Background The impact of cold spells on population health can be categorized into an independent main effect of extreme low temperatures and an added effect of prolonged low temperatures. However, studies on the added effects of cold spells on hospitalizations remain limited. Objective To investigate the added effects of cold spells on hospitalizations of residents in Hengyang City, Hunan Province, and to provide a scientific basis for establishing a cold spell early warning system. Methods Daily meteorological data, air pollutant data, and hospitalization data from six tertiary hospitals of four districts in Hengyang City from 2017 to 2023 were collected. A generalized linear model (GLM) combined with a distributed lag nonlinear model (DLNM) was used to assess the added effects of cold spells on non-accidental hospitalizations, as well as hospitalizations for circulatory system diseases and respiratory system diseases, after controlling the main effect of temperature. The modifying effects of cold spell characteristics (intensity and duration) and individual characteristics (gender and age) were also analyzed. Results Compared with non-cold spell periods, the relative risks (RRs) of total non-accidental hospitalizations and hospitalizations across disease categories, genders, and age groups were elevated during cold spells of varying intensities and durations. However, the total effects of cold spells exhibited a "U-shape" nonlinear relationship with intensity and decreased with prolonged duration. During high-intensity cold spells (daily average temperature < P₅ and lasting ≥ 2 d), the RR (95%CI) for non-accidental hospitalizations was 1.71 (1.21, 2.42); the RRs (95%CIs) for males and females were 1.99 (1.38, 2.84) and 1.47 (1.00, 2.16), respectively; for individuals < 65 years and ≥ 65 years, the RRs (95%CIs) were 1.59 (1.12, 2.26) and 1.93 (1.27, 2.92), respectively; and for circulatory and respiratory system diseases, the RRs (95%CIs) were 1.84 (1.22, 2.79) and 1.07 (0.71, 1.60), respectively. No statistically significant differences were observed between the above subgroups. The single-day lagged effects of cold spells displayed a two-peaked pattern. The single-day lag RR for total non-accidental hospitalizations peaked at lag 1 d after cold spell exposure, declined thereafter, and began to rise again after lag 5 d, reaching a second peak at lag 12–13 d before gradually decreasing. The lagged effects remained statistically significant during lag 8–18 d. The lag patterns of cold spell associations across disease categories, genders, and age groups were largely consistent with those of total hospitalizations. Conclusion Cold spells have a significant impact on non-accidental hospitalizations of residents in Hengyang City, with notable lagged effects. The findings provide important theoretical support for establishing a more targeted cold spell early warning system.

Diabetes is a common chronic non-infectious disease. Diabetic patients not only suffer from metabolic disorders, but are also prone to immune deficiencies and are at a higher risk of being infected with human papillomavirus (HPV). Many studies at home and abroad have shown that the HPV infection rate of patients with diabetes is higher than that of non-diabetic patients. Patients with diabetes can benefit from HPV vaccination, and the tolerance is good. HPV vaccination is recommended for diabetic patients. This article reviews the research on diabetes, HPV infection, and HPV vaccine, which will provide references for HPV vaccination in diabetic patients.

Objective To investigate the effect of curcumin regulating miR-142-5p targeting pleckstrin homology domain containing family A member 3(PLEKHA3)on proliferation,migration and apoptosis of adrenocortical carcinoma cells.Methods Adrenal cortical cancer cells were divided into NC group(normal culture),NC+60 μmol·L-1 curcumin(60 μmol·L-1 curcumin),NC+60 μmol·L-1curcumin+miR-142-5p group(60 μmol·L-1 curcumin and transfected with miR-142-5p mimic),NC+60 μmol·L-1 curcumin+miR-142-5p+PLEKHA3 group(60 μmol·L-1 curcumin and transfected with miR-142-5p mimic+PLEKHA3).Cell proliferation and migration abilities were detected by cell counting kit-8(CCK-8)and Transwell assays.Expression levels of apoptosis-related proteins were detected by Western blotting.At the animal level,a nude mouse model of human adrenal cortical tumor SW-13 cell transplantation was established and divided into control group and 15,30,45,60 μmol·L-1curcumin groups to verify the anti-adrenal cortical carcinoma effect of curcumin in vivo.Results The cell migration numbers in NC group,NC+60 μmol·L-1 curcumin group,NC+60 μmol·L-1+miR-142-5p group and NC+60 μmol·L-1+miR-142-5p+PLEKHA3 group were 135.76±17.42,37.11±10.08,98.31±14.88 and 24.39±5.28;the apoptosis rates were(3.27±0.11)％,(68.80±4.64)％,(25.47±2.39)％and(78.29±5.47)％;the protein expression levels of B-cell lymphoma 2(Bel-2)were 1.00±0.13,0.59±0.11,0.97±0.09 and 0.31±0.06;the protein expression levels of Bel-2 associated X protein were 1.00±0.08,1.38±0.11,0.69±0.05 and 1.93±0.18;there were statistically significant differences between NC group and NC+60 μmol·L-1 group(P＜0.05,P＜0.01).At the animal level,the volumes of the xenograft tumors in control group and 15,30,45 and 60 μmol·L-1 curcumin groups were(1 653.02±435.93),(1 148.77±327.18),(1 054.21±286.06),(996.89±257.62)and(670.64±157.32)mm3;the weights of the xenograft tumors were(1.00±0.17),(0.82±0.09),(0.76±0.12),(0.68±0.13)and(0.44±0.11)g,there were statistically significant differences between 15,30,45 and 60 μmol·L-1curcumin groups and control group(P＜0.05,P＜0.01).Conclusion Curcumin exerts anti-adrenal cortical cancer effects both in vitro and in vivo,may inhibit the proliferation and migration of adrenal cortical cancer cells and promote their apoptosis by regulating the miR-142-5p/PLEKHA3 signaling pathway.This provides a new potential target for the treatment of adrenal cortical cancer.

OBJECTIVE To provide a reference for the adjustment of antibacterial drug regimens， identification of adverse reactions， and personalized pharmaceutical care for patients with bullous pemphigoid and pulmonary aspergillosis combined with disseminated Nocardia farcinica infection. METHODS Clinical pharmacists participated in the entire treatment process of a patient with bullous pemphigoid and pulmonary aspergillosis combined with disseminated N. farcinica infection. Evidence-based medicine was used to assist in the selection of an initial combined drug regimen against nocardiosis， and timely communication with the microbiology laboratory to provide early antimicrobial susceptibility data. When the patient exhibited epilepsy， the suspected drugs were identified， and it was reminded that imipenem-cilastatin sodium could affect the efficacy of valproic acid. It was suggested to replace valproic acid with levetiracetam for anti-epileptic treatment and to discontinue imipenem-cilastatin sodium. During treatment， it was recommended to monitor the blood concentrations of voriconazole and linezolid， and assist in adjusting the dosage promptly based on the monitoring results. RESULTS The physicians accepted the recommendations of the clinical pharmacists. The patient’s condition improved， and they were discharged with medication. CONCLUSIONS Based on evidence-based medical evidence， antimicrobial susceptibility test results， and blood concentration monitoring data， clinical pharmacists assist clinicians in selecting a sensitive anti-infective regimen for the patient， identifying adverse reactions， adjusting the treatment regimen and providing full-course medication monitoring to ensure the safety and efficacy of clinical drug therapy.

PI3Kγ and PI3Kδ have important regulatory roles in the immune system, and targeting these two subtypes helps to reshape the tumor microenvironment. PI3Kγ and PI3Kδ are potential targets for tumor immunotherapy. In this study, a series of new pyrazolopyrimidine derivatives were designed and synthesized on the basis of our previously reported PI3K inhibitors, resulting in the discovery of compound 16l as a potent and selective PI3Kγ/δ dual inhibitor. Compound 16l demonstrated strong biochemical potencies against PI3Kγ and PI3Kδ with IC₅₀ values of 0.11 and 0.79 nmol·L^-1. In cell-based assays, it potently inhibited the PI3Kγ and PI3Kδ mediated Akt S473 phosphorylation with EC₅₀ values of 3 and 7 nmol·L^-1. In vivo, compound 16l exhibited acceptable pharmacokinetic properties in Sprague-Dawley (SD) rats and suppressed the tumor growth in a MC38 syngeneic mouse model. The animal experiments were approved by the Animal Ethics Committee of Hefei Institutes of Physical Science, Chinese Academy of Sciences (approval number: DWLL-2000-06). In addition, no appreciable human ether-a-go-go-related gene (hERG) inhibition was observed for compound 16l even at 30 μmol·L^-1. These results suggested that compound 16l might be a potential research tool for studying the PI3Kγ/δ mediated signaling pathways.

Abstract: The differential expression and subcellular localization of single-cell proteins are closely related to the physiological state and pathological mechanisms of the body. The development of single-cell protein in situ imaging methods provides powerful tools for spatial single-cell proteomics research and single-cell protein profiling. This article summarizes the single-cell protein imaging methods developed in recent years, including the circulating immunofluorescence imaging methods based on ordered multi-round antibody incubation, mass spectrometry imaging based on metal element labeled antibodies, fluorescence imaging based on DNA-barcoded antibody, gene encoded fluorescence protein imaging and spectral imaging based on Raman spectroscopy or X-ray spectroscopy, with brief explanation of the imaging principles of these methods. It focuses on the multiple performance, imaging resolution and signal amplification performance of these methods, and analyzes their application characteristics in practical scientific research and clinical work, in the hope of providing some reference for the development of more revolutionary single-cell imaging methods, and promoting the development of biomedical and precision medicine.

Objective:The emergence of polymyxin-resistant Klebsiella pneumoniae(KPN)in clinical settings necessitates an analysis of its antibiotic resistance characteristics,epidemiological features,and risk factors for its development.This study aims to provide insights for the prevention and control of polymyxin-resistant KPN infections. Methods:Thirty clinical isolates of polymyxin-resistant KPN were collected from the Third Xiangya Hospital of Central South University.Their antibiotic resistance profiles were analyzed.The presence of carbapenemase KPC,OXA-48,VIM,IMP,and NDM was detected using colloidal gold immunochromatography.Hypervirulent KPN was initially screened using the string test.Biofilm formation capacity was assessed using crystal violet staining.Combination drug susceptibility tests(polymyxin B with meropenem,tigecycline,cefoperazone/sulbactam)were conducted using the checkerboard method.Polymyxin-related resistance genes were detected by PCR.Multi-locus sequence typing(MLST)was performed for genotyping and phylogenetic tree construction.The study also involved collecting data from carbapenem-resistant(CR)-KPN polymyxin-resistant strains(23 strains,experimental group)and CR-KPN polymyxin-sensitive strains(57 strains,control group)to analyze potential risk factors for polymyxin-resistant KPN infection through univariate analysis and multivariate Logistic regression.The induction of resistance by continuous exposure to polymyxin B and colistin E was also tested. Results:Among the 30 polymyxin-resistant KPN isolates,28 were CR-KPN,all producing KPC enzyme.Four isolates were positive in the string test.Most isolates showed strong biofilm formation capabilities.Combination therapy showed additive or synergistic effects.All isolates carried the pmrA and phoP genes,while no mcr-1 or mcr-2 genes were detected.MLST results indicated that ST11 was the predominant type.The phylogenetic tree suggested that polymyxin-resistant KPN had not caused a hospital outbreak in the institution.The use of two or more different classes of antibiotics and the use of polymyxin were identified as independent risk factors for the development of polymyxin-resistant strains.Continuous use of polymyxin induced drug resistance. Conclusion:Polymyxin-resistant KPN is resistant to nearly all commonly used antibiotics,making polymyxin-based combination therapy a viable option.No plasmid-mediated polymyxin-resistant KPN has been isolated in the hospital.Polymyxin can induce resistance in KPN,highlighting the need for rational antibiotic use in clinical settings to delay the emergence of resistance.

Objective To evaluate the feasibility of confirming syphilis reactive blood donors.Methods The serum of donors with anti-TP reaction by ELISA were confirmed by treponema pallidum particle agglutination(TPPA)and Western blotting(WB).The results of two confirmation methods that were negative,suspicious or inconsistent were followed up and compared.At the same time,the analytical index values of the screening reagent A,B and C and their combinations were e-valuated and compared using the the receiver operating characteristic curve(ROC curve)based on the results of the two confirmation methods.Results The positive rate of 223 ELISA anti-TP reactive samples(including 124 double-reagent ELISA reactive samples and 99 single-reagent ELISA reactive samples)was 57.40%confirmed by TPPA and 38.57%con-firmed by WB(89.52%vs 17.17%by TPPA and 52.42%vs 21.21%by WB for double-reagent and single-reagent ELISA reactive samples).The confirmed negative rate of TPPA was 35.43%and that of WB was 42.60%(6.45%vs 71.72%of TP-PA and 29.84%vs 58.59%of WB for double-reagent and single-reagent ELISA reactive samples).According to Kappa test,the confirmed results between the two methods were not consistent,especially for those single-regent ELISA reactive sam-ples.Thirty six cases were followed up successfully,of which 17(47.22%)confirmed changes in the test results but the changes were irregular.Based on the confirmed results of TPPA and WB,the ROC curve analysis was performed on the anti-TP screening S/CO values of double-reagent ELISA reactive samples.When combining ELISA screening reagents as A/B and A/C,the optimal S/CO values of reagent A were 1.815,5.73 and 10.205,16.165,respectively.Conclusion TPPA and WB have poor consistency in the confirmation of ELISA anti-TP reactive blood samples,and the outcome of follow-up confirmation is unclear.The S/CO threshold of ROC curve is affected by the combination of confirmatory screening reagents,and it is difficult to confirm the results of ELISA anti-TP reactive blood donors.

The new generation of artificial intelligence technology,represented by deep learning,has emerged as a crucial driving force in the advancement of new drug research and development.This article creatively proposes a workflow named"Molecular Factory"for the design and optimization of drug molecules based on artificial intelligence technology.This workflow integrates intelligent molecular generation models,high-performance molecular docking algorithms,and accurate protein-ligand binding affinity prediction methods.It has been integrated as a core module into DrugFlow,a one-stop drug design software platform,providing a comprehensive set of mature solutions for the discovery and optimization of lead compounds.Utilizing the"Molecular Factory"module,we conducted the research of second-generation inhibitors against Menin that can combat drug resistance.Through the integration of computational and experimental approaches,we rapidly identified multiple promising compounds.Among them,compound RG-10 exhibited the IC50 values of 9.681 nmol/L,233.2 nmol/L,and 40.09 nmol/L against the wild-type Menin,M327I mutant,and T349M mutant,respectively.Compared to the positive reference molecule SNDX-5613,which has entered Phase Ⅱ clinical trials,RG-10 demonstrated significantly enhanced inhibitory activity against the M327I and T349M mutants.These findings fully demonstrate the unique advantages of the"Molecular Factory"technology in practical drug design and development scenarios.It can rapidly and efficiently generate high-quality active molecules targeting specific protein structures,holding significant value and profound implications for advancing new drug discovery.

[Objective]To investigate primary and secondary transfer of exfoliated cells from human hands on non-porous substrates such as plastic steering wheel or computer mouse.[Methods]DNA detection sensitivity and detection limit for mixed DNA profiling were examined to understand our laboratory's ability to test for trace DNA.Forensic swabs were used to collect samples from volunteers'one-hour-long unwashed hands,substrates touched by volunteers'immediately or 30 min following shaking hands,and individual A's daily-use substrates touched by individual B and then by individual A again.Simulations were conducted to assess the potential for introduction of another person's exfoliated cells from hands into routine casework samples.[Results]Our laboratory can obtain a full DNA profile from as little as 0.020 ng of DNA and detect minor components in a 1:9 mixed DNA sample.85%of samples from unwashed hands yielded a full DNA profile.Primary transfer of a full DNA profile was found in 77%of substrates touched by volunteers'dominant hand 30 min after hand washing,allowing differentiation between good and poor shedders,with no significant difference in genders and substrate types.75%of substrates touched 30 min after hand washing and then immediately following handshaking yielded the other individual's DNA profile(secondary transfer),with the number of short tandem repeat(STR)loci detected ranging from 0 to 23;the percentage and number decreased substantially when the substrates were touched 30 minutes later.No foreign DNA was detected in routine casework samples with introduced exfoliated cells from hands.When two individuals took turns touching items with their hands,the major contributor to the DNA profile was not always the individual who made the last contact.[Conclusions]Primary and secondary DNA transfer can be detected on non-porous substrates,and based on the deposit of hand exfoliated cells,individuals can be categorized as good or poor shedders,which is an important factor affecting detection of DNA transfer.Besides considering the laboratory's DNA detection sensitivity,if DNA is detected on substrates by hand contact,we need to take into account the potential for secondary transfer at different levels of activity when interpreting the results.