Spontaneously ruptured hepatocellular carcinoma on non-cirrhotic liver: A prospective case series.

BACKGROUND AND AIMS: Spontaneous ruptured hepatocellular carcinoma is an uncommon complication, and there are scarce data about non-cirrhotic patients. Tumor treatment is not standardized and the risk of peritoneal dissemination is unclear. AIM: we analyzed the treatment and survival in patients with rHCC on non-cirrhotic liver. METHODS: One hundred and forty-one non-cirrhotic patients with hepatocellular carcinoma diagnosed by histology were included in a multicenter prospective registry (2018-2022). Seven of them (5%) presented with hemoperitoneum due to spontaneous rupture. RESULTS: Liver disease was associated in three patients (42.9%). A single nodule was detected in three cases (42.9%). One patient had vascular invasion and none extrahepatic spread. Initial hemostatic therapy and sequential treatment was individualized. Patients with single nodule were treated: resection (one case) with recurrence at 4 months treated with TACE and sorafenib. TACE/TAE followed by surgery (two cases) one in remission 43 months later, the other had liver recurrence at 18 months and was transplanted. Patients with multiple lesions were treated: TAE/emergency surgery and subsequent systemic therapy (two cases), one received lenvatinib (1-year survival) and the other sorafenib (5-month survival). TAE and surgery with subsequent systemic therapy (one case). Initial hemostatic surgery, dying on admission (one case). No patient developed intraperitoneal metastasis. All patients with multiple lesions died by tumor. The 3-year survival rate was 42.9%. CONCLUSIONS: Initial hemostasis was achieved in all patients by TAE/TACE or surgery. Subsequent treatment was individualized, based on tumor characteristics, regardless of rupture. Long-time remission could be achieved in single nodule patients.

Significant heterogeneity in the diagnosis and long-term management of Wilson disease: Results from a large multicenter Spanish study.

There is uncertainty regarding Wilson's disease (WD) management. OBJECTIVES: To assess, in a multicenter Spanish retrospective cohort study, whether the approach to WD is homogeneous among centers. METHODS: Data on WD patients followed at 32 Spanish hospitals were collected. RESULTS: 153 cases, 58% men, 20.6 years at diagnosis, 69.1% hepatic presentation, were followed for 15.5 years. Discordant results in non-invasive laboratory parameters were present in 39.8%. Intrahepatic copper concentration was pathologic in 82.4%. Genetic testing was only done in 56.6% with positive results in 83.9%. A definite WD diagnosis (Leipzig score ≥4) was retrospectively confirmed in 92.5% of cases. Chelating agents were standard initial therapy (75.2%) with frequent modifications (57%), particularly to maintenance zinc. Enzyme normalization was not achieved by one third, most commonly in the setting of poor compliance, lack of genetic mutations and/or presence of cardiometabolic risk factors. Although not statistically significant, there were trends for sex differences in number of diagnosed cases, age at diagnosis and biochemical response. CONCLUSIONS: Significant heterogeneity in diagnosis and management of WD patients emerges from this multicenter study that includes both small and large reference centers. The incorporation of genetic testing will likely improve diagnosis. Sex differences need to be further explored.

Modular microring laser cavity sensor.

We propose and experimentally demonstrate a modular microring laser (MML) cavity for sensing applications. The proposed MML permits much more design freedom compared with a traditional simple ring cavity by decoupling the performance parameters into several regions in the cavity. Thus, the different biosensor performance parameters can be optimized semi-independently limiting the need for trade-offs on the design of the biosensing device. The first generation MML has been fabricated and tested. A fiber-to-fiber slope efficiency of up to 1.2%, a temperature coefficient of 1.35 GHz/K and a 3σ limit of detection (LOD) of 3.1 × 10-7 RIU without averaging and 6.0 × 10-8 RIU with a 60 s averaging, has been measured for the MML sensor, which is a record-low LOD in on-chip ring cavity optical sensors. Further optimization is possible, capitalizing on the key advantage of the MML concept, namely the potential for designing the laser cavity to achieve the desired optimization goals.

High index contrast photonic platforms for on-chip Raman spectroscopy.

Nanophotonic waveguide enhanced Raman spectroscopy (NWERS) is a sensing technique that uses a highly confined waveguide mode to excite and collect the Raman scattered signal from molecules in close vicinity of the waveguide. The most important parameters defining the figure of merit of an NWERS sensor include its ability to collect the Raman signal from an analyte, i.e. "the Raman conversion efficiency" and the amount of "Raman background" generated from the guiding material. Here, we compare different photonic integrated circuit (PIC) platforms capable of on-chip Raman sensing in terms of the aforementioned parameters. Among the four photonic platforms under study, tantalum oxide and silicon nitride waveguides exhibit high signal collection efficiency and low Raman background. In contrast, the performance of titania and alumina waveguides suffers from a strong Raman background and a weak signal collection efficiency, respectively.

Al2O3:Yb3+ integrated microdisk laser label-free biosensor.

Whispering gallery mode resonator lasers hold the promise of an ultralow intrinsic limit of detection. However, the widespread use of these devices for biosensing applications has been hindered by the complexity and lack of robustness of the proposed configurations. In this work, we demonstrate biosensing with an integrated microdisk laser. Al2O3doped with Yb3+ was utilized because of its low optical losses as well as its emission in the range 1020-1050 nm, outside the absorption band of water. Single-mode laser emission was obtained at a wavelength of 1024 nm with a linewidth of 250 kHz while the microdisk cavity was submerged in water. A limit of detection of 300 pM (3.6 ng/ml) of the protein rhS100A4 in urine was experimentally demonstrated, showing the potential of the proposed devices for biosensing.

High optical gain in erbium-doped potassium double tungstate channel waveguide amplifiers.

We report on the optical-gain properties of channel waveguides patterned into lattice-matched KGdxLuyEr1-x-y(WO4)2 layers grown onto undoped KY(WO4)2 substrates by liquid phase epitaxy. A systematic investigation of gain is performed for five different Er3+ concentrations in the range of 0.75 to 10at.% and different pump powers and signal wavelengths. In pump-probe-beam experiments, relative internal gain, i.e., signal enhancement minus absorption loss of light propagating in the channel waveguide, is experimentally demonstrated, with a maximum value of 12 ± 5 dB/cm for signals at the peak-emission wavelength of 1534.7 nm.

Low-loss, broadband and high fabrication tolerant vertically tapered optical couplers for monolithic integration of Si3N4 and polymer waveguides.

A low-loss, broadband and high fabrication tolerant optical coupler for the monolithic integration of Si3N4 and polymer waveguides is designed and experimentally demonstrated. The coupler is based on the adiabatic vertical tapering of the Si3N4 waveguides. Low-loss operation is experimentally verified at both 976 and 1460-1635 nm wavelengths. Measured losses per coupler are as low as 0.12 and 0.14 dB at 976 and 1550 nm, respectively, and below 0.2 dB at both wavelengths for lateral misalignments between the Si3N4 and polymer waveguides up to 1.0 µm.

Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.

BACKGROUND & AIMS: Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. METHODS: 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. RESULTS: Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis. CONCLUSIONS: One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. LAY SUMMARY: Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.

Temperature-dependent absorption and emission of potassium double tungstates with high ytterbium content.

We study the spectroscopic properties of thin films of potassium ytterbium gadolinium double tungstates, KYb0.57Gd0.43(WO4)2, and potassium ytterbium lutetium double tungstates, KYb0.76Lu0.24(WO4)2, specifically at the central absorption line near 981 nm wavelength, which is important for amplifiers and lasers. The absorption cross-section of both thin films is found to be similar to those of bulk potassium rare-earth double tungstates, suggesting that the crystalline layers retain their spectroscopic properties albeit having >50 at.% Yb3+ concentration. The influence of sample temperature is investigated and found to substantially affect the measured absorption cross-section. Since amplifiers and lasers typically operate above room temperature due to pump-induced heating, the temperature dependence of the peak-absorption cross-section of the KYb0.57Gd0.43(WO4)2 is evaluated for the sample being heated from 20 °C to 170 °C, resulting in a measured reduction of peak-absorption cross-section at the transitions near 933 nm and 981 nm by ~40% and ~52%, respectively. It is shown that two effects, the change of Stark-level population and linewidth broadening due to intra-manifold relaxation induced by temperature-dependent electron-phonon interaction, contribute to the observed behavior. The effective emission cross-sections versus temperature have been calculated. Luminescence-decay measurements show no significant dependence of the luminescence lifetime on temperature.

The value of serum aspartate aminotransferase and gamma-glutamyl transpetidase as biomarkers in hepatotoxicity.

BACKGROUND & AIMS: The current definition of the pattern of liver injury in hepatotoxicity (DILI) is given by the R (ratio) value, dividing alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in upper limits of normal at DILI onset. We aimed to explore the validity of using aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) as biomarkers of hepatocelullar and cholestatic damage, respectively, when calculating the R value. METHODS: Clinical, laboratory and histological data from 588 DILI episodes included in the Spanish DILI Registry were analyzed. Linear regression analysis was performed to establish the most appropriate cut-off points for hepatocellular and cholestatic patterns when calculating R with AST and GGT. RESULTS: The overall agreement between ALT/ALP and AST/ALP was 76%, with 96%, 61% and 41% agreement in the hepatocellular (R ≥ 5), cholestatic (R ≤ 2) and mixed groups respectively (P < 0.001). Classified by the causative drug, the agreement was higher (87-95%) among drug classes that mainly present with hepatocellular damage and lower (48-58%) for those in which cholestatic-mixed injury predominate (P < 0.001)). The overall agreement between ALT/ALP and ALT/GGT was weak (59%), except for in hepatocellular cases that showed a good agreement (94%) (P = 0.001). Pattern of injury according to liver histology demonstrated 65%, 68% and 47% agreement for ALT/ALP, AST/ALP and ALT/GGT ratios respectively. CONCLUSIONS: AST can reliably replace ALT when calculating pattern of liver injury in DILI, while GGT can only substitute ALP when the R value scores as hepatocellular. The biochemical signature of causative drugs does influence the validity of the ratios with AST or GGT.

Erbium-doped spiral amplifiers with 20 dB of net gain on silicon.

Spiral-waveguide amplifiers in erbium-doped aluminum oxide on a silicon wafer are fabricated and characterized. Spirals of several lengths and four different erbium concentrations are studied experimentally and theoretically. A maximum internal net gain of 20 dB in the small-signal-gain regime is measured at the peak emission wavelength of 1532 nm for two sample configurations with waveguide lengths of 12.9 cm and 24.4 cm and concentrations of 1.92 × 10(20) cm(-3) and 0.95 × 10(20) cm(-3), respectively. The noise figures of these samples are reported. Gain saturation as a result of increasing signal power and the temperature dependence of gain are studied.

Low-loss sharp bends in polymer waveguides enabled by the introduction of a thin metal layer.

Embodying a thin metallic layer underneath the core of a sharply bent polymer waveguide is shown in this work to considerably reduce the total losses of both the quasi-transverse-electric and quasi-transverse-magnetic modes. The computational results show a total loss as low as ~0.02 dB/90° for the quasi-transverse-electric mode for radii between 6 and 13 µm at the wavelength of 1.55 µm, which corresponds to a 10-fold improvement over the purely dielectric counterpart. The radii range exhibiting such low total loss can be tuned by properly selecting the parameters of the structure. For the quasi-transverse-magnetic mode, the metal layer reduces the total losses modestly for radii ranging from 3 to 10 µm. Simulation results for different structural parameters are presented.

Comparison of INNO-LIPA and TRUGENE assays for genotyping and drug-resistance mutations in chronic hepatitis B virus infection.

OBJECTIVE: Hepatitis B virus (HBV) genotyping and detection of resistance to drugs have become essential in epidemiological and clinical diagnosis. Our main objective was to determine the prevalence of HBV genotypes and drug-resistance mutations in chronic asymptomatic carriers and chronic HBV sufferers comparing 2 detection assays. METHODS: Serum samples from 28 chronic HBV patients and 22 chronic asymptomatic carriers were analyzed. For HBV genotyping, the INNO-LIPA and TRUGENE™ HBV genotyping kits were evaluated. For drug-resistance mutations, INNO-LIPA DR v2 and INNO-LIPA DR v3 prototype and the TRUGENE™ HBV genotyping kit were evaluated. RESULTS: In HBV genotyping, concordant results were 98% and both assays were able to detect more than one genotype. Different genotypes were detected, the most prevalent being D (46%) and A (26%). In relation to drug-resistance mutations, the sensitivity of the line probe assay was lower than TRUGENE because INNO-LIPA could not detect two mutations (S202G and V214A). CONCLUSIONS: Both assays are easy and suitable for detecting HBV genotype and drug-resistance mutations and for routine laboratory use. However, TRUGENE presented better sensitivity in both analyses and it is possible to conduct both on the same sample. This assay is also able to detect primary and secondary mutations.

Loss compensation in long-range dielectric-loaded surface plasmon-polariton waveguides.

Loss compensation in long-range dielectric-loaded surface plasmon-polariton waveguides is theoretically analyzed when rare-earth-doped double tungstate crystalline material is used as the gain medium in three different waveguide configurations. We study the effect of waveguide geometry on loss compensation at the telecom wavelength of 1.55 µm, and demonstrate that a material gain as small as 12.5 dB/cm is sufficient for lossless propagation of plasmonic modes with sub-micron lateral confinement when using waveguide ridges with gain.

Evolution of hepatitis B virus during long-term therapy in patients with chronic hepatitis B.

BACKGROUND: Long-term lamivudine (LAM), adefovir (ADV) and entecavir (ETV) treatment induce the emergence of drug-resistant hepatitis B virus (HBV) in patients with chronic hepatitis B infection. AIM: To evaluate the LAM, ADV and ETV resistance mutations detected in our patient group. MATERIALS AND METHODS: Twenty patients who had received at least two years of treatment with nucleoside/tide analogues were enrolled in this study. Patients with detectable HBV DNA were analyzed in order to detect resistance mutations and in this group of patients treatment was change. RESULTS: Three patients developed LAM resistance mutations (2 presented rtM204I and one rtL180M+rtM204V/I) and one patient showed rtN236T ADV resistance mutation. During ADV and LAM treatment, one patient developed ADV plus LAM resistance mutations (rtI163V+rtL180M+rtA181V+rtN236T), in this case, HBV strains harbouring polymerase mutations did not develop LAM associated rtM204V/I primary mutation. In addition, ETV resistance mutations (rtL180M+rtT184A+rtS202G+rtM204V) were detected in one patient. CONCLUSIONS: These findings suggest that monotherapy resulted in a limited virological response and combination strategies including potent antiviral agents should be recommended for patients with resistant mutations.

Spectroscopic study of solvent effects on the electronic absorption spectra of flavone and 7-hydroxyflavone in neat and binary solvent mixtures.

The solvatochromic characteristics of flavone and 7-hydroxyflavone were investigated in neat and binary solvent mixtures. The spectral shifts of these solutes were correlated with the Kamlet and Taft parameters (α, ß and π*) using linear solvation energy relationships. The multiparametric analysis indicates that both specific hydrogen bond donor ability and non-specific dipolar interactions of the solvents play an important role in absorption maxima of flavone in pure solvents. The hydrogen bond acceptor ability of the solvent was the main parameter affecting the absorption maxima of 7-hydroxyflavone. The simulated absorption spectra using a TD-DFT method were in good agreement with the experimental ones for both flavones. Index of preferential solvation was calculated as a function of solvent composition. Preferential solvation by ethanol was detected in cyclohexane-ethanol and acetonitrile-ethanol mixtures for flavone and in acetonitrile-ethanol mixtures for 7-hydroxyflavone. These results indicate that intermolecular hydrogen bonds between solute and solvent are responsible for the non-linear variation of the solvatochromic shifts on the mole fraction of ethanol in the analyzed binary mixtures.

Effect of low glycaemic index or load dietary patterns on glycaemic control and cardiometabolic risk factors in diabetes: systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To inform the update of the European Association for the Study of Diabetes clinical practice guidelines for nutrition therapy. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, and the Cochrane Library searched up to 13 May 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials of three or more weeks investigating the effect of diets with low glycaemic index (GI)/glycaemic load (GL) in diabetes. OUTCOME AND MEASURES: The primary outcome was glycated haemoglobin (HbA1c). Secondary outcomes included other markers of glycaemic control (fasting glucose, fasting insulin); blood lipids (low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), non-HDL-C, apo B, triglycerides); adiposity (body weight, BMI (body mass index), waist circumference), blood pressure (systolic blood pressure (SBP) and diastolic blood pressure (DBP)), and inflammation (C reactive protein (CRP)). DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias. Data were pooled by random effects models. GRADE (grading of recommendations assessment, development, and evaluation) was used to assess the certainty of evidence. RESULTS: 29 trial comparisons were identified in 1617 participants with type 1 and 2 diabetes who were predominantly middle aged, overweight, or obese with moderately controlled type 2 diabetes treated by hyperglycaemia drugs or insulin. Low GI/GL dietary patterns reduced HbA1c in comparison with higher GI/GL control diets (mean difference −0.31% (95% confidence interval −0.42 to −0.19%), P<0.001; substantial heterogeneity, I2=75%, P<0.001). Reductions occurred also in fasting glucose, LDL-C, non-HDL-C, apo B, triglycerides, body weight, BMI, systolic blood pressure (dose-response), and CRP (P<0.05), but not blood insulin, HDL-C, waist circumference, or diastolic blood pressure. A positive dose-response gradient was seen for the difference in GL and HbA1c and for absolute dietary GI and SBP (P<0.05). The certainty of evidence was high for the reduction in HbA1c and moderate for most secondary outcomes, with downgrades due mainly to imprecision. CONCLUSIONS: This synthesis suggests that low GI/GL dietary patterns result in small important improvements in established targets of glycaemic control, blood lipids, adiposity, blood pressure, and inflammation beyond concurrent treatment with hyperglycaemia drugs or insulin, predominantly in adults with moderately controlled type 1 and type 2 diabetes. The available evidence provides a good indication of the likely benefit in this population. STUDY REGISTRATION: ClinicalTrials.gov NCT04045938.

Clinical Characteristics and Outcome of Drug-Induced Liver Injury in the Older Patients: From the Young-Old to the Oldest-Old.

Older patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥ 65 years) were categorized according to age: "young" (< 65 years); "young-old" (65-74 years); "middle-old" (75-84 years); and "oldest-old" (≥ 85 years). All elderly groups had an increasingly higher comorbidity burden (P < 0.001) and polypharmacy (P < 0.001). There was a relationship between jaundice and hospitalization (P < 0.001), and both were more prevalent in the older age groups, especially in the oldest-old (88% and 69%, respectively), and the DILI episode was more severe (P = 0.029). The proportion of females decreased across age groups from the young to the middle-old, yet in the oldest-old there was a distinct female predominance. Pattern of liver injury shifted towards cholestatic with increasing age among top culprit drugs amoxicillin-clavulanate, atorvastatin, levofloxacin, ibuprofen, and ticlopidine. The best cutoff point for increased odds of cholestatic DILI was 65 years. Older patients had increased non-liver-related mortality (P = 0.030) as shown by the predictive capacity of the Model for End-Stage Liver Disease score (odds ratio (OR) = 1.116; P < 0.001), and comorbidity burden (OR = 4.188; P = 0.001) in the 6-month mortality. Older patients with DILI exhibited an increasingly predominant cholestatic phenotype across a range of culprit drugs, other than amoxicillin-clavulanate, with increased non-liver-related mortality and require a different approach to predict outcome. The oldest DILI patients exhibited a particular phenotype with more severe DILI episodes and need to be considered when stratifying older DILI populations.