A vanguard randomised feasibility trial comparing three regimens of peri-operative oxygen therapy on recovery after major surgery

International recommendations encourage liberal administration of oxygen to patients having surgery under general anaesthesia, ostensibly to reduce surgical site infection. However, the optimal oxygen regimen to minimise postoperative complications and enhance recovery from surgery remains uncertain. The hospital operating theatre randomised oxygen (HOT-ROX) trial is a multicentre, patient- and assessor-blinded, parallel-group, randomised clinical trial designed to assess the effect of a restricted, standard care, or liberal peri-operative oxygen therapy regimen on days alive and at home after surgery in adults undergoing prolonged non-cardiac surgery under general anaesthesia. Here, we report the findings of the internal vanguard feasibility phase of the trial undertaken in four large metropolitan hospitals in Australia and New Zealand that included the first 210 patients of a planned overall 2640 trial sample, with eight pre-specified endpoints evaluating protocol implementation and safety. We screened a total of 956 participants between 1 September 2019 and 26 January 2021, with data from 210 participants included in the analysis. Median (IQR [range]) time-weighted average intra-operative F_iO₂ was 0.30 (0.26–0.35 [0.20–0.59]) and 0.47 (0.44–0.51 [0.37–0.68]) for restricted and standard care, respectively (mean difference (95%CI) 0.17 (0.14–0.20), p < 0.001). Median time-weighted average intra-operative F_iO₂ was 0.83 (0.80–0.85 [0.70–0.91]) for liberal oxygen therapy (mean difference (95%CI) compared with standard care 0.36 (0.33–0.39), p < 0.001). All feasibility endpoints were met. There were no significant patient adverse events. These data support the feasibility of proceeding with the HOT-ROX trial without major protocol modifications.     

Functional outcomes and complications after treatment of distal radius fracture in patients sixty years and over: A systematic review and network meta-analysis

AimThis network meta-analysis aims to compare functional outcomes and complications between conservative treatment and surgery for distal radius fractures in patients aged 60 years and over.MethodsWe searched the PubMed, EMBASE, and Web of Science databases for randomized controlled trials (RCTs) assessing the effect of conservative treatment and surgery for distal radius fractures in patients aged 60 years and over. Primary outcomes included grip strength and overall complications. Secondary outcomes included Disabilities of the Arm, Shoulder, and Hand (DASH) scores, Patient-Rated Wrist Evaluation (PRWE) scores, wrist range of motion and forearm rotation, and radiographic assessment. All continuous outcomes were assessed using standardized mean differences (SMDs) with 95% confidence intervals (CIs), and binary outcomes were assessed using odds ratio (OR) with 95% CIs. The surface under the cumulative ranking curve (SUCRA) was used to determine a hierarchy of treatments. Cluster analysis was performed for grouping treatments based on the SUCRA values of primary outcomes.ResultsFourteen RCTs were included to compare conservative treatment, volar lockedplate (VLP), K-wires fixation, and external-fixation. VLP outperformed conservative treatment for 1-year and minimum 2-year grip strength (SMD; 0.28 [0.07 to 0.48] and 0.27 [0.02 to 0.53], respectively). VLP yielded the optimal grip strength at 1-year and minimum 2-year follow-up (SUCRA; 89.8% and 86.7%, respectively). In a subgroup analysis of patients aged 60 to 80 years old, VLP outperformed conservative treatment in DASH and PRWE scores (SMD, 0.33 [0.10, 0.56] and 0.23 [0.01, 0.45], respectively). In addition, VLP had the fewest complications (SUCRA = 84.3%). Cluster analysis suggested that VLP and K-wire fixation were more effective treatment groups.ConclusionEvidence to date demonstrates that VLP provides measurable benefits in grip strength and fewer complications to those 60 years of age and over, and that benefit is not reflected in current practice guidelines. There is a subgroup of patients where K-wire fixation outcomes are similar to those of VLP; defining this subgroup may yield substantial societal benefits.     

Heart Failure With Preserved Ejection Fraction in Diabetes: Mechanisms and Management

Diabetes mellitus (DM) is a major cause of heart failure in the Western world, either secondary to coronary artery disease or from a distinct entity known as “diabetic cardiomyopathy.” Furthermore, heart failure with preserved ejection fraction (HFpEF) is emerging as a significant clinical problem for patients with DM. Current clinical data suggest that between 30% and 40% of patients with HFpEF suffer from DM. The typical structural phenotype of the HFpEF heart consists of endothelial dysfunction, increased interstitial and perivascular fibrosis, cardiomyocyte stiffness, and hypertrophy along with advanced glycation end products deposition. There is a myriad of mechanisms that result in the phenotypical HFpEF heart including impaired cardiac metabolism and substrate utilization, altered insulin signalling leading to protein kinase C activation, advanced glycated end products deposition, prosclerotic cytokine activation (eg, transforming growth factor-β activation), along with impaired nitric oxide production from the endothelium. Moreover, recent investigations have focused on the role of endothelial-myocyte interactions. Despite intense research, current therapeutic strategies have had little effect on improving morbidity and mortality in patients with DM and HFpEF. Possible explanations for this include a limited understanding of the role that direct cell-cell communication or indirect cell-cell paracrine signalling plays in the pathogenesis of DM and HFpEF. Additionally, integrins remain another important mediator of signals from the extracellular matrix to cells within the failing heart and might play a significant role in cell-cell cross-talk. In this review we discuss the characteristics and mechanisms of DM and HFpEF to stimulate potential future research for patients with this common, and morbid condition.     

Antagomir-30d对大鼠骨髓基质干细胞成骨分化的影响

目的：探讨miR-30d拮抗剂（antagomir-30d）正性调控大鼠骨髓基质干细胞（BMSCs）的成骨分化作用并确认转染的最佳浓度。方法：BMSCs培养并分组，分为不同浓度的antagomir-30d（antagomir-30d组）、阴性对照（NC组）和未做转染的BMSCs（空白组）；将不同浓度的antagomir-30d及其NC转染至BMSCs后进行成骨诱导。通过RT-PCR技术进行比较，测定成骨基因碱性磷酸酶（ALP）、骨钙素（OC）、Runt相关转录因子2（RUNX2）的mRNA的表达情况，并确定最佳转染浓度及其转染效率。通过ALP染色验证antagomir-30d对成骨分化的调控作用。结果：RT-PCR结果表明，antagomir-30d体外可以促进BMSCs的成骨分化。不同浓度antagomir-30d组的成骨基因表达量随浓度变化而改变，当antagomir-30d转染浓度为150 nmol/L时，ALP、OC、RUNX2的mRNA水平均显著高于空白组和NC组（P＜0.05）。Antagomir-30d的转染最佳浓度为150 nmol/L，此时ALP染色结果显示其活性最高，成骨分化作用好。结论：Antagomir-30d体外正性调控BMSCs的成骨分化，其转染至BMSCs的最佳浓度为150 nmol/L。     

Stratification of Gallstones in the Gallbladder

A clinical approach to the diagnosis of congenital cardiac malformations is described which the authors have found effective in exposing the important signs and their significance. Each available diagnostic method is evaluated separately before all data are correlated.

Clinical diagnosis based on history, physical examination, roentgenography and electrocardiography was 94 per cent accurate in a series of cases seen in office consultation and 90 per cent accurate in a series of hospital cases reviewed. The significance of the various signs and symptoms that are routinely searched for in the physical examination is discussed.

The salient points in the clinical diagnosis of the common entities are presented.     

FOXP3 positive regulatory T-cells in cutaneous and systemic CD30 positive T-cell lymphoproliferations

The CD30-positive lymphoproliferations encompass a spectrum of disorders that share histological and phenotypic similarities but differ markedly in clinical behaviour. The basis for this diversity is not known, but it has been proposed that immune suppression by cytokines and/or regulatory T-cells (Tregs) may be implicated. In this study, skin biopsies from lymphomatoid papulosis (LyP) (n = 14), primary cutaneous anaplastic large cells lymphoma (C-ALCL) (n = 13) and systemic anaplastic large cells lymphoma (S-ALCL) with (n = 9) or without (n = 6) ALK expression were examined by immunohistology for FOXP3 expression in tumour cells and tumour infiltrating Tregs. Labelling of a majority of the neoplastic cells was seen in one case of C-ALCL. Another three cases (one LyP and two C-ALCL) displayed weak labelling of very occasional atypical T-cells. In the remaining 38 cases the atypical lymphoid infiltrate was FOXP3 negative. By contrast, all biopsies contained tumour infiltrating FOXP3-positive Tregs. Significant higher numbers were recorded in ALK negative S-ALCL and LyP than in C-ALCL and S-ALCL positive for ALK. In conclusion, it is shown that FOXP3 expression in cutaneous and systemic CD30-positive lymphoproliferations is generally confined to tumour infiltrating Tregs. These cells may have influence upon the clinical behaviour, possibly depending upon the net degree of Treg mediated immune suppression of tumour cells relative to tumour infiltrating, cytotoxic effector cells, thereby implicating the more favourable outcome of LyP compared to C-ALCL.     

Investigational therapies targeting lymphocyte antigens for the treatment of non-Hodgkin’s lymphoma

Introduction: The advent of the anti-CD20 mAb rituximab has opened a new era in the treatment of non-Hodgkin’s lymphomas (NHL), markedly altering standard treatment strategies. Moreover, the proof-of-concept that targeting a specific lymphocyte surface antigen may induce a highly effective and safe targeted killing of malignant cells has opened the door to the development of a plethora of novel mAbs directed towards different B- and T-cell-specific antigens.

Areas covered: This review discusses the recent available clinical data about new-generation anti-CD20 mAbs characterized by increased antibody- (obinutuzumab) or complement-dependent cyotoxicity (ofatumumab) as well as novel investigational agents targeting other lymphocyte antigens (e.g., CD19, CD22, CD30, CD40, CD52, CCR4), which are currently under investigation for B- and T-cell NHL treatment. In addition, antibody–drug conjugates (inotuzumab ozogamicin, brentuximab vedotin, polatuzumab vedotin), bispecific T-cell engagers (blinatumomab) and a new class of antibodies targeting cytotoxic T-lymphocyte-associated antigen 4, programmed death 1 or programmed death ligand 1 (immune checkpoint inhibitors) are specifically considered.

Expert opinion: Among the novel mAbs challenging rituximab, obinutuzumab seems to be in the most advanced phase, with the results of randomized trials awaited shortly. Brentuximab vedotin is increasing its role in T-cell NHL. Furthermore, immune checkpoint inhibitors have the potential to acquire a great relevance in NHL therapy.