Effects of SARS-CoV-2 infection on incidence and treatment strategies of hepatocellular carcinoma in people with chronic liver disease

BACKGROUND Chronic liver disease(CLD)was associated with adverse clinical outcomes among people with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.AIM To determine the effects of SARS-CoV-2 infection on the incidence and treatment strategy of hepatocellular carcinoma(HCC)among patients with CLD.METHODS A retrospective,territory-wide cohort of CLD patients was identified from an electronic health database in Hong Kong.Patients with confirmed SARS-CoV-2 infection[coronavirus disease 2019(COVID-19)+CLD]between January 1,2020 and October 25,2022 were identified and matched 1:1 by propensity-score with those without(COVID-19-CLD).Each patient was followed up until death,outcome event,or November 15,2022.Primary outcome was incidence of HCC.Secondary outcomes included all-cause mortality,adverse hepatic outcomes,and different treatment strategies to HCC(curative,non-curative treatment,and palliative care).Analyses were further stratified by acute(within 20 d)and post-acute(21 d or beyond)phases of SARS-CoV-2 infection.Incidence rate ratios(IRRs)were estimated by Poisson regression models.RESULTS Of 193589 CLD patients(>95%non-cirrhotic)in the cohort,55163 patients with COVID-19+CLD and 55163 patients with COVID-19-CLD were included after 1:1 propensity-score matching.Upon 249-d median follow-up,COVID-19+CLD was not associated with increased risk of incident HCC(IRR:1.19,95%CI:0.99-1.42,P=0.06),but higher risks of receiving palliative care for HCC(IRR:1.60,95%CI:1.46-1.75,P<0.001),compared to COVID-19-CLD.In both acute and post-acute phases of infection,COVID-19+CLD were associated with increased risks of allcause mortality(acute:IRR:7.06,95%CI:5.78-8.63,P<0.001;post-acute:IRR:1.24,95%CI:1.14-1.36,P<0.001)and adverse hepatic outcomes(acute:IRR:1.98,95%CI:1.79-2.18,P<0.001;post-acute:IRR:1.24,95%CI:1.13-1.35,P<0.001),compared to COVID-19-CLD.CONCLUSION Although CLD patients with SARS-CoV-2 infection were not associated with increased risk of HCC,they were more likely to receive palliative treatment than those without.The detrimental effects of SARS-CoV-2 infection persisted in post-acute phase.

Cancers of the lung, head and neck on the rise: perspectives on the genotoxicity of air pollution

Outdoor air pollution has been recently classified as a class I human carcinogen by the World Health Organization(WHO). Cumulative evidence from across the globe shows that polluted air is associated with increased risk of lung, head and neck, and nasopharyngeal cancers—all of which affect the upper aerodigestive tract. Importantly, these cancers have been previously linked to smoking. In this article, we review epidemiologic and experimental evidence of the genotoxic and mutagenic effects of air pollution on DNA, purportedly a key mechanism for cancer development. The alarming increase in cancers of the upper aerodigestive tract in Asia suggests a need to focus government efforts and research on reducing air pollution, promoting clean energy, and investigating the carcinogenic effects of air pollution on humans.

The Comparison of the Effect of Oat and Shiitake Mushroom Powder to Prevent Body Weight Gain in Rats Fed High Fat Diet

Preventing obesity could be done by lowering plasma TAG that inhibits adipogenesis. Oat and mushroom beta-glucans in the diet has been reported to lower plasma lipid;however the data focusing on their effects on TAG and obesity are insufficient. In the present study, lowering plasma triacylglycerol, fat deposition, body weight gain (BWG) in rats fed a high fat diet (HFD) was evaluated. Rats in the control group were given HFD only and rats in the treatment group fed HFD enriched with 0.2%, 0.6% and 1.8% (wt:wt) beta-glucan from oats (LD-O, MD-O, HD-O) or mushroom (LD-M, MD-M, HD-M). After 6 weeks dietary intervention, the rats fed HD-M showed significantly lower plasma TAG, total fat mass, white adipose tissue, inguinal fat and BWG level more than HD-O treated rats (p < 0.05). The underlying mechanism in lowering plasma TAG, fat pad masses and BWG in HD-M was increasing ratio of fat faecal to faecal weight which was significantly higher than HD-O (p < 0.05). This study demonstrated that the preventing obesity via lowering plasma TAG and fat deposition was different depending on beta-glucan origin, either from oats and Shiitake mushroom.

Benefits and harms of screening for hepatocellular carcinoma in high-risk populations: systematic review and meta-analysis

Objective:The incidence and mortality of hepatocellular carcinoma(HCC)have been increasing around the world.Current guidelines recommend HCC screening in high-risk population.However,the strength of evidence of ben-efits and harms of HCC screening to support the recommendation was unclear.The objective is to systematically synthesize current evidence on the benefits and harms of HCC screening.Methods:We searched PubMed and nine other databases until August 20,2021.We included cohort studies and RCTs that compared the benefits and harms of screening and non-screening in high-risk population of HCC.Case series studies that reported harms of HCC screening were also included.Pooled risk ratio(RR),according to HCC screening status,was calculated for each benefit outcome(e.g.,HCC mortality,survival rate,proportion of early HCC),using head-to-head meta-analysis.The harmful outcomes(e.g.,proportion of physiological harms provided by non-comparative studies were pooled by prevalence of meta-analysis).Analysis on publication bias and quality of life,subgroup analysis,and sensitivity analysis were also conducted.Results:We included 70 studies,including four random clinical trials(RCTs),63 cohort studies,three case se-ries studies.The meta-analysis of RCTs showed HCC screening was significantly associated with reduced HCC mortality(RR[risk ratio],0.73[95%CI,0.56-0.96];I^(2)=75.1%),prolonged overall survival rates(1-year,RR,1.72[95%CI,1.13-2.61];I^(2)=72.5%;3-year,RR,2.86[95%CI,1.78-4.58];I^(2)=10.1%;and 5-year,RR,2.76[95%CI,1.37-5.54];I^(2)=28.3%),increased proportion of early HCC detection(RR,2.68[95%CI,1.77-4.06];I^(2)=50.4%).Similarly,meta-analysis of cohort studies indicated HCC screening was more effective than non-screening.However,pooled proportion of physiological harms was 16.30%(95%CI:8.92%-23.67%)and most harms were of a mild to moderate severity.Conclusion:The existing evidence suggests HCC screening is more effective than non-screening in high-risk pop-ulation.However,harms of screening should not be ignored.

A pH-sensitive supramolecular nanosystem with chlorin e6 and triptolide co-delivery for chemo-photodynamic combination therapy

The combination of Ce6,an acknowledged photosensitizer,and TPL,a natural anticancer agent,has been demonstrated as a useful strategy to reinforce the tumor growth suppression,as well as decrease the systemic side effects compared with their monotherapy.However,in view of the optimal chemo-photodynamic combination efficiency,there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL,and stimuli-responsively burst release drugs in tumor site.Herein,we described the synergistic antitumor performance of a pH-sensitive supramolecular nanosystem,mediated by the host–guest complexing betweenβ-CD and acid pH-responsive amphiphilic co-polymer mPEG-PBAE-mPEG,showing the shell–core structural micelles with the tightβ-CD layer coating.Both Ce6 and TPLwere facilely co-loaded into the spherical supramolecular NPs(TPL+Ce6/NPs)by one-step nanoprecipitation method,with an ideal particle size(156.0 nm),acid pH-responsive drug release profile,and enhanced cellular internalization capacity.In view of the combination benefit of photodynamic therapy and chemotherapy,as well as co-encapsulation in the fabricated pH-sensitive supramolecular NPs,TPL+Ce6/NPs exhibited significant efficacy to suppress cellular proliferation,boost ROS level,lower MMP,and promote cellular apoptosis in vitro.Particularly,fluorescence imaging revealed that TPL+Ce6/NPs preferentially accumulated in the tumor tissue area,with higher intensity than that of free Ce6.As expected,upon 650-nm laser irradiation,TPL+Ce6/NPs exhibited a cascade of amplified synergistic chemo-photodynamic therapeutic benefits to suppress tumor progression in both hepatoma H22 tumor-bearingmice and B16 tumor-bearingmice.More importantly,lower systemic toxicitywas found in the tumor-bearingmice treated with TPL+Ce6/NPs.Overall,the designed supramolecular TPL+Ce6/NPs provided a promising alternative approach for chemo-photodynamic therapy in tumor treatment.

Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery

The therapeutic potential of small nucleic acids such as small interfering RNA(siRNA) to treat lung diseases has been successfully demonstrated in many in vivo studies. A major barrier to their clinical application is the lack of a safe and efficient inhaled formulation.In this study, spray freeze drying was employed to prepare dry powder of small nucleic acids.Mannitol and herring sperm DNA were used as bulking agent and model of small nucleic acid therapeutics, respectively. Formulations containing different solute concentration and DNA concentration were produced. The scanning electron microscope(SEM) images showed that the porosity of the particles increased as the solute concentration decreased. Powders prepared with solute concentration of 5% w/v were found to maintain a balance between porosity and robustness. Increasing concentration of DNA improved the aerosol performance of the formulation. The dry powder formulation containing 2% w/w DNA had a median diameter of 12.5 μm, and the aerosol performance study using next generation impactor(NGI) showed an emitted fraction(EF) and fine particle fraction(FPF) of 91% and 28% respectively. This formulation(5% w/v solute concentration and 2% w/w nucleic acid) was adopted subsequently to produce siRNA powder. The gel retardation and liquid chromatography assays showed that the siRNA remained intact after spray freeze drying even in the absence of delivery vector. The siRNA powder formulation exhibited a high EF of 92.4%and a modest FPF of around 20%. Further exploration of this technology to optimise inhaled siRNA powder formulation is warranted.

Adrenomedullin and diabetes

Adrenomedullin(ADM) is a peptide hormone widely expressed in different tissues, especially in the vasculature. Apart from its vasodilatatory and hypotensive effect, it plays multiple roles in the regulation of hormonal secretion, glucose metabolism and inflammatory response. ADM regulates insulin balance and may participate in the development of diabetes. The plasma level of ADM is increased in people with diabetes, while in healthy individuals the plasma ADM concentration remains low. Plasma ADM levels are further increased in patients with diabetic complications. In type 1 diabetes, plasma ADM level is correlated with renal failure and retinopathy, while in type 2 diabetes its level is linked with a wider range of complications. The elevation of ADM level in diabetes may be due to hyperinsulinemia, oxidative stress and endothelial injury. At the same time, a rise in plasma ADM level can trigger the onset of diabetes. Strategies to reduce ADM level should be explored so as to reduce diabetic complications.

Pharmacological efficacy of the traditional Chinese medicinal formula Kun-Tai-1A in the treatment of letrozole-induced polycystic ovary syndrome

Background:Polycystic ovary syndrome(PCOS)is an endocrine disorder that occurs in women of child-bearing age.Moreover,PCOS patients have decreased pregnancy rates and clomiphene citrate resistance.The traditional Chinese medicine formula Kun-Tai-1S(KT1S),consisting of the seahorse species hippocampus,has been reported to elicit therapeutic effects in patients with PCOS.However,given the limited resources and global demand for wild hippocampus,whether KT1S with or without hippocampus can elicit similar therapeutic effects has not been confirmed.Methods:KT1S and Kun-Tai-1A(KT1A,KT1S without dry hippocampus)were used to treat a letrozole-induced rat model of PCOS with an established disease.The serum levels of testosterone,luteinizing hormone,anti-Müllerian hormone,and estradiol were determined,the luteinizing hormone/follicle-stimulating hormone ratio was determined,and the ovarian pathology was evaluated.Results:Similar to the therapeutic effects of cyproterone acetate,both the KT1S and KT1A treatments reduced the body weight and ovarian and uterine indices in the rats with PCOS.The serum levels of testosterone,anti-Müllerian hormone,and luteinizing hormone and the luteinizing hormone/follicle-stimulating hormone ratio were significantly lower in the KT1S and KT1A treatment groups compared to the model group(P<0.01 and P<0.05,respectively).Moreover,the histopathological assessment results suggested that both the KT1S and KT1A treatments significantly ameliorated the PCOS pathology in the rats with an established disease,with a reduced number of cystic and atretic follicles and an increased number of corpora lutea being observed in the ovaries.Notably,there was no obvious difference in the disease outcomes between the KT1S and KT1A-treated groups.Network pharmacology analysis revealed that 4’,7-dihydroxyflavanone,sinpemine A,quercetin,8-isopentenyl-kaempferol,and luteolin in KT1A may promote estrogen signaling;furthermore,the nitric oxide regulation pathway is also closely involved.Conclusion:KT1A and KT1S treatments both significantly ameliorated the PCOS-related pathology in rats,suggesting that the hippocampus component is dispensable for KT1S-mediated amelioration.Given the limited resources and global demand for wild hippocampus for use in complementary medicines,our findings may help conserve this species.Together,our results suggest that KT1A is a promising approach for treating PCOS.

The meta-analyses on effectiveness and safety of colorectal cancer screening

To the Editor:The colorectal cancer(CRC)is the fourthmost common cause of cancer deaths in China that was treated as a public health threat,accounting for approximately 10%of all the cancer-caused mortalities each year.[1]It usually takes decades to develop from a polyp to full CRC,[2]which allows a time window for detecting precancerous lesions and taking early steps for preventions and treatments.

Cold-Induced Reprogramming of Subcutaneous White Adipose Tissue Assessed by Single-Cell and Single-Nucleus RNA Sequencing

Adipose browning has demonstrated therapeutic potentials in several diseases.Here,by conducting transcriptomic profiling at the single-cell and single-nucleus resolution,we reconstituted the cellular atlas in mouse inguinal subcutaneous white adipose tissue(iWAT)at thermoneutrality or chronic cold condition.All major nonimmune cells within the iWAT,including adipose stem and progenitor cells(ASPCs),mature adipocytes,endothelial cells,Schwann cells,and smooth muscle cells,were recovered,allowing us to uncover an overall and detailed blueprint for transcriptomes and intercellular cross-talks and the dynamics during white adipose tissue brown remodeling.Our findings also unravel the existence of subpopulations in mature adipocytes,ASPCs,and endothelial cells,as well as new insights on their interconversion and reprogramming in response to cold.The adipocyte subpopulation competent of major histocompatibility complex class Ⅱ(MHCⅡ)antigen presentation is potentiated.Furthermore,a subcluster of ASPC with CD74 expression was identified as the precursor of this MHCⅡ^(+)adipocyte.Beige adipocytes are transdifferented from preexisting lipid generating adipocytes,which exhibit developmental trajectory from de novo differentiation of amphiregulin cells(Aregs).Two distinct immune-like endothelial subpopulations are present in iWAT and are responsive to cold.Our data reveal fundamental changes during cold-evoked adipose browning.

Fat cell-secreted adiponectin mediates physical exercise-induced hippocampal neurogenesis: an alternative anti-depressive treatment?

Psychological depression is drawing accumulating attention nowadays, due to the skyrocketing incidence worldwide and the enormous burdens it incurs. Physical exercise has been long recog- nized for its therapeutic effects on depressive disorders, although knowledge of the underlying mechanisms remains limited. Suppressed hippocampal neurogenesis in adult brains has been regarded, at least partly, contributive to depression, whereas physical exercise that restores neuro- genesis accordingly exerts the anti-depressive action. Several recent publications have suggested the potential role of adiponectin, a protein hormone secreted by peripheral mature adipocytes, in mediating physical exercise-triggered enhancement of hippocampal neurogenesis and alleviation of depression. Here, we briefly review these novel findings and discuss the possibility of counter- acting depression by modulating adiponectin signaling in the hippocampus with interventions including physical exercise and administration of pharmacological agents.

Brain delivering RNA-based therapeutic strategies by targeting mTOR pathway for axon regeneration after central nervous system injury

Injuries to the central nervous system(CNS)such as stroke,brain,and spinal cord trauma often result in permanent disabilities because adult CNS neurons only exhibit limited axon regeneration.The brain has a surprising intrinsic capability of recovering itself after injury.However,the hostile extrinsic microenvironment significantly hinders axon regeneration.Recent advances have indicated that the inactivation of intrinsic regenerative pathways plays a pivotal role in the failure of most adult CNS neuronal regeneration.Particularly,substantial evidence has convincingly demonstrated that the mechanistic target of rapamycin(mTOR)signaling is one of the most crucial intrinsic regenerative pathways that drive axonal regeneration and sprouting in various CNS injuries.In this review,we will discuss the recent findings and highlight the critical roles of mTOR pathway in axon regeneration in different types of CNS injury.Importantly,we will demonstrate that the reactivation of this regenerative pathway can be achieved by blocking the key mTOR signaling components such as phosphatase and tensin homolog(PTEN).Given that multiple mTOR signaling components are endogenous inhibitory factors of this pathway,we will discuss the promising potential of RNA-based therapeutics which are particularly suitable for this purpose,and the fact that they have attracted substantial attention recently after the success of coronavirus disease 2019 vaccination.To specifically tackle the blood-brain barrier issue,we will review the current technology to deliver these RNA therapeutics into the brain with a focus on nanoparticle technology.We will propose the clinical application of these RNA-mediated therapies in combination with the brain-targeted drug delivery approach against mTOR signaling components as an effective and feasible therapeutic strategy aiming to enhance axonal regeneration for functional recovery after CNS injury.

Intercellular and inter-organ crosstalk in browning of white adipose tissue:molecular mechanism and therapeutic complications

Adipose tissue(AT)is highly plastic and heterogeneous in response to environmental and nutritional changes.The development of heat-dissipating beige adipocytes in white AT(WAT)through a process known as browning(or beiging)has garnered much attention as a promising therapeutic strategy for obesity and its related metabolic complications.This is due to its inducibility in response to thermogenic stimulation and its association with improved metabolic health.WAT consists of adipocytes,nerves,vascular endothelial cells,various types of immune cells,adipocyte progenitor cells,and fibroblasts.These cells contribute to the formation of beige adipocytes through the release of protein factors that significantly influence browning capacity.In addition,inter-organ crosstalk is also important for beige adipocyte biogenesis.Here,we summarize recent findings on fat depot-specific differences,secretory factors participating in intercellular and inter-organ communications that regulate the recruitment of thermogenic beige adipocytes,as well as challenges in targeting beige adipocytes as a potential anti-obese therapy.

Metabolic actions of FGF21:molecular mechanisms and therapeutic implications

Fibroblast growth factor 21(FGF21)is an atypical member of the FGF family that functions as an endocrine factor.In obese animals,elevation of plasma FGF21 levels by either pharmacological or genetic approaches reduces body weight,decreases hyperglycemia and hyperlipidemia,alleviates fatty liver and increases insulin sensitivity.FGF21 exerts its pleiotropic metabolic effects through its actions on multiple targets,including adipose tissue,liver,brain and pancreas.The expression of FGF21 is under the control of both peroxisome proliferator-activated receptor gamma(PPARγ)and peroxisome proliferator.-activated receptor alpha(PPARα).A growing body of evidence suggests that the metabolic benefits of these two nuclear receptors are mediated in part by induction of FGF21.In humans,plasma levels of FGF21 are elevated in obese subjects and patients with type 2 diabetes,but are reduced in patients with autoimmune diabetes.This review summarizes recent advances in understanding the physiological roles of FGF21 and the molecular pathways underlying its actions,and also discusses the future prospective of developing FGF21 or its agonists as therapeutic agents for obesity-related medical complications.

Cultural adaptation and content validity of a Chinese translation of the‘Person-Centered Primary Care Measure’:findings from cognitive debriefing

Objectives To develop an equivalent Chinese translation of the Person-Centered Primary Care Measure(PCPCM)and to establish its cultural adaptability and content validity through cognitive debriefing.Design The original English PCPCM was first translated into Chinese by double forward-translation by professional translators.The reconciliated Chinese version was then doubly back-translated into English by two other professional translators blinded to the forward-translation.On affirmation on its linguistic equivalence with the developers of the original English PCPCM,the reconciliated Chinese PCPCM was sent for cognitive debriefing with 20 Chinese-speaking primary care subjects by a trained interviewer using structured probing questions to collect their opinions on the clarity,comprehensibility and relevance of each item and response option in the Measure.Setting Subjects were invited from a primary care clinic in Hong Kong to undergo the cognitive debriefing interviews.The interviews were divided into four groups chronologically to allow revision of the items to be made in between.Participants Ten males and 10 females above the age of 18 completed the cognitive interviews.They were all Cantonese-speaking Chinese recruited by convenience sampling.Subjects with cognitive impairment,could not read Chinese,too old or too sick to complete the interviews were excluded from the study.Results An average of 3.3 min(range 3-4 min)was required for the subjects to self-complete the Measure.All items were generally perceived to be easily understood and relevant.Modifications were made to items with the content validity index(CVI)on clarity or understanding<0.8 in each round of the interviews or if a majority of the subjects suggested rewording.Revisions were made to two items in the Chinese PCPCM throughout the whole cognitive debriefing process before the final version was confirmed.The average CVI on clarity of the Chinese PCPCM items ranged from 0.75 to 1.The average CVI on understanding ranged from 0.7 to 1.The average CVI on relevance ranged from 0.55 to 1.Conclusions The content validity of the PCPCM was ascertained in terms of its clarity,understandability and relevance to allow further testing of its psychometric properties in a larger Chinese population.

Comparative effectiveness of different hepatocellular carcinoma screening intervals or modalities:a systematic review and meta-analysis

Background:Current guidelines recommend hepatocellular carcinoma(HCC)screening in high-risk populations.However,the ideal HCC screening interval and screening modality have not been determined.This study aimed to compare the screening efficacy among different modalities with various intervals.Methods:PubMed and other nine databases were searched through June 30,2021.Binary outcomes were pooled using risk ratio(RR)with 95%confidence intervals(CIs).Survival rates were also pooled using RR with 95%CIs because most eligible studies only provided the number of survival patients instead of hazard ratio.Results:In all,13 studies were included.Two random controlled trials(RCTs)and six cohort studies compared screening intervals for ultrasonography(US)screening and found no significant differences between shorter(3-or 4-month)and longer(6-or 12-month)screening intervals in terms of early HCC proportion,HCC significant mortality,1-year survival rate;screening at 6-month interval significantly increased the proportion of early HCC(RR=1.17,95%confidence interval[CI]:1.08-1.26)and prolonged the 5-year survival rate(RR=1.39,95%CI:1.07-1.82)relative to the 12-month interval results.Three other RCTs and two cohort studies compared different screening modalities in cirrhosis or chronic hepatitis B,which indicated no statistical differences in the proportion of early HCC(RR=0.89,95%CI:0.40-1.96)and HCC mortality(RR=0.69,95%CI:0.23-2.09)between the biannual US and annual computed tomography(CT screening).Biannual US screening showed a lower proportion of early HCC than biannual magnetic resonance imaging(MRI)(RR=0.60,95%CI:0.37-0.97)and biannual US combined with annual CT(RR=1.31,95%CI:1.13-1.51)screening.The proportion of early HCC in the contrast-enhanced US group was slightly higher than that in the B-mode US(RR=1.08,95%CI:1.00-1.23)group.Conclusions:The evidence suggests that 6 months may be the best HCC screening interval for US screening.The effectiveness of CT and MRI is better than US during same screening intervals.However,MRI and CT are more expensive than US,and CT also can increase the risk of radiation exposure.The selection of CT or MRI instead of US should be carefully considered.Registration:No.CRD42020148258 at PROSPERO website(https://www.crd.york.ac.uk/PROSPERO/).

一氧化氮研究三十年:自优而劣（英文）

In the last thirty years,it became over whelmingly apparent that the endothelium releases relaxing factors(EDRF),which diffuse to the underlying vascular smooth muscle cells and elicit endothelium-dependent vasodilatations.The best characterized EDRF is nitric oxide(NO)formed by endothelial NO synthase(e NOS).In the vascular smooth muscle cells,NO stimulates soluble guanylate cyclase which normally produces cyclic GMP.NO release by e NOS can be augmented by increases in shear stress or by activation of endothelial cell membrane receptors(e.g.in response toα2-adrenergic agonists,serotonin,vasopressin,adenosine diphosphate and bradykinin).The ability of the endothelial cell to release NO can be up-regulated by estrogens,repeated increases in blood flow,exercise,diet(ω3-unsaturated fatty acids,polyphenols),and down-regulated by oxidative stress and increased presence of oxidized low density lipoproteins(LDL).The bioavailability of NO is curtailed by aging,smoking,environmental pollution or obesity and in hypertension and diabetes.In addition to lesser direct relaxation of the underlying vascular smooth muscle,a decreased release of NO also permits the production of vasoconstrictor prostanoids and/or endothelin-1.Blunted endothelium-dependent relaxations can also be due to unresponsiveness of the vascular smooth muscle to NO.Finally,in coronary arteries,hypoxia and certain quinonescause acute augmentations of vasoconstrictor responses that depend on the presence of NO and the biased activation of soluble guanylate cyclase which produces cyclic IMP rather than cyclic GMP.Since hypoxia is implicated in exaggerated vasoconstrictions observed in coronary artery disease,the emerging role of this non-canonical cyclic nucleotide may help identifying novel therapeutic targets.

Ce6 nanoassemblies:Molecular mechanism and strategies for combinational anticancer therapy Special Collection:Aggregation-Induced Processes and Functions

Nowadays,cancer has become the leading cause of death worldwide,driving the need for effective therapeutics to improve patient prognosis.Photodynamic therapy(PDT)has been widely applied as an antitumor modality,owing to its minimal invasiveness,localized tumor damage,and high safety profile.However,its efficacy is limited by poor stability of photosensitizers,inadequate tumor accumulation,and a complex tumor microenvironment.To overcome these challenges,extensive endeavors have been made to explore the co-assembly of the widely used photosensitizer chlorin e6(Ce6)with various functional small molecules to enhance pharmacodynamic activity.This review provides a comprehensive overview of current studies on Ce6-based nanoparticles for effective PDT and precise delivery of functional molecules.The self-assembly mechanism will be discussed in detail,with a focus on potential strategies for combinational therapy with PDT.

Effectiveness of post-COVID-19 primary care attendance in improving survival in very old patients with multimorbidity:a territory-wide target trial emulation

Objectives Older individuals with multimorbidity are at an elevated risk of infection and complications from COVID-19.Effectiveness of post-COVID-19 interventions or care models in reducing subsequent adverse outcomes in these individuals have rarely been examined.This study aims to examine the effectiveness of attending general outpatient within 30 days after discharge from COVID-19 on 1-year survival among older adults aged 85 years or above with multimorbidity.Design Retrospective cohort study emulating a randomised target trial using electronic health records.Setting We used data from the Hospital Authority and the Department of Health in Hong Kong,which provided comprehensive electronic health records,COVID-19 confirmed case data,population-based vaccination records and other individual characteristics for the study.Participants Adults aged 85 years or above with multimorbidity who were discharged after hospitalisation for COVID-19 between January 2020 and August 2022.Interventions Attending a general outpatient within 30 days of last COVID-19 discharge defined the exposure,compared to no outpatient visit.Main outcome measures Primary outcome was all-cause mortality within one year.Secondary outcomes included mortality from respiratory,cardiovascular and cancer causes.Results A total of 6183 eligible COVID-19 survivors were included in the analysis.The all-cause mortality rate following COVID-19 hospitalisation was lower in the general outpatient visit group(17.1 deaths per 100 person-year)compared with non-visit group(42.8 deaths per 100 person-year).After adjustment,primary care consultations within 30 days after discharge were associated with a significantly greater 1-year survival(difference in 1-year survival:11.2%,95%CI 8.1%to 14.4%).We also observed significantly better survival from respiratory diseases in the general outpatient visit group(difference in 1-year survival:6.3%,95%CI 3.5%to 8.9%).In a sensitivity analysis for different grace period lengths,we found that the earlier participants had a general outpatient visit after COVID-19 discharge,the better the survival.Conclusions Timely primary care consultations after COVID-19 hospitalisation may improve survival following COVID-19 hospitalisation among older adults aged 85 or above with multimorbidity.Expanding primary care services and implementing follow-up mechanisms are crucial to support this vulnerable population’s recovery and well-being.

Application of flash nanoprecipitation to fabricate poorly water-soluble drug nanoparticles

Nanoparticles are considered to be a powerful approach for the delivery of poorly watersoluble drugs. One of the main challenges is developing an appropriate method for preparation of drug nanoparticles. As a simple, rapid and scalable method, the flash nanoprecipitation(FNP) has been widely used to fabricate these drug nanoparticles, including pure drug nanocrystals, polymeric micelles,polymeric nanoparticles, solid lipid nanoparticles, and polyelectrolyte complexes. This review introduces the application of FNP to produce poorly water-soluble drug nanoparticles by controllable mixing devices, such as confined impinging jets mixer(CIJM), multi-inlet vortex mixer(MIVM) and many other microfluidic mixer systems. The formation mechanisms and processes of drug nanoparticles by FNP are described in detail. Then, the controlling of supersaturation level and mixing rate during the FNP process to tailor the ultrafine drug nanoparticles as well as the influence of drugs, solvent, anti-solvent, stabilizers and temperature on the fabrication are discussed. The ultrafine and uniform nanoparticles of poorly watersoluble drug nanoparticles prepared by CIJM, MIVM and microfluidic mixer systems are reviewed briefly. We believe that the application of microfluidic mixing devices in laboratory with continuous process control and good reproducibility will be benefit for industrial formulation scale-up.