Granthamdodd7304

Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.

Orotracheal intubation of infants using direct laryngoscopy can be challenging. We aimed to investigate whether video laryngoscopy with a standard blade done by anaesthesia clinicians improves the first-attempt success rate of orotracheal intubation and reduces the risk of complications when compared with direct laryngoscopy. We hypothesised that the first-attempt success rate would be higher with video laryngoscopy than with direct laryngoscopy.

In this multicentre, parallel group, randomised controlled trial, we recruited infants without difficult airways abnormalities requiring orotracheal intubation in operating theatres at four quaternary children's hospitals in the USA and one in Australia. We randomly assigned patients (11) to video laryngoscopy or direct laryngoscopy using random permuted blocks of size 2, 4, and 6, and stratified by site and clinician role. Guardians were masked to group assignment. The primary outcome was the proportion of infants with a successful first attempt at orotracheal i group compared with 15 (5%) in the direct laryngoscopy group (-3·7% [-6·5 to -0·9]; p=0·0087). Fewer oesophageal intubations occurred in the video laryngoscopy group (n=1 [<1%]) compared with in the direct laryngoscopy group (n=7 [3%]; -2·3 [-4·3 to -0·3]; p=0·028).

Among anaesthetised infants, using video laryngoscopy with a standard blade improves the first-attempt success rate and reduces complications.

Anaesthesia Patient Safety Foundation, Society for Airway Management, and Karl Storz Endoscopy.

Anaesthesia Patient Safety Foundation, Society for Airway Management, and Karl Storz Endoscopy.

Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia.

We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. selleck inhibitor All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1-2·3 × 10

cells per kg and adults received UCART19 doses of 6 × 10

cells, 6-8 × 10

cells, or 1·8-2·4 × 10

cells in a dose-escalation study. The primary outcowed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%.

These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable.

Servier.

Servier.

Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision.

TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (11) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8-10 weeks, or total mesorectal excision. Where the transanal endoscopUK.

Cancer Research UK.Caspase-4 is an intracellular sensor for cytosolic bacterial lipopolysaccharide (LPS) and underlies infection-elicited pyroptosis. It is unclear whether and how caspase-4 detects host-derived factors to trigger pyroptosis. Here we show that mitochondrial permeability transition (MPT) activates caspase-4 by promoting the assembly of a protein complex, which we term the Apaf-1 pyroptosome, for the execution of facilitated pyroptosis. MPT, when induced by bile acids, calcium overload, or an adenine nucleotide translocator 1 (ANT1) activator, triggers assembly of the pyroptosome comprised of Apaf-1 and caspase-4 with a stoichiometry ratio of 72. Unlike the direct cleavage of gasdermin D (GSDMD) by caspase-4 upon LPS ligation, caspase-4 activated in the Apaf-1 pyroptosome proceeds to cleave caspase-3 and thereby GSDME to induce pyroptosis. Caspase-4-initiated and GSDME-executed pyroptosis underlies cholestatic liver failure. These findings identify Apaf-1 pyroptosome as a pivotal machinery for cells sensing MPT signals and may shed light on understanding how cells execute intrinsic pyroptosis under sterile conditions.Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p less then 5 × 10-5) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.