Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

Severe odontogenic infections

Background : Severe odontogenic infections are serious potentially lethal conditions. Following the death of a patient in the authors' institution this study was initiated to determine the risk factors, management and outcome of a consecutive series of patients.
Methods : All patients admitted to the Royal Adelaide Hospital under the care of the Oral and Maxillofacial Surgery Unit with odontogenic infections in calendar year 2003 were investigated. Detailed information relative to their pre-presentation history, surgical and anaesthetic management and outcome was obtained and analysed.
Results : Forty-eight patients, 32M, 16F, average age 34.5, range 19 to 88 years were treated. All presented with pain and swelling, with 21 (44 per cent) having trismus. Forty-four (92 per cent) were as a result of dental neglect and four (8 per cent) were regular dental patients having endodontic treatment which failed. Of those known to have been treated prior to presentation, most had been on antibiotics. Most patients had aggressive surgical treatment with extraction, surgical drainage, high dose intravenous antibiotics and rehydration. The hospital stay was 3.3 (range 1–16) days. Patients requiring prolonged intubation and high dependency or intensive care (40 per cent) had longer hospitalization. No patient died and all fully recovered.
Conclusion : Severe odontogenic infections are a serious risk to the patient's health and life. Management is primarily surgical with skilled anaesthetic airway management. Antibiotics are required in high intravenous doses as an adjunct and not as a primary treatment.     

Radiation dose reduction during hysterosalpingography: an application of scanning-beam digital radiography

Hysterosalpingography was performed in 31 patients by means of a low-dose scanning-beam digital radiographic system. The technique permits adequate evaluation of gynecologic abnormalities while allowing significant reduction in radiation: 2.4-mR (6.1 X 10(-7) C/kg) exposure to the skin and 0.7-mrad (7 X 10(-6) Gy) mean dose to the ovaries per image obtained. Sixteen patients demonstrated readily recognizable and documented abnormalities, corroborated by laparoscopy, laparotomy, or other supportive evidence.     

缺血性卒中或短暂性脑缺血发作患者的卒中预防指南

这份新声明旨在为缺血性卒中或短暂性脑缺血发作存活者的缺血性卒中预防提供全面和及时的循证推荐，循证推荐包括对危险因素的控制，动脉粥样硬化性疾病的干预措施，心源性栓塞的抗栓治疗以及非心源性卒中抗血小板药的应用。另外，还为其他多种特殊情况下复发性卒中的预防提供了推荐、包括动脉夹层分离、卵圆孔未闭、高同型半胱氨酸血症、高凝状态、镰状细胞病、脑静脉窦血栓形成、女性卒中（特别是与妊娠和绝经后激素替代治疗相关卒中），脑出血后肮凝药的应用，以及该指南在高危人群中执行和应用的特殊措施。     

Comorbidities of migraine: a user-friendly overview

Comorbidity of migraine is important from a number of different perspectives. Co-occurrence of different diseases may complicate diagnosis as a high degree of symptomatic overlap may occur among conditions associated with migraine. Furthermore, comorbidity has also important implications for treatment. The commonest comorbidities of migraine are represented by psychiatric disorders, epilepsy, tremor, stroke, and cardiovascular abnormalities.     

Synthesis and characterization of dextran carboxylates for the specific chemical modification of human hemoglobin

The present study deals with the fixing of benzenehexacarboxylate (BHC) on dextran, with the aim of obtaining polyanionic polymers capable of decreasing the oxygen affinity of hemoglobin (Hb) by interacting with its phosphate binding site (allosteric site). The covalent coupling of these polymers onto oxyHb has been investigated for the synthesis of oxygen carriers with low oxygen affinity. This type of covalent conjugate could be of interest in intravascular use. Several steps were necessary to synthesize dextran with linked BHC (DEX-BHC). In each step, the structure of the modified dextran was determined by means of gel permeation chromatography, ¹H and ¹³C NMR spectroscopy, and low-angle laser light scattering. The aim was to determine the conditions of the reaction which lead to a minimization of cross-linking phenomena. The DEX-BHC obtained (0,27 mmol BHC/g polymer) decreased the oxygen affinity of Hb in the same way as the natural effector, 2,3-diphosphoglycerate (2,3-DPG) i.e., by reacting specifically with the amines of the protein allosteric site. This decrease in oxygen affinity was more accentuated after covalent coupling onto oxyHb, which means that the fixing point was probably localized in the 2,3-DPG binding site.