BACKGROUNDNo therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODSWe conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao 2 ) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao 2 ) to the fraction of inspired oxygen (Fio 2 ) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTSA total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS

Vascular inflammation may induce a number of diseases, including organ damage or failure, heart attack and stroke. The present study aimed to investigate the use of wogonin, a compound extracted from herbs, to mediate inflammatory reactions in vascular inflammation. Wogonin was loaded in a well‑characterized polymeric biomaterial carrier. In mice with streptozotocin‑induced vascular inflammation, wogonin treatment regulated the production of inflammatory cytokines, including interleukin‑6, tumor necrosis factor‑α and granulocyte macrophage colony‑stimulating factor. To understand the impact of wogonin on major immune cells, macrophages were treated with wogonin in vitro. It was determined that wogonin did not affect macrophage viability, and that wogonin regulated the relative ratio of M1 versus M2 macrophages. In addition, in co‑culture, wogonin decreased inflammatory cytokine production and regulated the activation of macrophage surface markers including CD80, CD86 and CD40. Results from the present study may aid in our understanding of the effects of wogonin in regulating inflammation, especially its effects on macrophages.

Background Cleidocranial dysplasia (CCD) is a rare autosomal dominant disorder mainly characterized by hypoplastic or absent clavicles, delayed closure of the fontanelles, multiple dental abnormalities, and short stature. Runt-related transcription factor 2 (RUNX2) gene variants can cause CCD, but are not identified in all CCD patients. Methods In this study, we detected genetic variants in seven unrelated children with CCD by targeted high-throughput DNA sequencing or Sanger sequencing. Results All patients carried a RUNX2 variant, totally including three novel pathogenic variants (c.722_725delTGTT, p.Leu241Serfs*8; c.231_232delTG, Ala78Glyfs*82; c.909C > G, p.Tyr303*), three reported pathogenic variants (c.577C > T, p.Arg193*; c.574G > A, p.Gly192Arg; c.673 C > T, p.Arg225Trp), one likely pathogenic variant (c.668G > T, p.Gly223Val). The analysis of the variant source showed that all variants were de novo except the two variants (c.909C > G, p.Tyr303*; c.668G > T, p.Gly223Val) inherited from the patient’s father and mother with CCD respectively. Further bioinformatics analysis indicated that these variants could influence the structure of RUNX2 protein by changing the number of H-bonds or amino acids. The experimental result showed that the Gly223Val mutation made RUNX2 protein unable to quantitatively accumulate in the nucleus. Conclusions The present study expands the pathogenic variant spectrum of RUNX2 gene, which will contribute to the diagnosis of CCD and better genetic counseling in the future.

Dysfunction of glucokinase (GCK) caused by mutations in the GCK gene is the main cause of maturity‐onset diabetes of the young type‐2 (MODY2, also known as GCK‐MODY), which is usually present in adolescence or young adulthood. MODY2 is characterized by mild, stable fasting hyperglycemia that presents at birth, usually 5.4–8.3 mmol L−1, and rarely develops complications from diabetes. The treatment of MODY2 prefers a manageable diet rather than the use of insulin. Previous studies have identified GCK mutations only by online software prediction or enzyme kinetic analysis and thermolability assays which are complicated to be conducted. In this study, six mutations in the GCK gene, including four novel mutations and two mutations that are previously reported, are identified. All the six locations are highly conserved according to the sequencing alignment. Moreover, missense mutations are strongly predicted to be pathogenic using online programs. Functional studies show that mutations in GCK mutation do not affect insulin secretion but affect glycogen synthesis. These findings demonstrate that GCK mutations decrease glycogen synthesis, which leads to hyperglycemia in MODY2. Meanwhile, this study provides a new perspective and methods for identifying pathogenic mutations in GCK.