微粒蛋白质组学研究进展

目的：比较高效价抗人球（效价≥1：512）蛋白、抗人球蛋白试剂（效价≥1：4）（低效价）与微柱凝胶法在自身免疫性溶血性贫血（AIHA）实验室检测中的优势。方法：首先以微柱凝胶法直抗试验筛选阳性血液标本,然后对上述标本分别用高效价抗人球蛋白（效价≥1：512）、抗人球蛋白试剂（效价≥1：4）做直抗半定量试验,γ中和试验。结果：微柱凝胶法易出现假阳性,抗人球蛋白试剂（效价≥1：4）易出现假阴性。高效价抗人球（效价≥1：512）未发现假阳性,而且凝集梯度明显,易于结果判断分析。结论：高效价抗人球（效价≥1：512）在AIHA直抗试验中,较抗人球蛋白试剂（效价≥1：4）与微柱凝胶法具有结果更加准确的明显优势。     

Psychiatric comorbidity in cardiovascular inpatients: costs, net gain, and length of hospitalization

Objective

Although psychiatric comorbidity often goes undetected and untreated in cardiovascular patients, it is not clear whether the costs for a special treatment of psychiatric comorbidity are appropriately reflected in the reimbursement system. To investigate the economic impact of psychiatric comorbidity, we compared costs, returns, net gain, and duration of hospitalization in cardiovascular inpatients with and without psychiatric comorbidity.

Methods

For a period of 2 years, we analyzed costs, net gain, and other outcome variables according to the diagnosis-related group (DRG) system for cardiovascular inpatients of a German university department (n=940). Psychiatric disorders were diagnosed by the treating physicians based on clinical criteria and results from the Patient Health Questionnaire (PHQ). With respect to the outcome variables, we compared patients with and without a psychiatric disorder, controlling for sociodemographic characteristics.

Results

The average total costs of hospitalization (mean±S.E.) for cardiovascular patients without psychiatric comorbidity and for patients with psychiatric comorbidity differed significantly (€5142±210 vs. €7663±571; d=0.39). The increased costs for patients with psychiatric comorbidity were related to elevated returns, but the net gain for patients without psychiatric comorbidity was €277±119. In contrast, the treatment of internal medicine patients with psychiatric disorders resulted in a net loss of −€624±324 (overall group difference, d=−0.25).

Conclusion

Psychiatric comorbidity in cardiovascular inpatients leads to higher costs that are not reflected in the current reimbursement system in Germany. The inappropriate reimbursement of psychiatric comorbidity in cardiovascular inpatients may result in a serious undertreatment of these patients.     

Galvanic vestibular stimulation reduces the pathological rightward line bisection error in neglect-a sham stimulation-controlled study

Patients with right hemisphere lesions often show left spatial neglect and the typical rightward deviation in horizontal line bisection. Previous studies have shown that sensory stimulation modulates line bisection. A less well-known but promising sensory stimulation method is galvanic vestibular stimulation (GVS). This non-invasive technique leads to activation of the vestibular cortices and adjacent cortical areas in the temporo-parietal cortex via polarization effects of the vestibular nerves. This is accomplished by application of weak direct currents, delivered by two electrodes attached to the mastoids. Despite the relative benefits of GVS its effects on line bisection have not yet been studied in neglect patients. Thus, the present study investigated the impact of GVS on performance in a modified line bisection task in right-brain damaged patients with versus without leftsided visual neglect. In neglect patients, but not in control patients, left-cathodal and right-cathodal GVS significantly reduced the rightward line bisection error as compared to Baseline (without GVS) and sham stimulation. A larger decrease of the rightward line bisection error was observed during right-cathodal GVS. Sham stimulation showed no specific effects on line bisection. The beneficial effects of GVS might be due to activation of preserved structures of the lesioned right posterior parietal cortex which is known to be involved in line bisection.     

Financial implications of obesity

The obesity epidemic continues to grow. As the number of obese people increases, it is logical to expect an increasing number of obese patients and increasing costs to care for these patients. Orthopedic surgeons will see many of these patients who need treatment for injuries and chronic conditions. Care of obese patients requires more work and time in providing nonoperative and operative care. No system has been proposed to handle reimbursement disparities, particularly for providers. The model for health care will change and, along with it, should be all parties coming together to address inequalities and inequities in care for obese and morbidly obese patients.     

Similar recovery of liver function after response to all‐oral HCV therapy in patients with cirrhosis with and without HIV coinfection

Among patients with cirrhosis, recovery of liver function after SVR to all‐oral direct‐acting antivirals (DAA) in HIV/HCV coinfection could be different to that in HCV monoinfection. Because of this, we compared the changes in several markers of liver function between HCV‐monoinfected and HIV/HCV‐coinfected patients with cirrhosis who achieved SVR12 to DAA combinations. In this retrospective cohort study, cirrhotics included in the HEPAVIR‐DAA and GEHEP‐MONO cohorts were selected if they had SVR12 to all‐oral DAAs. Patients treated with atazanavir were excluded. Liver function improvement was defined as Child‐Pugh‐Turcotte (CPT) decrease ≥1 and/or MELD decrease ≥2 between baseline and SVR12. Liver function worsening was defined as a CPT increase ≥1 and/or MELD increase ≥2 and/or decompensations between baseline and SVR12. We included 490 patients, 270 (55%) of them with HIV coinfection. Liver function improved in 50 (56%) HCV‐infected individuals and in 82 (57%) HIV/HCV‐coinfected patients (P = 0.835). Liver function worsened in 33 (15%) HCV‐monoinfected patients and in 33 (13%) HIV/HCV‐coinfected patients (P = 0.370). Factors independently related with liver function improvement were male gender [adjusted OR (AOR) 2.1 (95% confidence interval, 95% CI: 1.03‐4.2), P = 0.040], bilirubin < 1.2 mg/dL (AOR 1.8 [95% CI: 1.004‐3.3], P = 0.49), and INR < 1.3 (AOR 2.4 [95% CI: 1.2‐5.0], P = 0.019) at baseline. After multivariate analysis, albumin < 3.5 g/dL was associated with liver function worsening (AOR 6.1 [95% CI: 3‐12.5], P < 0.001). Liver function worsening and improvement rates after responding to DAA are similar among HCV‐monoinfected and HIV/HCV‐coinfected cirrhotics. Gender, INR, bilirubin, and albumin levels were associated with liver function changes after response to DAAs.     

In vitro resistance profile of hepatitis C virus NS5A inhibitor velpatasvir in genotypes 1 to 6

Velpatasvir is a pan‐genotypic hepatitis C virus (HCV) NS5A inhibitor, which is used with sofosbuvir for treatment of infection with HCV genotypes 1‐6. In vitro resistance studies were performed to characterize NS5A changes that might confer reduced velpatasvir susceptibility in vivo. Resistance selection studies using HCV replicon cells for subtypes 1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a identified NS5A resistance‐associated substitutions (RASs) at nine positions, most often 28M/S/T, 31F/I/M/P/V and 93D/H/N/S. In subtype 1a, RASs were selected at positions 31 and/or 93, while in subtype 1b, replicons with two or more RASs at positions 31, 54 or 93 were selected. Y93H was selected in subtypes 1a, 1b, 2a, 3a and 4a. In subtype 5a or 6a, L31P or P32L/Q was selected, respectively. Velpatasvir susceptibility of 358 replicons from genotypes 1 to 6 containing one or more NS5A RASs was also evaluated. The majority (63%) of subtypes 1a and 1b single RAS‐containing replicons retained susceptibility to velpatasvir (<2.5‐fold change in EC₅₀). High levels of resistance to velpatasvir were observed for six single mutants in subtype 1a, including M28G, A92K, Y93H/N/R/W and for one mutant, A92K, in subtype 1b. Most single mutants in subtypes 2a, 2b, 3a, 4a and 5a displayed low levels of reduced velpatasvir susceptibility. High‐level resistance was observed for C92T and Y93H/N in subtype 2b, Y93H/S in 3a, and L31V and P32A/L/Q/R in 6a, and several double mutants in these subtypes. Overall, velpatasvir maintained activity against most common RASs that are known to confer resistance to first‐generation NS5A inhibitors.     

TLL1 variants do not predict hepatocellular carcinoma development in HCV cirrhotic patients treated with direct‐acting antivirals

Tolloid‐like 1 gene (TLL1) variant rs17047200 has been associated with hepatocellular carcinoma (HCC) in Japanese hepatitis C virus (HCV) patients with sustained virological response (SVR) to interferon or direct‐acting antiviral (DAA)‐based regimens. We investigated whether this holds true also in Caucasian cirrhotic patients cured by DAAs. Consecutive Caucasian HCV cirrhotics receiving DAA between December 2014 and December 2016 in a single centre were enrolled. Cirrhosis was defined histologically (METAVIR F4) or by liver stiffness measurement (LSM > 11.9 kPa). TLL1 rs17047200 was analysed by TaqMan SNP genotyping assay. 452 patients were enrolled: median age 63 (28‐87) years, 58% males, 47% HCV‐1b, LSM 19.1 (12.0‐75.0) kPa and Fibrosis‐4 (FIB‐4) score 4.9 (0.3‐46.0). 96% patients achieved an SVR. TLL1 genotype was AA in 329 (73%) and AT/TT in 123 (27%) (MAF = 0.14, HWE P > 0.05). Patients’ clinical features were similar across TLL1 genotypes. After 33 (3‐47) months from DAA start, 31 patients developed HCC, with a 3‐year estimated cumulative probability being 7.5% (95% CI: 5%‐10%). The cumulative incidence of HCC was 9% in TLL1 AA vs 7% in AT/TT patients (P = 0.55). Male sex (HR: 3.78, 95% CI: 1.4‐10.1, P = 0.008), diabetes (HR: 3.5, 95% CI: 1.68‐7.27, P = 0.001) and FIB‐4 (HR: 1.09, 95% CI: 1.03‐1.14, P = 0.001) were baseline‐independent predictors of HCC. The incidence of HCC was not influenced by TLL1 genotypes even when considering an additional group of 348 noncirrhotic patients, being 2% in AA vs 1% AT/TT patients (P = 0.58). In a large cohort of Caucasian HCV cirrhotics treated with DAA, TLL1 variants do not predict HCC development.     

High sustained virologic response in genotypes 3 and 6 with generic NS5A inhibitor and sofosbuvir regimens in chronic HCV in myanmar

Exclusive HCV therapy clinical trials with genotype 6 patients in high prevalence areas have been sparse. We analysed the safety and efficacy of two generic, pangenotypic NS5A/NS5B combination oral DAA regimens, primarily in genotypes 3 and 6, in a real‐world setting: (a) daclatasvir/sofosbuvir (DCV/SOF) ± ribavirin (RBV) and (b) Velpatasvir/sofosbuvir (VEL/SOF ± RBV). Between December 2015 and November 2017, data from 522 patients were analysed, 311 of whom were treated with DCV/SOF ± RBV for 12/24 weeks (genotype 3: n = 193, genotype 6: n = 89) and 211 were treated with VEL/SOF ± RBV for 12/24 weeks (genotype 3: n = 83, genotype 6: n = 77). Overall SVR rates were high for both DCV/SOF ± RBV (96.1%, n = 299/311) and VEL/SOF ± RBV (95.3%, n = 201/211), and there was a good adverse event profile. Treatment naïve status and inclusion of RBV (in advanced fibrosis/cirrhosis) were significant independent predictors of achieving SVR12, while type of DAA regimen was not predictive. In this large cohort of genotypes 3 (n = 276) and 6 (n = 166; n = 127 unique subtype of 6c‐l), high SVR rates of 94.9% (n = 262/276) and 95.2% (n = 158/166), respectively, were noted. In conclusion, generic and pangenotypic DCV/SOF and VEL/SOF ± RBV regimens were highly effective and safe, in genotypes 3 and 6 chronic HCV in Myanmar. These efficacious pangenotypic regimens suggest that baseline genotype testing can be eliminated moving forward. While RBV may still be needed for those with advanced fibrosis/cirrhosis, in a global elimination strategy it would not be practical even if it does compromise SVR in a minority with difficult to treat characteristics.