Neurocritical care involves complex pathophysiological mechanisms, and its incidence is higher, injuries are more severe, and treatment is more challenging in high-altitude environments. This consensus, based on the latest domestic and international evidence-based medical data, establishes a standardized, goal-oriented framework for neurocritical care management applicable in high-altitude regions and nationwide. The consensus was developed following international standards for evidence quality assessment and underwent two rounds of Delphi expert consultation, resulting in 32 recommendation statements covering three parts: management systems, monitoring and assessment, and core strategies. Key updates include: advocating for the establishment of independent neurocritical care units and implementing precise tiered diagnosis and treatment based on the "Five Differences in Critical Care" concept; constructing a "trinity" multimodal brain monitoring system centered on cerebral blood flow, cerebral oxygenation, and brain function, emphasizing routine bedside transcranial Doppler ultrasound, cerebral oximetry, and continuous electroencephalography monitoring; shifting management strategies from mild hypothermia therapy to targeted temperature management, and defining the "446" target management pathway for the supercritical stage; emphasizing the assessment of static and dynamic cerebrovascular autoregulation functions through multimodal methods to achieve individualized optimal mean arterial pressure management; elevating cerebrospinal fluid management goals to the level of "glymphatic system" function maintenance; implementing a multidisciplinary collaborative, whole-process management model focusing on patients' long-term neurological functional outcomes; de-escalation criteria include multidimensional indicators such as recovery of brain structure, restoration of cerebrovascular autoregulation, improvement in cerebrospinal fluid dynamics, and reduction in biomarker levels; and integrating cutting-edge technologies like artificial intelligence into post-critical care management and rehabilitation planning. This consensus systematically integrates the entire process of neurocritical care management, reflecting the modern connotation of goal-oriented, dynamic, and multimodal integration in neurocritical care medicine. It aims to adapt to new trends such as deepening understanding of pathophysiological mechanisms, the integration of medicine and engineering, and the empowerment of artificial intelligence, thereby further advancing the discipline of critical care medicine.

BACKGROUND:The lactate threshold is a crucial physiological indicator for assessing the aerobic metabolic capacity and training level of endurance athletes,representing the intensity point at which lactate production and clearance reach a dynamic equilibrium within the organism.The traditional lactate threshold training,which is a prolonged and stable-intensity training,aims to enhance the aerobic endurance and lactate clearance efficiency of athletes.In recent years,with the advancement of exercise physiology,double lactate threshold training has emerged as an innovative training modality,drawing extensive attention from both the academic circle and practitioners.Nevertheless,current systematic research on double lactate threshold training remains limited,particularly in aspects such as its physiological mechanisms,optimal implementation plans,and long-term effects.OBJECTIVE:To systematically sort out the development course of double lactate threshold training,deeply analyze its fundamental connotations,objectively assess its application effects,and investigate its physiological action mechanisms,with the expectation of providing scientific basis and guidance for the improvement and optimization of endurance sports training theories and practices.METHODS:With the search terms of"lactate threshold training,double lactate threshold training,lactate training,threshold training,endurance training,Norwegian training method,Norwegian training mode,Norwegian training experience,"a systematic search was conducted in databases,including PubMed,Web of Science,Embase,Medline,Cochrane Library,CNKI,WanFang,and VIP.After screening,8articles met the requirements,involving 8 training cases,and 14 top international athletes,and sports events include 800 m,1 500 m,5 000 m,10 000 m,and cross-country running(9.5 km for men and 4.5 km for women).RESULTS AND CONCLUSION:(1)For the first time,double lactate threshold training was defined as a training strategy aimed at improving aerobic and speed capabilities,involving separate aerobic and anaerobic threshold training sessions within a single training day(aerobic training load intensity requirement of 0.7-2.0 mmol/L,anaerobic training load intensity requirement of 2.0-4.5 mmol/L),with a training frequency of＞2 times per week and a training volume of 120-160 km per week.(2)Double lactate threshold training has positive effects on muscle adaptability and plasticity(dimension and elasticity),increasing aerobic and anaerobic capabilities,and alleviating central neural fatigue and peripheral fatigue.(3)The main mechanisms by which double lactate threshold training yields effects may include hormone secretion,protein synthesis and inhibitory regulation,muscle fiber recruitment and cell swelling,mitochondrial biosynthesis and improvement in the chain of respiratory function,and neurotransmitter regulation.(4)In the practical application of double lactate threshold training,factors such as individualized training plans,load intensity design and monitoring for threshold training days,and applicable sports events should be fully considered.For the systematic improvement of double lactate threshold training,further exploration is still needed in terms of application subjects,training plans,action mechanisms,effect evaluation,and safe application.

BACKGROUND:The lactate threshold is a crucial physiological indicator for assessing the aerobic metabolic capacity and training level of endurance athletes,representing the intensity point at which lactate production and clearance reach a dynamic equilibrium within the organism.The traditional lactate threshold training,which is a prolonged and stable-intensity training,aims to enhance the aerobic endurance and lactate clearance efficiency of athletes.In recent years,with the advancement of exercise physiology,double lactate threshold training has emerged as an innovative training modality,drawing extensive attention from both the academic circle and practitioners.Nevertheless,current systematic research on double lactate threshold training remains limited,particularly in aspects such as its physiological mechanisms,optimal implementation plans,and long-term effects.OBJECTIVE:To systematically sort out the development course of double lactate threshold training,deeply analyze its fundamental connotations,objectively assess its application effects,and investigate its physiological action mechanisms,with the expectation of providing scientific basis and guidance for the improvement and optimization of endurance sports training theories and practices.METHODS:With the search terms of"lactate threshold training,double lactate threshold training,lactate training,threshold training,endurance training,Norwegian training method,Norwegian training mode,Norwegian training experience,"a systematic search was conducted in databases,including PubMed,Web of Science,Embase,Medline,Cochrane Library,CNKI,WanFang,and VIP.After screening,8articles met the requirements,involving 8 training cases,and 14 top international athletes,and sports events include 800 m,1 500 m,5 000 m,10 000 m,and cross-country running(9.5 km for men and 4.5 km for women).RESULTS AND CONCLUSION:(1)For the first time,double lactate threshold training was defined as a training strategy aimed at improving aerobic and speed capabilities,involving separate aerobic and anaerobic threshold training sessions within a single training day(aerobic training load intensity requirement of 0.7-2.0 mmol/L,anaerobic training load intensity requirement of 2.0-4.5 mmol/L),with a training frequency of＞2 times per week and a training volume of 120-160 km per week.(2)Double lactate threshold training has positive effects on muscle adaptability and plasticity(dimension and elasticity),increasing aerobic and anaerobic capabilities,and alleviating central neural fatigue and peripheral fatigue.(3)The main mechanisms by which double lactate threshold training yields effects may include hormone secretion,protein synthesis and inhibitory regulation,muscle fiber recruitment and cell swelling,mitochondrial biosynthesis and improvement in the chain of respiratory function,and neurotransmitter regulation.(4)In the practical application of double lactate threshold training,factors such as individualized training plans,load intensity design and monitoring for threshold training days,and applicable sports events should be fully considered.For the systematic improvement of double lactate threshold training,further exploration is still needed in terms of application subjects,training plans,action mechanisms,effect evaluation,and safe application.

OBJECTIVE To evaluate the efficacy， safety， and cost-effectiveness of brivaracetam （BRV） as adjunctive therapy in patients with drug-resistant focal epilepsy.METHODS PubMed， Embase， Cochrane Library， Web of Science， CNKI， Wanfang， and official health technology assessment （HTA） agency websites were searched from inception to January 31， 2026 for HTA reports， systematic reviews/meta-analyses， and pharmacoeconomic studies on BRV. After literature screening and quality assessment， a descriptive analysis was performed.RESULTS A total of 21 publications were included： 13 systematic reviews/meta-analyses， 7 pharmacoeconomic studies （including one study that simultaneously conducted a systematic review/meta-analysis）， and 2 HTA reports. Regarding efficacy， BRV significantly improved the 50% responder rate [risk ratio （RR）＝1.81] and seizure-freedom rate （RR＝5.89） versus placebo. Among third-generation anti-seizure medications （ASMs）， BRV ranked 1st-2nd for seizure freedom， while its 50% responder rate was at a moderate level. The optimal adult dose for seizure freedom was 100 mg/d. Regarding safety， BRV was well tolerated， overall adverse event rates did not differ from placebo， though withdrawal due to adverse event rates were higher than with placebo. Tolerability ranked 1st-2nd among the third-generation ASMs. Psychiatric/behavioral adverse event rates were lower with BRV （6.4%） than with levetiracetam （14.1%）. Regarding cost-effectiveness， BRV showed pharmacoeconomic advantages in countries with lower drug pricing （Australia， Finland） and only in high-risk subgroups in Japan， but did not show such advantages at current prices in the US or Italy. BRV has been included in China’s national reimbursement drug list in 2025， and the economic conclusions drawn during its initial market launch are outdated and require re-evaluation.CONCLUSIONS BRV has proven efficacy and good safety， especially suitable for patients intolerant to levetiracetam. However， due to pricing and medical insurance policies， the cost-effectiveness of BRV after its inclusion in China’s national reimbursement drug list still needs to be re-evaluated.

Metal ion-promoted chemodynamic therapy(CDT) combined with photodynamic therapy(PDT) offers broad application prospects for enhancing anti-tumor effects. In this study, glycyrrhizic acid(GA), copper ions(Cu~(2+)), and norcantharidin(NCTD) were co-assembled to successfully prepare a natural small-molecule, carrier-free hydrogel(NCTD Gel) with excellent material properties. Under 808 nm laser irradiation, NCTD Gel responded to the tumor microenvironment(TME) and acted as an efficient Fenton reagent and photosensitizer, catalyzing the conversion of endogenous hydrogen peroxide(H_2O_2) within the tumor into oxygen(O_2), and hydroxyl radicals(·OH, type Ⅰ reactive oxygen species) and singlet oxygen(~1O_2, type Ⅱ reactive oxygen species), while depleting glutathione(GSH) to stabilize reactive oxygen species and alleviate tumor hypoxia. In vitro and in vivo experiments demonstrated that NCTD Gel exhibited significant CDT/PDT synergistic therapeutic effects. Further safety evaluation and metabolic testing confirmed its good biocompatibility and safety. This novel hydrogel is not only simple to prepare, safe, and cost-effective but also holds great potential for clinical transformation, providing insights and references for the research and development of metal ion-mediated hydrogel-based anti-tumor therapies.
Hydrogels/chemistry* ; Animals ; Photochemotherapy ; Humans ; Mice ; Antineoplastic Agents/administration & dosage* ; Photosensitizing Agents/chemistry* ; Neoplasms/metabolism* ; Female ; Copper/chemistry* ; Reactive Oxygen Species/metabolism* ; Tumor Microenvironment/drug effects* ; Cell Line, Tumor ; Male

This study aims to explore the mechanism through which Yishen Jiangtang Decoction(YSJTD) regulates endoplasmic reticulum stress(ERS)-mediated NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome to improve diabetic nephropathy(DN) in db/db mice. Thirty db/db mice were randomly divided into the model group, YSJTD group, ERS inhibitor 4-phenylbutyric acid(4-PBA) group, with 10 mice in each group. Additionally, 10 db/m mice were selected as the control group. The YSJTD group was orally administered YSJTD at a dose of 0.01 mL·g~(-1), the 4-PBA group was orally administered 4-PBA at a dose of 0.5 mg·g~(-1), and the control and model groups were given an equal volume of carboxylmethyl cellulose sodium. The treatments were administered once daily for 8 weeks. Food intake, water consumption, and body weight were recorded every 2 weeks. After the intervention, fasting blood glucose(FBG), glycosylated hemoglobin(HbA1c), urine microalbumin(U-mALB), 24-hour urine volume, serum creatinine(Scr), and blood urea nitrogen(BUN) were measured. Inflammatory markers interleukin-1β(IL-1β) and interleukin-18(IL-18) were detected using the enzyme-linked immunosorbent assay(ELISA). Renal pathology was assessed through hematoxylin-eosin(HE), periodic acid-Schiff(PAS), and Masson staining, and transmission electron microscopy(TEM). Western blot was used to detect the expression levels of glucose-regulated protein 78(GRP78), C/EBP homologous protein(CHOP), NLRP3, apoptosis-associated speck-like protein containing CARD(ASC), cysteinyl aspartate-specific proteinase(caspase-1), and gasdermin D(GSDMD) in kidney tissues. The results showed that compared to the control group, the model group exhibited poor general condition, increased weight and food and water intake, and significantly higher levels of FBG, HbA1c, U-mALB, kidney index, 24-hour urine volume, IL-1β, and IL-18. Compared to the model group, the YSJTD and 4-PBA groups showed improved general condition, increased body weight, decreased food intake, and lower levels of FBG, U-mALB, kidney index, 24-hour urine volume, and IL-1β. Specifically, the YSJTD group showed a significant reduction in IL-18 levels compared to the model group, while the 4-PBA group exhibited decreased water intake and HbA1c levels compared to the model group. Although there was a decreasing trend in water intake and HbA1c in the YSJTD group, the differences were not statistically significant. No significant differences were observed in BUN, Scr, and kidney weight among the groups. Renal pathology revealed that the model group exhibited more severe renal damage compared to the control group. Kidney sections from the model group showed diffuse mesangial proliferation in the glomeruli, tubular edema, tubular dilation, significant inflammatory cell infiltration in the interstitium, and increased glycogen staining and blue collagen deposition in the basement membrane. In contrast, the YSJTD and 4-PBA groups showed varying degrees of improvement in renal damage, glycogen staining, and collagen deposition, with the YSJTD group showing more significant improvements. TEM analysis indicated that the model group had extensive cytoplasmic edema, homogeneous thickening of the basement membrane, fewer foot processes, and widening of fused foot processes. In the YSJTD and 4-PBA groups, cytoplasmic swelling of renal tissues was reduced, the basement membrane remained intact and uniform, and foot process fusion improved.Western blot results indicated that compared to the control group, the model group showed upregulation of GRP78, CHOP, GSDMD, NLRP3, ASC, and caspase-1 expression. In contrast, both the YSJTD and 4-PBA groups showed downregulation of these markers compared to the model group. These findings suggest that YSJTD exerts a protective effect against DN by alleviating NLRP3 inflammasome activation through the inhibition of ERS, thereby improving the inflammatory response in db/db DN mice.
Animals ; Endoplasmic Reticulum Stress/drug effects* ; Diabetic Nephropathies/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Inflammasomes/drug effects* ; Male ; Kidney/pathology* ; Endoplasmic Reticulum Chaperone BiP ; Humans ; Interleukin-18/genetics* ; Mice, Inbred C57BL

OBJECTIVE: To explore the effect of nano-hydroxyapatite/collagen composite (nHAC) on bone graft fusion after anterior cervical discectomy and fusion (ACDF) in patients with cervical spondylosis and low bone mass. METHODS: A retrospective analysis was conducted on 47 patients with low bone mass who underwent ACDF from 2017 to 2021. They were divided into the nHAC group and the allogeneic bone group according to different bone graft materials. The nHAC group included 26 cases, with 8 males and 18 females;aged 50 to 78 years old with an average of (62.81±7.79) years old;the CT value of C₂-C₇ vertebrae was (264.16±36.33) HU. The allogeneic bone group included 21 cases, with 9 males and 12 females;aged 54 to 75 years old with an average of (65.95±6.58) years old;the CT value of C₂-C₇ vertebrae was (272.39±40.44) HU. The visual analogue scale (VAS), neck disability index (NDI), and Japanese Orthopaedic Association (JOA) spinal cord function score were compared before surgery, 1 week after surgery, and at the last follow-up to evaluate the clinical efficacy. Imaging assessment included C₂-C₇ Cobb angle, surgical segment height, intervertebral fusion, and whether the cage subsidence occurred at 1 week after surgery and the last follow-up. RESULTS: The follow-up duration ranged from 26 to 39 months with an average of (33.27±3.34) months in the nHAC group and 26 to 41 months with an average of (31.86±3.57) months in the allogeneic bone group. At 1 week after surgery and the last follow-up, the VAS, NDI scores, and JOA scores in both groups were significantly improved compared with those before surgery, with statistically significant differences (P<0.05). At 1 week after surgery, the C₂-C₇ Cobb angles in the nHAC group and the allogeneic bone group were (14.26±10.32)° and (14.28±8.20)° respectively, which were significantly different from those before surgery (P<0.05). At the last follow-up, the C₂-C₇ Cobb angles in both groups were smaller than those at 1 week after surgery, with statistically significant differences (P<0.05). At 1 week after surgery, the height of the surgical segment in the nHAC group was (31.65±2.55) mm, and that in the allogeneic bone group was (33.63±3.26) mm, which were significantly different from those before surgery (P<0.05). At the last follow-up, the height of the surgical segment in both groups decreased compared with that at 1 week after surgery, with statistically significant differences (P<0.05). At the last follow-up, 39 surgical segments were fused and 6 cages subsided in the nHAC group;40 surgical segments were fused and 7 cages subsided in the allogeneic bone group;there was no statistically significant difference between the two groups (P>0.05). Compared with the CT value of vertebrae without cage subsidence, the CT value of vertebrae with cage subsidence in both groups was significantly lower, with a statistically significant difference (P<0.05). CONCLUSION The application of nHAC in ACDF for patients with low bone mass can achieve effective fusion of the surgical segment. There is no significant difference in improving clinical efficacy, intervertebral fusion, and cage subsidence compared with the allogeneic bone group. With the extension of follow-up time, the C₂-C₇ Cobb angle decreases, the height of the surgical segment is lost, and the cage subsides in both the nHAC group and the allogeneic bone group, which may be related to low bone mass. Low bone mass may be one of the risk factors for cervical spine sequence changes, surgical segment height loss, and cage subsidence after ACDF.
Humans ; Male ; Female ; Middle Aged ; Spondylosis/physiopathology* ; Spinal Fusion/methods* ; Cervical Vertebrae/surgery* ; Aged ; Diskectomy ; Durapatite ; Retrospective Studies ; Collagen/chemistry*

Objective:To analyze the applied effect of artificial intelligence(AI)rehabilitation system combined with telemedicine platform in individualized rehabilitation treatment for patients with long-term coma,so as to realize individual management for them.Methods:An AI rehabilitation system that aimed to patients with long-term coma was designed by integrating data of multimodal sensors included inertial sensor,image sensor and bioelectric sensor.A telemedicine platform,which included seven modules(patient management,consultation management,video communication,data transmission,electronic medical records,cost management and system maintenance),was designed by using a browser/server(B/S)architecture.The changes of patients'condition were followed up,and the full process of the management for rehabilitation treatment and the individualization of treatment plan were realized.A total of 60 inpatients whose coma duration exceeded 28 days were selected from the Coma Awakening Center of Dongguan Shipai Hospital between October 1,2021 and September 30,2022.They were randomly divided into control group(n=30)and observation group(n=30)by random number table.The control group received physical therapy and rehabilitation training based on evaluation results of rehabilitation,while the observation group adopted AI rehabilitation system combined with the telemedicine platform to conduct intervention.The consciousness levels,quality of life,hospital stay duration and treatment costs of two group were compared after intervention.Results:The Glasgow Coma Scale(GCS)scores,Coma Recovery Scale-Revised(CRS-R)scores,and Persistent Vegetative State(PVS)scores of two groups after intervention were significantly higher than those before intervention,and these indicators of observation group were significantly higher than them of control group after intervention,and the differences were significant(t=7.187,15.586,9.293,P<0.05),respectively.There were not significant differences in Glasgow Outcome Scale(GOS)scores and Activities of Daily Living(ADL)scores between two groups before intervention(P>0.05),and these scores of two groups were significantly increased after intervention,and these scores of observation group were significantly higher than them of control group after intervention,and the differences were significant(t=7.584,6.755,P<0.05).Additionally,the hospital stay duration and treatment costs of observation group were significantly less than those of control group,and the differences were significant(t=20.965,9.503,P<0.05).Conclusion:The intervention of AI rehabilitation system combines with a telemedicine platform on patients with long-term coma can enhance GCS,CRS-R,PVS,GOS and ADL scores,and reduce hospital stay duration and treatment cost.

Objective:To construct a structural equation model for neck work-related musculoskeletal disorders (WMSDs) in the footwear industry and analyze the mediating effect of fatigue in the model.Methods:From November 2018 to December 2019, stratified cluster sampling was adopted to select all the workers (3565 people) from 7 footwear enterprises in Fujian Province as the research subjects. The incidence of WMSDs, fatigue and work-related condition were investigated by using the Chinese version of the Musculoskeletal Disorders Questionnaire. A structural equation model of individual factors, work type, work posture, work organization factors, and fatigue on neck WMSDs was constructed to analyze the mediating effect of fatigue among them.Results:The incidence rate of WMSDs in the neck of footwear workers was 39.6% (1413/3565) , and the incidence rate of neck fatigue was 46.6% (1662/3565) .The final structural equation model was constructed with a χ2/ df of 9.927, a goodness-of-fit index of 0.961, an adjusted goodness-of-fit index of 0.946, and a root mean square error of approximation of 0.050. Except for the χ2/ df, all other fit indicators met the standard. Individual factors and work posture factors had a direct effect on neck WMSDs, with standardized path coefficients of 0.101 and 0.077, respectively ( P<0.05) . Individual factors, work type, work posture, and work organization had indirect effects on neck WMSDs through fatigue, the standardized path coefficients of indirect effects were 0.163, 0.090, 0.206, 0.105, respectively, and the standardized path coefficients of the total effect were 0.264, 0.090, 0.282, and 0.105 respectively ( P<0.05) . The indirect effects of individual factors and work posture factors on neck WMSDs through fatigue accounted for 61.74% and 73.05% of the total effects, respectively. The standardized path coefficient of fatigue on WMSDs was 0.689 ( P<0.001) , with the highest coefficient among all paths. Conclusion:Individual factors, work type, work posture, and work organization factors are important influencing factors in the occurrence and development of neck WMSDs in the footwear industry, and fatigue plays an important mediating role in them.

Objective To explore the pharmacokinetic characteristics of sufentanil in individuals with normal body mass index(BMI),overweight BMI,and different CYP3A4/5 enzyme genotypes.Methods The patients receiving laparoscopic surgery under general anesthesia in the First Affiliated Hospital of Army Medical University from November 2020 to September 2021 were prospectively recruited in this study.Before the operation,the oral swabs were collected from all the patients for genotyping using the human CYP3A4/5 gene kit.Based on the potential impact of combination of their polymorphisms on sufentanil metabolism and the proportion of different genotype combinations of CYP3A4/5 enzymes,the patients were divided into groups I(3A4 homozygous mutation or 3A4 heterozygous mutation+3A5 homozygous mutation),II(3A4 heterozygous mutation+3A5 heterozygous mutation),and III(3A4 wild type or 3A4 heterozygous mutation+3A5 wild type).According to their BMI,they were also assigned into a normal body weight group(18.5～24.0 kg/m2)and an overweight group(24～<28 kg/m2),and the differences in drug metabolism parameters were statistically analyze between the 2 groups.After routine general anesthesia induction(sufentanil 0.5 μg/kg),venous blood samples were collected to detect the changes in its concentration using high performance liquid chromatography-mass spectrometry(HPLC-MS).The pharmacokinetic data of sufentanil were calculated between the normal BMI group and overweight group in all participants and between the 2 body weight groups among those with different genotype combinations.Results Among the 90 participants completing the blood drug concentration test,8 patients had their blood samples contaminated(including 1 case with an anesthesia duration of<2 h),and 3 were excluded due to low weight or overweight.Eventually,79 participants were included in the pharmacokinetic analysis on the normal body weight group and the overweight group.Compared with the normal body weight group,the central compartment volume of distribution in the overweight group was significantly reduced(P<0.05),while no obvious differences were observed between the 2 groups in terms of peripheral compartment volume of distribution,total clearance rate,peripheral compartment clearance rate,distribution half-life,clearance half-life,and area under the blood concentration-time curve.In group Ⅰ(n=26),the overweight patients(n=13)had significantly reduced central compartment volume of distribution,peripheral compartment volume of distribution,and peripheral compartment clearance rate when compared with the normal body weight patients(n=13)(P<0.05),while no differences were observed in other pharmacokinetic parameters.In groups Ⅱ(n=25)and Ⅲ(n=28),the overweight patients and normal body weight patients had no statistical differences in all pharmacokinetic parameters.Conclusion Among the patients with the same genotype combination of CYP3A4/5 mutations,there was no difference in the metabolism of sufentanil between the overweight and normal weight patients.Additionally,in the population of 3A4 homozygous mutation or 3A4 heterozygous mutation+3A5 homozygous mutation,the overweight patients have smaller peripheral distribution range of sufentanil,and weakened metabolic process.