Citations

CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.

Objective It is unclear whether endoscopic assessment of scars after colorectal endoscopic mucosal resection (EMR) has to include biopsies, even if endoscopy is negative. Vice versa, endoscopic diagnosis of recurrent adenoma may not require biopsy before endoscopic reinterventions. We prospectively analysed various endoscopic modalities in the diagnosis of recurrence following EMR. Design We conducted a prospective study of patients undergoing colonoscopy after EMR of large (≥20 mm) colorectal neoplasia. Endoscopists predicted recurrence and confidence level with four imaging modes: high-definition white light (WL) and narrow-band imaging (NBI) with and without near focus (NF). Separately, 26 experienced endoscopists assessed offline images. Results Two hundred and thirty patients with 255 EMR scars were included. The prevalence of recurrent adenoma was 24%. Diagnostic values were high for all modes (negative predictive value (NPV) ≥97%, positive predictive value (PPV) ≥81%, sensitivity ≥90%, specificity ≥93% and accuracy ≥93%). In high-confidence cases, NBI with NF had NPV of 100% (95% CI 98% to 100%) and sensitivity of 100% (95% CI 93% to 100%). Use of clips at initial EMR increased diagnostic inaccuracy (adjusted OR=1.68(95% CI 1.01 to 2.75)). In offline assessment, specificity was high for all imaging modes (mean: ≥93% (range: 55%–100%)), while sensitivity was significantly higher for NBI-NF (82%(72%–93%)%)) compared with WL (69%(38%–86%); p<0.001), WL-NF (68%(55%–83%); p<0.001) and NBI (71%(59%–90%); p<0.001). Conclusion Our study demonstrates very high sensitivity and accuracy for all four imaging modalities, especially NBI with NF, for diagnosis of recurrent neoplasia after EMR. Our data strongly suggest that in cases of high confidence negative optical diagnosis based on NBI-NF, no biopsy is needed to confirm absence of recurrence during colorectal EMR follow-up. A high confidence positive optical diagnosis can lead to immediate resection of any suspicious area. In all cases of low confidence, biopsy is still required. Trial registration number NCT02668198 .

Objective This systematic review and meta-analysis aim to evaluate the risk factors associated with postoperative opioid-induced respiratory depression (OIRD). Design Systematic review and meta-analysis. Data sources PubMed-MEDLINE, MEDLINE in-process, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed and Clinicaltrials.gov (January 1946 to November 2017). Eligibility criteria The inclusion criteria were: (1) adult patients 18 years or older who were administered opioids after surgery and developed postoperative OIRD (OIRD group); (2) all studies which reported both OIRD events and associated risk factors; (3) all studies with reported data for each risk factor on patients with no OIRD (control group) and (4) published articles in English language. Data analysis We used a random effects inverse variance analysis to evaluate the existing evidence of risk factors associated with OIRD. Newcastle-Ottawa scale scoring system was used to assess quality of study. Results Twelve observational studies were included from 8690 citations. The incidence of postoperative OIRD was 5.0 cases per 1000 anaesthetics administered (95% CI: 4.8 to 5.1; total patients: 841 424; OIRD: 4194). Eighty-five per cent of OIRD occurred within the first 24 hours postoperatively. Increased risk for OIRD was associated with pre-existing cardiac disease (OIRD vs control: 42.8% vs 29.6%; OR: 1.7; 95% CI: 1.2 to 2.5; I 2 : 0%; p<0.002), pulmonary disease (OIRD vs control: 17.8% vs 10.3%; OR: 2.2; 95% CI: 1.3 to 3.6; I 2 : 0%; p<0.001) and obstructive sleep apnoea (OIRD vs control: 17.9% vs 16.5%; OR: 1.4; 95% CI: 1.2 to 1.7; I 2 : 31%; p=0.0003). The morphine equivalent daily dose of the postoperative opioids was higher in the OIRD group than in the control; (24.7±14 mg vs 18.9±13.0 mg; mean difference: 2.8; 95% CI: 0.4 to 5.3; I 2 : 98%; p=0.02). There was no significant association between OIRD and age, gender, body mass index or American Society of Anesthesiologists physical status. Conclusion Patients with cardiac, respiratory disease and/or obstructive sleep apnoea were at increased risk for OIRD. Patients with postoperative OIRD received higher doses of morphine equivalent daily dose.

BACKGROUNDABO‐incompatible platelet transfusions are common, and transfusions with ABO‐incompatible plasma are increasing with the use of group A plasma and group O whole blood (WB) in emergencies. Many centers screen blood products for anti‐A and/or anti‐B titers to help prevent hemolysis from ABO‐incompatible transfusions, yet titer methods and definition of high titers are not standardized.STUDY DESIGN AND METHODSThis international multicenter study collected data on anti‐A and anti‐B titer practices for plasma, apheresis platelet (AP), and WB units from January 2015 through December 2017 to determine the prevalence of high‐titer units using local definitions.RESULTSA total of 87,701 plasma, AP and WB units were screened for high‐titer anti‐A and/or anti‐B. High‐titer detection rates for group A plasma ranged 0%–13.6%; group A AP 2.7%–9.3%; group O AP 2.3%–65.7%; and group O WB 6.4%–20.7%. At the one center that collected group B AP, the high‐titer rate was 10.9%. High‐titer rates varied from month to month, as well as between years for a given month. There was no clear pattern of when high‐titer units were donated.CONCLUSIONThe prevalence of high‐titer plasma, AP, and WB units varies by titer method and local definition of high titer. Even at the lowest titer threshold of 50, a significant proportion of units had a high‐titer antibody, although the clinical relevance of this finding needs further investigation.

Significance The energy-producing organelle mitochondrion contains its own compact genome, which is separate from the nuclear genome. In nearly all mammals, this mitochondrial genome is inherited exclusively from the mother, and transmission of paternal mitochondria or mitochondrial DNA (mtDNA) has not been convincingly demonstrated in humans. In this paper, we have uncovered multiple instances of biparental inheritance of mtDNA spanning three unrelated multiple generation families, a result confirmed by independent sequencing across multiple unrelated laboratories with different methodologies. Surprisingly, this pattern of inheritance appears to be determined in an autosomal dominantlike manner. This paper profoundly alters a widespread belief about mitochondrial inheritance and potentially opens a novel field in mitochondrial medicine.