The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis.

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

First report of leaf blight caused by Nigrospora hainanensis on Euonymus japonicus in China.

Euonymus japonicus Thunb., belonging to the family Celastreace and native to East Asia, is a widely cultivated evergreen ornamental woody plant with important ecological and economic values. In May 2023, serious leaf blight of E. japonicus occurred in the campus green space at Guiyang University, Guizhou Province, China (26°55'85"N, 106°78'04"E). Early symptom appeared as small, circular light brown spots on the edges or tips of the leaves. Then, the spot developed visible necrosis, initially light brown to dark brown halos with clear margins. Subsequently, severely infected leaves appear totally wilt, and significantly decrease their ornamental values. In a 0.07-ha field, the disease incidence reached to 40-55%. To identify the pathogen, ten typical symptomatic E. japonicus leaves were collected. They were initially immersed in 75% ethanol for 3 min, and by sodium hypochlorite (4% NaClO) solution for 45 s, and ultimately rinsed with sterile distilled water (dH2O) five times for not less than 1 min each time, then, placed the leaves on potato dextrose agar (PDA) medium and cultured for 5 days at 25°C in constant temperature incubator. Cultures were purified to yield eight isolates. Early colonies are white and regularly rounded, gradually turning dark brown to black with fluffy mycelium. Conidia were single celled, smooth, black, spherical or ellipsoidal. The conidia size of the representative strain, GY-2 and GY-3, was averagely 12.3-17.3 µm × 10.8-17 µm (n = 50). The conidiogenous cells were monoblastic, hyaline, globose or ampulliform. Morphology-based identification revealed the strain as Nigrospora spp. (Wang et al., 2017). For further confirmation, PCR of GY-2 and GY-3 DNA was performed with the primers ITS1/ITS4 (White et al., 1990), Bt2a-F/Bt2b-R (Glass and Don-aldson 1995), and TEF1-728F/TEF1-986R (Carbone and Kohn 1999). Sequences of the ITS region, TUB and TEF1 genes from the strain GY-2 and GY-3 were deposited in GenBank. (GY-2: OR999377, PP112221 and PP150467; GY-3: PP406871, PP421045 and PP421046, respectively). BLAST analysis showed GY-2 100%, 100%, and 98.36%; GY-3 99.43%, 98.21% and 100% (ITS region, TEF1, and TUB) identity to N. hainanensis sequences (accession numbers. NR_153480.1, KY019415.1, and KY019464.1; KX986094.1, OP611475.1, and KY019597.1). Additionally, tandem sequences of ITS, TUB and TEF1 constructed by MEGA 7.0 confimed the homology through the phylogenetic tree. Pathogenicity tests were conducted on healthy plants grown, each 5 mm diameter of active growing mycelium plug of isolate GY-2 was attached to 15 leaves from five healthy 2-year-old E. japonicu plants. The same number of leaves in the control group were treated with non-inoculated plugs only. All the plants were incubated at 25°C and 75% relative humidity with a 16-h/8-h photoperiod. After 10 days, no symptoms appeared on the leaves of the control group. In contrast, symptomatic blight appeared on all leaves inoculated with GY-2. Pathogenicity tests were performed five times. Pure strains were re-isolated from diseased leaves and, confirmed to be N. hainanensis based on the above methods. Recently, Nigrospora oryzae was reported as causal agent of leaf spots on Euonymus japonicus in China (Xu et al., 2023). To our knowledge, this study is the first report of N. hainanensis causing leaf blight on E. japonicu. Identification of the etiological agent may provide assistance for sustainable management in the future.

Improvement of straw decomposition and rice growth through co-application of straw-decomposing inoculants and ammonium nitrogen fertilizer.

BACKGROUND: The growth of rice is reduced by the slow decomposition of accumulated straw, which competes with rice for soil nitrogen nutrient. In recent year, straw-decomposing inoculants (SDIs) that can accelerate straw decomposition and ammonium nitrogen (N) fertilizer that can quickly generate available N is increasingly adopted in China. However, it is still unknown whether the N demand of straw decomposition and crop growth can be simultaneously met through the co-application of SDIs and ammonium N fertilizer. RESULTS: In this study, we investigated the effect of the co-application of SDIs and ammonium bicarbonate on decomposition rate of wheat straw, rice growth and rice yield over two consecutive years in rice-wheat rotation system. Compound fertilizer (A0) was used as control. The ratios of ammonium bicarbonate addition were 20% (A2), 30% (A3) and 40% (A4), respectively, without SDIs or with SDIs (IA2, IA3, IA4). Our results revealed that without SDIs, compared with A0, straw decomposition rate, rice growth and yield were improved under A2; However, under A3, rice yield was decreased due to the slow decomposition rate of straw and limited growth of rice during late growth stage. Combining SDIs and N fertilizer increased straw decomposition rate, rice growth rate and yield more than that of N fertilizer alone, especially under IA3. Compared with A0, straw decomposition rate, tiller number, aboveground biomass, leaf area index, root length, and nitrogen use efficiency were significantly increased by 16%, 8%, 27%, 12%, 17%, and 15% under IA3. Consequently, the average rice yield of IA3 was increased to 10,856 kg/ha, which was 13% and 9% higher, respectively, than of A0 and A2. CONCLUSION: Our results indicated that ammonium bicarbonate application alone carried a risk of nutrient deficiency during late growth stage and yield decline. Therefore, the co-application of SDIs and 30% ammonium N fertilizer substitution can be a favorable practice to simultaneously accelerate straw decomposition and increase rice crop growth.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and the Risk of Fracture: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Osteoporosis and hyperlipidemia are closely correlated and statins might be associated with a decreased risk of fracture. We aimed to investigate the association between proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and the risk of fracture. The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to October 22, 2022. Randomized clinical trials (RCTs) that addressed to fracture events of participants using alirocumab, evolocumab, bococizumab or inclisiran, with a follow-up of ≥ 24 weeks were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95% confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. 30 trials assessing PCSK9i among 95, 911 adults were included. There were no significant associations between PCSK9i therapy and the risk of major osteoporotic fracture [OR 1.08 (95% Cl 0.87-1.34), p = 0.49], hip fracture [OR 1.05 (95% Cl 0.73-1.53), p = 0.79], osteoporotic non-vertebral fracture [OR 1.03 (95% Cl 0.80-1.32), p = 0.83], and total fracture [OR 1.03 (95% Cl 0.88-1.19), p = 0.74] over a period of 6-64 months. No significant associations were detected in any of the sensitivity analyses and subgroup analyses stratified by the type of PCSK9i, follow-up duration, age, sex, sample size, and patient profile. Pooled results of our meta-analysis showed that exposure to PCSK9i was not associated with reduced risks of fracture in the short term.

Population attributable fractions of modifiable risk factors for microvascular complications of type 2 diabetes in China: An analysis using national cross-sectional data.

AIM: To assess the population attributable fractions (PAFs) for modifiable risk factors for microvascular complications of type 2 diabetes (T2D) in China. MATERIALS AND METHODS: Data collected from the China National HbA1c Surveillance System from 2009 to 2013 were used. The PAFs of four predefined risk factors, including an HbA1c of 7% or higher, blood pressure (BP) of 130/80 mmHg or higher, low-density lipoprotein-cholesterol (LDL-C) of 1.8 mmol/L or higher and body mass index (BMI) of 24 kg/m2 or higher, were calculated for diabetic microvascular complications, including diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN). PAFs were further adjusted for age, sex and duration of diabetes. RESULTS: In total, there were 998 379 participants with T2D from nationwide mainland China included in this analysis. As for DR, an HbA1c of 7% or higher, BP of 130/80 mmHg or higher, LDL-C of 1.8 mmol/L or higher and BMI of 24 kg/m2 or higher conferred PAFs of 16.2%, 15.2%, 5.8% and 2.8%, respectively. In the case of DKD, BP of 130/80 mmHg or higher provided a PAF of 25.2%, followed by an HbA1c of 7% or higher (13.9%), BMI of 24 kg/m2 or higher (8.0%) and LDL-C of 1.8 mmol/L or higher (5.6%). As for DSPN, an HbA1c of 7% or higher, BP of 130/80 mmHg or higher, LDL-C of 1.8 mmol/L or higher and BMI of 24 kg/m2 or higher contributed to PAFs of 14.2%, 11.7%, 5.9% and 5.8%, respectively. PAFs for diabetic microvascular complications were mildly to moderately reduced after adjusting for participants' age, sex and duration of diabetes. CONCLUSIONS: Suboptimal glycaemic and BP control were the main contributors to diabetic microvascular complications, while the PAFs of unmet LDL-C and BMI control targets were quite limited for diabetic microvascular complications. In addition to glycaemic control, BP control should be especially prioritized in the management of diabetic microvascular complications to further reduce the disease burden.

Engineering topological states in a two-dimensional honeycomb lattice.

In this work, we use first-principles calculations to determine the interplay between spin-orbit coupling (SOC) and magnetism which can not only generate a quantum anomalous Hall state but can also result in topologically trivial states although some honeycomb systems host large band gaps. By employing tight-binding model analysis, we have summarized two types of topologically trivial states: one is due to the coexistence of quadratic non-Dirac and linear Dirac bands in the same spin channel that act together destructively in magnetic materials (such as, CrBr3, CrCl3, and VBr3 monolayers); the other one is caused by the destructive coupling effect between two different spin channels due to small magnetic spin splitting in heavy-metal-based materials, such as, BaTe(111)-supported plumbene. Further investigations reveal that topologically nontrivial states can be realized by removing the Dirac band dispersion of the magnetic monolayers for the former case (such as in alkali metal doped CrBr3), while separating the two different spin channels from each other by enhancing the magnetic spin splitting for the latter case (such as in half-iodinated silicene). Thus, our work provides a theoretical guideline to manipulate the topological states in a two-dimensional honeycomb lattice.

Strain-tunable magnetism and topological states in layered VBi2Te4.

Similar to the magnetic topological insulator of MnBi2Te4, recent studies have demonstrated that VBi2Te4 is also an ideal candidate to explore many intriguing quantum states. Different from the strong interlayer antiferromagnetic (AFM) coupling in layered MnBi2Te4, based on first-principles calculations, we find that the energy difference between AFM and ferromagnetic (FM) orders in layered VBi2Te4 is much smaller than that of MnBi2Te4. Specifically, it is found that the interlayer FM coupling can be readily achieved by applying strain. Further electronic band structures reveal that the VBi2Te4 bilayer is a time-reversal symmetry broken quantum spin Hall insulator with a spin Chern number of CS = 1, which is essentially different from the QAH state with a Chern number of C = 1 in the MnBi2Te4 bilayer. Most strikingly, the topological states of the magnetic VBi2Te4 bilayer can be well tuned by strain, whose topological phase diagram is mapped out as a function of strain by employing continuum model analyses. All of these results indicate that the layered VBi2Te4 not only enriches the family of magnetic topological materials, but also provides a promising platform to explore more exotic quantum phenomena.

Selective Substrate-Orbital-Filtering Effect to Realize the Large-Gap Quantum Spin Hall Effect.

Although Pb harbors a strong spin-orbit coupling effect, pristine plumbene (the last group-IV cousin of graphene) hosts topologically trivial states. Based on first-principles calculations, we demonstrate that epitaxial growth of plumbene on the BaTe(111) surface converts the trivial Pb lattice into a quantum spin Hall (QSH) phase with a large gap of ∼0.3 eV via a selective substrate-orbital-filtering effect. Tight-binding model analyses show the pz orbital in half of the Pb overlayer is selectively removed by the BaTe substrate, leaving behind a pz-px,y band inversion. Based on the same working principle, the gap can be further increased to ∼0.5-0.6 eV by surface adsorption of H or halogen atoms that filters out the other half of the Pb pz orbitals. The mechanism of selective substrate-orbital-filtering is general, opening an avenue to explore large-gap QSH insulators in heavy-metal-based materials. It is worth noting that plumbene has already been widely grown on various substrates experimentally.

SGLT2 inhibitors and lower limb complications: an updated meta-analysis.

BACKGROUND: To exam the associations between the use of sodium glucose co-transporter 2 inhibitor (SGLT2i) and the risk of lower limb complications, and to analyze the associated factors. METHODS: Pubmed, Medline, Embase, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from the inception to November 2020. Randomized controlled trials of SGLT2i conducted in population containing diabetic patients with reports of amputation, peripheral arterial disease (PAD) and diabetic foot (DF) events were included. Random-effect model, fixed-effect model and meta-regression analysis were accordingly used. RESULT: The numbers of SGLT2i users versus non-SGLT2i users in the analyses of amputation, PAD and DF were 40,925/33,414, 36,446/28,685 and 31,907/25,570 respectively. Compared with non-SGLT2i users, the risks of amputation and PAD were slightly increased in patients with canagliflozin treatment (amputation: OR = 1.60, 95% CI 1.04 to 2.46; PAD: OR = 1.53, 95 % CI 1.14 to 2.05). Meta-regression analyses indicated that greater weight reduction in SGLT2i users was significantly associated with the increased risks of amputation (ß = - 0.461, 95% CI - 0.726 to - 0.197), PAD (ß = - 0.359, 95% CI - 0.545 to - 0.172) and DF (ß = - 0.476, 95% CI - 0.836 to - 0.116). Lower baseline diastolic blood pressure (ß = - 0.528, 95% CI - 0.852 to - 0.205), more systolic blood pressure reduction (ß = - 0.207, 95% CI - 0.390 to - 0.023) and more diastolic blood pressure reduction (ß = - 0.312, 95% CI - 0.610 to - 0.015) were significantly associated with the increased risks of amputation, PAD and DF respectively in patients with SGLT2i treatment. CONCLUSIONS: The risks of amputation and PAD were slightly increased in patients with canagliflozin treatment. Reductions in body weight and blood pressure were associated with lower limb complications in patients with SGLT2i treatment.

Dipeptidyl peptidase-4 inhibitor treatment and the risk of bullous pemphigoid and skin-related adverse events: A systematic review and meta-analysis of randomized controlled trials.

AIMS: This meta-analysis aimed to evaluate the risk of developing bullous pemphigoid (BP) and other skin-related adverse events (AEs) in patients with type 2 diabetes (T2DM) undergoing dipeptidyl peptidase-4 inhibitor (DPP-4i) treatment in randomized controlled trials (RCTs). METHODS: In this meta-analysis, the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases were searched for RCTs, which involve patients with T2DM reporting skin-related AEs. RCTs that comparatively evaluated the effects of DPP-4i treatment and placebo on patients with T2DM and reported skin-related AEs were included in the analysis. The odds ratio (OR) and 95% confidence interval (CI) were calculated using the Peto's methods. The GRADE approach was used to rate the quality of evidence. RESULTS: A total of 46 randomized placebo-controlled trials, including 3 trials with reports of BP (n = 38 011), that reported skin-related AEs were included (n = 59 332). Compared to the placebo group, the risk of developing BP was significantly higher in the DPP-4i treatment group (OR = 7.38, 95% CI 2.00-27.25, I2 = 0%, P = .003; quality rating: very low). Additionally, DPP-4i treatment was associated with an increased overall risk of developing skin-related AEs (OR = 1.22, 95% CI 1.02-1.46, I2 = 32%, P = .03; quality rating: moderate). CONCLUSIONS: This meta-analysis suggested that treatment with DPP-4is, including sitagliptin, saxagliptin, and linagliptin, was associated with an increased risk of developing BP. Additionally, the risk of developing skin-related AEs increased when all DPP-4is were combined. Skin lesion, especially BP, should be monitored in patients with diabetes undergoing DPP-4i treatment. Future studies should evaluate the susceptible population and develop strategies for early detection of skin-related AEs.

Impact of diabetes mellitus on clinical outcomes after heart transplantation.

PURPOSE: Diabetes mellitus (DM) is common among recipients of heart transplantation (HTx) but its impact on clinical outcomes is unclear. We evaluated the associations between pretransplant DM and posttransplant DM (PTDM) and outcomes among adults receiving HTx at a single center. METHODS: We performed a retrospective study (range 01/2008 - 07/2018), n = 244. The primary outcome was survival; secondary outcomes included acute rejection, cardiac allograft vasculopathy, infection requiring hospitalization, macrovascular events, and dialysis initiation post-transplant. Comparisons were performed using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: Pretransplant DM was present in 75 (30.7%) patients and was associated with a higher risk for infection requiring hospitalization (p < 0.05), but not with survival or other outcomes. Among the 144 patients without pretransplant DM surviving to 1 year, 29 (20.1%) were diagnosed with PTDM at the 1-year follow-up. After multivariable adjustment, PTDM diagnosis at 1-year remained associated with worse subsequent survival (hazard ratio 2.72, 95% confidence interval 1.03-7.16). Predictors of PTDM at 1-year included cytomegalovirus seropositivity and higher prednisone dose (> 5 mg/day) at 1-year follow-up. CONCLUSIONS: Compared to HTx recipients without baseline DM, those with baseline DM have a higher risk for infections requiring hospitalization, and those who develop DM after HTx have worse survival.

Unusual erythematous plaque with white scales, a case of acquired syphilis in a child and literature review.

BACKGROUND: Syphilis in children is uncommon with the mode of infection for this rare condition likely being congenital or acquired. While most acquired cases of syphilis in children result from sexual abuse, children can also be infected with syphilis through kissing, breastfeeding, sharing of daily necessities or pre-chewed food. Here, we report a case of acquired secondary syphilis in a child due to consumption of pre-chewed-food and provide a review of the literature on the characteristics of acquired syphilis in preschool children. CASE PRESENTATION: A 3-year-old girl presented with erythematous plaques and scales on her head, neck, and thighs as well as flat red papules with a moist, well circumscribed surface covered with a grayish-white film. The grandmother who cared for the girl was in the habit of pre-chewing food before giving it to the girl. The child and grandmother tested positive for RPR. The girl, who was not sexually abused, was diagnosed with acquired secondary syphilis, resulting from the transmission of pre-chewed food from her grandmother. CONCLUSIONS: Our case report and literature review reveal that close contact among family members can result in the transmission of syphilis. We recommend that pre-chewing food should be discouraged by caregivers when caring for their children to avoid disease transmission.

Efficient visible light photocatalytic NO abatement over SrSn(OH)6 nanowires loaded with Ag/Ag2O cocatalyst.

SrSn(OH)6 (SSOH) possesses a high oxidation potential in the valence band (VB), which is suitable for photocatalytic oxidation removal of pollutants. However, the electrons in the VB of these catalysts are difficult to transition to the conduction band (CB) under visible light, which makes it difficult to utilize sunlight effectively. In this work, Ag/Ag2O is loaded on the surface of SSOH nanowires, which stimulates the interfacial charge-transfer transition on SSOH. Compared with pure-phase SSOH, the NO abatement ratio of Ag/Ag2O-SSOH under visible light irradiation is increased to 45.10%. The e- in the VB of Ag2O are excited into the CB under visible light, and are further transferred to the Ag to react with O2 to produce superoxide radicals. The photo-excited e- in the VB of SSOH enter into the VB of Ag2O through interfacial charge-transfer transition to recombine with the photo-generated holes in the VB of Ag2O, thereby leaving photo-generated holes in the VB of SSOH. The holes in the VB of SSOH have sufficient oxidizing ability to oxidize the adsorbed hydroxyl groups into hydroxyl radicals. This work provides a new perspective for photocatalytic removal of pollutants by wide band gap photocatalyst under visible light.

Age, sex, disease severity, and disease duration difference in placebo response: implications from a meta-analysis of diabetes mellitus.

BACKGROUND: The placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine. METHODS: Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373. RESULTS: Significantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = - 0.12%, 95% CI, - 0.16 to - 0.07%) and weight reduction (ES = - 0.40 kg, 95% CI, - 0.50 to - 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = - 0.22%, 95% CI, - 0.32 to - 0.11%) versus oral types (ES = - 0.09%, 95% CI, - 0.14 to - 0.04%) in T2DM (P = 0.03). Older age (ß = - 0.01, 95% CI, - 0.02 to - 0.01, P < 0.01) and longer diabetes duration (ß = - 0.02, 95% CI, - 0.03 to - 0.21 × 10-2, P = 0.03) was significantly associated with more HbA1c reduction by placebo in T1DM. However, younger age (ß = 0.02, 95% CI, 0.01 to 0.03, P = 0.01), lower male percentage (ß = 0.01, 95% CI, 0.22 × 10-2, 0.01, P < 0.01), higher baseline BMI (ß = - 0.02, 95% CI, - 0.04 to - 0.26 × 10-2, P = 0.02), and higher baseline HbA1c (ß = - 0.09, 95% CI, - 0.16 to - 0.01, P = 0.02) were significantly associated with more HbA1c reduction by placebo in T2DM. Shorter diabetes duration (ß = 0.06, 95% CI, 0.06 to 0.10, P < 0.01) was significantly associated with more weight reduction by placebo in T2DM. However, the associations between baseline BMI, baseline HbA1c, and placebo response were insignificant after the adjusted analyses. CONCLUSION: The placebo response in diabetes mellitus was systematically outlined. Age, sex, disease severity (indirectly reflected by baseline BMI and baseline HbA1c), and disease duration were associated with placebo response in diabetes mellitus. The association between baseline BMI, baseline HbA1c, and placebo response may be the result of regression to the mean.

The association between the biological disease-modifying anti-rheumatic drugs and the incidence of diabetes: A systematic review and meta-analysis.

Whether the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) would influence the risk of new-onset diabetes remains uncertain. Therefore, we performed a systematic review and meta-analysis to evaluate the association between the use of bDMARDs and the incidence of diabetes in patients with systemic inflammatory conditions. Pubmed, Medline, Embase and the Cochrane Central Register of Controlled Trials were searched for studies published from January 2000 to March 2020. Studies conducted in systemic inflammatory conditions with reports of the incidence of diabetes in subjects treated with bDMARDs were included. With 22 randomized controlled trials and 3 cohort studies included, the overall result indicated that compared with non-bDMARD treatment, the use of bDMARDs was significantly associated with decreased incidence of diabetes in patients with systemic inflammatory conditions (RR = 0.56, 95 % CI, 0.43 to 0.74, P < 0.001, I2 = 69 %), especially in patients with in rheumatoid arthritis (RR = 0.54, 95 % CI, 0.38 to 0.76, P = 0.0005, I2 = 26). Reduced risk of new-onset diabetes was observed in studies with follow-up more than 1 year (RR = 0.73, 95 % CI, 0.54 to 0.99, P = 0.04, I2 = 88). New-onset diabetes was less frequent in patients with TNF-α inhibitor treatment (RR = 0.54, 95 % CI, 0.48 to 0.60, P < 0.001, I2 = 42 %) and abatacept treatment (RR = 0.44, 95 % CI, 0.34 to 0.58, P < 0.001, I2 = 3 %), which might be associated with the inhibition of TNF-α mediated inflammatory responses and dysregulated T cell activation and immune responses respectively. Further investigations are required to validate the glucose metabolism protective effect of bDMARDs and clarify the underlying mechanisms of the crosstalk between bDMARDs and diabetes.

Role of Chitin Deacetylase 1 in the Molting and Metamorphosis of the Cigarette Beetle Lasioderma serricorne.

Chitin deacetylases (CDAs) are chitin-modifying enzymes known to play vital roles in insect metamorphosis and development. In this study, we identified and characterized a chitin deacetylase 1 gene (LsCDA1) from the cigarette beetle Lasioderma serricorne. LsCDA1 contains a 1614 bp open reading frame encoding a protein of 537 amino acids that includes domain structures typical of CDAs. LsCDA1 was mainly expressed in the late larval and late pupal stages. In larval tissues, the highest level of LsCDA1 was detected in the integument. The expression of LsCDA1 was induced by 20-hydroxyecdysone (20E) in vivo, and it was significantly suppressed by knocking down the expression of ecdysteroidogenesis genes and 20E signaling genes. RNA interference (RNAi)-aided silencing of LsCDA1 in fifth-instar larvae prevented the larval-pupal molt and caused 75% larval mortality. In the late pupal stage, depletion of LsCDA1 resulted in the inhibition of pupal growth and wing abnormalities, and the expression levels of four wing development-related genes (LsDY, LsWG, LsVG, and LsAP) were dramatically decreased. Meanwhile, the chitin contents of LsCDA1 RNAi beetles were significantly reduced, and expressions of three chitin synthesis pathway genes (LsTRE1, LsUAP1, and LsCHS1) were greatly decreased. The results suggest that LsCDA1 is indispensable for larval-pupal and pupal-adult molts, and that it is a potential target for the RNAi-based control of L. serricorne.

Adjuvant Chemotherapy Candidates in Stage I Lung Adenocarcinomas Following Complete Lobectomy.

BACKGROUND: This study aimed to explore adjuvant chemotherapy (ACT) candidates based on a recurrence risk-scoring model in completely lobectomized stage I patients with lung adenocarcinoma (LAD). METHODS: A retrospective study was performed on 4606 patients (non-ACT group: n = 3514; ACT group: n = 1092) who underwent complete lobectomy for LAD at Shanghai Chest Hospital from 2008 to 2014. The nomogram predicting recurrence-free survival (RFS) was developed in the non-ACT group using Cox proportional hazards regression. The nomogram-based risk score was calculated in the entire cohort. Differences of RFS between the non-ACT and ACT groups were compared as stratified by the risk score. The score cut-off points were determined using the X-tile software. RESULTS: Six independent predictors, including age, sex, tumor size, pathological subtype, visceral pleural invasion (VPI), and lymphovascular invasion (LVI) were associated with RFS. The nomogram more accurately predicted RFS than the 8th TNM staging {C-index: 0.784 [95% confidence interval (CI) 0.756-0.812] vs. 0.719 (95% CI 0.689-0.749), p = 0.0017}. A significant RFS difference was observed among the low-, intermediate- and high-risk groups (p < 0.0001), as divided by the optimal cut-points of risk score (203 and 244). ACT did not improve RFS for patients at intermediate-risk, or was even detrimental for low-risk patients; however, improved RFS was observed in ACT receivers at high-risk (p = 0.0416). ACT candidates with a risk score ≥ 245 constituted 2.6% of stage I patients. CONCLUSIONS: The nomogram provided an individual prediction of RFS for stage I LAD following lobectomy. High-risk patients (score ≥ 245) may benefit from postoperative ACT.

Outcomes of patients with infection related to a ventricular assist device after heart transplantation.

BACKGROUND: Despite significant advances in durable mechanical support survival, infectious complications remain the most common adverse event after ventricular assist device (VAD) implantation and the leading cause of early death after transplantation. In this study, we aim to describe our local infectious epidemiology and review short-term survival and infectious incidence rates in the post-transplantation period and assess risk factors for infectious episodes after transplantation. METHODS: Retrospective single-center study of all consecutive adult heart transplant patients from 2008 to 2017. Survival data were estimated and summarized using the Kaplan-Meier method. We quantified and evaluated the difference in the incidence rate between patients with and without infection using a Fine-Gray model. The outcome of interest is the time to first infection diagnosis with post-transplant death as the competing event. RESULTS: Among 278 heart transplant patients, 74 (26.5%) underwent LVAD implantation. Twenty-one patients (28.3%) developed an infection while supported by an LVAD. When compared to patients supported by an LVAD without a preceding infection, BMI was significantly greater (31.2 vs 27.8 kg/m2 , P = .03). Median follow-up post-transplantation was 3.01 years. Significant risk factors for the competing risk regression for infection after heart transplantation include LVAD infection (HR 1.94, [95% CI] 1.11-3.39, P = .020) and recipient COPD (HR 2.14, [95% CI] 1.39-3.32, P = .001) when adjusted for recipient age, gender, hypertension, diabetes mellitus, and body mass index. CONCLUSIONS: Patients with LVAD-related infection had a significantly increased risk of infectious complications after heart transplantation. Further research on the avoidance of induction agents and reduced maintenance immunosuppression in this patient population is warranted.

Possible realization of the high-temperature and multichannel quantum anomalous Hall effect in graphene/CrBr3 heterostructures under pressure.

The recent studies of magno-assisted tunnelling in ferromagnetic van der Waals heterostructures formed by graphene and ultrathin CrBr3 films (D. Ghazaryan et al., Nat. Electron., 2018, 1, 344) offer broader opportunities for exploration of novel quantum phenomena, especially for realizing the graphene-based quantum anomalous Hall effect (QAHE). Based on first-principles approaches, we reveal that three types of graphene/CrBr3 (Gr/CrBr3) heterostructures exhibit metallic band behavior due to strong charge-transfer at the interfaces of these heterosystems. Remarkably, the pressure-induced QAHE can be achieved in Gr/CrBr3 and CrBr3/Gr/CrBr3 systems. Further low energy k·p model analyses show that the nontrivial topological properties are mainly attributed to the Rashba spin-orbit coupling (SOC), but not to the intrinsic SOC of graphene. Moreover, a multichannel device prototype is proposed in the superlattices composed of Gr/CrBr3 and normal insulator (such as hexagonal boron nitride) layers. Our work provides an experimentally feasible scheme for realizing the high-temperature and multichannel QAHE in graphene-based heterostructures.

Complex epidermal growth factor receptor mutations and their responses to tyrosine kinase inhibitors in previously untreated advanced lung adenocarcinomas.

BACKGROUND: Two or more different epidermal growth factor receptor (EGFR) mutations can be detected within a single tumor sample, which represents complex mutations. However, the frequency and efficacy of tyrosine kinase inhibitor (TKI) treatments for patients harboring these mutations are unknown. METHODS: From January 2011 to January 2017, patients diagnosed with EGFR mutations were screened. The effectiveness of TKIs in patients with complex mutations was retrospectively analyzed. RESULTS: A total of 16,840 subjects were screened, and there were 5898 positive patients. One hundred eighty-seven patients (3.2% of all patients with EGFR mutations) had complex EGFR mutations, and 51 of the patients with advanced adenocarcinoma were treated with TKIs as a first-line treatment. The objective response rates for patients who had Del-19+21L858R mutations (n = 15), Del-19/21L858R+atypical mutations (n = 16), double atypical mutations (n = 8), and complex mutations with a primary drug-resistant pattern (n = 12) were 75.0%, 60.0%, 71.0%, and 8.3%, respectively. The median progression-free survival times for the 4 groups were 18.2 months (95% confidence interval [CI], 10.6-25.9 months), 9.7 months (95% CI, 3.3-15.8 months), 9.6 months (95% CI, 3.3-19.0 months), and 1.4 months (95% CI, 0.4-2.3 months), respectively. CONCLUSIONS: These results from the largest sample size suggest that EGFR-TKI therapy is effective in patients with Del-19+21L858R mutations, Del-19/21L858R+atypical mutations, and double atypical mutations but is less effective in patients with a primary drug-resistant pattern. Patients with the Del-19+21L858R mutations may, therefore, benefit more from treatment with first-generation TKIs. Cancer 2018;124:2399-406. © 2018 American Cancer Society.