Maintenance durvalumab after first-line chemotherapy in patients with HER2-negative advanced oesophago-gastric adenocarcinoma: results from the randomised PLATFORM study.

BACKGROUND: PLAnning Treatment For Oesophago-gastric Cancer: a Randomised Maintenance Therapy Trial (PLATFORM) is an adaptive phase II study assessing the role of maintenance therapies in advanced oesophago-gastric (OG) adenocarcinoma. We evaluated the role of the anti-programmed death-ligand 1 (PD-L1) inhibitor durvalumab in these patients. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2-negative locally advanced or metastatic OG adenocarcinoma with disease control or response to 18 weeks of platinum-based first-line chemotherapy were randomised to active surveillance or maintenance durvalumab. The primary endpoint was progression-free survival (PFS). Safety was assessed in all patients who had commenced surveillance visits or received at least one dose of durvalumab. Exploratory survival analyses according to PD-L1 Combined Positive Score (CPS) and immune (biomarker-positive) or angiogenesis dominant (biomarker-negative) tumour microenvironment (TME) phenotypes were conducted. RESULTS: Between March 2015 and April 2020, 205 patients were randomised to surveillance (n = 100) and durvalumab (n = 105). No significant differences were seen in PFS [hazard ratio (HR) 0.84, P = 0.13] and overall survival (OS; HR 0.98, P = 0.45) between surveillance and durvalumab. Five patients randomised to durvalumab demonstrated incremental radiological responses compared with none with surveillance. Treatment-related adverse events occurred in 77 (76.2%) durvalumab-assigned patients. A favourable effect in OS with durvalumab over surveillance in CPS ≥5 and immune biomarker-positive patients was observed compared with CPS <5 and biomarker-negative subgroups, respectively: CPS ≥5 versus <5: HR 0.63, 95% confidence interval (CI) 0.32-1.22 versus HR 0.93, 95% CI 0.44-1.96; biomarker-positive versus negative: HR 0.60, 95% CI 0.29-1.23 versus HR 0.84, 95% CI 0.42-1.65. CONCLUSION: Maintenance durvalumab does not improve PFS in patients with OG adenocarcinoma who respond to first-line chemotherapy but induced incremental radiological responses in a subset of patients. TME characterisation could refine patient selection for anti-PD-L1 therapy above PD-L1 CPS alone.

The Brominated Flame Retardant Hexabromocyclododecane Causes Systemic Changes in Polyunsaturated Fatty Acid Incorporation in Mouse Lipids.

Brominated flame retardants are used in many household products to reduce flammability, but often leach into the surrounding environment over time. Hexabromocyclododecane (HBCD) is one brominated flame retardant detected in human blood across the world. HBCD exposure can result in neurological problems and altered lipid metabolism, but to date the two remain unlinked. As lipids constitute ∼50% of brain dry weight, lipid metabolism plays a critical role in neuronal function and homeostasis. To determine the effect of HBCD exposure on brain lipid metabolism, young adult male C57BL/6 mice were exposed to 1 mg/kg HBCD every 3 days for 28 days. Major lipid classes were found to change across brain regions, including the membrane glycerolipids phosphatidylcholine and phosphatidylethanolamine, and sphingolipids such as hexosylceramide. In addition, saturated, monounsaturated, and polyunsaturated fatty acids were enriched within brain lipid species. To understand the source of the brain lipidomic alterations, the blood and liver lipidomes and the cecal microbiome were evaluated. The liver and blood demonstrated changes amongst multiple lipid classes, including triacylglycerol suppression, as well as altered esterified fatty acid content. Significant alterations were also detected in the cecal microbiome, with decreases in the Firmicutes to Bacteriodetes ratio, changes in beta diversity, and pathway alterations associated with metabolic pathways and amino acid biosynthesis. These data demonstrate that HBCD can induce lipidomic alterations across brain regions and organs and supports a potential role of the microbiome in these alterations.

Characterizing hepatitis B virus infection in children in the Democratic Republic of Congo to inform elimination efforts.

Objective: Despite global reductions in hepatitis B virus (HBV) prevalence, an estimated 6.2 million children are infected, two-thirds of whom live in the WHO Africa region. We sought to characterize childhood HBV to inform elimination efforts in the Democratic Republic of Congo (DRC), one of the largest and most populous African countries. Methods: Using the most recent (2013-14) nationally representative Demographic and Health Survey in the DRC, we analyzed HBV surface antigen (HBsAg) on dried blood spots and associated survey data from children aged 6-59 months. We estimated HBsAg-positivity prevalence nationally, regionally, and by potential correlates of infection. We evaluated spatial variation in HBsAg-positivity prevalence, overall and by age, sex, and vaccination status. Findings: Using data from 5,679 children, we found national HBsAg-positivity prevalence was 1.3% (95% CI: 0.9%-1.7%), but ranged from 0.0% in DRC's capital city province, Kinshasa, to 5.6% in northwestern Sud-Ubangi Province. Prevalence among boys (1.8%, 95% CI: 1.2%-2.7%) was double that among girls (0.7%, 95%CI: 0.4%-1.3%). Tetanus antibody-negativity, rurality, and lower household wealth were also significantly associated with higher HBsAg-positivity prevalence. We observed no difference in prevalence by age. Children had higher HBsAg-positivity odds if living with ≥1 HBsAg-positive adult household member (OR: 2.3, 95%CI: 0.7-7.8), particularly an HBsAg-positive mother (OR: 7.2, 95%CI:1.6-32.2). Conclusion: In the largest national survey of HBV among children and household contacts in the DRC, we found that childhood HBV prevalence was 10-60 times the global target of 0.1%. We highlight specific regions and populations for further investigation and focused prevention efforts.

Resolving multi-image spatial lipidomic responses to inhaled toxicants by machine learning.

Regional responses to inhaled toxicants are essential to understand the pathogenesis of lung disease under exposure to air pollution. We evaluated the effect of combined allergen sensitization and ozone exposure on eliciting spatial differences in lipid distribution in the mouse lung that may contribute to ozone-induced exacerbations in asthma. Lung lobes from male and female BALB/c mice were cryosectioned and acquired by high resolution mass spectrometry imaging (MSI). Processed MSI peak annotations were validated by LC-MS/MS data from scraped tissue slides and microdissected lung tissue. Images were normalized and segmented into clusters. Interestingly, segmented clusters overlapped with stained serial tissue sections, enabling statistical analysis across biological replicates for morphologically relevant lung regions. Spatially distinct lipids had higher overall degree of unsaturated fatty acids in distal lung regions compared to proximal regions. Furthermore, the airway and alveolar epithelium exhibited significantly decreased sphingolipid and glycerophospholipid abundance in females, but not in males. We demonstrate the potential role of lipid saturation in healthy lung function and highlight sex differences in regional lung lipid distribution following ozone exposure. Our study provides a framework for future MSI experiments capable of relative quantification across biological replicates and expansion to multiple sample types, including human tissue.

Traumatic Brain Injury as an Independent Predictor of Futility in the Early Resuscitation of Patients in Hemorrhagic Shock.

This review explores the concept of futility timeouts and the use of traumatic brain injury (TBI) as an independent predictor of the futility of resuscitation efforts in severely bleeding trauma patients. The national blood supply shortage has been exacerbated by the lingering influence of the COVID-19 pandemic on the number of blood donors available, as well as by the adoption of balanced hemostatic resuscitation protocols (such as the increasing use of 1:1:1 packed red blood cells, plasma, and platelets) with and without early whole blood resuscitation. This has underscored the urgent need for reliable predictors of futile resuscitation (FR). As a result, clinical, radiologic, and laboratory bedside markers have emerged which can accurately predict FR in patients with severe trauma-induced hemorrhage, such as the Suspension of Transfusion and Other Procedures (STOP) criteria. However, the STOP criteria do not include markers for TBI severity or transfusion cut points despite these patients requiring large quantities of blood components in the STOP criteria validation cohort. Yet, guidelines for neuroprognosticating patients with TBI can require up to 72 h, which makes them less useful in the minutes and hours following initial presentation. We examine the impact of TBI on bleeding trauma patients, with a focus on those with coagulopathies associated with TBI. This review categorizes TBI into isolated TBI (iTBI), hemorrhagic isolated TBI (hiTBI), and polytraumatic TBI (ptTBI). Through an analysis of bedside parameters (such as the proposed STOP criteria), coagulation assays, markers for TBI severity, and transfusion cut points as markers of futilty, we suggest amendments to current guidelines and the development of more precise algorithms that incorporate prognostic indicators of severe TBI as an independent parameter for the early prediction of FR so as to optimize blood product allocation.

Inpatient Psychiatric Care in the United States: Former Patients' Perspectives on Opportunities for Quality Improvement.

Patient-centered care is a salient value expressed by stakeholders, but a commitment to implementing patient-centered care environments lags in the context of inpatient psychiatry. The current study aimed to describe patients' suggestions for improving the quality of inpatient psychiatry. We fielded a national survey online in 2021, in which we asked participants to report their recommendations for care improvement through a free-response box. We used an inductive qualitative approach to synthesize responses into themes. Most responses described negative experiences, with suggested improvements implied as the inverse or absence of the respondent's negative experience. Among 510 participants, we identified 10 themes: personalized care, empathetic connection, communication, whole health approach, humane care, physical safety, respecting patients' rights and autonomy, structural environment, equitable treatment, and continuity of care and systems. To implement the value of patient-centered care, we suggest that those in positions of power prioritize improvement initiatives around these aspects of care that patients find most in need of improvement.

What does the Developmental Neuropsychological Assessment-II (NEPSY-II) measure in children ages 7 to 12? A structural and psychometric analysis.

The Developmental Neuropsychological Assessment - II (NEPSY-II) is a widely used assessment battery in pediatric settings, but its internal structure has not been adequately examined. This study employed a rational, empirical approach to examine the construct validity of 23 NEPSY-II subtest scores from children ages 7-12 (M = 9.99, SD = 2.76) in the NEPSY-II norming sample (N = 600; 50% girls). Competing higher-order models based on prior research, hypothesized NEPSY-II domains, and conceptual subtest classifications were evaluated via confirmatory factor analysis and a sequential approach to model comparisons. The results supported the multidimensionality of NEPSY-II subtests and the organization of subtests by hypothesized neuropsychological domains. The best fitting model included a general factor and four first-order factors. Factor loadings from the general factor to first-order factors were very strong. However, general factor loadings for most subtests were less than .50 (range = .21-.69, M = .44), and domain-specific effects for all subtests, independent of the general factor, were even lower (range = .00-.45, M = .44). Interestingly, all subtests demonstrated strong subtest-specific effects, but it is not clear what construct(s) the subtest-specific effects represent. Findings support NEPSY-II authors' emphasis on subtest-level interpretations rather than composite-level interpretations and highlight that NEPSY-II subtest scores should be interpreted carefully and with caution.

NF-κB Inducing Kinase Attenuates Colorectal Cancer by Regulating Noncanonical NF-κB Mediated Colonic Epithelial Cell Regeneration.

BACKGROUND & AIMS: Dysregulated colonic epithelial cell (CEC) proliferation is a critical feature in the development of colorectal cancer. We show that NF-κB-inducing kinase (NIK) attenuates colorectal cancer through coordinating CEC regeneration/differentiation via noncanonical NF-κB signaling that is unique from canonical NF-kB signaling. METHODS: Initial studies evaluated crypt morphology/functionality, organoid generation, transcriptome profiles, and the microbiome. Inflammation and inflammation-induced tumorigenesis were initiated in whole-body NIK knockout mice (Nik-/-) and conditional-knockout mice following administration of azoxymethane and dextran sulfate sodium. RESULTS: Human transcriptomic data revealed dysregulated noncanonical NF-kB signaling. In vitro studies evaluating Nik-/- crypts and organoids derived from mature, nondividing CECs, and colonic stem cells exhibited increased accumulation and stunted growth, respectively. Transcriptomic analysis of Nik-/- cells revealed gene expression signatures associated with altered differentiation-regeneration. When assessed in vivo, Nik-/- mice exhibited more severe colitis with dextran sulfate sodium administration and an altered microbiome characterized by increased colitogenic microbiota. In the inflammation-induced tumorigenesis model, we observed both increased tumor burdens and inflammation in mice where NIK is knocked out in CECs (NikΔCEC). Interestingly, this was not recapitulated when NIK was conditionally knocked out in myeloid cells (NikΔMYE). Surprisingly, conditional knockout of the canonical pathway in myeloid cells (RelAΔMYE) revealed decreased tumor burden and inflammation and no significant changes when conditionally knocked out in CECs (RelAΔCEC). CONCLUSIONS: Dysregulated noncanonical NF-κB signaling is associated with the development of colorectal cancer in a tissue-dependent manner and defines a critical role for NIK in regulating gastrointestinal inflammation and regeneration associated with colorectal cancer.

Links Between Obstructive Sleep Apnea and Myocardial Blood Flow Changes Impacting Adverse Cardiovascular Disease-related Outcomes.

PURPOSE OF REVIEW: Recent studies have demonstrated an association between obstructive sleep apnea (OSA) and abnormal myocardial blood flow (MBF), myocardial flow reserve (MFR), and coronary microvascular dysfunction (CMD). Here, we review the evidence and describe the potential underlying mechanisms linking OSA to abnormal MBF. Examining relevant studies, we assess the impact of OSA-specific therapy, such as continuous positive airway pressure (CPAP), on MBF. RECENT FINDINGS: Recent studies suggest an association between moderate to severe OSA and abnormal MBF/MFR. OSA promotes functional and structural abnormalities of the coronary microcirculation. OSA also promotes the uncoupling of MBF to cardiac work. In a handful of studies with small sample sizes, CPAP therapy improved MBF/MFR. Moderate to severe OSA is associated with abnormal MFR, suggesting an association with CMD. Evidence suggests that CPAP therapy improves MBF. Future studies must determine the clinical impact of improved MBF with CPAP.

The contribution of cannabis use to the increased psychosis risk among minority ethnic groups in Europe.

BACKGROUND: We examined whether cannabis use contributes to the increased risk of psychotic disorder for non-western minorities in Europe. METHODS: We used data from the EU-GEI study (collected at sites in Spain, Italy, France, the United Kingdom, and the Netherlands) on 825 first-episode patients and 1026 controls. We estimated the odds ratio (OR) of psychotic disorder for several groups of migrants compared with the local reference population, without and with adjustment for measures of cannabis use. RESULTS: The OR of psychotic disorder for non-western minorities, adjusted for age, sex, and recruitment area, was 1.80 (95% CI 1.39-2.33). Further adjustment of this OR for frequency of cannabis use had a minimal effect: OR = 1.81 (95% CI 1.38-2.37). The same applied to adjustment for frequency of use of high-potency cannabis. Likewise, adjustments of ORs for most sub-groups of non-western countries had a minimal effect. There were two exceptions. For the Black Caribbean group in London, after adjustment for frequency of use of high-potency cannabis the OR decreased from 2.45 (95% CI 1.25-4.79) to 1.61 (95% CI 0.74-3.51). Similarly, the OR for Surinamese and Dutch Antillean individuals in Amsterdam decreased after adjustment for daily use: from 2.57 (95% CI 1.07-6.15) to 1.67 (95% CI 0.62-4.53). CONCLUSIONS: The contribution of cannabis use to the excess risk of psychotic disorder for non-western minorities was small. However, some evidence of an effect was found for people of Black Caribbean heritage in London and for those of Surinamese and Dutch Antillean heritage in Amsterdam.

Spatial clusters of human and livestock anthrax define high-risk areas requiring intervention in Lao Cai Province, Vietnam 1991-2022.

Anthrax, a widespread zoonosis in low and middle-income countries with low disease awareness and insufficient livestock vaccination coverage, has been known in Lao Cai Province in northern Vietnam for years before its apparent absence in 2009, which requires investigation as this infection is frequently reported from neighbouring provinces and countries. We aimed to describe the seasonal patterns of anthrax (1991-2008), compare livestock anthrax vaccine coverage to disease occurrence (1991- 2022), and delineate the high-risk areas to inform local disease surveillance in the province. We illustrated the seasonal pattern of anthrax and provided a comparison between livestock vaccine coverage and disease occurrence by purely spatial SaTScan (Poisson model, 25% population at risk) to detect spatial clusters of human and livestock anthrax using population derived from zonal statistics routines. The number of cases, crude cumulative incidence, and spatial clusters of human and livestock anthrax were mapped in QGIS. Results indicate peak anthrax incidence from May to October. Buffalo, domestic cattle, and horses accounted for 75% of total animal cases. Horse anthrax was more common in Lao Cai than in its neighbours and often occurred in years with human mortality. Vaccination covered less than 30% of the livestock population. We found an apparent pattern where anthrax was controlled from 1998-2003 with higher vaccine coverage (>20%) and identified spatial clusters of human and livestock anthrax in Muong Khuong, Bao Thang, and Bac Ha districts of Lao Cai. The local public health and veterinary agencies are recommended to revisit the high-risk areas and communicate with neighbouring provinces for a regional approach to anthrax surveillance and control.

How is bioelectrical impedance used in neonatal intensive care? A scoping review.

Poor growth and nutrition management in the neonatal period can have a negative impact upon both the short- and long-term outcomes for the infant. Improvements in bioelectrical impedance technology and accompanying licencing agreements now make this enhanced device available for use in infants as small as 23 weeks gestational age. An exploration of this technology and its use is now timely. The aim of the scoping review was to answer the following question: in preterm and sick term infants in the neonatal intensive care unit, how is bioelectrical impedance being utilized, in what situations, and when? The scoping review was conducted using Arksey and O'Malley's (Int J Soc Res Methodol 8(1):19-32, 2005) framework. Forty-nine papers were initially identified and 16 were included in the scoping review. Three studies were experimental designs, and 13 were observational studies. The review found that BIA was used in neonatal intensive care in three main ways, for, (1) fluid status evaluation, (2) as a measure of adequate nutrition and growth, (3) to validate the technology as an outcome measure in neonates. CONCLUSION: There is a paucity of recent robust research papers which investigate the use of bioelectrical impedance in preterm neonates. Available evidence spans a range of 30 years, with technological advancement reducing the application of older studies to the modern neonatal setting. Although this technology may be helpful for decision-making around fluid management and nutrition, in preterm infants, robust evidence is needed to demonstrate the clinical benefit of bioelectrical impedance beyond that of usual care. WHAT IS KNOWN: • Clinical decisions regarding neonatal nutrition and fluid management are currently based upon the interpretation of vital signs, fluid balance, weight trend, biochemical markers, and physical examination. • Bioelectrical Impedance Analysis (BIA) is a non-invasive method of assessing body composition which is now available to be used in infants as small as 23 weeks gestation. WHAT IS NEW: • Bioelectrical Impedance has been used in three main ways in the NICU, for fluid status evaluation, for measuring nutrition and growth and to validate BIA as an outcome. • There is a lack of recent robust research data to support the use of the device within clinical decision making in neonatal intensive care.

COVID-19 Mitigation Activities in Inpatient Psychiatry Were Associated With Patient-Reported Institutional Betrayal, Changes in Trust, and Fear of Getting Sick.

Institutional betrayal occurs when the institutions that people depend on fail to protect them from harm, which was exemplified by a failure to manage COVID-19 risks. Inpatient psychiatry provides a rich context for which to understand the effects of institutional betrayal, and this is amplified in the context of the COVID-19 pandemic. Using a retrospective cohort design, we administered an online survey to former patients (n = 172) of inpatient psychiatry hospitalized at the height of the COVID-19 pandemic (March 2020 to February 2021) to understand the relationship between facilities' use of COVID-19 mitigation activities (ie, offering or requiring face masks, keeping patients and staff 6 feet apart, access to hand sanitizer, use of telemedicine for clinical consults, and routine cleanliness of the unit) and former patients' reports of institutional betrayal, changes in their trust in mental healthcare providers, fear of getting sick, and having contracted or witnessed someone else contract COVID-19. The quantity of COVID-19 mitigation activities was monotonically negatively associated with the probability of reporting any betrayal, the probability of reduced trust in mental healthcare providers, and the probability of being afraid of getting sick always or most of the time while hospitalized. COVID-19 mitigation activities either directly affected these psychological outcomes, or facilities that engaged in robust mitigation had greater cultures of safety and care quality. Additional qualitative work is needed to understand these mechanisms.

Why Patient-Centered Built Environment Standards Matter More Than Numbers of Beds in Inpatient Psychiatry.

This article canvasses extant literature about values, evidence, and standards for inpatient psychiatry units' design. It then analyzes apparent trade-offs between quality of care and access to care using empirical and ethical lenses. From this analysis, the authors conclude that standards for the built environment of inpatient psychiatric care should align with patient-centeredness, even if a downstream consequence of implementing new patient-centered designs is a reduction in beds, although this secondary outcome is unlikely.

Alternate Electrode Placements to Facilitate Frontal Electroencephalography Monitoring in Anesthetized and Critically Ill Patients.

BACKGROUND: Frontal electroencephalography (EEG) monitoring can be useful in guiding the titration of anesthetics, but it is not always feasible to place electrodes in the standard configuration in some circumstances, including during neurosurgery. This study compares 5 alternate configurations of the Masimo Sedline Sensor. METHODS: Ten stably sedated patients in the intensive care unit were recruited. Frontal EEG was monitored in the standard configuration (bifrontal upright) and 5 alternate configurations: bifrontal inverse, infraorbital, lateral upright, lateral inverse, and semilateral. Average power spectral densities (PSDs) with 95% CIs in the alternate configurations were compared to PSDs in the standard configuration. Two-one-sided-testing with Wilcoxon signed-rank tests assessed equivalence in the spectral edge frequency (SEF-95), EEG power, and relative delta (0.5 to 3.5 Hz), alpha (8 to 12 Hz), and beta (20 to 30 Hz) power between each alternate and standard configurations. RESULTS: After the removal of unanalyzable tracings, 7 patients were included for analysis in the infraorbital configuration and 9 in all other configurations. In the lateral upright and lateral inverse configurations, PSDs significantly differed from the standard configuration within the 15 to 20 Hz band. The greatest decrease in EEG power was in the lateral inverse configuration (median: -97 dB; IQR: -130, -62 dB). The largest change in frequency distribution of EEG power was in the infraorbital configuration; median SEF-95 change of -1.4 Hz (IQR: -2.8, 0.7 Hz), median relative delta power change of +7.3% (IQR: 1.4%, 7.9%), and median relative alpha power change of -0.6% (IQR: -5.7%, 0.0%). CONCLUSIONS: These 5 alternate Sedline electrode configurations are suitable options for monitoring frontal EEG when the standard configuration is not possible.

Maternal Smoking and Risk of Hypertensive Disorders of Pregnancy: Effect Modification by Body Mass Index and Gestational Weight Gain.

BACKGROUND: Although smoking cigarettes has been shown to have a protective effect on preeclampsia, quitting smoking also results in weight gain. Weight gain leading to an obese body mass index is a risk factor for hypertensive disorders of pregnancy (HDP). METHODS: The objective of this study was to explore the relationship between smoking status, body mass index, and gestational weight gain on the risk of HDP. A cross-sectional analysis was performed utilizing US birth certificate data. We examined HDP risks in relation to maternal smoking, body mass index, and gestational weight gain. Associations were expressed as rate ratios with 95% CIs and adjusted for potential confounders. Clinically important outcomes of smoking throughout pregnancy were also evaluated. RESULTS: Of the 22 191 568 women studied, HDP rates among nonsmokers, those who quit smoking, and persistent smokers were 6.8%, 8.6%, and 7.0%, respectively. The rate ratio of HDP was higher for women who quit smoking, especially evident among those with excessive gestational weight gain. Corrections for exposure misclassification and unmeasured confounding strengthened the associations among women who quit smoking. There was an almost 6-fold increase in the rate of stillbirth for persistent smokers (2.3%) compared with those who quit smoking (0.4%) and nonsmokers (0.4%). CONCLUSIONS: Women who quit smoking during pregnancy were more likely to gain excessive weight and develop HDP. Although quitting smoking during pregnancy may be associated with an increase in the risk of HDP, it is also associated with a reduced risk of stillbirth. Pregnant women counseled to quit smoking should also receive counseling on nutrition and exercise to prevent excessive gestational weight gain.