Quality adjusted coverage of family planning services in low- and middle-income countries: Analysis of 33 countries using Demographic and Health Survey data.

Background: Monitoring service quality for family planning programmes in low- and middle-income countries (LMICs) has been challenging due to data availability. Self-reported service quality from Demographic and Health Surveys (DHS) can provide additional information on quality beyond simple service contact. Methods: The DHS collects need, use and counselling for contraceptives. We used this data from 33 LMICs to develop quality-adjusted demand for modern family planning satisfied indicator (DFPSq). We compared it with the crude indicator (demand for family planning satisfied (DFPS)) and performed an equity analysis. Median, interquartile ranges (IQR) and the absolute and relative gap by country were used to describe the findings. Results: The median DFPS was 49% (IQR = 41-57%) and the median DPFSq was 19% (IQR = 14-27%). We found similar relative differences in the gap stratified by SES indicating quality was universally low. One exception is that adolescents had a higher relative gap (70%, IQR = 57-79%) compared to adults (54%, IQR = 46-68%), indicating lower quality access. Conclusions: Severe and pervasive quality gaps exist in family planning services across most LMICs. Our novel DFPSq indicator is one additional tool for monitoring access and quality of service that is critical to meet the family planning needs of women.

A novel echocardiographic parameter considering left ventricular afterload during V-A ECMO support.

BACKGROUND: Left ventricular stroke work index (LVSWI) and cardiac power index (CPI) account for the haemodynamic load of the left ventricle and are promising prognostic values in cardiogenic shock. However, accurately and non-invasively measuring these parameters during veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is challenging and potentially biased by the extracorporeal circulation. This study aimed to investigate, in an ovine model of cardiogenic shock, whether Pressure-Strain Product (PSP), a novel speckle-tracking echocardiography parameter, (1) can correlate with pressure-volume catheter-based LVSWI and CPI, and (2) can be load-independent during the flow modification of V-A ECMO. METHODS: Nine Dorset-cross ewes (51 ± 4 kg) were included. After cardiogenic shock was induced, full support V-A ECMO (X L/min based on 60 mL/kg/min) commenced. At seven time points during 24-h observation, echocardiographic parameters as well as pressure-volume catheter-based LVSWI and CPI were simultaneously measured with X and following X-1 L/min of ECMO flow. PSP was calculated by multiplying global circumferential strain or global radial strain, and mean arterial pressure, for PSPcirc or PSPrad, respectively. RESULTS: PSPcirc showed a stronger correlation with LVSWI (correlation coefficient, CC = .360, p < .001) and CPI (CC = .283, p < .001) than other echocardiographic parameters. The predictability of PSPcirc for pressure-volume catheter-based LVSWI (AUC .82) and CPI (AUC .80) was also higher than other echocardiographic parameters. No statistically significant differences were identified between the two ECMO flow variations in PSPcirc (p = .558). CONCLUSIONS: A novel echocardiographic parameter, PSP, may non-invasively predict pressure-volume catheter-based LVSWI and CPI in a load-independent manner in a cardiogenic shock supported by V-A ECMO.

Echocardiographic surrogate of left ventricular stroke work in a model of brain stem death donors.

BACKGROUND: The commonest echocardiographic measurement, left ventricular ejection fraction, can not necessarily predict mortality of recipients following heart transplantation potentially due to afterload dependency. Afterload-independent left ventricular stroke work index (LVSWI) is alternatively recommended by the current guideline; however, pulmonary artery catheters are rarely inserted in organ donors in most jurisdictions. We propose a novel non-invasive echocardiographic parameter, Pressure-Strain Product (PSP), as a potential surrogate of catheter-based LVSWI. This study aimed to investigate if PSP could correlate with catheter-based LVSWI in an ovine model of brain stem death (BSD) donors. The association between PSP and myocardial mitochondrial function in the post-transplant hearts was also evaluated. METHODS: Thirty-one female sheep (weight 47 ± 5 kg) were divided into two groups; BSD (n = 15), and sham neurologic injury (n = 16). Echocardiographic parameters including global circumferential strain (GCS) and global radial strain (GRS) and pulmonary artery catheter-based LVSWI were simultaneously measured at 8-timepoints during 24-h observation. PSP was calculated as a product of GCS or GRS, and mean arterial pressure for PSPcirc or PSPrad, respectively. Myocardial mitochondrial function was evaluated following 6-h observation after heart transplantation. RESULTS: In BSD donor hearts, PSPcirc (n = 96, rho = .547, p < .001) showed the best correlation with LVSWI among other echocardiographic parameters. PSPcirc returned AUC of .825 to distinguish higher values of cardiomyocyte mitochondrial function (cut-off point; mean value of complex 1,2 O2 Flux) in post-transplant hearts, which was greater than other echocardiographic parameters. CONCLUSIONS: PSPcirc could be used as a surrogate of catheter-based LVSWI reflecting mitochondrial function.

Tigilanol tiglate is an oncolytic small molecule that induces immunogenic cell death and enhances the response of both target and non-injected tumors to immune checkpoint blockade.

BACKGROUND: Tigilanol tiglate (TT) is a protein kinase C (PKC)/C1 domain activator currently being developed as an intralesional agent for the treatment of various (sub)cutaneous malignancies. Previous work has shown that intratumoral (I.T.) injection of TT causes vascular disruption with concomitant tumor ablation in several preclinical models of cancer, in addition to various (sub)cutaneous tumors presenting in the veterinary clinic. TT has completed Phase I dose escalation trials, with some patients showing signs of abscopal effects. However, the exact molecular details underpinning its mechanism of action (MoA), together with its immunotherapeutic potential in oncology remain unclear. METHODS: A combination of microscopy, luciferase assays, immunofluorescence, immunoblotting, subcellular fractionation, intracellular ATP assays, phagocytosis assays and mixed lymphocyte reactions were used to probe the MoA of TT in vitro. In vivo studies with TT used MM649 xenograft, CT-26 and immune checkpoint inhibitor refractory B16-F10-OVA tumor bearing mice, the latter with or without anti-programmed cell death 1 (PD-1)/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb treatment. The effect of TT at injected and non-injected tumors was also assessed. RESULTS: Here, we show that TT induces the death of endothelial and cancer cells at therapeutically relevant concentrations via a caspase/gasdermin E-dependent pyroptopic pathway. At therapeutic doses, our data demonstrate that TT acts as a lipotoxin, binding to and promoting mitochondrial/endoplasmic reticulum (ER) dysfunction (leading to unfolded protein responsemt/ER upregulation) with subsequent ATP depletion, organelle swelling, caspase activation, gasdermin E cleavage and induction of terminal necrosis. Consistent with binding to ER membranes, we found that TT treatment promoted activation of the integrated stress response together with the release/externalization of damage-associated molecular patterns (HMGB1, ATP, calreticulin) from cancer cells in vitro and in vivo, characteristics indicative of immunogenic cell death (ICD). Confirmation of ICD in vivo was obtained through vaccination and rechallenge experiments using CT-26 colon carcinoma tumor bearing mice. Furthermore, TT also reduced tumor volume, induced immune cell infiltration, as well as improved survival in B16-F10-OVA tumor bearing mice when combined with immune checkpoint blockade. CONCLUSIONS: These data demonstrate that TT is an oncolytic small molecule with multiple targets and confirms that cell death induced by this compound has the potential to augment antitumor responses to immunotherapy.

Development has the answer: Unraveling psychiatric disorders via thalamocortical organoids.

Dissecting the role of the thalamus in neuropsychiatric disorders requires new models to analyze complex genetic interactions. In this issue of Cell Stem Cell, Shin et al. use patient-derived thalamocortical organoids to investigate 22q11.2 microdeletion impact on thalamic development, revealing significant transcriptional dysregulation linked to psychiatric disorders.

3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression.

Cancer genomes are composed of many complex structural alterations on chromosomes and extrachromosomal DNA (ecDNA), making it difficult to identify non-coding enhancer regions that are hijacked to activate oncogene expression. Here, we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) to characterize enhancer hijacking. HAPI analysis of HiChIP data from 34 cancer cell lines identified enhancer hijacking events that activate both known and potentially novel oncogenes such as MYC, CCND1 , ETV1 , CRKL , and ID4 . Furthermore, we found enhancer hijacking among multiple oncogenes from different chromosomes, often including MYC , on the same complex amplicons such as ecDNA. We characterized a MYC - ERBB2 chimeric ecDNA, in which ERBB2 heavily hijacks MYC 's enhancers. Notably, CRISPRi of the MYC promoter led to increased interaction of ERBB2 with MYC enhancers and elevated ERBB2 expression. Our HAPI analysis tool provides a robust strategy to detect enhancer hijacking and reveals novel insights into oncogene activation.

An appraisal of lung computer tomography in very early anti-inflammatory treatment of two different ovine ARDS phenotypes.

Mortality and morbidity of Acute Respiratory Distress Syndrome (ARDS) are largely unaltered. A possible new approach to treatment of ARDS is offered by the discovery of inflammatory subphenotypes. In an ovine model of ARDS phenotypes, matching key features of the human subphenotypes, we provide an imaging characterization using computer tomography (CT). Nine animals were randomized into (a) OA (oleic acid, hypoinflammatory; n = 5) and (b) OA-LPS (oleic acid and lipopolysaccharides, hyperinflammatory; n = 4). 48 h after ARDS induction and anti-inflammatory treatment, CT scans were performed at high (H) and then low (L) airway pressure. After CT, the animals were euthanized and lung tissue was collected. OA-LPS showed a higher air fraction and OA a higher tissue fraction, resulting in more normally aerated lungs in OA-LPS in contrast to more non-aerated lung in OA. The change in lung and air volume between H and L was more accentuated in OA-LPS, indicating a higher recruitment potential. Strain was higher in OA, indicating a higher level of lung damage, while the amount of lung edema and histological lung injury were largely comparable. Anti-inflammatory treatment might be beneficial in terms of overall ventilated lung portion and recruitment potential, especially in the OA-LPS group.

Cardiac contraction and relaxation are regulated by distinct subcellular cAMP pools.

Cells interpret a variety of signals through G-protein-coupled receptors (GPCRs) and stimulate the generation of second messengers such as cyclic adenosine monophosphate (cAMP). A long-standing puzzle is deciphering how GPCRs elicit different physiological responses despite generating similar levels of cAMP. We previously showed that some GPCRs generate cAMP from both the plasma membrane and the Golgi apparatus. Here we demonstrate that cardiomyocytes distinguish between subcellular cAMP inputs to elicit different physiological outputs. We show that generating cAMP from the Golgi leads to the regulation of a specific protein kinase A (PKA) target that increases the rate of cardiomyocyte relaxation. In contrast, cAMP generation from the plasma membrane activates a different PKA target that increases contractile force. We further validated the physiological consequences of these observations in intact zebrafish and mice. Thus, we demonstrate that the same GPCR acting through the same second messenger regulates cardiac contraction and relaxation dependent on its subcellular location.

Use of the Microguide mobile phone application for ENT conditions: a national review.

OBJECTIVE: Smartphone applications are used widely in healthcare, including antimicrobial applications such as Microguide. There has been no review of hospitals using this smartphone application for ENT conditions. METHODS: This study analysed all hospital accounts using Microguide and examined the ENT conditions that were listed. RESULTS: In total, 123 hospitals were included in this study; 45 ENT-related conditions were listed on Microguide across all hospitals, with an average of 8 conditions listed per hospital. CONCLUSION: There is a significant disparity of ENT conditions listed on Microguide. A suggested list is recommended to be included for ENT departments using Microguide, to help improve antimicrobial stewardship for the specialty.

How do medical students want to learn ENT? Perspectives from a consensus forum.

OBJECTIVE: The UK Medical Licensing Assessment curriculum represents a consensus on core content, including ENT-related content for newly qualified doctors. No similar consensus exists as to how ENT content should be taught at medical school. METHOD: A virtual consensus forum was held at the 2nd East of England ENT Conference in April 2021. A syllabus of ENT-related items was divided into 'Presentations', 'Conditions' and 'Practical procedures'. Twenty-seven students, 11 foundation doctors and 7 other junior doctors voted via anonymous polling for the best three of nine methods for teaching each syllabus item. RESULTS: For 'Presentations' and 'Conditions', work-based or clinical-based learning and small-group seminars were more popular than other teaching methods. For 'Practical procedures', practical teaching methods were more popular than theoretical methods. CONCLUSION: Students and junior doctors expressed a clear preference for clinical-based teaching and small-group seminars when learning ENT content. E-learning was poorly favoured despite its increasing use.

Frequent Premature Atrial Contractions Lead to Adverse Atrial Remodeling and Atrial Fibrillation in a Swine Model.

BACKGROUND: Frequent premature atrial complexes (PACs) are associated with future incident atrial fibrillation (AF), but whether PACs contribute to development of AF through adverse atrial remodeling has not been studied. This study aimed to explore the effect of frequent PACs from different sites on atrial remodeling in a swine model. METHODS: Forty swine underwent baseline electrophysiologic studies and echocardiography followed by pacemaker implantations and paced PACs (50% burden) at 250-ms coupling intervals for 16 weeks in 4 groups: (1) lateral left atrium (LA) PACs by the coronary sinus (Lat-PAC; n=10), (2) interatrial septal PACs (Sep-PAC; n=10), (3) regular LA pacing at 130 beats/min (Reg-130; n=10), and (4) controls without PACs (n=10). At the final study, repeat studies were performed, followed by tissue histology and molecular analyses focusing on fibrotic pathways. RESULTS: Lat-PACs were associated with a longer P-wave duration (93.0±9.0 versus 74.2±8.2 and 58.8±7.6 ms; P<0.001) and greater echocardiographic mechanical dyssynchrony (57.5±11.6 versus 35.7±13.0 and 24.4±11.1 ms; P<0.001) compared with Sep-PACs and controls, respectively. After 16 weeks, Lat-PACs led to slower LA conduction velocity (1.1±0.2 versus 1.3±0.2 [Sep-PAC] versus 1.3±0.1 [Reg-130] versus 1.5±0.2 [controls] m/s; P<0.001) without significant change in atrial ERP. The Lat-PAC group had a significantly increased percentage of LA fibrosis and upregulated levels of extracellular matrix proteins (lysyl oxidase and collagen 1 and 8), as well as TGF-ß1 (transforming growth factor-ß1) signaling proteins (latent and monomer TGF-ß1 and phosphorylation/total ratio of SMAD2/3; P<0.05). The Lat-PAC group had the longest inducible AF duration (terminal to baseline: 131 [interquartile range 30, 192] seconds versus 16 [6, 26] seconds [Sep-PAC] versus 22 [11, 64] seconds [Reg-130] versus -1 [-16, 7] seconds [controls]; P<0.001). CONCLUSIONS: In this swine model, frequent PACs resulted in adverse atrial structural remodeling with a heightened propensity to AF. PACs originating from the lateral LA produced greater atrial remodeling and longer induced AF duration than the septal-origin PACs. These data provide evidence that frequent PACs can cause adverse atrial remodeling as well as AF, and that the location of ectopic PACs may be clinically meaningful.

A novel speckle-tracking echocardiography parameter assessing left ventricular afterload.

BACKGROUND: Left ventricular stroke work index (LVSWI) and afterload-related cardiac performance (ACP) consider left ventricular (LV) afterload and could be better prognosticators in septic cardiomyopathy. However, their invasive nature prevents their routine clinical applications. This study aimed to investigate (1) whether a proposed speckle-tracking echocardiography parameter, Pressure-Strain Product (PSP), can non-invasively predict catheter-based LVSWI, ACP and serum lactate in an ovine model of septic cardiomyopathy; and (2) whether PSP can distinguish the sub-phenotypes of acute respiratory distress syndrome (ARDS) with or without sepsis-like conditions. METHODS: Sixteen sheep with ARDS were randomly assigned to either (1) sepsis-like (n = 8) or (2) non-sepsis-like (n = 8) group. Each ARDS and sepsis-like condition was induced by intravenous infusion of oleic acid and lipopolysaccharide, respectively. Pulmonary artery catheter-based LVSWI (the product of stroke work index, mean arterial pressure and .0136), ACP (the percentage of cardiac output measured to cardiac output predicted as normal) and serum lactate were measured simultaneously with transthoracic echocardiography. Two PSP indices were calculated by multiplying the mean arterial blood pressure and either global circumferential strain (PSPcirc) or radial strain (PSPrad). RESULTS: PSPcirc showed a significant correlation with LVSWI (r2 = .66, p < .001) and ACP (r2 = .82, p < .001) in the sepsis-like group. Although PSP could not distinguish subphenotypes, PSPcirc predicted LVSWI (AUC .86) and ACP (AUC .88), and PSPrad predicted serum lactate (AUC .75) better than LV ejection fraction, global circumferential and radial strain. CONCLUSIONS: A novel PSP has the potential to non-invasively predict catheter-based LVSWI and ACP, and was associated with serum lactate in septic cardiomyopathy.

EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and a Mouse Genetic Model.

Clear cell sarcoma (CCS) is a rare, aggressive malignancy that most frequently arises in the soft tissues of the extremities. It is defined and driven by expression of one member of a family of related translocation-generated fusion oncogenes, the most common of which is EWSR1::ATF1. The EWSR1::ATF1 fusion oncoprotein reprograms transcription. However, the binding distribution of EWSR1::ATF1 across the genome and its target genes remain unclear. Here, we interrogated the genomic distribution of V5-tagged EWSR1::ATF1 in tumors it had induced upon expression in mice that also recapitulated the transcriptome of human CCS. ChIP-sequencing of V5-EWSR1::ATF1 identified previously unreported motifs including the AP1 motif and motif comprised of TGA repeats that resemble GGAA-repeating microsatellites bound by EWSR1::FLI1 in Ewing sarcoma. ChIP-sequencing of H3K27ac identified super enhancers in the mouse model and human contexts of CCS, which showed a shared super enhancer structure that associates with activated genes.

FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma.

The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of NKX2-1-negative LUAD to facilitate a gastric identity. After Nkx2-1 deletion, FoxA1/2 mediate demethylation of gastric-defining genes through recruitment of TET3, an enzyme that induces DNA demethylation. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of regulatory elements and their 3D interactions at gastric loci. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching.

The O-GlcNAc dichotomy: when does adaptation become pathological?

O-Linked attachment of ß-N-acetylglucosamine (O-GlcNAc) on serine and threonine residues of nuclear, cytoplasmic, and mitochondrial proteins is a highly dynamic and ubiquitous post-translational modification that impacts the function, activity, subcellular localization, and stability of target proteins. Physiologically, acute O-GlcNAcylation serves primarily to modulate cellular signaling and transcription regulatory pathways in response to nutrients and stress. To date, thousands of proteins have been revealed to be O-GlcNAcylated and this number continues to grow as the technology for the detection of O-GlcNAc improves. The attachment of a single O-GlcNAc is catalyzed by the enzyme O-GlcNAc transferase (OGT), and their removal is catalyzed by O-GlcNAcase (OGA). O-GlcNAcylation is regulated by the metabolism of glucose via the hexosamine biosynthesis pathway, and the metabolic abnormalities associated with pathophysiological conditions are all associated with increased flux through this pathway and elevate O-GlcNAc levels. While chronic O-GlcNAcylation is well associated with cardiovascular dysfunction, only until recently, and with genetically modified animals, has O-GlcNAcylation as a contributing mechanism of cardiovascular disease emerged. This review will address and critically evaluate the current literature on the role of O-GlcNAcylation in vascular physiology, with a view that this pathway can offer novel targets for the treatment and prevention of cardiovascular diseases.

ARF6-dependent endocytic trafficking of the Interferon-γ receptor drives adaptive immune resistance in cancer.

Adaptive immune resistance (AIR) is a protective process used by cancer to escape elimination by CD8+ T cells. Inhibition of immune checkpoints PD-1 and CTLA-4 specifically target Interferon-gamma (IFNγ)-driven AIR. AIR begins at the plasma membrane where tumor cell-intrinsic cytokine signaling is initiated. Thus, plasma membrane remodeling by endomembrane trafficking could regulate AIR. Herein we report that the trafficking protein ADP-Ribosylation Factor 6 (ARF6) is critical for IFNγ-driven AIR. ARF6 prevents transport of the receptor to the lysosome, augmenting IFNγR expression, tumor intrinsic IFNγ signaling and downstream expression of immunosuppressive genes. In murine melanoma, loss of ARF6 causes resistance to immune checkpoint blockade (ICB). Likewise, low expression of ARF6 in patient tumors correlates with inferior outcomes with ICB. Our data provide new mechanistic insights into tumor immune escape, defined by ARF6-dependent AIR, and support that ARF6-dependent endomembrane trafficking of the IFNγ receptor influences outcomes of ICB.

A Unique Case of Atrial Fibrillation Secondary to Squamous Cell Lung Carcinoma.

Atrial fibrillation (AF) is widely considered to be the most prevalent cardiac arrhythmia with an incidence of roughly 1%-2% in the United States alone. The incidence of AF has been known to increase with advancing age and thus presents a significant burden on healthcare systems across the globe. AF arises as a result of several mechanisms including structural changes that occur in the heart over time. Here, we present a case in which a 63-year-old male with no past medical history except heavy tobacco use presented to the emergency department complaining of shortness of breath. He also endorsed having palpations and a productive cough for several weeks prior to presenting to the emergency department. An EKG revealed AF with a rapid ventricular response. His chest x-ray revealed an irregular opacification of the left lung; however, a chest computed tomography unveiled a left hilar mass extending to the left upper lobe. The mass was causing obstruction of the left upper lobe and encasement of the left main pulmonary artery and left atrium. This case highlights a rare etiology of AF. While many causes of AF have been elucidated, including hypertension and valvular heart disease, a much lesser-known cause includes lung carcinoma resulting in a mass effect on the heart. Representing almost 19% of all cancer deaths, lung cancer is the leading cause of cancer death. Although lung cancer screenings are recommended for certain populations, the majority of lung cancer cases present at an advanced stage, limiting treatment options. Our patient presents a unique case involving a lung mass causing AF due to the mass effect on the left heart. Although the patient had other risk factors for AF including advanced age and cigarette smoking, we propose that due to the anatomical location of his lung mass, his AF was a consequence of the squamous cell carcinoma of the lung. Although the mortality for lung cancer remains high, new treatments, including pembrolizumab, have the potential to drastically alter the way these cancers are treated.

Alfaisal University's Academic Success Center: An Individualized Peer-Assisted Learning Program for Mutual Tutor-Student Advancement.

INTRODUCTION: Peer-assisted learning (PAL) is an educational strategy whereby students teach other students. PAL presents many advantages to the institution, tutors, and tutees. It can benefit the university by presenting a cost-effective approach where the efforts and time of faculty are reduced. We describe a retrospective analysis detailing the structure, function, and effectiveness of the Academic Success Center (ASC) at Alfaisal University, Riyadh, Saudi Arabia, since 2020. The ASC encompasses various types of PAL methods. It is the only PAL program in Saudi Arabia whereby its tutors, referred to as student consultants, are compensated financially. METHODS: We retrospectively analyzed the total number of appointments, the total number of students who accessed the center, as well as the breakdown between different colleges and academic years, and their satisfaction level with the PAL mode of teaching. RESULTS: Our results indicate a high level of appointments for these PAL sessions increasing on a yearly basis and a high level of satisfaction from both the tutors and the tutees. CONCLUSION: PAL is an effective teaching and mentoring modality with high retention rates that has contributed to an increased sense of well-being among students who have utilized these services.

Application of anti-inflammatory treatment in two different ovine Acute Respiratory Distress Syndrome injury models: a preclinical randomized intervention study.

Whilst the presence of 2 subphenotypes among the heterogenous Acute Respiratory Distress Syndrome (ARDS) population is becoming clinically accepted, subphenotype-specific treatment efficacy has yet to be prospectively tested. We investigated anti-inflammatory treatment in different ARDS models in sheep, previously shown similarities to human ARDS subphenotypes, in a preclinical, randomized, blinded study. Thirty anesthetized sheep were studied up to 48 h and randomized into: (a) OA: oleic acid (n = 15) and (b) OA-LPS: oleic acid and subsequent lipopolysaccharide (n = 15) to achieve a PaO2/FiO2 ratio of < 150 mmHg. Then, animals were randomly allocated to receive treatment with methylprednisolone or erythromycin or none. Assessed outcomes were oxygenation, pulmonary mechanics, hemodynamics and survival. All animals reached ARDS. Treatment with methylprednisolone, but not erythromycin, provided the highest therapeutic benefit in Ph2 animals, leading to a significant increase in PaO2/FiO2 ratio by reducing pulmonary edema, dead space ventilation and shunt fraction. Animals treated with methylprednisolone displayed a higher survival up to 48 h than all others. In animals treated with erythromycin, there was no treatment benefit regarding assessed physiological parameters and survival in both phenotypes. Treatment with methylprednisolone improves oxygenation and survival, more so in ovine phenotype 2 which resembles the human hyperinflammatory subphenotype.

Volatile Organic Compounds in Disposable Diapers and Baby Wipes in the US: A Survey of Products and Health Risks.

Many thousands of diapers are worn by young children and the elderly, who have thin and sensitive skin that is highly vulnerable to chemicals, including volatile organic compounds (VOCs) that may be ingredients of these products or present as inadvertent or residual components. The levels and potential health risks of VOCs in diapers have not been reported previously. In this study, we collected 31 disposable hygiene products in the US market based on market share and analyzed 98 target VOCs using purge and trap sampling and thermal desorption/gas chromatography/mass spectrometer analysis. Exposures and risks were modeled using reasonable upper level exposure scenarios. Adult diapers contained the highest total target VOC concentration (median level of 23.5 µg/g), and the predominant VOCs were alkanes. In some diapers, the estimated noncancer risk from these VOCs was sometimes very large (hazard quotient of 1609) due to n-heptane. Baby diapers contained several known or suspected carcinogens, including benzene and 1,4-dioxane, and the lifetime cancer risk from some diapers approached 1 per million under a worst-case scenario. Store-brand products had higher levels of VOCs than generic brands, and products labeled "organic" or "for sensitive skin" did not necessarily have lower levels. Our results show that toxic VOCs were found in all tested disposable diapers and wipes at trace levels, and risks from using some diapers in high use exposure scenarios are high enough to warrant additional attention and possibly corrective measures. We recommend eliminating and monitoring toxic ingredients and disclosing all chemicals that may be in these products.