Explore the vast range of titles available.

Excess adiposity is a reversible etiologic risk factor for obstructive sleep apnea. In this trial, tirzepatide reduced the apnea–hypopnea index of participants with obstructive sleep apnea and obesity.

After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), drives Notch signalling and Krt5 pos basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5 pos basal-like state. Activated murine Krt5 pos LNEPs and diseased human AEC2s upregulate strikingly similar core pathways underlying migration and squamous metaplasia. While robust, HIF1α-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1α deletion or enhanced Wnt/β-catenin activity in Sox2 pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair. Xi et al.  show that after influenza infection, hypoxia drives Notch signalling to expand Krt5 + basal-like cells in the lung. On HIF1α loss, epithelial progenitors directly differentiate into alveolar type II cells and promote functional regeneration.

In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

In this multicenter, randomized trial, the administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic–ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment at 22 to 36 months of age than placebo and was associated with a higher rate of serious adverse events.

IntroductionThere is significant uncertainty in the use of pre-flight hypoxic challenge assessments for individuals using long term ventilation. Current BTS guidelines suggest that a SaO2 >95% precludes the need for any pre-flight assessment of the need for supplemental oxygen during flight.1 However, a study of 19 NIV users showed significant oxygen desaturations during a hypoxic flight challenge in 15 (79%) despite a baseline SaO2 >95%.2 MethodsWe examined the results of a pre-flight hypoxic challenge test (FIO215%) on all NIV patients who intend to travel by air and who have a baseline SaO2 ≥92%, for the period of 2014 to 2019 (retrospective analysis).ResultsEighty-seven patients were tested (18% chronic obstructive pulmonary disease, 52% genetic muscle disease, 9% sleep disorder (obstructive sleep apnoea/obesity hypoventilation syndrome), 8% restrictive lung disease from chest wall/spinal problems,13%genetic metabolic disease). Seventy-six percent had a baseline SaO2 >95% on air. Using current BTS criteria 13/87 (15%) ‘failed’ the flight test and would require supplemental oxygen during flight. Of the 22/87 with a baseline SaO292–95% 9 (41%) failed the test. Only 4/65 (6%) with a baseline SaO2 >95% failed. This compares with 6/12 (50%) NIV users with a baseline SaO2 >95% reported in the Mestry study2.DiscussionWe have confirmed that a non-negligible number of domiciliary NIV users, with a testing threshold above the current BTS recommendations, fail a hypoxic pre-flight challenge test. The clinical consequences of these observations and the impact of in-flight oxygen remain unknown. These findings encourage further research towards a multivariable predictive model.ReferencesMestry, et al. Hypoxic challenge flight assessments in patients with severe chest wall deformity or neuromuscular disease at risk for nocturnal hypoventilation. Thorax 2009;64:532–4.. Managing passengers with respiratory disease planning air travel: British Thoracic Society recommendations. British Thoracic Society Standards of Care Committee. http://dx.doi.org/10.1136/thorax.57.4.289

IntroductionIn 2022 the British Thoracic Society (BTS) published updated guidance (Coker RK, et al. Thorax 2022;0:1–22) on air travel for patients with respiratory conditions. These revised referral criteria for hypoxic challenge test (HCT), advising that patients on long term supplemental oxygen (O2) should ideally have their in-flight O2 flow determined by HCT.AimTo assess if performing HCT for patients on long-term O2 changed management beyond previous guidance (Ahmedzai, S et al. Thorax 2011;66: i1ei30) which recommended doubling baseline flow during flight.MethodAll HCTs performed between March 2022 and December 2024 were reviewed. Patients were included if they were current users of O2 (including those in nocturnal only O2). Children in nocturnal only O2 therapy started their test in air, provided baseline SpO2 was greater than 92%. All other children started their test at their prescribed daytime flow. During the test the O2 flow was increased in steps of 1 L/min, with a starting point of 1 L/min as this is the lowest flow widely available during flight.ResultsThree hundred and fifty-two HCTs were reviewed and 18 patients (11 female, mean±SD age 7.17±5.84 yrs) met the criteria for inclusion. Thirteen out of 18 were in nocturnal O2 therapy only. Two children had their baseline flow doubled during HCT. One had their baseline flow more than doubled, from 0.2 L/min to 2 L/min. Four children with starting flow <0.5 L/min had their flow increased to 1 L/min. Four children did not require any change in their O2 flow. Five children in nocturnal only O2 therapy and two with O2 use only when unwell did not require O2 during the test.ConclusionsIn this study, all children in 24-hr O2 did not require any change in their O2 flow during HCT. For children in nocturnal only O2 the results were variable. Almost half of these children did not require O2 therapy during HCT, creating uncertainty as to whether O2 should be prescribed during flight. It is still uncertain whether the new guidance provides useful additional clinical information.

Key Points Hypoxia and inflammation are frequently co-incidental microenvironmental features of sites of concentrated physiological or pathological immune activity. Hypoxia activates hypoxia-inducible factor, which is a major regulator of multiple aspects of immune cell function. Consequently, hypoxia plays a key role in the regulation of immunity and inflammation. The impact of hypoxia on immunity and inflammation is site-specific and cell type-specific. Pharmacological hydroxylase inhibition, which activates hypoxia-sensitive pathways, is profoundly protective in multiple models of inflammation. Hypoxia is a microenvironmental feature that is associated with physiological and pathological immunological niches. In this Review, Taylor and Colgan summarize the effects of physiological and pathological hypoxia on immune cells and processes and discuss the possibility of therapeutically targeting hypoxia-sensitive pathways. Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

Background In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. Methods Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4–6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. Results Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5–5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. Conclusion In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. Impact Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

Even though supplemental oxygen is used for the treatment of patients with hypoxemic respiratory failure, the most effective oxygenation targets are not known. In this randomized trial, a lower oxygenation target did not result in lower mortality than a higher target.

Background Endothelial cell (EC) injury accelerates the progression of diabetic macrovascular complications. Hypoxia is an important cause of EC injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is an important hypoxia regulatory protein. Our previous studies showed that high-glucose and hypoxic conditions could upregulate HIF-1α expression and enhance EC inflammatory injury, independently of the nuclear factor kappa-B (NF-κB) pathway. However, it is not clear whether HIF-1α plays a role in vascular disease through epigenetic-related mechanisms. Methods We conducted gene expression analysis and molecular mechanistic studies in human umbilical vein endothelial cells (HUVECs) induced by hyperglycemia and hypoxia using RNA sequencing (RNA-seq) and small interfering HIF-1α (si-HIF-1α). We determined HIF-1α and Jumonji domain-containing protein 1 A (JMJD1A) expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, analyzed inflammatory protein secretion in the cell supernatant by enzymelinked immunosorbent assay (ELISA), and assessed protein interaction between HIF-1α and JMJD1A by chromatin immunoprecipitation (Ch-IP). We used the Cell Counting Kit8 (CCK-8) assay to analyze cell viability, and assessed oxidative stress indicators by using a detection kit and flow cytometry. Results High glucose and hypoxia up-regulated HIF-1α expression, and down-regulated HIF-1α decreased the level of inflammation and oxidative stress in HUVECs. To determine the downstream pathways, we observed histone demethylases genes and related pathway by RNA-sEq. Among these, JMJD1A was the most upregulated gene in histone demethylases. Moreover, we observed that HIF-1α bound to the promoter of JMJD1A, and the ameliorative effects of si-HIF-1α on oxidative stress and inflammatory cytokines in high-glucose and hypoxia-induced HUVECs were reversed by JMJD1A overexpression. Furthermore, knockdown of JMJD1A decreased inflammatory and oxidative stress injury. To determine the JMJD1A-related factors, we conducted gene expression analysis on JMJD1A-knockdown HUVECs. We observed that downregulation of inflammation and the oxidative stress pathway were enriched and FOS and FOSB might be important protective transcription factors. Conclusions These findings provide novel evidence that the HIF-1α/JMJD1A signaling pathway is involved in inflammation and oxidative stress in HUVECs induced by high glucose and hypoxia. Also, this pathway might act as a novel regulator of oxidative stress and inflammatory-related events in response to diabetic vascular injury and thus contribute to the pathological progression of diabetes and vascular disease.