Acute acalculous cholecystitis with portal cavernoma: A case report with literature review.

Portal cavernoma cholangiopathy (PCC) refers to morphological changes in the intrahepatic, extrahepatic biliary system, along with the gallbladder (GB), induced by portal cavernoma (PC). Acute acalculous cholecystitis (AAC) represents an infrequent clinical manifestation of PCC. Given the inadequacy of documentation within medical literature, AAC may go undiagnosed among patients with PC presenting symptoms of right upper quadrant pain. The current study aims to report a case of acute acalculous cholecystitis secondary to portal cavernoma, focusing on radiological findings, with a brief review of literature.

Challenging Recurrence and Management of Squamous Cell Carcinoma in the Calcaneal Region: A Case Report.

Squamous cell carcinoma (SCC) is the second most common type of skin cancer. As ultraviolet exposure represents an important risk factor, SCC commonly occurs on the face, lips, scalp, hands, and heels. The foot is an unusual location to manifest SCC. In this report, we present a case of a 44-year-old woman with severe local recurrence of SCC in the right heel, four years after an initial excision of a primary, small lesion. For various reasons, the patient did not visit the clinic for follow-up assessment during this period. Considering the extent of the lesion and infection risk, the affected leg was amputated at one-third of the lower leg. This case report underlines the importance of educating patients about the risk of SCC and assisting them in attending follow-up visits. In addition, adequate attention should be given to foot lesions with suspicious appearance. Early detection would minimize systemic risks, including metastasis and infection, and maximize preserved function after surgical intervention.

Adipocytes Are the Only Site of Glutamine Synthetase Expression Within the Lactating Mouse Mammary Gland.

Background: Glutamine in milk is believed to play an important role in neonatal intestinal maturation and immune function. For lactating mothers, glutamine utilization is increased to meet the demands of the enlarged intestine and milk production. However, the source of such glutamine during lactation has not been studied. Objectives: We aimed to assess the effects of lactation on the expression of glutamine synthetase (GS) in the mammary gland and other tissues of lactating mice. Methods: Mouse tissues were sampled at 4 time points: 8-wk-old (virgin, control), post-delivery day 5 (PD5, early lactation), PD15 (peak lactation), and involution (4 days after weaning at PD21). We examined the gene expression and protein concentrations of GS and the first 2 enzymes of branched-chain amino acid catabolism: branched-chain aminotransferase 2 (BCAT2) and branched-chain ketoacid dehydrogenase subunit E1α (BCKDHA). Results: The messenger RNA (mRNA) expression and protein concentrations of GS in mammary glands were significantly lower at PD5 and PD15 compared with the control but were restored at involution. Within the mammary gland, GS protein was only detected in adipocytes with no evidence of presence in mammary epithelial cells. Compared with the control, mRNA and protein concentrations of BCAT2 and BCKDHA in mammary glands significantly decreased during lactation and involution. No changes in GS protein concentrations during lactation were found in the liver, skeletal muscle, and lung. In non-mammary adipose tissue, GS protein abundance was higher during lactation compared with the virgin. Conclusions: This work shows that, within the mouse mammary gland, GS is only expressed in adipocytes and that the relative GS abundance in mammary gland sections is lower during lactation. This suggests that mammary adipocytes may be a site of glutamine synthesis in the lactating mouse. Identifying the sources of glutamine production during lactation is important for optimizing milk glutamine concentration to enhance neonatal and maternal health.

Exploring Blood Cell Count-Derived Ratios as Practical Diagnostic Tools for Scabies in Vulnerable Populations.

Scabies is a neglected tropical disease and represents a considerable global burden. Although consensus diagnostic criteria for scabies have been recently published, diagnosing scabies infestation remains challenging in clinical practice. We investigated the diagnostic utility of complete blood cell count (CBC) and CBC-derived ratios obtained at diagnosis in a set of 167 patients who are Vietnamese with confirmed scabies. These parameters were compared with those of patients with dermatophytosis (N = 800) and urticaria (N = 2023), two diseases frequent in Vietnam, which can present with similar skin manifestations to scabies and tend to pose a diagnostic challenge in vulnerable populations. Our analysis revealed that white blood cell, monocyte, and eosinophil counts were significantly higher among patients with scabies than the other two diseases. Similarly, the monocyte-to-lymphocyte ratio (MLR) and eosinophil-to-lymphocyte ratio (ELR) were significantly higher among patients with scabies. The optimal cut-off values to distinguish scabies from dermatophytosis and urticaria were 0.094 for ELR (sensitivity: 74.85%, specificity: 70.7%) and 0.295 for MLR (sensitivity: 52.69%, specificity: 73.54%). CBC, ELR, and MLR are low-cost and easily calculated parameters that may be helpful for the diagnosis of scabies.

Enhanced photoelectrochemical water splitting by a 3D hierarchical sea urchin-like structure: ZnO nanorod arrays on TiO2hollow hemisphere.

A hierarchical sea urchin-like hybrid metal oxide nanostructure of ZnO nanorods deposited on TiO2porous hollow hemispheres with a thin zinc titanate interface layer is specifically designed and synthesized to form a combined type I straddling and type II staggered junctions. The HHSs, synthesized by electrospinning, facilitate light trapping and scattering. The ZnO nanorods offer a large surface area for improved surface oxidation kinetics. The interface layer of zinc titanate (ZnTiO3) between the TiO2HHSs and ZnO nanorods regulates the charge separation in a closely coupled hierarchy structure of ZnO/ZnTiO3/TiO2. The synergistic effects of the improved light trapping, charge separation, and fast surface reaction kinetics result in a superior photoconversion efficiency of 1.07% for the photoelectrochemical water splitting with an outstanding photocurrent density of 2.8 mA cm-2at 1.23 V versus RHE.

High-Precision Tailored Polymer Molecular Weights for Specific Photovoltaic Applications through Ultrasound-Induced Simultaneous Physical and Chemical Events.

It is highly challenging to reproducibly prepare semiconducting polymers with targeted molecular weight tailored for next-generation photovoltaic applications. Once such an easily accessible methodology is established, which can not only contribute to overcome the current limitation of the statistically determined nature of semiconducting polymers, but also facilitate rapid incorporation into the broad synthetic chemists' toolbox. Here, we describe a simple yet robust ultrasonication-assisted Stille polymerization for accessing semiconducting polymers with high-precision tailored molecular weights (from low to ultrahigh molecular weight ranges) while mitigating their interbatch variations. We propose that ultrasound-induced simultaneous physical and chemical events enable precise control of the semiconducting polymers' molecular weights with high reproducibility to satisfy all the optical/electrical and morphological demands of diverse types of high-performance semiconducting polymer-based devices; as demonstrated in in-depth experimental screenings in applications of both organic and perovskite photovoltaics. We believe that this methodology provides a fast development of new and existing semiconducting polymers with the highest-level performances possible on various photovoltaic devices.

Whole-Body Disposition and Physiologically Based Pharmacokinetic Modeling of Adeno-Associated Viruses and the Transgene Product.

To facilitate model-informed drug development (MIDD) of adeno-associated virus (AAV) therapy, here we have developed a physiologically based pharmacokinetic (PBPK) model for AAVs following preclinical investigation in mice. After 2E11 Vg/mouse dose of AAV8 and AAV9 encoding a monoclonal antibody (mAb) gene, whole-body disposition of both the vector and the transgene mAb was evaluated over 3 weeks. At steady-state, the following tissue-to-blood (T/B) concentration ratios were found for AAV8/9: ∼50 for liver; ∼10 for heart and muscle; ∼2 for brain, lung, kidney, adipose, and spleen; ≤1 for bone, skin, and pancreas. T/B values for mAb were compared with the antibody biodistribution coefficients, and five different clusters of organs were identified based on their transgene expression profile. All the biodistribution data were used to develop a novel AAV PBPK model that incorporates: (i) whole-body distribution of the vector; (ii) binding, internalization, and intracellular processing of the vector; (iii) transgene expression and secretion; and (iv) whole-body disposition of the secreted transgene product. The model was able to capture systemic and tissue PK of the vector and the transgene-produced mAb reasonably well. Pathway analysis of the PBPK model suggested that liver, muscle, and heart are the main contributors for the secreted transgene mAb. Unprecedented PK data and the novel PBPK model developed here provide the foundation for quantitative systems pharmacology (QSP) investigations of AAV-mediated gene therapies. The PBPK model can also serve as a quantitative tool for preclinical study design and preclinical-to-clinical translation of AAV-based gene therapies.

A systematic analysis and data mining of opioid-related adverse events submitted to the FAERS database.

The opioid epidemic has become a serious national crisis in the United States. An indepth systematic analysis of opioid-related adverse events (AEs) can clarify the risks presented by opioid exposure, as well as the individual risk profiles of specific opioid drugs and the potential relationships among the opioids. In this study, 92 opioids were identified from the list of all Food and Drug Administration (FDA)-approved drugs, annotated by RxNorm and were classified into 13 opioid groups: buprenorphine, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, tapentadol, and tramadol. A total of 14,970,399 AE reports were retrieved and downloaded from the FDA Adverse Events Reporting System (FAERS) from 2004, Quarter 1 to 2020, Quarter 3. After data processing, Empirical Bayes Geometric Mean (EBGM) was then applied which identified 3317 pairs of potential risk signals within the 13 opioid groups. Based on these potential safety signals, a comparative analysis was pursued to provide a global overview of opioid-related AEs for all 13 groups of FDA-approved prescription opioids. The top 10 most reported AEs for each opioid class were then presented. Both network analysis and hierarchical clustering analysis were conducted to further explore the relationship between opioids. Results from the network analysis revealed a close association among fentanyl, oxycodone, hydrocodone, and hydromorphone, which shared more than 22 AEs. In addition, much less commonly reported AEs were shared among dihydrocodeine, meperidine, oxymorphone, and tapentadol. On the contrary, the hierarchical clustering analysis further categorized the 13 opioid classes into two groups by comparing the full profiles of presence/absence of AEs. The results of network analysis and hierarchical clustering analysis were not only consistent and cross-validated each other but also provided a better and deeper understanding of the associations and relationships between the 13 opioid groups with respect to their adverse effect profiles.

Wavelet radiomics features from multiphase CT images for screening hepatocellular carcinoma: analysis and comparison.

Early detection of liver malignancy based on medical image analysis plays a crucial role in patient prognosis and personalized treatment. This task, however, is challenging due to several factors, including medical data scarcity and limited training samples. This paper presents a study of three important aspects of radiomics feature from multiphase computed tomography (CT) for classifying hepatocellular carcinoma (HCC) and other focal liver lesions: wavelet-transformed feature extraction, relevant feature selection, and radiomics features-based classification under the inadequate training samples. Our analysis shows that combining radiomics features extracted from the wavelet and original CT domains enhance the classification performance significantly, compared with using those extracted from the wavelet or original domain only. To facilitate the multi-domain and multiphase radiomics feature combination, we introduce a logistic sparsity-based model for feature selection with Bayesian optimization and find that the proposed model yields more discriminative and relevant features than several existing methods, including filter-based, wrapper-based, or other model-based techniques. In addition, we present analysis and performance comparison with several recent deep convolutional neural network (CNN)-based feature models proposed for hepatic lesion diagnosis. The results show that under the inadequate data scenario, the proposed wavelet radiomics feature model produces comparable, if not higher, performance metrics than the CNN-based feature models in terms of area under the curve.

Environmental allergen reduction in asthma management: an overview.

Asthma is a prevalent non-communicable disease that affects both children and adults. Many patients with severe, uncontrolled asthma could not achieve total control despite using anti-asthmatic drugs. There is increasing evidence that allergy to environmental allergens, including both indoor and outdoor allergens, is associated with asthma symptoms and severe asthma. Frequently reported sensitized allergens were dust mites, cockroaches, grass pollens, molds, pets, and rodents in allergic asthma patients, although the patterns of widespread allergens differed from each country. Allergen avoidance is the cornerstone of asthma management, especially in sensitized subjects. This review summarizes environmental allergen avoidance and clarifies their effects on asthma control. Despite contrasting results about the impact of allergen exposure reduction on asthma control, several studies supported the beneficial effects of reducing asthma-related symptoms or risk of exacerbations as a nondrug therapy. Identifying environmental allergens is helpful for asthma patients, and further studies on clinically effective avoidance methods are required.

Phenyl glycosides from Bacopa monnieri with their antioxidant and anti-inflammatory activities.

Bacopa monnieri (L.) Wettst (Plantaginaceae), is traditionally used in many countries as neural tonic and memory enhancer, or to relieve acute pain and inflammation. This study described the isolation and identification of one new, bacomoside D3 (1), and seven known phenyl glycosides (2 - 8). The structures of isolates were established by analysis of their spectroscopic data or hydrolysis followed by HPLC analysis together with a comparison to those reported in the literature. These compounds were evaluated for antioxidant and anti-inflammatory activities. Among them, compounds 4 and 5 exhibited strong DPPH radical scavenging activity with IC50 values of 9.77 ± 0.08 and 3.50 ± 0.04 µM, respectively. Compounds 2 and 5 significantly inhibited TNF-α production in LPS-stimulated RAW264.7 cells with IC50 values of 40.60 ± 3.05 and 38.19 ± 1.75 µM, respectively. Furthermore, the active compounds could be efficient inhibitors of oxidants by interfering with the DPPH activity in silico study.

Octafluoronaphthalene as a thermal-annealing-free volatile solid additive enables high-performance organic solar cells.

A thermal annealing-free solid additive octafluoronaphthalene was developed for high-performance organic solar cells. In an additive-modified device, an impressive power conversion efficiency of 18.59% from 17.27% was achieved with simultaneously enhanced current density from 26.86 to 27.53 mA cm-2 and fill factor from 74.34% to 78.85%.

Intradiscal Glucocorticoid Injection in Discogenic Back Pain and Influence on Modic Changes: A Systematic Review and Meta-analysis of RCTs.

BACKGROUND: The benefit of intradiscal glucocorticoid injection (IGI) for discogenic low back pain (LBP) remains controversial. OBJECTIVES: The objective of this study was to systematically assess and meta-analyze the efficacy of IGI compared with these control groups. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A comprehensive literature search was performed screening PubMed and Embase through May 2022. Only randomized controlled trials (RCTs) comparing IGI to control groups in adult patients with discogenic lumbar back pain were included. A random effects model was used to pool mean differences of pain intensity (visual analaog scale [VAS] 0-100), and physical function assessed with the Oswestry Disability Index (ODI). Subgroup analyses were stratified by Modic magnetic resonance imaging findings. RESULTS: Seven studies met inclusion criteria with a total of 626 patients. The short-term (< 3 months) follow-up showed a significant pooled mean difference in both pain intensity (-20.1; 95% CI, -25.5 to -14.7) and physical function (-9.9; 95% CI, -16.1 to -3.6). In the intermediate -term follow-up (3 to < 6 months), only physical function remained significantly better in the glucocorticoid group (-13.1; 95% CI, -22.3 to -3.9). There was no clinically meaningful or significant difference in pain scores and physical function at the long-term (>= 6 months) follow-up. A subgroup analysis did not demonstrate an effect of Modic (type I) changes on the efficacy of IGI. LIMITATIONS: A limited number of studies was available and consequently publication bias could not be evaluated using a funnel plot. Statistical heterogeneity was detected among the included studies. CONCLUSION: We conclude that IGI reduces discogenic LBP intensity and improves physical function effectively at short-term follow-up, and continues to improve physical function at intermediate-term. However, 6 months posttreatment, outcomes are similar in comparison to the control groups. The type of Modic change does not appear to be related with the response to IGI. KEY WORDS: Low back pain, lumbar back pain, intradiscal glucocorticoid injection, modic changes, meta-analysis.

New Dibenzocyclooctadiene Lignans and Phenolics from Kadsura heteroclite with Anti-Inflammatory Activity.

A chemical investigation of K. heteroclite led to isolation of two new dibenzocyclooctadienes (1 and 2) together with 14 known compounds (3-16) by using multiple chromatographic techniques. New compounds (1 and 2) were obtained and identified by spectroscopic methods (HR-ESI-MS, 1D and 2D NMR, and ECD) as well as by comparison of their experimental data with those reported in the literatures. All the isolates were evaluated for their ability to modulate TNF-α production in lipopolysaccharide (LPS) stimulated RAW264.7 cells. Among them, compound 5 displayed the most inhibition against tumor necrosis factor (TNF)-α production with IC50 value of 6.16±0.14 µM. Whereas, compounds (1, 3, and 6) showed the significant inhibition (IC50 values ranging from 9.41 to 14.54 µM), and compounds (2, 4, 9, 10, 13, 15, and 16) exhibited moderate inhibition (IC50 values ranging from 19.27 to 40.64 µM) toward TNF-α production, respectively.

Four new lignans obtained from the leaves of Schisandra cauliflora and their effect on skeletal muscle cell proliferation.

Plants of the Schisandra genus are commonly used in folk medicinal remedies. Some Schisandra species and their lignans have been reported to improve muscle strength. In the present study, four new lignans, named schisacaulins A-D, together with three previously described compounds ananonin B, alismoxide, and pregomisin were isolated from the leaves of S. cauliflora. Their chemical structures were determined by extensive analyses of HR-ESI-MS, NMR, and ECD spectra. Schisacaulin D and alismoxide significantly stimulated skeletal muscle cell proliferation by increasing the number of fused myotubes and expression of myosin heavy chain (MyHC) which may be good candidates for the treatment of sarcopenia.

Light trapping by porous TiO2 hollow hemispheres for high efficiency photoelectrochemical water splitting.

Photocatalytic water splitting has recently received increasing attention as a green fuel source. The controlled nano-geometry of the photocatalytic material can improve light harvesting. In this study, as a proof of concept, hollow hemisphere (HHS)-based films of TiO2 material were created by a conventional electrospray method and subsequently applied for photoelectrochemical (PEC) water splitting. To preserve the morphology of the HHS structure, a hydrolysis precipitation phase separation method (HPPS) was developed. As a result, the TiO2 HHS-based thin films presented a maximum PEC water splitting efficiency of ca. 0.31%, almost two times that of the photoanode formed by TiO2 nanoparticle-based films (P25). The unique morphology and porous structure of the TiO2 HHSs with reduced charge recombination and improved light absorption are responsible for the enhanced PEC performance. Light scattering by the HHS was demonstrated with total reflection internal fluorescence microscopy (TRIFM), revealing the unique light trapping phenomenon within the HHS cavity. This work paves the way for the rational design of nanostructures for photocatalysis in fields including energy, environment, and organosynthesis.

Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes.

We hypothesize that different routes of administration may lead to altered pharmacokinetics/pharmacodynamics (PK/PD) behavior of antibody-drug conjugates (ADCs) and may help to improve their therapeutic index. To evaluate this hypothesis, here we performed PK/PD evaluation for an ADC administered via subcutaneous (SC) and intratumoral (IT) routes. Trastuzumab-vc-MMAE was used as the model ADC, and NCI-N87 tumor-bearing xenografts were used as the animal model. The PK of multiple ADC analytes in plasma and tumors, and the in vivo efficacy of ADC, after IV, SC, and IT administration were evaluated. A semi-mechanistic PK/PD model was developed to characterize all the PK/PD data simultaneously. In addition, local toxicity of SC-administered ADC was investigated in immunocompetent and immunodeficient mice. Intratumoral administration was found to significantly increase tumor exposure and anti-tumor activity of ADC. The PK/PD model suggested that the IT route may provide the same efficacy as the IV route at an increased dosing interval and reduced dose level. SC administration of ADC led to local toxicity and reduced efficacy, suggesting difficulty in switching from IV to SC route for some ADCs. As such, this manuscript provides unprecedented insight into the PK/PD behavior of ADCs after IT and SC administration and paves the way for clinical evaluation of these routes.

Spatiotemporal Patterns of Deaths of Despair Across the U.S., 2000-2019.

INTRODUCTION: Deaths of despair (i.e., suicide, drug/alcohol overdose, and chronic liver disease and cirrhosis) have been increasing over the past 2 decades. However, no large-scale studies have examined geographic patterns of deaths of despair in the U.S. This ecologic study identifies geographic and temporal patterns of individual and co-occurring clusters of deaths of despair. METHODS: All individuals aged ≥10 years who died in the U.S. between 2000 and 2019 and resided within the 48 contiguous states and Washington, District of Columbia were included (N=2,171,105). Causes of death were limited to deaths of despair, namely suicide, drug/alcohol overdose, and chronic liver disease and cirrhosis. Univariate and multivariate space-time scan statistics were used to identify individual and co-occurring clusters with excess risk of deaths of despair. County-level RRs account for heterogeneity within each cluster. Analyses were conducted from late 2021 to early 2022. RESULTS: Six suicide clusters, four overdose clusters, nine liver disease clusters, and three co-occurring clusters of all three types of deaths were identified. A large portion of the western U.S., southeastern U.S., and Appalachia/rust belt were contained within the co-occurring clusters. The co-occurring clusters had average county RRs ranging from 1.17 (p<0.001) in the southeastern U.S. to 4.90 (p<0.001) in the western U.S. CONCLUSIONS: Findings support identifying and targeting risk factors common to all types of deaths of despair when planning public health interventions. Resources and policies that address all deaths of despair simultaneously may be beneficial for the areas contained within the co-occurring high-risk clusters.

Exploring attitude-behaviour dynamics during COVID-19: How fear of infection and working from home influence train use and the attitude toward this mode.

Research on the relationships between travel-related attitudes and travel behaviour has recently been reinvigorated by new theorizing as well as new empirical models. While traditional theories assume a rather static role of attitudes, i.e. acting as stable predispositions that cause behaviours in a unidirectional manner, recent models assume that attitudes and behaviours mutually influence each other over time. This study aims at better understanding attitude-behaviour dynamics by capitalizing on the circumstances presented by the ongoing COVID-19 pandemic. It assesses how the fear of COVID-19 infection and (the attitude towards) working-from-home influence train use as well as train use attitudes. To explore the (within-person) reciprocal relationships between these variables, random-intercept cross-lagged panel models were estimated using a 4-wave longitudinal dataset collected during the COVID-19 pandemic from a large panel of train travellers in the Netherlands. The results indicate that train use and the attitude towards train use reciprocally influence each other. Those with stronger fears of infection in one wave tend to use the train less in a subsequent wave, but higher use of the train in one wave also reduces the fear of infection in the next. We also found that working from home (WFH) and travelling by train operate as substitutes for one another. Moreover, people who work from home frequently become more fearful of infection. All the findings are consistent with cognitive dissonance theory that people develop attitudes that align with their behaviours. The paper concludes with several policy implications related to changing attitudes and promoting train use.

Correlation of IL36RN and CARD14 mutations with clinical manifestations and laboratory findings in patients with generalised pustular psoriasis.

Background Generalized pustular psoriasis (GPP) is a chronic disease associated with genetic factors related to mutations of the interleukin 36 receptor antagonist gene (IL36RN) and the caspase recruitment domain 14 gene (CARD14). However, the relevance of these mutations to the clinical features and severity of GPP remains unclear. Aims Our objective was to correlate the presence of IL36RN and CARD14 mutations with the clinical and laboratory findings in patients with GPP. Methods This cross-sectional descriptive study was conducted in 64 subjects with GPP. Clinical manifestations were recorded and the severity was graded as mild, moderate, or severe. Routine laboratory tests were performed and blood samples were collected for Sanger sequencing. The clinical data of patients were compared among the different mutation groups. Results The two main variants of IL36RN were c.115+6T > C (p.Arg10ArgfsX1) and c.227C > T (p.Pro76Leu). The major CARD14 mutations were c.2458C > T (p.Arg820Trp), c.1641C > T (p.Arg547Ser), and c.1753G > A transitions. Provocative factors were uncommon in the group with both IL36RN and CARD14 mutations. Drugs (unspecified), especially herbals, were the most common triggers. A history of psoriasis was frequent in patients with only CARD14 mutations, but fever was uncommon. The c.1641C > T mutation was associated with leukocytosis > 15000/mm3 and the c.1753G > A mutation was associated with hypoalbuminemia <3.8g/dL. Both the c.115+6T > C and c.227C > T variants of IL36RN were associated with fever ≥38.5°C while the c.115+6T > C variant was also associated with geographic tongue. No gene mutations were associated with the total severity and severity grades. Limitations Four patients without the two major IL36RN mutations were excluded from the study. Conclusion The presence of IL36RN and CARD14 mutations were associated with a history of psoriasis, various provocative factors, fever, leukocytosis, hypoalbuminemia, and geographic tongue. Further studies to explore the role of these mutations in therapeutic efficacy and disease outcomes are necessary.