Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636). PATIENTS AND METHODS: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability. RESULTS: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths. CONCLUSIONS: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.

Low-loss and broadband wafer-scale optical interposers for large-scale heterogeneous integration.

We design, fabricate, and demonstrate a low-loss and broadband optical interposer with high misalignment tolerance for large-scale integration of many chips using thermal compression flip-chip bonding. The optical interposer achieves flip-chip integration with photonic integrated circuit die containing evanescent couplers with inter-chip coupling loss of 0.54dB and ±3.53µm 3-dB misalignment tolerance. The loss measurement spectrum indicated wavelength-insensitive loss across O-band and C-band with negligible spectral dependence. Further, we demonstrate 1 to 100 wafer-scale equal power splitting using equal power splitters (EPS) and a path length matching design fabricated using a wafer-scale fabrication technique.

Sleep quality according to chronotype in nurses working 8-hour shifts.

BACKGROUND: To date, studies have been focused on sleep disturbances of nurses working during night shifts. There is a lack of understanding regarding the sleep quality of nurses working in the rapid rotation system for each type of shift work. AIMS: To determine the relationship between chronotype and sleep quality according to shift type (i.e. day, evening and night shifts) in nurses working 8-hour rotating shifts. METHODS: A cross-sectional, descriptive study was conducted from two tertiary hospitals in South Korea from December 2021 to September 2022, including nurses working 8-hour rotating shifts (N = 74). They completed questionnaires to measure general, occupational and sleep-related characteristics, chronotype, insomnia severity and daytime sleepiness. Additionally, sleep parameters were collected from actigraphy and sleep diaries for 7 days. RESULTS: A total of 64% of nurses had an evening chronotype and 37% of nurses had an intermediate chronotype. Nurses had significantly less total sleep time and worsened sleep latency and efficiency during the day shift compared to other shift types. Compared to nurses with an intermediate chronotype, those with an evening chronotype had poorer sleep quality during day shift work. CONCLUSIONS: Strategies to enhance nurses' sleep quality during day shifts should consider a two-level approach: individual approaches, such as improving sleep hygiene, and administrative approaches, such as establishing a chronotype-based shift system for scheduling.

Monolithic silicon photonic 32x32 thin-CLOS AWGR for all-to-all interconnections.

This paper reports the design, fabrication, and experimental demonstration of a monolithic silicon photonic (SiPh) 32×32 Thin-CLOS arrayed waveguide grating router (AWGR) for scalable SiPh all-to-all interconnection fabrics. The 32×32 Thin-CLOS makes use of four 16-port silicon nitride AWGRs, which are compactly integrated and interconnected by a multi-layer waveguide routing method. The fabricated Thin-CLOS has 4 dB insertion loss, < -15 dB adjacent channel crosstalk, and < -20 dB non-adjacent channel crosstalk. System experiments operated on the 32×32 SiPh Thin-CLOS demonstrate error-free communication at 25 Gb/s.

Pericardial diverticulum arising from the right lateral superior aortic recess: a mimicker of cystic anterior mediastinal mass.

AIM: To report the prevalence of pericardial diverticulum of the right lateral superior aortic recess (RSAR) on computed tomography (CT), to analyse the structural CT findings of whether or not the structure is large enough to be seen on chest radiographs, and to describe changes in size and shape of RSAR on follow-up CT. MATERIALS AND METHODS: A well-circumscribed, fluid-attenuation lesion in the anterior mediastinum with the following CT features was defined as a pericardial diverticulum of the RSAR: no enhancing wall, communication with the RSAR, abutment to the heart with an acute angle, and moulding by adjacent structures. Chest CT images of 31 patients with the diverticulum were evaluated, including four selected from 1,130 consecutive patients (0.4%). RESULTS: The diverticulum projected ventrally from the RSAR and its largest size on axial CT ranged between 12-56 mm. Although the RSAR and the largest diverticular portion were usually seen on the same axial image (n=19), the latter sometimes lay above (n=1) or below (n=11) the former. On sagittal images, the last 11 diverticula resembled teardrops hanging from the RSAR by small stems. All of the 24 patients, each with 1-31 follow-up CT examinations, showed size fluctuations ranging between 1-46 mm (mean, 16 mm) during a follow-up period of 0.5-172 months (mean, 65 months). The diverticulum was not identifiable in five cases and was identifiable but did not show a connection with the RSAR in three cases when the diverticulum was smallest in size. CONCLUSIONS: In cases of cystic anterior mediastinal mass, a deliberate search for its connection with the RSAR on all available CT images including previous studies is necessary for the diagnosis of pericardial diverticulum of the RSAR.

Factors for risk stratification of patients with actinic keratosis using integrated analysis of clinicopathological features and gene expression patterns.

BACKGROUND: Actinic keratosis (AK) is considered as precursor lesion of invasive squamous cell carcinoma. Molecular studies on AK are limited because of too small size of the biopsy specimen to obtain enough DNA or RNA. METHODS: Twenty biopsy cases of AK, followed by second same-sited biopsies, were included. Ten cases were diagnosed with total regression (regression group), while the other 10 were diagnosed with invasive carcinoma (progression group) in the follow-up biopsies. Using digital spatial profiling (DSP) technology, whole-gene expression analysis defined by specific regions of interest was performed for all 20 cases. After the clinicopathological features were assessed, separate and integrated analyses of these features and gene expression patterns were performed using machine-learning technology. All analyses were performed on both lesion keratinocytes (KT) and infiltrated stromal lymphocytes (LC). RESULTS: Among the 18,667 genes assessed, 33 and 72 differentially expressed genes (DEGs) between the regression and progression groups were found in KT and LC respectively. The primary genes distinguishing the two groups were KRT10 for KT and CARD18 for LC. Clinicopathological features were weaker in risk stratification of AK progression than the gene expression patterns. Pathways associated with various cancers were upregulated in the progression group of KT, whereas the nucleotide-binding oligomerization domain (NOD)-like receptor signalling pathway was upregulated in the progression of LC. CONCLUSION: Gene expression patterns were effective for risk stratification of AK progression, and their distinguishing power was higher than that of clinicopathological features.

Photonic spiking neural networks with event-driven femtojoule optoelectronic neurons based on Izhikevich-inspired model.

Photonic spiking neural networks (PSNNs) potentially offer exceptionally high throughput and energy efficiency compared to their electronic neuromorphic counterparts while maintaining their benefits in terms of event-driven computing capability. While state-of-the-art PSNN designs require a continuous laser pump, this paper presents a monolithic optoelectronic PSNN hardware design consisting of an MZI mesh incoherent network and event-driven laser spiking neurons. We designed, prototyped, and experimentally demonstrated this event-driven neuron inspired by the Izhikevich model incorporating both excitatory and inhibitory optical spiking inputs and producing optical spiking outputs accordingly. The optoelectronic neurons consist of two photodetectors for excitatory and inhibitory optical spiking inputs, electrical transistors' circuits providing spiking nonlinearity, and a laser for optical spiking outputs. Additional inclusion of capacitors and resistors complete the Izhikevich-inspired optoelectronic neurons, which receive excitatory and inhibitory optical spikes as inputs from other optoelectronic neurons. We developed a detailed optoelectronic neuron model in Verilog-A and simulated the circuit-level operation of various cases with excitatory input and inhibitory input signals. The experimental results closely resemble the simulated results and demonstrate how the excitatory inputs trigger the optical spiking outputs while the inhibitory inputs suppress the outputs. The nanoscale neuron designed in our monolithic PSNN utilizes quantum impedance conversion. It shows that estimated 21.09 fJ/spike input can trigger the output from on-chip nanolasers running at a maximum of 10 Gspike/second in the neural network. Utilizing the simulated neuron model, we conducted simulations on MNIST handwritten digits recognition using fully connected (FC) and convolutional neural networks (CNN). The simulation results show 90% accuracy on unsupervised learning and 97% accuracy on a supervised modified FC neural network. The benchmark shows our PSNN can achieve 50 TOP/J energy efficiency, which corresponds to 100 × throughputs and 1000 × energy-efficiency improvements compared to state-of-art electrical neuromorphic hardware such as Loihi and NeuroGrid.

Preoperative volume assessment using bioelectrical impedance analysis for minimizing blood loss during hepatic resection.

BACKGROUND: Maintaining low central venous pressure (CVP) is an effective strategy to reduce blood loss during hepatic resection. As an alternative to measuring CVP, which requires the placement of a central venous catheter, bioelectrical impedance analysis (BIA) is a noninvasive method recently used for monitoring volume status in critically ill patients. METHODS: We investigated 192 patients who underwent hepatic resection from January 2017 to December 2020. The ratio of extracellular water:total body water (ECW/TBW), as an index of volume status, was measured using InBody S10 (Biospace, Seoul, Korea). The correlation between the ECW/TBW and CVP was determined, and their influences on operative outcomes were analyzed. RESULTS: ECW/TBW and CVP showed a significant correlation; an ECW/TBW <0.378 correlated with a CVP <5 mmHg (R2 = 0.839, P<0.001). Estimated blood loss (EBL) was significantly increased in patients with an ECW/TBW ≥0.378 compared to those with a ratio <0.378 (508 ± 321 vs. 324 ± 193, mL, P<0.001). Identified predictors for an EBL ≥500 mL were operative time (odds ratio [OR], 1.008; 95% confidence interval [CI], 1.001-1.015; P = 0.021) and an ECW/TBW <0.378 (OR, 0.263; 95% CI, 0.121-0.572; P = 0.001). CONCLUSIONS: BIA can be utilized for preoperative volume assessment to minimize blood loss during hepatic resection.

Intraoperative near-infrared imaging of parathyroid glands: A comparison of first- and second-generation technologies.

BACKGROUND: Intraoperative near-infrared imaging (NIFI) of parathyroid glands (PG) by first-generation technology had limited image quality and depth penetration. Second-generation NIFI has recently been introduced. Our aim was to compare (1) capability to detect PG and (2) image quality between older and newer technologies. METHODS: Accurately detecting PG, as well as, quality of autofluorescence (AF) was compared between an older charge-coupled device (CCD) camera and a newer complementary metal-oxide semiconductor (CMOS). χ2 , t test, and analysis of variance were used for analysis. RESULTS: There were 300 patients who underwent parathyroidectomy (PTX) and/or thyroidectomy (THY) with NIFI, 200 with CCD, and 100 with CMOS. Although both NIFI technologies detected >94% of PG, CMOS was superior to CCD. Comparing AF quality, mean pixel intensity of PG compared with the background was higher with CMOS compared with CCD. When comparing PG detected by NIFI before visual identification by a surgeon, both CCD and CMOS had similar results (25% vs. 22%; p = .3). CONCLUSION: Both NIFI cameras were excellent at detecting PG. Second-generation NIFI (CMOS) displayed higher detection rates and AF intensity. Although surgeons identified majority of PG before NIFI detection, 25% of PG were identified with NIFI first, suggesting future advancements of this technology may expand its applications during parathyroid/thyroid operations.

Prognostic effects of histology-based tumour microenvironment scores in resected distal bile duct cancer.

AIMS: Histology-based tumour microenvironment (TME) scores are useful in predicting the prognosis of gastrointestinal cancer. However, their prognostic roles in distal bile duct cancer (DBDC) have not been previously studied. This study aimed to evaluate the prognostic significance of the TME scores using the Klintrup-Mäkinen (KM) grade, tumour stroma percentage (TSP) and the Glasgow microenvironment score (GMS) in resected DBDC. METHODS AND RESULTS: Eighty-one patients with DBDC who underwent curative resection were enrolled. DBDC was graded according to KM grade, TSP and GMS. A high KM grade was found in 19 patients (24%) and a high TSP was found in 47 patients (58%). A high TSP was significantly correlated with a low KM grade (P < 0.001). The distribution of the GMS, which was developed by combining the KM grade and TSP, was as follows: 0 (n = 19, 24%), 1 (n = 19, 24%) and 2 (n = 43, 52%). A low KM grade, high TSP and high GMS were significantly associated with short overall survival (OS) (P < 0.001) and relapse-free survival (RFS) (P < 0.001). Furthermore, multivariate analysis showed that a low KM grade [hazard ratio (HR) = 3.826; confidence interval (CI) = 1.650-8.869; P = 0.014], high TSP (HR = 2.193; CI = 1.173-4.100, P = 0.002) and high GMS (HR = 7.148; CI = 2.811-18.173) were independent prognostic factors for short RFS; a low KM grade (HR = 4.324; CI = 1.594-11.733) and high GMS (HR = 6.332; CI = 2.743-14.594) were independent prognostic factors for short OS. CONCLUSION: Histology-based TME scores, including the KM grade, TSP and GMS, are useful for predicting the survival of patients with resected DBDC.

A risk prediction model for the development of subsequent primary melanoma in a population-based cohort.

BACKGROUND: Guidelines for follow-up of patients with melanoma are based on limited evidence. OBJECTIVES: To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. METHODS: Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population-based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow-up via the cancer registry. Discrimination and calibration were assessed. RESULTS: The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C-statistic was 0·73 [95% confidence interval (CI) 0·68-0·77], 0·65 (95% CI 0·62-0·68) and 0·65 (95% CI 0·61-0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87-5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. CONCLUSIONS: The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow-up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow-up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.

Gender difference in the effect of uric acid on striatal dopamine in early Parkinson's disease.

BACKGROUND AND PURPOSE: High uric acid (UA) levels have been shown to exert a neuroprotective effect in Parkinson's disease (PD) by inhibiting oxidative stress in the nigrostriatal pathway. However, the association between striatal dopamine activity and UA level has not been clarified. METHODS: A total of 213 patients with early PD were enrolled. All patients underwent positron emission tomography using 18 F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane and a venous blood test for quantification of serum UA. All patients were stratified into either the lower UA group or the higher UA group using the median UA level. After normalizing the positron emission tomography images, differences in the regional standardized uptake value ratios (SUVRs) were analyzed with a volume-of-interest template. All tested SUVRs were also compared after categorizing patients by gender. RESULTS: The UA affected dopamine transporter SUVRs in different ways by gender. In female patients, the higher UA level group showed a smaller reduction in dopamine transporter uptake in the posterior putamen, whereas there was no such association observed in male patients. CONCLUSIONS: Higher UA levels were correlated with higher dopamine transporter uptake in the putamen in female patients with early PD. This finding suggests that UA has a neuroprotective effect, as demonstrated by the relatively preserved striatal dopamine activity in women.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

Nobiletin: Targeting the Circadian Network to Promote Bioenergetics and Healthy Aging.

The circadian clock is the biological mastermind governing orderly execution of bodily processes throughout the day. In recent years, an emerging topic of broad interest is clock-modulatory agents, including small molecules both of synthetic and natural origins, and their potential applications in disease models. Nobiletin is a naturally occurring flavonoid with the greatest abundance found in citrus peels. Extensive research has shown that Nobiletin is endowed with a wide range of biological activities, yet its mechanism of action remains unclear. We recently found through unbiased chemical screening that Nobiletin impinges on the clock machinery to activate temporal control of downstream processes within the cell and throughout the body. Using animal models of diseases and aging, we and others illustrate potent beneficial effects of Nobiletin on cellular energetics in both periphery and brain to promote healthy aging. Given its excellent safety profile, Nobiletin may represent a promising candidate molecule for development of nutraceutical and chronotherapeutic agents against chronic and age-related neurodegenerative diseases.

Augmented decision-making for acral lentiginous melanoma detection using deep convolutional neural networks.

BACKGROUND: Several studies have achieved high-level performance of melanoma detection using convolutional neural networks (CNNs). However, few have described the extent to which the implementation of CNNs improves the diagnostic performance of the physicians. OBJECTIVE: This study is aimed at developing a CNN for detecting acral lentiginous melanoma (ALM) and investigating whether its implementation can improve the initial decision for ALM detection made by the physicians. METHODS: A CNN was trained using 1072 dermoscopic images of acral benign nevi, ALM and intermediate tumours. To investigate whether the implementation of CNN can improve the initial decision for ALM detection, 60 physicians completed a three-stage survey. In Stage I, they were asked for their decisions solely on the basis of dermoscopic images provided to them. In Stage II, they were also provided with clinical information. In Stage III, they were provided with the additional diagnosis and probability predicted by the CNN. RESULTS: The accuracy of ALM detection in the participants was 74.7% (95% confidence interval [CI], 72.6-76.8%) in Stage I and 79.0% (95% CI, 76.7-81.2%) in Stage II. In Stage III, it was 86.9% (95% CI, 85.3-88.4%), which exceeds the accuracy delivered in Stage I by 12.2%p (95% CI, 10.1-14.3%p) and Stage II by 7.9%p (95% CI, 6.0-9.9%p). Moreover, the concordance between the participants considerably increased (Fleiss-κ of 0.436 [95% CI, 0.437-0.573] in Stage I, 0.506 [95% CI, 0.621-0.749] in Stage II and 0.684 [95% CI, 0.621-0.749] in Stage III). CONCLUSIONS: Augmented decision-making improved the performance of and concordance between the clinical decisions of a diverse group of experts. This study demonstrates the potential use of CNNs as an adjoining, decision-supporting system for physicians' decisions.

Demonstration of distributed collaborative learning with end-to-end QoT estimation in multi-domain elastic optical networks.

This paper proposes a distributed collaborative learning approach for cognitive and autonomous multi-domain elastic optical networking (EON). The proposed approach exploits a knowledge-defined networking framework which leverages a broker plane to coordinate the operations of multiple EON domains and applies machine learning (ML) to support autonomous and cognitive inter-domain service provisioning. By employing multiple distributed ML blocks learning domain-level features and working with broker plane aggregation ML blocks (through the chain rule-based training), the proposed approach enables to develop cognitive networking applications that can fully exploit the multi-domain EON states while obviating the need for the raw and confidential intra-domain data. In particular, we investigate end-to-end quality-of-transmission estimation application using the distributed learning approach and propose three estimator designs incorporating the concepts of multi-task learning (MTL) and transfer learning (TL). Evaluations with experimental data demonstrate that the proposed designs can achieve estimation accuracies very close to (with differences less than 0.5%) or even higher than (with MTL/TL) those of the baseline models assuming full domain visibility.

Observation of incoherently coupled dark-bright vector solitons in single-mode fibers.

We report experimental observation of incoherently coupled dark-bright vector solitons in single-mode fibers. Properties of the vector solitons accord well with those predicted by the respective systems of incoherently coupled nonlinear Schrödinger equations. To our knowledge, this is the first experimental observation of temporal incoherently coupled dark-bright solitons in single-mode fibers.

Sub-wavelength-pitch silicon-photonic optical phased array for large field-of-regard coherent optical beam steering.

This paper reports on large field-of-regard, high-efficiency, and large aperture active optical phased arrays (OPAs) for optical beam steering in LIDAR systems. The fabricated 5 mm-long silicon photonic OPA with a 1.3 µm waveguide pitch achieved adjacent waveguide crosstalk below -12dB. A relatively large and uniform emission aperture has been achieved with a low-contrast silicon nitride assisted grating (~20 dB/cm) whose emission profile can be further optimized using an apodized design. The fabricated silicon-photonic OPA demonstrated > 40° lateral beam steering with no sidelobes in a ± 33° field-of-regard and 3.3° longitudinal beam steering via wavelength tuning by 20 nm centered at 1550 nm. We have fully integrated the silicon photonic OPA device with electronic controls and successfully demonstrated 2-dimensional coherent optical beam steering of pre-planned far-field patterns. Future improvements include placement of a distributed Bragg reflector (DBR) underneath the grating emitter in order to achieve nearly a factor of two improvement in emission efficiency.

Late-onset extensive haematoma mimicking cellulitis.

Cellulitis is a microbial infection of the deep dermis and the subcutaneous tissue. Several non-infectious disorders, such as contact dermatitis, insect bites, stasis dermatitis, and lipodermatosclerosis, masquerade as infectious cellulitis. There are no specific criteria for the diagnosis of cellulitis; thus, it is challenging to correctly diagnose true cellulitis. For previously assumed cellulitis cases that were refractory to conventional antimicrobial treatment, thoroughly investigating the circumstances of symptom initiation, recording the medical history, and performing an attentive physical examination of the patient is critical for distinguishing true cellulitis from conditions that mimic cellulitis. The inquiry should be personalised according to the patient's age and the prescribed medication. Furthermore, imaging studies, including ultrasonography and magnetic resonance imaging, should be considered on certain occasions to non-invasively aid the differential diagnosis.

Early development of de novo hepatocellular carcinoma after direct-acting agent therapy: Comparison with pegylated interferon-based therapy in chronic hepatitis C patients.

Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P < .0001, hazard ratio 176.174, 95% confidence interval 10.768-2882.473) and in patients treated with direct-acting agents (P < .0001, hazard ratio 128.402, 95% confidence interval 8.417-1958.680). In conclusion, the rate of early development of hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response.