Volume 135 · Issue 10 · 2022

Severe asthma is "asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming 'uncontrolled’ or which remains 'uncontrolled’ despite this therapy." The state of control was defined by symptoms, exacerbations and the degree of airflow obstruction. Therefore, for the diagnosis of severe asthma, it is important to have evidence for a diagnosis of asthma with an assessment of its severity, followed by a review of comorbidities, risk factors, triggers and an assessment of whether treatment is commensurate with severity, whether the prescribed treatments have been adhered to and whether inhaled therapy has been properly administered. Phenotyping of severe asthma has been introduced with the definition of a severe eosinophilic asthma phenotype characterized by recurrent exacerbations despite being on high dose ICS and sometimes oral corticosteroids, with a high blood eosinophil count and a raised level of nitric oxide in exhaled breath. This phenotype has been associated with a Type-2 (T2) inflammatory profile with expression of interleukin (IL)-4, IL-5, and IL-13. Molecular phenotyping has also revealed non-T2 inflammatory phenotypes such as Type-1 or Type-17 driven phenotypes. Antibody treatments targeted at the T2 targets such as anti-IL5, anti-IL5Rα, and anti-IL4Rα antibodies are now available for treating severe eosinophilic asthma, in addition to anti-immunoglobulin E antibody for severe allergic asthma. No targeted treatments are currently available for non-T2 inflammatory phenotypes. Long-term azithromycin and bronchial thermoplasty may be considered. The future lies with molecular phenotyping of the airway inflammatory process to refine asthma endotypes for precision medicine.

Over the last 20 years, it has become possible to use a precision medicine approach to the management of chronic obstructive pulmonary disease (COPD). Clinical and physiological features as well as a blood biomarker can be used to target treatments to patients most likely to benefit and avoid treatment in patients less likely to benefit. Future advances in a precision medicine approach to COPD will depend on more precise characterization of individual patients, possibly using quantitative imaging, new physiological techniques, novel biomarkers and genetic profiling. Precision medicine has led to significant improvements in the management of COPD and clinicians should use all available information to optimize the treatment of individual patients.

Non-alcoholic fatty liver disease (NAFLD) is one of the fastest-growing diseases, and its global prevalence is estimated to increase >50% by 2030. NAFLD is comorbid with metabolic syndrome, obesity, type 2 diabetes, and insulin resistance. Despite extensive research efforts, there are no pharmacologic or biological therapeutics for the treatment of NAFLD. Bile acids and sphingolipids are well-characterized signaling molecules. Over the last few decades, researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism. Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis, inflammation, and fibrosis in patients with NAFLD. This clinical observation has been recapitulated in animal models, which are well-accepted by experts in the hepatology field. Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD. Moreover, the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology. In this review, we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD. A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease worldwide. It refers to a range of liver conditions affecting people who drink little or no alcohol. NAFLD comprises non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH), the more aggressive form of NAFLD. NASH is featured by steatosis, lobular inflammation, hepatocyte injury, and various degrees of fibrosis. Although much progress has been made over the past decades, the pathogenic mechanism of NAFLD remains to be fully elucidated. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear hormone receptor that is highly expressed in hepatocytes. Hepatic HNF4α expression is markedly reduced in NAFLD patients and mouse models of NASH. HNF4α has been shown to regulate bile acid, lipid, glucose, and drug metabolism. In this review, we summarize the recent advances in the understanding of the pathogenesis of NAFLD with a focus on the regulation of HNF4α and the role of hepatic HNF4α in NAFLD. Several lines of evidence have shown that hepatic HNF4α plays a key role in the initiation and progression of NAFLD. Recent data suggest that hepatic HNF4α may be a promising target for treatment of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is becoming increasingly common as the global economy grows and living standards improve. Timely and effective preventions and treatments for NAFLD are urgently needed. Retinol-binding protein-4 (RBP4), the protein that transports retinol through the circulation, was found to be positively related to diabetes, obesity, cardiovascular disease, and other metabolic diseases. Observational studies on the association between serum RBP4 level and the prevalence of NAFLD found contradictory results. Some of the underlying mechanisms responsible for this association have been revealed, and the possible clinical implications of treating NAFLD by targeting RBP4 have been demonstrated. Future studies should focus on the predictive value of RBP4 on NAFLD development and its potential as a therapeutic target in NAFLD.

Schnitzler syndrome is a rare disease of adult-onset with main features including chronic urticarial rash, recurrent fever, arthralgia or arthritis, monoclonal gammopathy of undetermined significance (MGUS), and marked systemic inflammation. Schnitzler syndrome is often underdiagnosed. Patients with Schnitzler syndrome may present to dermatologists and allergists for urticaria, hematologists for MGUS, or rheumatologists for arthritis. It is important to recognize Schnitzler syndrome for its remarkable response to interleukin (IL)-1 blockade. Besides, many cases of Schnitzler-like syndromes do not meet the diagnostic criteria of classical Schnitzler syndrome but display excellent response to IL-1 inhibitors. The overly produced IL-1 is the result of a somatic mosaic gain of function mutation of NLRP3 (nucleotide-binding oligomerization domain [NOD]-like receptor [NLR] family pyrin domain containing 3) gene in some patients with Schnitzler-like syndromes. Inflammasome activation is evident in patients with classical Schnitzler syndrome although no NLRP3 gene mutation is identified. Collectively, Schnitzler syndrome and Schnitzler-like syndromes represent a spectrum of IL-1 mediated adult-onset autoinflammatory diseases.

Immunotherapy that targets checkpoints, especially programmed cell death protein 1 and programmed cell death ligand 1, has revolutionized cancer therapy regimens. The overall response rate to mono-immunotherapy, however, is limited, emphasizing the need to potentiate the efficacy of these regimens. The functions of immune cells are modulated by multiple stimulatory and inhibitory molecules, including lymphocyte activation gene 3 (LAG-3). LAG-3 is co-expressed together with other inhibitory checkpoints and plays key roles in immune suppression. Increasing evidence, particularly in the last 5 years, has shown the potential of LAG-3 blockade in anti-tumor immunity. This review provides an update on the biological properties and clinical applications of LAG-3 in cancers.

The pandemic of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to major public health challenges globally. The increasing viral lineages identified indicate that the SARS-CoV-2 genome is evolving at a rapid rate. Viral genomic mutations may cause antigenic drift or shift, which are important ways by which SARS-CoV-2 escapes the human immune system and changes its transmissibility and virulence. Herein, we summarize the functional mutations in SARS-CoV-2 genomes to characterize its adaptive evolution to inform the development of vaccination, treatment as well as control and intervention measures.

Background: The complete mesogastrium excision (CME) based on D2 radical gastrectomy is believed to significantly reduce the local-regional recurrence compared with D2 radical gastrectomy in advanced gastric cancer, and it is widely used in China. This study aimed to explore whether D2 + CME is superior to D2 on surgical outcomes during gastrectomy from Chinese data. Methods: Feasible studies comparing the D2 + CME (D2 + CME group) and D2 (D2 group) published up to March 2020 are searched from electronic databases. The data showing surgical and complication outcomes are extracted to be pooled and analyzed. Results: Fourteen records including 1352 patients were included. The D2 + CME group had a shorter mean operative time (weighted mean difference [WMD] = -16.72 min, 95% confidence interval [CI]: -26.56 to - 6.87 min, P < 0.001), lower mean blood loss (WMD = -39.08 mL, 95% CI: -49.94 to -28.21 mL, P < 0.001), higher mean number of retrieved lymph nodes (WMD = 2.13, 95% CI: 0.58-3.67, P = 0.007), shorter time to first flatus (WMD =-0.31 d, 95% CI: -0.53 to - 0.10 d, P = 0.005), and postoperative hospital days (WMD =-1.09, 95% CI: -1.92 to -0.25, P = 0.010) than the D2 group. Subgroup analysis suggested that the advantages from the D2 + CME group were obvious in traditional open radical gastrectomy, proximal gastrectomy, and distal gastrectomy compared with D2 group. The evaluations of post-operative complications showed that the patients who underwent D2 + CME had a lower incidence of post-operative complications than the patients who underwent D2 surgery alone (relative risk [RR] = 0.65, 95% CI: 0.45-0.87, P = 0.003). The D2 radical gastrectomy plus CME improved 3-year overall survival (OS) (RR = 1.16, 95% CI: 1.02-1.32, P = 0.020) and lowered the local recurrence rate (RR = 0.51, 95% CI: 0.28-0.94, P = 0.030). The patients undergoing laparoscopic surgery or total gastrectomy had more significant advantages compared between D2 + CME and D2 groups in 3-year OS. Conclusion: The data from China show that D2 radical gastrectomy plus CME are reliable procedures and safety compared to D2 radical gastrectomy with faster recovery, lower risk, and better prognosis.

Background: Endoscopic bariatric therapies can help address widening management gaps in obesity. Their ability to facilitate weight loss is largely tied to influences on appetite through perturbations of gastric emptying and accommodation. As these tools gain traction in obesity therapy, their physiologic underpinnings require exploration, which may enhance efficacy, tolerance, and patient-tailored care. Methods: We prospectively assessed consecutive subjects with fluid-filled intragastric balloons (IGBs) (n = 18) placed between October 2016 and June 2017 or underwent endoscopic sleeve gastroplasty (ESG) (n = 23) from March 2018 to June 2018. Patients underwent physiologic appraisal at 3 months with 13C-spirulina-based gastric emptying breath test to determine time to half emptying (T50), as well as maximum tolerated volume (MTV) of a standard nutrient drink test. Changes in T50 and MTV at 3 months were compared with percent total body weight loss (%TBWL) at 3 and 6 months using best-fit linear regression. Results: The change in T50 at 3 months correlated with %TBWL at 3 months for IGB (P = 0.01) and ESG (P = 0.01) but with greater impact on %TBWL in IGB compared to ESG (R2 = 0.42 vs. 0.26). Change in T50 at 3 months was predictive of weight loss at 6 months for IGB (P = 0.01) but not ESG (P = 0.11). ESG was associated with greater decrease in MTV compared to IGB (340.25 ± 297.97 mL vs. 183.00 ± 217.13 mL, P = 0.08), indicting an enhanced effect on satiation through decreased gastric accommodation. Changes in MTV at 3 months did not correlate with %TBWL for either IGB (P = 0.26) or ESG (P = 0.49) but trended toward significance for predicting %TBWL at 6 months for ESG (P = 0.06) but not IGB (P = 0.19). Conclusion: IGB and ESG both induce weight loss but likely through distinct gastric motor function phenotypes, and gastric emptying may predict future weight loss in patients with IGB.

Backgrounds: Inadequate sleep duration is associated with a higher risk of type 2 diabetes and the relationship is nonlinear. We aim to assess the curve relationship between night sleep duration and the incidence of type 2 diabetes in China. Methods: A cohort of 11,539 participants from the REACTION study without diabetes at baseline (2011) were followed until 2014 for the development of type 2 diabetes. The average number of hours of sleep per night was grouped. Incidence rates and odds ratios (ORs) were calculated for the development of diabetes in each sleep duration category. Results: Compared to people who sleep for 7 to 8 h/night, people with longer sleep duration (≥9 h/night) had a greater risk of type 2 diabetes (OR: 1.27; 95% CI: 1.01-1.61), while shorter sleep (<6 h/night) had no significant difference in risk of type 2 diabetes. When the dataset was stratified based on selected covariates, the association between type 2 diabetes and long sleep duration became more evident among individuals <65 years of age, male, body mass index <24 kg/m2 or with hypertension or hyperlipidemia, no interaction effects were observed. Furthermore, compared to people persistently sleeping 7 to 9 h/night, those who persistently slept ≥9 h/night had a higher risk of type 2 diabetes. The optimal sleep duration was 6.3 to 7.5 h/night. Conclusions: Short or long sleep duration was associated with a higher risk of type 2 diabetes. Persistently long sleep duration increased the risk.