Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells.

Although inhibition of T cell coinhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. In the present study, we show that type 1 interferon (IFN-I) regulates coinhibitory receptor expression on human T cells, inducing PD-1/TIM-3/LAG-3 while inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses established the dynamic regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors (TFs) and TF footprint analysis revealed two regulator modules with different temporal kinetics that control expression of coinhibitory receptors and IFN-I response genes, with SP140 highlighted as one of the key regulators that differentiates LAG-3 and TIGIT expression. Finally, we found that the dynamic IFN-I response in vitro closely mirrored T cell features in acute SARS-CoV-2 infection. The identification of unique TFs controlling coinhibitory receptor expression under IFN-I response may provide targets for enhancement of immunotherapy in cancer, infectious diseases and autoimmunity.

Discovery of an Active RAG Transposon Illuminates the Origins of V(D)J Recombination.

Co-option of RAG1 and RAG2 for antigen receptor gene assembly by V(D)J recombination was a crucial event in the evolution of jawed vertebrate adaptive immunity. RAG1/2 are proposed to have arisen from a transposable element, but definitive evidence for this is lacking. Here, we report the discovery of ProtoRAG, a DNA transposon family from lancelets, the most basal extant chordates. A typical ProtoRAG is flanked by 5-bp target site duplications and a pair of terminal inverted repeats (TIRs) resembling V(D)J recombination signal sequences. Between the TIRs reside tail-to-tail-oriented, intron-containing RAG1-like and RAG2-like genes. We demonstrate that ProtoRAG was recently active in the lancelet germline and that the lancelet RAG1/2-like proteins can mediate TIR-dependent transposon excision, host DNA recombination, transposition, and low-efficiency TIR rejoining using reaction mechanisms similar to those used by vertebrate RAGs. We propose that ProtoRAG represents a molecular "living fossil" of the long-sought RAG transposon.

Multi-omic machine learning predictor of breast cancer therapy response.

Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment1. The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic therapy2. Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded by ERBB2)-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery3 were then correlated with multi-omic features in these diagnostic biopsies. Here we show that response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.

BRAF-MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas.

BACKGROUND: Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy. METHODS: Eligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF-MEK inhibitor combination vemurafenib-cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data. RESULTS: Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events. CONCLUSIONS: In this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF-MEK inhibitor combination vemurafenib-cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.).

Neutralizing Antibody Responses to Viral Infections Are Linked to the Non-classical MHC Class II Gene H2-Ob.

Select humans and animals control persistent viral infections via adaptive immune responses that include production of neutralizing antibodies. The precise genetic basis for the control remains enigmatic. Here, we report positional cloning of the gene responsible for production of retrovirus-neutralizing antibodies in mice of the I/LnJ strain. It encodes the beta subunit of the non-classical major histocompatibility complex class II (MHC-II)-like molecule H2-O, a negative regulator of antigen presentation. The recessive and functionally null I/LnJ H2-Ob allele supported the production of virus-neutralizing antibodies independently of the classical MHC haplotype. Subsequent bioinformatics and functional analyses of the human H2-Ob homolog, HLA-DOB, revealed both loss- and gain-of-function alleles, which could affect the ability of their carriers to control infections with human hepatitis B (HBV) and C (HCV) viruses. Thus, understanding of the previously unappreciated role of H2-O (HLA-DO) in immunity to infections may suggest new approaches in achieving neutralizing immunity to viruses.

Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling.

Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.

SGLT2 inhibitor dapagliflozin protects the kidney in a murine model of Balkan nephropathy.

Proximal tubular uptake of aristolochic acid (AA) forms aristolactam (AL)-DNA adducts, which cause a p53/p21-mediated DNA damage response and acute tubular injury. Recurrent AA exposure causes kidney function loss and fibrosis in humans (Balkan endemic nephropathy) and mice and is a model of (acute kidney injury) AKI to chronic kidney disease (CKD) transition. Inhibitors of the proximal tubule sodium-glucose transporter SGLT2 can protect against CKD progression, but their effect on AA-induced kidney injury remains unknown. C57BL/6J mice (15-wk-old) were administered vehicle or AA every 3 days for 3 wk (10 and 3 mg/kg ip in females and males, respectively). Dapagliflozin (dapa, 0.01 g/kg diet) or vehicle was initiated 7 days prior to AA injections. All dapa effects were sex independent, including a robust glycosuria. Dapa lowered urinary kidney-injury molecule 1 (KIM-1) and albumin (both normalized to creatinine) after the last AA injection and kidney mRNA expression of early DNA damage response markers (p53 and p21) 3 wk later at the study end. Dapa also attenuated AA-induced increases in plasma creatinine as well as AA-induced up-regulation of renal pro-senescence, pro-inflammatory and pro-fibrotic genes, and kidney collagen staining. When assessed 1 day after a single AA injection, dapa pretreatment attenuated AL-DNA adduct formation by 10 and 20% in kidney and liver, respectively, associated with reduced p21 expression. Initiating dapa application after the last AA injection also improved kidney outcome but in a less robust manner. In conclusion, the first evidence is presented that pretreatment with an SGLT2 inhibitor can attenuate the AA-induced DNA damage response and subsequent nephropathy.NEW & NOTEWORTHY Recurrent exposure to aristolochic acid (AA) causes kidney function loss and fibrosis in mice and in humans, e.g., in the form of the endemic Balkan nephropathy. Inhibitors of the proximal tubule sodium-glucose transporter SGLT2 can protect against CKD progression, but their effect on AA-induced kidney injury remains unknown. Here we provide the first evidence in a murine model that pretreatment with an SGLT2 inhibitor can attenuate the AA-induced DNA damage response and subsequent nephropathy.

A single dominant locus restricts retrovirus replication in YBR/Ei mice.

Differential responses to viral infections are influenced by the genetic makeup of the host. Studies of resistance to retroviruses in human populations are complicated due to the inability to conduct proof-of-principle studies. Inbred mouse lines, which have a range of susceptible phenotypes to retroviruses, are an ideal tool to identify and characterize mechanisms of resistance and define their genetic underpinnings. YBR/Ei mice become infected with Mouse Mammary Tumor Virus, a mucosally transmitted murine retrovirus, but eliminate the virus from their pedigrees. Virus elimination correlates with a lack of virus-specific neonatal oral tolerance, which is a major mechanism for blocking the anti-virus response in susceptible mice. Virus control is unrelated to virus-neutralizing antibodies, cytotoxic CD8+ T cells, NK cells, and NK T cells, which are the best characterized mechanisms of resistance to retroviruses. We identified a single, dominant locus that controls the resistance mechanism, which we provisionally named attenuation of virus titers (Avt) and mapped to the distal region of chromosome 18. IMPORTANCE Elucidation of the mechanism that mediates resistance to retroviruses is of fundamental importance to human health, as it will ultimately lead to knowledge of the genetic differences among individuals in susceptibility to microbial infections.

Spinal cord ischemia and reinterventions following thoracic endovascular repair for acute type B aortic dissections.

OBJECTIVE: The technical aspects of thoracic endovascular aortic repair (TEVAR) for acute type B aortic dissection (TBAD), specifically the location of proximal seal zone (PSZ) (need to cover the left subclavian artery [LSA]), distal seal zone (DSZ) (length of aortic coverage), benefit of LSA revascularization, and prophylactic lumbar drainage are still debated. Each of these issues has potential benefits but also has known risks. This study aims to identify factors associated with reintervention and spinal cord ischemia (SCI) following TEVAR for acute TBAD with a zone 3 entry tear. METHODS: The Vascular Quality Initiative was queried for TEVARs performed for acute TBAD with zone 3 entry tear, zone 3 proximal zone of disease, treated with TEVAR extending between zone 2 and zone 5. The primary outcomes were SCI and related reintervention. Secondary outcomes were stroke, arm ischemia, and retrograde type A dissection (RTAD). The exposure variables were PSZ 2 vs 3, DSZ 4 vs 5, prophylactic lumbar drain, and LSA revascularization. Univariate analyses were conducted with χ2 analysis, and multivariable logistic regression was used to evaluate association with outcomes. RESULTS: Of 583 patients who met inclusion criteria, 266 had PSZ 2 and 317 had PSZ 3. On univariate analysis, PSZ 2 was associated with a higher rate of reintervention, but PSZ2 was not significant on multivariable analysis after accounting for age, sex, race, smoking, PSZ, DSZ, prophylactic lumbar drain, and LSA patency. PSZ 2 was not associated with SCI, arm ischemia, or RTAD. PSZ 2 was associated with a trend towards a higher rate of stroke. DSZ 4 and DSZ 5 were performed in 161 and 422 TEVARs, respectively, and DSZ 5 was associated with a higher rate of SCI on univariate (3 [1.9%] vs 39 [9.2%]; P = .01) and multivariable (odds ratio, 7.384; 95% confidence interval, 2.193-24.867; P = .001) analyses. Prophylactic lumbar drain placement was not statistically significantly associated with SCI, but lack of postoperative LSA patency was associated with SCI (odds ratio, 2.966; 95% confidence interval, 1.016-8.656; P = .05). CONCLUSIONS: This study found that PSZ 2 was not associated with lower reinterventions or higher rates of SCI but trended towards a higher rate of stroke than PSZ 3. Additionally, DSZ 5 was strongly associated with SCI when compared with DSZ 4, highlighting the importance of limiting aortic coverage to coverage of the proximal entry tear when possible.

Biomarkers of peanut allergy in children over time.

BACKGROUND: Various biomarkers are used to define peanut allergy (PA). We aimed to observe changes in PA resolution and persistence over time comparing biomarkers in PA and peanut sensitised but tolerant (PS) children in a population-based cohort. METHODS: Participants were recruited from the EAT and EAT-On studies, conducted across England and Wales, and were exclusively breastfeed babies recruited at 3 months old and followed up until 7-12 years old. Clinical characteristics, skin prick test (SPT), sIgE to peanut and peanut components and mast cell activation tests (MAT) were assessed at 12 months, 36 months and 7-12 years. PA status was determined at the 7-12 year time point. RESULTS: The prevalence of PA was 2.1% at 7-12 years. Between 3 and 7-12 year, two children developed PA and one outgrew PA. PA children had larger SPT, higher peanut-sIgE, Ara h 2-sIgE and MAT (all p < .001) compared to PS children from 12 months onwards. SPT, peanut-sIgE, Ara h 2-sIgE and MAT between children with persistent PA, new PA, outgrown PA and PS were statistically significant from 12 months onwards (p < .001). Those with persistent PA had SPT, peanut-sIgE and Ara h 2-sIgE that increased over time and MAT which was highest at 36 months. New PA children had increased SPT and peanut-sIgE from 36 months to 7-12 years, but MAT remained low. PS children had low biomarkers across time. CONCLUSIONS: In this cohort, few children outgrow or develop new PA between 36 months and 7-12 years. Children with persistent PA have raised SPT, peanut-sIgE, Ara h 2-sIgE and MAT evident from infancy that consistently increase over time.

Telemedicine with special focus on allergic diseases and asthma-Status 2022: An EAACI position paper.

Efficacious, effective and efficient communication between healthcare professionals (HCP) and patients is essential to achieve a successful therapeutic alliance. Telemedicine (TM) has been used for decades but during the COVID-19 pandemic its use has become widespread. This position paper aims to describe the terminology and most important forms of TM among HCP and patients and review the existing studies on the uses of TM for asthma and allergy. Besides, the advantages and risks of TM are discussed, concluding that TM application reduces costs and time for both, HCP and patients, but cannot completely replace face-to-face visits for physical examinations and certain tests that are critical in asthma and allergy. From an ethical point of view, it is important to identify those involved in the TM process, ensure confidentiality and use communication channels that fully guarantee the security of the information. Unmet needs and directions for the future regarding implementation, data protection, privacy regulations, methodology and efficacy are described.

The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Serologic measurements for peanut allergy: Predicting clinical severity is complex.

Allergist-immunologists use serologic peanut allergy testing to maximize test sensitivity and specificity while minimizing cost and inconvenience. Recent advances toward this goal include a better understanding of specific IgE (sIgE) and component testing, epitope-sIgE assays, and basophil activation testing. Predicting reaction severity with serologic testing is challenged by a range of co-factors that influence reaction severity, such as the amount and form of any allergen consumed and comorbid disease. In 2020, the Allergy Immunology Joint Task Force on Practice Parameters recommended Ara h 2-sIgE as the most cost-effective diagnostic test for peanut allergy because of its superior performance, when compared with skin prick testing and serum IgE. Basophil activation testing, a functional test of allergic response not evaluated in the Joint Task Force on Practice Parameters guideline, is a promising option for both allergy diagnosis and prognosis. Similarly, epitope-sIgE testing may improve prediction of reaction thresholds, but further validation is needed. Despite advances in food allergy testing, many of these tools remain limited by cost, accessibility, and feasibility. In addition, there is a need for further research on how atopic dermatitis may be modifying serologic food allergy severity assessments. Given these limitations, allergy test selection requires a shared decision-making approach so that a patient's values and preferences regarding financial impact, inconvenience, and psychological effects are considered in the context of clinician expertise on the timing and use of optimized testing.

Skin as the target for allergy prevention and treatment.

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a TH2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, such as the gut, may be crucial for lowering the risk and preventing atopic diseases, particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in patients with atopic dermatitis, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1, and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and topical calcineurin inhibitors, along with pioneering trials proposed to change their current use (Prevention of Allergy via Cutaneous Intervention and Stopping Eczema and ALlergy). We provide an overview of the novel therapies that enhance the skin barrier, such as probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and interleukin and janus kinases inhibitors. Last, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy and the experimental use of single-dose of adeno-associated virus vector gene immunotherapy.

Epidemiology of alcohol use and alcohol use disorders among people living with HIV on antiretroviral therapy in Northwest Tanzania: implications for ART adherence and case management.

Alcohol use disorders (AUD) among people living with HIV (PLHIV) are associated with poor health outcomes. This cross-sectional study examined current alcohol use and AUD among 300 PLHIV on ART at four HIV care centres in Northwest Tanzania. Participants' data were collected using questionnaires. Alcohol use was assessed using Alcohol Use Disorders Identification Test (AUDIT). Logistic regression was used to examine associations between each outcome (current drinking and AUD) and sociodemographic and clinical factors. Association between alcohol use and ART adherence was also studied. The median age of participants was 43 years (IQR 19-71) and 41.3% were male. Twenty-two (7.3%) participants failed to take ART at least once in the last seven days. The prevalence of current drinking was 29.3% (95% CI 24.2-34.8%) and that of AUD was 11.3% (8.2%-15.5%). Males had higher odds of alcohol use (OR 3.03, 95% CI 1.79-5.14) and AUD (3.89, 1.76-8.60). Alcohol use was associated with ART non-adherence (OR = 2.78, 1.10-7.04). There was a trend towards an association between AUD and non-adherence (OR = 2.91, 0.92-9.21). Alcohol use and AUD were common among PLHIV and showed evidence of associations with ART non-adherence. Screening patients for alcohol use and AUD in HIV clinics may increase ART adherence.

Effectiveness of preoxygenation strategies: a systematic review and network meta-analysis.

BACKGROUND: Preoxygenation is universally recommended before induction of general anaesthesia to prolong safe apnoea time. The optimal technique for preoxygenation is unclear. We conducted a systematic review to determine the preoxygenation technique associated with the greatest effectiveness in adult patients having general anaesthesia. METHODS: We searched six databases for randomised controlled trials of patients aged ≥16 yr, receiving general anaesthesia in any setting and comparing different preoxygenation techniques and methods. Our primary effectiveness outcome was safe apnoea time, and secondary outcomes included incidence of arterial oxygen desaturation; lowest SpO2 during airway management; time to end-tidal oxygen concentration of 90%; and [Formula: see text] and [Formula: see text] at the end of preoxygenation. We assessed the quality of evidence according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) recommendations. RESULTS: We included 52 studies of 3914 patients. High-flow nasal oxygen with patients in a head-up position was most likely to be associated with a prolonged safe apnoea time when compared with other strategies, with a mean difference (95% credible interval) of 291 (138-456) s and 203 (79-343) s compared with preoxygenation with a facemask in the supine and head-up positions, respectively. Subgroup analysis of studies without apnoeic oxygenation also showed high-flow nasal oxygen in the head-up position as the highest ranked technique, with a statistically significantly delayed mean difference (95% credible interval) safe apnoea time compared with facemask in supine and head-up positions of 222 (63-378) s and 139 (15-262) s, respectively. High-flow nasal oxygen was also the highest ranked technique for increased [Formula: see text] at the end of preoxygenation. However, the incidence of arterial desaturation was less likely to occur when a facemask with pressure support was used compared with other techniques, and [Formula: see text] was most likely to be lowest when preoxygenation took place with patients deep breathing in a supine position. CONCLUSIONS: Preoxygenation of adults before induction of general anaesthesia was most effective in terms of safe apnoea time when performed with high-flow nasal oxygen with patients in the head-up position in comparison with facemask alone. Also, high-flow nasal oxygen in the head-up position is likely to be the most effective technique to prolong safe apnoea time among those evaluated. Clinicians should consider this technique and patient position in routine practice. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42022326046.

Inequalities in the recovery of colorectal cancer services during the COVID-19 pandemic: a national population-based study.

AIM: Evidence is lacking on whether there were inequalities in the recovery of colorectal cancer (CRC) services within the English National Health Service (NHS) following the COVID-19 pandemic. The aim of this study was to evaluate recovery according to patient age and socioeconomic status. METHOD: Using routinely collected data, CRC patients diagnosed and treated in the English NHS were identified for two timeframes: the 'initial pandemic period' (April-June 2020) and the 'pandemic period' (April 2020-March 2022). Poisson models evaluated changes in numbers of diagnoses, major resections, adjuvant chemotherapy and neoadjuvant radiotherapy use for each timeframe, relative to the equivalent pre-pandemic timeframe (April-June 2019 and April 2018-March 2020, respectively), stratified by age and socioeconomic status. Tumour stage at presentation was evaluated over time. RESULTS: Substantial deficits in diagnoses, major resections and adjuvant chemotherapy were identified in the initial pandemic period, whilst the use of neoadjuvant radiotherapy increased. Overall, these deficits recovered. Patients outside screening age, and in the most deprived group, had greater deficits in diagnoses and major resections. There was no evidence of stage migration by June 2021. CONCLUSIONS: CRC services showed recovery to baseline during the pandemic. However, evident inequalities must be addressed in ongoing recovery efforts. Long-term outcomes will fully establish the impact of the pandemic on CRC patients.

Admission avoidance hospital at home.

BACKGROUND: Admission avoidance hospital at home provides active treatment by healthcare professionals in the patient's home for a condition that would otherwise require acute hospital inpatient care, and always for a limited time period. This is the fourth update of this review. OBJECTIVES: To determine the effectiveness and cost of managing patients with admission avoidance hospital at home compared with inpatient hospital care. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and CINAHL on 24 February 2022, and checked the reference lists of eligible articles. We sought ongoing and unpublished studies by searching ClinicalTrials.gov and WHO ICTRP, and by contacting providers and researchers involved in the field. SELECTION CRITERIA: Randomised controlled trials recruiting participants aged 18 years and over. Studies comparing admission avoidance hospital at home with acute hospital inpatient care. DATA COLLECTION AND ANALYSIS: We followed the standard methodological procedures expected by Cochrane and the Effective Practice and Organisation of Care (EPOC) Group. We performed meta-analysis for trials that compared similar interventions, reported comparable outcomes with sufficient data, and used individual patient data when available. We used the GRADE approach to assess the certainty of the body of evidence for the most important outcomes. MAIN RESULTS: We included 20 randomised controlled trials with a total of 3100 participants; four trials recruited participants with chronic obstructive pulmonary disease; two trials recruited participants recovering from a stroke; seven trials recruited participants with an acute medical condition who were mainly older; and the remaining trials recruited participants with a mix of conditions. We assessed the majority of the included studies as at low risk of selection, detection, and attrition bias, and unclear for selective reporting and performance bias. For an older population, admission avoidance hospital at home probably makes little or no difference on mortality at six months' follow-up (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.68 to 1.13; P = 0.30; I2 = 0%; 5 trials, 1502 participants; moderate-certainty evidence); little or no difference on the likelihood of being readmitted to hospital after discharge from hospital at home or inpatient care within 3 to 12 months' follow-up (RR 1.14, 95% CI 0.97 to 1.34; P = 0.11; I2 = 41%; 8 trials, 1757 participants; moderate-certainty evidence); and probably reduces the likelihood of living in residential care at six months' follow-up (RR 0.53, 95% CI 0.41 to 0.69; P < 0.001; I2 = 67%; 4 trials, 1271 participants; moderate-certainty evidence). Hospital at home probably results in little to no difference in patient's self-reported health status (2006 patients; moderate-certainty evidence). Satisfaction with health care received may be improved with admission avoidance hospital at home (1812 participants; low-certainty evidence); few studies reported the effect on caregivers. Hospital at home reduced the initial average hospital length of stay (2036 participants; low-certainty evidence), which ranged from 4.1 to 18.5 days in the hospital group and 1.2 to 5.1 days in the hospital at home group. Hospital at home length of stay ranged from an average of 3 to 20.7 days (hospital at home group only). Admission avoidance hospital at home probably reduces costs to the health service compared with hospital admission (2148 participants; moderate-certainty evidence), though by a range of different amounts and using different methods to cost resource use, and there is some evidence that it decreases overall societal costs to six months' follow-up. AUTHORS' CONCLUSIONS: Admission avoidance hospital at home, with the option of transfer to hospital, may provide an effective alternative to inpatient care for a select group of older people who have been referred for hospital admission. The intervention probably makes little or no difference to patient health outcomes; may improve satisfaction; probably reduces the likelihood of relocating to residential care; and probably decreases costs.

Airway management in patients with suspected or confirmed cervical spine injury: Guidelines from the Difficult Airway Society (DAS), Association of Anaesthetists (AoA), British Society of Orthopaedic Anaesthetists (BSOA), Intensive Care Society (ICS), Neuro Anaesthesia and Critical Care Society (NACCS), Faculty of Prehospital Care and Royal College of Emergency Medicine (RCEM).

BACKGROUND: There are concerns that airway management in patients with suspected or confirmed cervical spine injury may exacerbate an existing neurological deficit, cause a new spinal cord injury or be hazardous due to precautions to avoid neurological injury. However, there are no evidence-based guidelines for practicing clinicians to support safe and effective airway management in this setting. METHODS: An expert multidisciplinary, multi-society working party conducted a systematic review of contemporary literature (January 2012-June 2022), followed by a three-round Delphi process to produce guidelines to improve airway management for patients with suspected or confirmed cervical spine injury. RESULTS: We included 67 articles in the systematic review, and successfully agreed 23 recommendations. Evidence supporting recommendations was generally modest, and only one moderate and two strong recommendations were made. Overall, recommendations highlight key principles and techniques for pre-oxygenation and facemask ventilation; supraglottic airway device use; tracheal intubation; adjuncts during tracheal intubation; cricoid force and external laryngeal manipulation; emergency front-of-neck airway access; awake tracheal intubation; and cervical spine immobilisation. We also signpost to recommendations on pre-hospital care, military settings and principles in human factors. CONCLUSIONS: It is hoped that the pragmatic approach to airway management made within these guidelines will improve the safety and efficacy of airway management in adult patients with suspected or confirmed cervical spine injury.

Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease.

Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we show that both alternative splicing and alternative polyadenylation, two major steps in pre-mRNA processing, are significantly altered in non-alcoholic fatty liver disease (NAFLD). Moreover, we find that Serine and Arginine Rich Splicing Factor 10 (SRSF10) binding is enriched adjacent to consensus polyadenylation motifs and its expression is significantly decreased in NAFLD, suggesting a role mediating pre-mRNA dysregulation in this condition. Consistently, inactivation of SRSF10 in mouse and human hepatocytes in vitro, and in mouse liver in vivo, was found to dysregulate polyadenylation of key metabolic genes such as peroxisome proliferator-activated receptor alpha (PPARA) and exacerbate diet-induced metabolic dysfunction. Collectively our work implicates dysregulated pre-mRNA polyadenylation in obesity-induced liver disease and uncovers a novel role for SRSF10 in this process.