[A retrospective study of 96 cases of adrenal metastases].

Objective: To analyze the clinical characteristics, etiological composition, imaging features, and prognosis of adrenal metastases. Methods: This study is a retrospective case series that included 96 patients with pathologically confirmed adrenal metastases who were treated at West China Hospital, Sichuan University, from 2007 to 2017. Clinical features such as sex, age, tumor size, biochemical tests, imaging characteristics, postoperative pathology, treatment methods, and prognosis were collected and analyzed. The prognosis of patients and its influencing factors were analyzed by Kaplan-Meier survival curve and single-factor Cox risk proportional model. Results: Among the 96 included patients, 64 were male and 32 were female, with a median age of 60 years. There were 89 cases of unilateral adrenal metastases, five cases of bilateral metastases, and two cases with unspecified laterality. The median diameter of the metastases was 3.5 cm×2.9 cm, with an average CT value of 31 HU. Thirty-four cases of adrenal hormones were evaluated, and no abnormality was found.The primary tumor sites were as follows: lung (n=36), kidney (n=19), liver (n=12), pancreas (n=7), rectum (n=3), stomach (n=2), and one case each of tumor in the esophagus, skin, thyroid, left maxillary muscle, breast, bladder, cervix, chest wall, and gastrointestinal tract. There were three cases with unknown primary tumors. The most common pathological type was lung adenocarcinoma (20.8%, 20/96), followed by hepatocellular carcinoma (9.4%, 9/96) and high-grade invasive urothelial carcinoma of the kidney (8.3%, 8/96). Thirty-nine cases were diagnosed concurrently with the primary tumor, while 37 cases were diagnosed after the primary tumor, with a median interval of 15 months (range: 2-144 months). There was no significant correlation between the death risk of adrenal metastatic tumor patients and gender, age, and the size of the metastatic tumor (all P>0.05). There were 4 patients with radiotherapy and chemotherapy alone, 19 patients with surgery alone, and 6 patients with combined radiotherapy and chemotherapy. The median overall survival was 1, 3, and 7 years, respectively. Conclusions: Adrenal metastases were mostly diagnosed at the same time as the primary tumor or within 15 months after the diagnosis of the primary tumor. Unilateral metastasis is common. The lungs are the most common primary lesion, followed by the kidney and liver. CT is the preferred method for the diagnosis of adrenal metastases, and the plain CT value is more than 30 HU. The overall prognosis of adrenal metastases is poor. The prognosis was better for patients who underwent surgery combined with radiotherapy and chemotherapy than those who received only surgery or radiotherapy and chemotherapy alone.

Effect of SOCS1 on diabetic renal injury through regulating TLR signaling pathway.

OBJECTIVE: To clarify the effect of suppressor of cytokine signaling 1 (SOCS1) on diabetic nephropathy (DN)-induced renal injury by regulating the Toll-like receptor (TLR) signaling pathway. MATERIALS AND METHODS: The Sprague-Dawley rats were divided into control group (n=10) and DN group (established with streptozotocin injection, n=20). The DN rats were administrated with SOCS1 lentivirus to upregulate the in vivo expression. The rat blood glucose was detected to confirm the successful preparation of the DN model. The hepatic and renal function indexes, including blood urea nitrogen (BUN), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and creatinine (CR) were detected. The pathological lesions in the kidney were observed via hematoxylin-eosin (HE) staining. Besides, the serum levels of the inflammatory factors in rats were detected via enzyme-linked immunosorbent assay (ELISA). The relative levels of genes in the TLR signaling pathway were detected via RT-PCR and Western blotting. RESULTS: The blood glucose level in rats of the DN group was significantly enhanced, indicating the successful modeling. The expression of SOCS1 was significantly upregulated in rats administrated with SOCS1 lentivirus. The contents of BUN, ALP, ALT, and CR in rats of SOCS1 overexpression group were significantly lower than those in the DN group. The inflammatory infiltration in the kidney and the glomerular injury were pronounced in the DN group. The serum levels of interleukin-1 (IL-1), interferon-γ (INF-γ), and tumor necrosis factor-α (TNF-α) were significantly declined in SOCS1 overexpression group. Besides, the mRNA expressions of myeloid differential protein-88 (MyD88), TLR2, and INF-γ, and the protein expression of TLR2 were all remarkably downregulated in SOCS1 overexpression group. CONCLUSIONS: SOCS1 can promote renal injury repair in DN rats by inhibiting the TLR pathway. Therefore, SOCS1 is expected to be a new target for the repair of DN renal injury.

Efficacy of Omega-3 Polyunsaturated Fatty Acids Supplementation in Managing Overweight and Obesity: A Meta-Analysis of Randomized Clinical Trials.

OBJECTIVE: Studies in rodents and humans have indicated that omega-3 polyunsaturated fatty acids (n-3 PUFA) may reduce weight. The aim of this meta-analysis was to evaluate evidence for the efficacy of n-3 PUFA in managing overweight and obesity. METHODS: We performed a systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials until May 2015. Two reviewers independently determined the eligibility of studies and assessed the reporting quality of included randomized controlled trials (RCTs). RESULTS: A total of 11 RCTs involving 617 participants were included in this meta-analysis. Based on the meta-analysis of nine studies, a statistically nonsignificant difference was revealed in weight loss between n-3 PUFA and placebo (p=0.99; weighted mean difference [WMD]: 0.00; 95% confidence interval [CI] -0.42 to 0.43), whereas n-3 PUFA was superior to placebo in reducing serum triglyceride levels (p=0.0007; standard median difference [Std MD]: -0.59; 95% CI -0.93 to -0.25). Based on meta-analysis of seven studies, the analysis of aggregated data showed a significant reduction in waist circumference (p=0.005; WMD: -0.53; 95% CI -0.90 to -0.16). There were no significant differences in body mass index, total serum levels of cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and fasting glucose levels. CONCLUSIONS: The evidence from RCTs showed that n-3 PUFA might effectively reduce waist circumference and triglyceride levels in overweight and obese adults, but n-3 PUFA may not effectively reduce body weight. Given the small number and poor quality of RCTs included in the meta-analysis, these results are inconclusive. A large-scale, well-designed RCT is needed to further address this issue.

Efficacy and safety of combination therapy with vildagliptin and metformin versus metformin uptitration in Chinese patients with type 2 diabetes inadequately controlled with metformin monotherapy: a randomized, open-label, prospective study (VISION).

AIMS: To compare the efficacy and safety of combination of vildagliptin and metformin therapy with metformin uptitration in Chinese patients with type 2 diabetes (T2DM) inadequately controlled with low-dose metformin. METHODS: In this 24-week prospective, randomized, multicentre, open-label study, patients with T2DM inadequately controlled with metformin ≤1000 mg daily were divided 1 : 1 : 1 : 1 into four prespecified subgroups based on age and body mass index (BMI). Patients in each subgroup were randomized 5 : 1 to receive either vildagliptin (50 mg twice daily) plus metformin [500 mg twice daily; vildagliptin and low-dose metformin (VLDM) group] or metformin uptitration [1000 mg twice daily; high-dose metformin (HDM) group]. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline at week 24. The key secondary endpoints included percentage of patients achieving target HbA1c without adverse gastrointestinal (GI) events and mean change in fasting plasma glucose (FPG) from baseline to week 24. RESULTS: A total of 3084 patients were randomized. HbA1c reduction of 0.54% at week 24 in the VLDM group was non-inferior and statistically superior compared with 0.40% in the HDM group (P < 0.0001). VLDM's non-inferiority to HDM was confirmed in the four subgroups and its superiority was shown for all subgroups (p < 0.05) except for the subgroup of patients aged <60 years with a BMI of ≥24 kg/m(2) . Compared with HDM, VLDM significantly increased the percentage of patients achieving HbA1c ≤6.5% and HbA1c ≤6.5% without GI events. FPG levels in the VLDM group were lower at week 24 numerically than in the HDM group. The two treatment arms had similar safety profiles. CONCLUSIONS: VLDM was non-inferior and statistically superior to HDM in glycaemic control in Chinese patients with T2DM inadequately controlled with low-dose metformin.

Serum ferritin is associated with carotid atherosclerotic plaques but not intima-media Thickness in patients with abnormal glucose metabolism.

BACKGROUND: We investigated the association between serum ferritin and carotid artery lesions in populations with abnormal glucose metabolism. METHODS: We included 70 participants with abnormal glucose metabolism and 170 participants with normal glucose metabolism and measured their baseline serum ferritin levels. During follow-up carotid intima-media thickness and carotid plaque were evaluated. RESULTS: Serum ferritin levels were higher in the participants with abnormal glucose metabolism (p<0.01). We further divided the patients with abnormal glucose metabolism into subgroups with and without intima-media proliferation, and found that ferritin was excluded from the final equation in the logistic regression. Furthermore, age, waist circumference, ferritin, 2h-PG, and total cholesterol were significantly different between the subgroups with and without carotid plaque. When the above data were included in a logistic regression model, the p values obtained for age, ferritin, and 2h-PG were 0.004, 0.032, and 0.011, respectively. CONCLUSIONS: In the Chinese population, serum ferritin levels are significantly increased in patients with abnormal glucose metabolism. The carotid intima-media thickness showed no independent relationship with serum ferritin in patients with abnormal glucose metabolism. However, high serum ferritin is an important risk factor for carotid atherosclerosis in these patients.

Increased plasma DPP4 activities predict new-onset atherosclerosis in association with its proinflammatory effects in Chinese over a four year period: A prospective study.

OBJECTIVE: DPP4, a novel proinflammatory cytokine, is involved in the inflammatory process through its interaction with IGF-II/M6P receptor. We aimed to investigate whether it could predict new-onset atherosclerosis in Chinese. METHODS: A prospective study was conducted of 590 adults (213 men and 377 women) aged 18-70 years without atherosclerosis examined in 2007(baseline) and 2011(follow-up). Circulating DPP4 activity, inflammatory markers, IGF-II/M6P receptor and common carotid artery Intima-Media Thickness (C-IMT) were measured at baseline and four years later. RESULTS: At baseline, individuals in the highest quartile of DPP4 activity had higher age, WHR, BMI, SBP, fasting insulin, 2h-PG, TG, LDL-C, IL-6, hs-CRP, IGF-II/M6P-R, C-IMT and lower HDL-C compared with individuals in the lowest quartile. After a 4-year follow-up, 71 individuals developed atherosclerosis. In multiple linear regression analysis, baseline DPP4 activity was an independent predictor of an increase in inflammatory markers, IGF-II/M6P receptor, and C-IMT over a 4-year period (all P < 0.01). In multivariable-adjusted models, the odds ratio (OR) for incident atherosclerosis comparing the highest with the lowest quartiles of DPP4 activity was 3.17 (95%CI 1.33-7.58) after adjustment for confounding risk factors (P = 0.009). The incidence of atherosclerosis owing to DPP4 activity increased by 12.41%. CONCLUSIONS: DPP4 activity is an important predictor of the onset of inflammation and atherosclerosis in apparently healthy Chinese. This finding may have important implications for understanding the proinflammatory role of DPP-4 in the pathogenesis of atherosclerosis.

High-level of xylanase production by the thermophilic Paecilomyces themophila J18 on wheat straw in solid-state fermentation.

The production of extracellular xylanase by a newly isolated thermophilic fungus, Paecilomyces themophila J18, on the lignocellulosic materials was studied in solid-state fermentation (SSF). The strain grew well at 50 degrees C and produced a high-level of xylanase activity using the selected lignocellulosic materials, especially wheat straw. Production of xylanase by P. themophila J18 on wheat straw was enhanced by optimizing the particle size of wheat straw, nitrogen source, initial moisture level, growth temperature and initial pH of the culture medium. Under the optimized conditions, yield as high as 18,580 Ug(-1) of carbon source of xylanase was achieved. No CMCase activity was observed. The xylanase exhibited remarkable stability and retained more than 50% of its original activity at 70 degrees C for 4h at pH 7.0-8.0. Therefore, P. themophila J18 could to be a promising microorganism for thermostable, cellulase-free xylanase production in SSF.

Elevated serum neopterin level: its relation to endotoxaemia and sepsis in patients with major burns.

The present study was conducted to determine the relationship between levels of neopterin and endotoxin in the circulation, and whether the neopterin level was related to the development of severe sepsis after extensive burns. This prospective study included 35 patients with burn size greater than 30% (30-98%), and 22 healthy volunteers who served as a comparison group. Neopterin levels increased in most patients on day 3 post-burn, but they were not significantly correlated with the extent of the burn surface (P > 0 center dot 05). A high serum neopterin level was found in patients with sepsis (n = 15), and a marked elevation persisted throughout the observation period. The difference between septic and non-septic patients (n = 20) became significant on 14 and 28 days post-burn. Although the presence of early endotoxaemia did not influence the alterations in serum neopterin, patients with endotoxaemia had much higher neopterin values than those who showed no endotoxaemia from the second week onward (P < 0 center dot 05-0 center dot 01). In addition, circulating endotoxin and neopterin levels were positively correlated in patients who developed endotoxaemia on day 14 (r = 0 center dot 368, P < 0 center dot 05) and day 21 (r = 0 center dot 439, P < 0 center dot 01) after major burns. These results suggest that thermal injury can lead to an elevation of serum neopterin independent of the burn surface area. The initial increase in the neopterin level may be a part of the acute-phase response to tissue injury itself, whereas the endotoxin release in the circulation may be responsible for the continuous induction of neopterin during the late stage. In addition, the presence of a constant high neopterin level is associated with a critical event in the development of severe burn sepsis.

Reduction of circulating prostaglandin E2 level by antiserum against core lipopolysaccharide in a rabbit model of multiple organ failure.

OBJECTIVE: To determine the potential role of prostaglandin E2 (PGE2) in the development of multiple organ dysfunction or failure (MOF), the possible effects of antiserum directed against Re chemotype lipopolysaccharide (LPS, from Re mutant of Escherichia coli F515) on circulating PGE2 level and survival rate, and whether there is an elevation in the plasma LPS concentration that could account for the induction of arachidonic acid metabolite in a rabbit model of MOF caused by acute hypovolemic insult. DESIGN, MATERIALS, AND METHODS: An animal model of MOF in rabbits, engendered by feeding live Escherichia coli O111:B4 before hemorrhagic shock (35-40 mm Hg for 60 min), was used in the present study. Re-LPS antiserum was given intravenously in the treatment group at the onset of hemorrhage and 4 hours after resuscitation. The animals that received equal volumes of normal rabbit serum and antiserum served as the control group. MEASUREMENTS AND MAIN RESULTS: The circulating PGE2 level was not increased at the end of shock (p > 0.05), but it was found to be significantly elevated 24 hours after hemorrhage and resuscitation in both groups. However, Re-LPS antiserum administration markedly decreased peak PGE2 level (p < 0.05) and attenuated multiple organ damage caused by acute insult. Concomitantly, there were also lower LPS concentrations in the treatment group as compared with the control group (p < 0.05-0.01). The survival rate was significantly increased in antiserum-treated rabbits 96 hours postinjury (treatment vs. control: 58.0% vs. 11.1%, p < 0.01). CONCLUSIONS: The results suggest that an excessive generation and release of PGE2 may be involved in the pathogenesis of immunosuppression and MOF following hemorrhage and resuscitation. Re-LPS antiserum has an inhibitory effect on overproduction of circulating PGE2 and the ability to improve survival with MOF. Gut-derived endotoxemia, bacterial translocation, or both, could account, at least in part, for the PGE2 formation and release in animals response to acute hypovolemic insult.

Role of gut-derived endotoxaemia and bacterial translocation in rats after thermal injury: effects of selective decontamination of the digestive tract.

This study was performed to investigate: (1) the role of gut-derived endotoxin/bacterial translocation in the pathogenesis of sepsis, and (2) the possible effects of selective decontamination of the digestive tract (SDD) on mortality in rats following 40 per cent full-thickness scald injury. In the SDD-treated group, Enterobacteriaceae and yeasts were eradicated from the caecal mucosa, while the mucosal flora consisting of mainly anaerobes was well preserved, within 3 days. The incidence of bacterial translocation to the mesenteric lymph nodes (MLN) and viscerae was significantly lowered on postburn days 1, 3 and 5 (P < 0.05-0.01). Meanwhile, pretreatment with SDD resulted in reductions of the faecal endotoxin levels in different segments of intestinal tract to less than 0.5 per cent (0.04-0.45 per cent) of the untreated control; there was also a significant attenuation of the elevation of endotoxin concentrations in both portal and systemic blood. Intestinal diamine oxidase (DAO) activity returned to baseline on day 5 in rats receiving SDD but not in controls. The 5-day survival rate in the SDD-treated group was elevated by 26.7 per cent as compared with controls (P < 0.05). These data suggested that endotoxin/bacterial translocation took place early and commonly, which in turn contributed to postburn sepsis and mortality. SDD was effective in preventing gut origin endotoxaemia and bacterial translocation, and improving the survival rate in rats following severe thermal injuries.

Inhibitory effects of low-dose polymyxin B on hemorrhage-induced endotoxin/bacterial translocation and cytokine formation in rats.

The current experiments were performed to determine the effects of a subtherapeutic dose of polymyxin B sulfate on gut origin endotoxemia/bacterial translocation, and tumor necrosis factor (TNF) and interleukin-1 (IL-1) release following hemorrhagic shock (30 mm Hg, 90 min) in rats. The results showed that significant portal and systemic endotoxemia took place in the control group (portal, 0.269 to 0.845 endotoxin units (EU)/mL; systemic, 0.164 to 0.655 EU/mL), but not in the treatment group (except 0.5 hour in portal blood: 0.207 +/- 0.094 EU/mL). Concomitantly, the incidence of bacterial translocation to the mesenteric lymph nodes and viscera were reduced significantly at 0.5, 2, 6, and 24 hours postresuscitation in animals receiving polymyxin B (p < 0.05 to 0.01), whereas there were no differences with respect to number of translocating bacteria between the two groups (p > 0.05). Marked elevation of plasma TNF levels and IL-1 activities of peritoneal macrophages were also found in untreated controls at 0.5 to 2 hours (p < 0.05) and 6 to 24 hours (p < 0.05 to 0.01), respectively, but prevented by administration of low-dose polymyxin B. The 48-hour survival rate was improved from 41.7% in the control group to 75.0% in the treatment ones (p > 0.05). These data suggest that pretreatment with a subtherapeutic dose of polymyxin B is effective to inhibit hemorrhage-induced endotoxin/bacterial translocation from the gut and excessive TNF and IL-1 production.

The association of circulating endotoxaemia with the development of multiple organ failure in burned patients.

In this study, we examined the relationship of plasma endotoxin levels to the development of multiple organ failure (MOF), and the outcome in patients with thermal injury. A prospective cohort study of 17 patients admitted with burns covering more than 70 per cent of body surface area was undertaken. Circulating endotoxin concentrations were measured by modified limulus amoebocyte lysate assay in serial samples of plasma. Seven out of 17 burned patients developed MOF according to multiple criteria. The plasma endotoxin concentrations of patients with MOF were 0.512-1.127 EU/ml, which were significantly higher than that of 10 patients without MOF (0.216-0.553 EU/ml), on 3, 14, 21 and 28 days postburn (p < 0.05-0.01). A significantly higher incidence of positive endotoxin tests (> or = 0.120 EU/ml) was found in patients who developed MOF as compared to those patients who did not develop MOF during the observation period (p < 0.05). As the mean endotoxin levels increased, the incidence of MOF and death rate also increased, and persistent endotoxemia carried a poor prognosis. The present investigation provides further evidence that endotoxemia in severely burned patients commonly occurs. Circulating endotoxin has also been found to be strongly associated with the development of MOF and mortality following major burn injury.

Gut-derived endotoxemia and multiple system organ failure following gunshot wounds combined with hemorrhagic shock: an experimental study in the dog.

The purpose of this study was to explore the causative effects of high-velocity bullet injury (5.56 mm, 930 m/sec) combined with hemorrhagic shock on gut-derived endotoxemia and multiple system organ dysfunction or failure. The concentration of endotoxin in both portal and systemic blood was markedly increased after gunshot wounds together with hemorrhagic shock (p < 0.05-0.01). The portal/systemic lipopolysaccharide ratio persistently decreased in the combined wound (CW) group at 24 to 72 hours after injury, and it was much lower in the CW group than that in the single gunshot wound (SW) group. Also, a significant increase of fecal endotoxin content was found in the CW group as compared to the SW group (118.30 +/- 75.36 vs. 8.89 +/- 3.32 micrograms/g, p < 0.01), which was paralleled with the population of gram-negative bacilli in the intestinal tract. The incidence of multiple system organ failure, multiorgan dysfunction (including single organ failure) in the CW group were 30.8% (4 of 13) and 38.5% (5 of 13), respectively. These results suggested that severe trauma could lead to gut origin endotoxemia and bacterial translocation, which might play an important role in the pathogenesis of sepsis and multiple system organ failure following gunshot wounds.

The potential etiologic role of tumor necrosis factor in mediating multiple organ dysfunction in rats following intestinal ischemia-reperfusion injury.

Endogenous inflammatory cytokines may function as mediators in the development of remote organ damage in response to local ischemic insult. This study was designed to (a) explore the potential role of tumor necrosis factor (TNF) formation in the pathogenesis of systemic tissue injury, (b) determine the relationship between induction of TNF and gut-derived endotoxemia and/or bacterial translocation, and (c) evaluate the protective effect of anti-TNF monoclonal antibody (MoAb) for vital organs following intestinal ischemia-reperfusion in rats. Animals were subjected to superior mesenteric artery occlusion (SMAO) for 45 min. Systemic plasma TNF levels increased rapidly after the onset of reperfusion, reaching a peak value 2 h later (P < 0.01). TNF elevation was found to be associated with gut origin endotoxemia, where the maximal TNF levels occurred approximately 2 h after the initial appearance of endotoxin in portal vein. Prophylactic treatment with anti-TNF MoAb markedly blunted the elevation in plasma TNF levels and afforded protection from the development of hypotension, vital organs dysfunction, and metabolic acidosis. Significant improvement in 48-h survival rate was observed by administration of anti-TNF MoAb prior to inducing ischemia (P = 0.007). These findings suggest that intestinal ischemia-reperfusion could result in TNF production, which may play a key role in mediating subsequent septic response and systemic tissue injury. It seems likely that passage of endotoxin and bacteria from the gut can be responsible for the TNF formation

Protective effect of Re-LPS antiserum on experimental multiple system organ failure.

This study examines the possible beneficial effect of Re-LPS (F515) antiserum on experimental multiple system organ failure (MSOF) in rabbits. The results showed that the plasma LPS level was significantly decreased, and it took a shorter period to clear up LPS in experimental than in control rabbits after receiving Re-LPS antiserum. Pretreatment with antiserum can markedly improve the function of the liver, lungs, kidneys, blood and gastrointestinal tract. The MSOF incidence in the group of rabbits receiving immune sera was only 11.2% and the survival rate was raised by about 40.0%. The results suggest that early passive immunotherapy may neutralize gut-derived endotoxin, inhibit endotoxin-induced mediators release and prevent development of severe complications due to sepsis. It is therefore postulated that LPS core antiserum may provide a prophylactic effect on the development of experimental MSOF.

Special spectacles facilitating debridement. Report of use in 300 cases.

According to the difference of light reflection of tissue with different degree of viability, spectacles were made from glass permitting light of certain wavelength to pass to help distinguish viable from nonviable tissue. They were used in debridement of wounds in 300 patients. The results showed that the quality of debridement was improved as evidenced by better healing and shorter healing time. These spectacles were helpful, especially for young and unexperienced operators to distinguish viable from nonviable tissue. They were also used to predict flap viability in plastic surgery.

[Clinical observation on hypercortisolism treated with amino-glutethimide].

We reported the clinical results in 13 cases of hypercortisolism treated with amino-glutethimide (AG), which was developed by Tiantsin Research Institute of Medical Industry. Of the thirteen cases nine were confirmed by surgery and histology, and the others were diagnosed clinically. Clinical improvements have been achieved in ten of the thirteen cases over a therapeutic course of 8 to 12 wk with a daily dosage of 1.0 to 2.0 g of AG. Plasma and urinary corticosteroids, as well as plasma testosterone levels were significantly decreased after one-month treatment followed, however, by somewhat return and fluctuation. The high levels of blood glucose and serum insulin were declined after therapy consistent with the decrement of corticoids. Serum potassium levels in hypokalemic patients returned to normal after one month of therapy. Radial bone mineral contents in patients with low bone density returned or closed to normal after three-month treatment. The main side effects of AG are anorexia, nausea, drowsy, tierdness, skin rashes, etc, which are mild and transient. Adrenal hypofunction was seen in one case after treatment.