Impact of Event Scale -8. The children admitted to PICU scored worse on all measures in comparison with the healthy controls, with 20% scoring at risk for psychiatric disorder, 34% with high levels of post-traumatic stress symptoms, 38% at risk for fatigue disorder, and 80% scoring at risk for sleep disturbance. In the PICU group, multivariable regression analyses identified septic illness as an independent predictor of post-traumatic stress symptoms and family status, past child health problems, and PICU length of stay as predictors of reduced general mental well-being. CONCLUSIONS: Our findings indicate that a significant minority of school-aged children admitted to PICU are at risk for reduced mental and physical well-being in the short term. Symptoms of poor mental well-being were linked to both vulnerability factors and critical illness factors.

Modifier 22 for acetabular fractures in morbidly obese patients: does it affect reimbursement?

BACKGROUND: Modifier 22 in the American Medical Association's Current Procedural Terminology (CPT®) book is a billing code for professional fees used to reflect an increased amount of skill, time, and work required to complete a procedure. There is little disagreement that using this code in the setting of surgery for acetabulum fractures in the obese patient is appropriate; however, to our knowledge, the degree to which payers value this additional level of complexity has not been determined. QUESTIONS/PURPOSES: We asked whether (1) the use of Modifier 22 increased reimbursements in morbidly obese patients and (2) there was any difference between private insurance and governmental payer sources in treatment of Modifier 22. METHODS: Over a 4-year period, we requested immediate adjudication with payers when using Modifier 22 for morbidly obese patients with acetabular fractures. We provided payers with evidence of the increased time and effort required in treating this population. Reimbursements were calculated for morbidly obese and nonmorbidly obese patients. Of the 346 patients we reviewed, 57 had additional CPT® codes or modifiers appended to their charges and were excluded, leaving 289 patients. Thirty (10%) were morbidly obese and were billed with Modifier 22. Fifty-three (18%) were insured by our largest private insurer and 69 (24%) by governmental programs (Medicare/Medicaid). Eight privately insured patients (15%) and seven governmentally insured patients (10%) were morbidly obese and were billed with Modifier 22. For our primary question, we compared reimbursement rates between patients with and without Modifier 22 for obesity within the 289 patients. We then performed the same comparison for the 53 privately insured patients and the 69 governmentally insured patients. RESULTS: Overall, there was no change in mean reimbursement when using Modifier 22 in morbidly obese patients, compared to nonmorbidly obese patients (USD 2126 versus USD 2149, p < 0.94). There was also no difference in mean reimbursements with Modifier 22 in either the privately insured patients (USD 3445 versus USD 2929, p = 0.16) or the governmentally insured patients (USD 1367 versus USD 1224, p=0.83). CONCLUSIONS: Despite educating payers on the increased complexity and time needed to deal with morbidly obese patients with acetabular fractures, we have not seen an increased reimbursement in this challenging patient population. This could be a disincentive for many centers to treat these challenging injuries. Further efforts are needed to convince government payer sources to increase compensation in these situations. LEVEL OF EVIDENCE: Level IV, economic and decision analyses. See Instructions for Authors for a complete description of levels of evidence.

Neuropsychologic function three to six months following admission to the PICU with meningoencephalitis, sepsis, and other disorders: a prospective study of school-aged children.

OBJECTIVE: To assess short-term neuropsychological function and academic performance in school children following admission to intensive care and to explore the role of critical neurologic and systemic infection. DESIGN: A prospective observational case-control study. SETTING: Two PICUs. SUBJECTS: A consecutive sample of 88 children aged 5-16 years (median age=10.00, interquartile range=6.00-13.00) who were admitted to intensive care between 2007 and 2010 with meningoencephalitis, septic illness, or other critical illnesses. They were assessed 3 to 6 months following discharge, and their performance was compared with that of 100 healthy controls. Patients were without prior neurologic or neurodevelopmental disorder. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data encompassing demographic and critical illness details were obtained, and children were assessed using tests of intellectual function, memory, and attention. Questionnaires addressing academic performance were returned by teachers. After adjusting for covariates, the children admitted to PICUs significantly underperformed on neuropsychological measures in comparison to healthy controls (p<0.02). Teachers deemed more children admitted to PICUs than controls as performing educationally worse and having problems with school work (ps=0.001), as well as performing below average on aspects of executive function and attention (ps<0.04). Analysis of the effect of illness type on outcome revealed that aspects of neuropsychological function, such as memory function, and teacher-rated academic performance were most reduced in children with meningoencephalitis and septic illness. In the PICU group, multivariable linear regression revealed that worse performance on a composite score of neuropsychologic impairment was more prevalent when children were younger, from a lower social class, and had experienced seizures during their admission (ps<0.02). CONCLUSIONS: Admission to intensive care is followed by deficits in neuropsychologic performance and educational difficulties, with more severe difficulties noted following meningoencephalitis and septic illness. These results highlight the importance of future studies on cognition and educational outcome incorporating type of illness as a moderating factor.

Children's self-reported quality of life after intensive care treatment.

OBJECTIVES: A number of studies have reported on parental/clinician reports of children's quality of life after intensive care treatment. The aim of this study was to establish children's own views of their outcome. [corrected]. DESIGN: Prospective cohort study. [corrected]. SETTING: Twenty-one bed PICU in a tertiary Children's Hospital. PATIENTS: Ninety-seven children aged over 7 yr, with no preexisting learning difficulties, consecutively admitted to PICU over an 18 month period INTERVENTIONS: Patients completed the Pediatric Quality of Life Inventory and a post-traumatic stress screener, at 3 months and again at 1 year (n = 72) after discharge from PICU. MEASUREMENTS AND MAIN RESULTS: At 3 months post-discharge, the mean total Pediatric Quality of Life Inventory score reported by the PICU group was lower than that reported in the literature for a non-clinical community sample (PICU mean = 79.1 vs community mean = 83.9, p = 0.003), but by 1 year, they were comparable (82.2, p = 0.388). The mean physical functioning subscale score remained lower (PICU mean=81.6 vs. community mean=88.5, p = 0.01), but improved significantly from 73.4 at 3 months (p = 0.001).Sub-group analyses revealed that the elective group reported higher emotional functioning than the community sample (91.0, p=0.005 at 3 months and 88.2, p = 0.038 at 1 year vs community mean=78.5), and made significant gains in social functioning between timepoints (79.1 to 91.4, p = 0.015).Finally, although total PedsQL scores at 1 year were not associated with measures of severity of illness during admission, they were significantly negatively associated with concurrent post-traumatic stress symptom scores (r = -0.40, p = 0.001). CONCLUSIONS: The self-report version of the Pediatric Quality of Life Inventory proved to be a feasible and sensitive tool for assessing health related quality of life in this group of PICU survivors.

Chemoradiation-induced pneumonitis in patients with unresectable stage III non-small cell lung cancer: A systematic literature review and meta-analysis.

INTRODUCTION: High-grade pneumonitis is a severe and potentially life-threatening adverse event associated with concurrent chemoradiation (cCRT) in patients with non-small cell lung cancer (NSCLC). The aim of this study was to summarize and quantify the incidence of severe (grade 3-5) cCRT-induced pneumonitis in unresectable stage III NSCLC patients. METHODS: A systematic literature review and meta-analysis were performed in accordance with PRISMA guidelines. Published literature was searched for randomized controlled trials (RCTs), observational studies, and non-randomized trials from 2014 to April 2020. The primary outcome of interest was incidence of grade 3-5 pneumonitis. RESULTS: Included were 17 studies for the review and 11 for the meta-analysis (1,788 participants); all studies examined radiation-related pneumonitis (RP). The pooled incidence of cCRT-induced grade 3-5 RP in unresectable stage III NSCLC patients was estimated to be 3.62% [95% confidence interval (CI): 1.65-6.21] in RCTs, 5.98% [95% CI: 2.26-12.91] in observational studies, and 7.85% [95% CI: 4.08-13.10] in observational studies using platinum-based doublet chemotherapies. CONCLUSION: These results suggest the incidence of severe and fatal RP in patients with unresectable stage III NSCLC treated with cCRT ranges from 3.62% to 7.85%, with incidence varying by study design and chemotherapy regimen. Estimates of RP incidence were higher in the real-world setting compared to RCTs. These results can be used to contextualize the baseline risk of cCRT-induced pneumonitis in unresectable stage III NSCLC to better understand the adverse event of pneumonitis associated with novel immunotherapy treatments indicated for concomitant use with this modality.

Interaction of bacterial genera associated with therapeutic response to immune checkpoint PD-1 blockade in a United States cohort.

BACKGROUND: Recent studies show that human gut microbial composition can determine whether a patient is a responder or non-responder to immunotherapy but have not identified a common microbial signal shared by responding patients. The functional relationship between immunity, intestinal microbiota, and NSCLC response to immune checkpoint inhibitor/inhibition (ICI) in an American cohort remains unexplored. METHODS: RNAlater-preserved fecal samples were collected from 65 pre-treatment (baseline) and post-treatment stage III/IV NSCLC patients undergoing ICI therapy, categorized as responders or non-responders according to RECIST criteria. Pooled and individual responder and non-responder microbiota were transplanted into a gnotobiotic mouse model of lung cancer and treated with ICIs. 16S rDNA and RNA sequencing was performed on patient fecal samples, 16S rDNA sequencing on mouse fecal samples, and flow cytometric analysis on mouse tumor tissue. RESULTS: Responder patients have both a different microbial community structure than non-responders (P = 0.004) and a different bacterial transcriptome (PC2 = 0.03) at baseline. Taxa significantly enriched in responders include amplicon sequence variants (ASVs) belonging to the genera Ruminococcus, Akkermansia, and Faecalibacterium. Pooled and individual responder microbiota transplantation into gnotobiotic mice decreased tumor growth compared to non-responder colonized mice following ICI (P = 0.023, P = 0.019, P = 0.008, respectively). Responder tumors showed an increased anti-tumor cellular phenotype following ICI treatment. Responder mice are enriched with ASVs belonging to the genera Bacteroides, Blautia, Akkermansia, and Faecalibacterium. Overlapping taxa mapping between human and mouse cohorts correlated with tumor size and weight revealed a network highlighting responder-associated ASVs belonging to the genera Colidextribacter, Frisingicoccus, Marvinbryantia, and Blautia which have not yet been reported. CONCLUSIONS: The role of isolate-specific function and bacterial gene expression in gut microbial-driven responsiveness to ICI has been underappreciated. This work supports further investigation using isolate-driven models to characterize the mechanisms underlying this phenomenon.

Procedures for preventing juvenile violence in Switzerland: the Zurich model.

The Swiss legal system places strong emphasis on risk assessment and treatment of potentially violent offenders. Especially after the 2001 Zug massacre, there is close cooperation between the judicial and mental health systems to prevent violence through early detection and intervention. A case study of a risk management program for a dangerous seventeen-year-old delinquent youth illustrates this approach.

Preoperative nutrition-enhanced recovery after surgery protocol for thoracic neoplasms.

OBJECTIVES: Because patients' preoperative nutritional status influences the outcomes, we have used a preoperative nutrition program for surgical patients for a 2-year period and compared the results with those from a cohort treated in the previous 2 years. METHODS: We retrospectively reviewed curative thoracic neoplasm resections from July 15, 2016, to July 15, 2018, in patients who had received a preoperative nutritional-enhanced recovery after surgery (N-ERAS) protocol. The protocol consisted of 5 days of an oral immunonutrition drink 3 times daily, daily receipt of probiotics, and a carbohydrate-loading drink the night before surgery. The historical control cohort (standard group) included those patients who had undergone surgery by the same surgeon during the previous 24 months. We excluded patients who had undergone esophageal, diagnostic, benign, emergency, or palliative procedures. Nonparametric and parametric statistical tests were used to analyze the data. RESULTS: The data from 462 patients were analyzed: 229 N-ERAS patients and 233 standard patients. No significant demographic or caseload differences were found between the 2 groups. The major significant outcome differences included fewer postoperative complications (30 [13.1%] in the N-ERAS group vs 60 [25.8%] in the standard group; P < .001) and shorter hospital stays (3.8 ± 1.9 days for the N-ERAS group vs 4.4 ± 2.6 days for the standard group; P = .001). Use of the N-ERAS protocol resulted in a 16% reduction ($2198; P < .001) in the mean direct hospital costs/patient. Consequently, for the N-ERAS cohort, the hospital was likely saved $503,342 during the 2-year period for the 229 patients just by using the N-ERAS protocol. CONCLUSIONS: Thoracic surgeons should consider using the nontoxic, patient-compliant N-ERAS protocol for their patients, with an expectation of improved clinical results at lower hospital costs-an important consideration when exploring methods to decrease costs because hospitals are increasingly being paid by a negotiated prospective bundled payment reimbursement model.

Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension.

OBJECTIVE: To evaluate the safety of intravenous (IV) sildenafil, an inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase, in treating near-term and term newborns with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: This was an open-label, dose-escalation trial in newborns with PPHN and an oxygenation index (OI) > 15. Sildenafil was delivered by continuous IV infusion for at least 48 hours and up to 7 days. RESULTS: Five centers enrolled a total of 36 neonates with PPHN at a mean of 34 +/- 17 hours of age; 29 of these neonates were already receiving inhaled nitric oxide (iNO). A significant improvement in OI (28.7 to 19.3; P = .0002) was observed after 4 hours of sildenafil infusion in the higher dose cohorts. Thirty-five neonates survived; 1 neonate required extracorporeal membrane oxygenation (ECMO) support. In 4 neonates, sildenafil was stopped due to adverse events. Seven neonates were enrolled before developing the need for iNO. In these neonates, OI improved significantly by 4 hours after initiation of sildenafil infusion (24.6 to 14.7; P = .009); 6 neonates completed treatment without the need for iNO or ECMO. CONCLUSIONS: IV sildenafil was well tolerated, and acute and sustained improvements in oxygenation were noted in those neonates who received the higher infusion doses.