Iron burden and endocrine complications in transfusion-dependent thalassemia patients In Sarawak, Malaysia: a retrospective study.

INTRODUCTION: Thalassaemia is one of the major health problems in Malaysia. With safe blood transfusion regime, the lifespan of patients with transfusion-dependent thalassaemia (TDT) has improved but at the cost of a higher risk of developing endocrine disorders. It is crucial for us to monitor the iron overload to prevent end organ damage. This study aims to evaluate the iron burden and prevalence of endocrinopathies in patients with TDT in Sarawak. MATERIALS AND METHODS: This retrospective cohort study was conducted between January 2020 to June 2020 in six government hospitals in Sarawak. A total of 89 patients with TDT, aged 10 years and above, were recruited. RESULTS: Out of the 89 patients, there were 54 males (60.7%) and 35 females (39.3%) with a median age of 21 years (range 10.0-65.0). Sixty-seven (75.3%) patients had betathalassaemia major and 15 (16.9%) patients had haemoglobin E beta-thalassaemia (HbE beta-thalassaemia), remaining seven patients had other genotypes. Thirty-one (34.8%) patients had mean serum ferritin 2500ng/ml and above, and 44 (66.6%) had liver iron concentration (LIC) ≥7mg/g. The prevalence of endocrine disorders in our cohort was 69.7%. The most common endocrinopathies were short stature (n=46, 51.7%), followed by hypogonadism (n=24, 26.9%), delayed puberty (n=23, 25.8%), hypothyroidism (n=10, 11.2%), diabetes mellitus (n=9, 10.1%), impaired glucose tolerance (n=6, 6.7%) and hypoparathyroidism (n=3, 3.3%). Endocrinopathies were significantly associated with age (p=0.01), age at initiating regular blood transfusion (p<0.01) and duration of regular blood transfusion (p<0.01). CONCLUSION: Our data shows that the development of endocrinopathies in TDT can be time dependent. Early detection of endocrine-related complications and prompt treatment with iron chelation therapy are important to improve morbidity and mortality. A multidisciplinary approach with good patient-doctor collaboration is the key to improving patient care in our settings.

[Prognostic value of skeletal muscle measured by CT at the T4 level in advanced EGFR-positive non-small cell lung cancer patients treated with ecotinib].

Objective: To investigate the prognostic value of skeletal muscle measured by CT at the level of the fourth thoracic vertebra (T4) in advanced epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients treated with ecotinib. Methods: The study retrospectively reviewed clinical and pathological characteristics of 176 patients with advanced EGFR-positive NSCLC who received ecotinib and underwent chest CT scans at Wuhan Union Hospital between January 2017 and October 2020. Among them, 70 were male and 106 were female, with ages ranging from 27 to 80 (58.6±10.6) years. As of August 21, 2021, the median follow-up duration was 19.2 months (95%CI: 15.3 to 23.7 months). The optimal cut-off value of skeletal muscle density (T4-SMD) on CT images at the T4 level were determined using X-tile software. Kaplan-Meier analysis and log-rank test were used to plot progression-free survival curves. Cox proportional hazards regression models were employed to analyze factors influencing 1-year progression-free survival (PFS), and a nomogram prognostic model was constructed accordingly. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were utilized to evaluate the predictive value of the nomogram. Results: The T4-SMD [M (Q1,Q3)] of 176 patients was 42.56 (37.05, 45.93) HU. Patients were divided into low T4-SMD group (n=122) and high T4-SMD group (n=54) based on the cut-off value (The values for males and females were 49.44 and 41.41 HU, respectively) of T4-SMD. The median PFS time and 1-year PFS rate in the low T4-SMD group were significantly lower than those in the high T4-SMD group [10.4 (95%CI: 9.3-11.8) vs 13.7 (95%CI: 11.1-18.5) months, 36.1% vs 59.3%, respectively, P=0.034]. Eastern Cooperative Oncology Group performance status (HR=3.308, 95%CI: 1.183-9.247, P=0.023), lactate dehydrogenase level (HR=1.852, 95%CI: 1.037-3.307, P=0.037), systemic immune-inflammation index (HR=1.772, 95%CI: 1.019-3.080, P=0.043), and T4-SMD (HR=0.563, 95%CI: 0.325-0.974, P=0.040) were prognostic factors for 1-year PFS in advanced EGFR-positive NSCLC patients treated with ecotinib. A nomogram for predicting 1-year PFS of advanced EGFR-positive NSCLC patients treated with ecotinib was constructed based on the four indicators selected by multivariate Cox regression analysis. The area under the ROC curve of the nomogram was 0.775 (95%CI: 0.676-0.874). The calibration curve showed good consistency between the predicted and actual 1-year PFS. DCA demonstrated good clinical prediction effectiveness of the nomogram. Conclusion: Low T4-SMD is a prognostic risk factor for patients with advanced EGFR-positive NSCLC receiving icotinib therapy.

[Advances in basic research on choline and central nervous system development and related disorders].

Choline is an essential nutrient that plays an integral role in all stages of the life cycle, with increasing interest in the relationship between choline and neurodevelopment. Choline is a major component in the synthesis of phospholipids, phosphatidylcholine and sphingolipids, and is an essential nutrient for methyl metabolism, acetylcholine synthesis and cell signaling. Choline plays an important role in neurogenesis and neural migration during fetal development, potentially influencing the development and prognosis of neurological disorders, but its mechanism of action is not yet clear. This article reviews the source and metabolism of choline, the effects and mechanism of choline on neurodevelopment and central nervous system related disorders.

[Research advances on the mechanism of Wnt/ß-catenin signaling pathway in body surface wound healing].

Wound healing is a slow and complex biological process, including inflammatory reaction, cell proliferation, cell differentiation, cell migration, angiogenesis, extracellular matrix deposition, tissue remodeling, and so on. Wnt signaling pathway can be divided into classical pathway and non-classical pathway. Wnt classical pathway, also known as Wnt/ß-catenin signaling pathway, plays an important role in cell differentiation, cell migration, and maintenance of tissue homeostasis. Many inflammatory factors and growth factors are involved in the upstream regulation of this pathway. The activation of Wnt/ß-catenin signaling pathway plays an important role in the occurrence, development, regeneration, repair and related treatment of skin wounds. This article review the relationship between Wnt/ß-catenin signaling pathway and wound healing, meanwhile summarizes its effects on important processes of wound healing, such as inflammation, cell proliferation, angiogenesis, hair follicle regeneration, and skin fibrosis, as well as the role of inhibitors of Wnt signaling pathway in wound healing.

The effect of driving pressure-guided ventilation strategy on the patients with mechanical ventilation: a meta-analysis of randomized controlled trials.

OBJECTIVE: The aim of this study was to evaluate the effect of driving pressure (DP) guided ventilation strategy on the patients with mechanical ventilation in the hospital. MATERIALS AND METHODS: The articles published in PubMed, the Cochrane Library, the China National Knowledge Information (CNKI), Wei Pu, Wan Fang database and Web of Science from inception to September 2021 were retrieved. The Q test and the I² statistic were used to assess statistical heterogeneity. Risks ratios (RR) with 95% confidence intervals (CI) were calculated for mortality. RESULTS: Seven studies (n=1,405 patients) were included. Five studies reported an adjusted Risk Ratio (RR) of mortality. Compared with the control group, the DP guided ventilation group was associated with a decreased mortality (RR 0.56; 95% confidence interval [CI], 0.39-0.79; p=0.001; I2 = 23%) using a fixed-effects model without significant heterogeneity. The control group had significantly higher driving pressure level than DP guided group (MD -3.03, 95%CI, -5.72 - -0.34, I2=100%, p=0.03); PaO2/FiO2 was significantly higher in DP guided group than in control group (MD 43.37; 95%CI, 12.58-74.15; I2=97%, p=0.006). There was no statistically significant difference in respiratory compliance, complications, platform pressure, duration of mechanical ventilation and the length of hospital stay between the DP guided group and the control group. CONCLUSIONS: The results suggested that the driving pressure guided ventilation strategy could decrease the mortality and increase oxygenation index (OI). However, further high-quality randomized controlled trials (RCTs) are needed to verify the impact of driving pressure on mechanically ventilated patients.

[Clinical research progress and implications of therapeutic vaccines for cervical cancer and precancerous lesions: a qualitative systematic review].

Objective: To systematically summarize and analyze the clinical research progress of therapeutic vaccines for cervical cancer or precancerous lesions. Methods: English databases (PubMed, Embase, Web of Science, Cochrane library, Proquest, and ClinicalTrails.gov) and Chinese databases (SinoMed, CNKI, WanFang, and VIP Database) were systematically searched to collect literature on therapeutic vaccines for cervical cancer or precancerous lesions from inception to February 18, 2021. After screening, we evaluated the risk of bias of included studies, and combed the basic information of the literature, research designs, information of vaccines, study patients, outcome indicators and so on, qualitatively summarized the clinical research progress. Results: A total of 71 studies were included in this systematic review, including 14 random controlled trials, 15 quasi-random controlled trials, 4 cohort studies, 1 case-control study, 34 case series studies and 3 case reports. The study patients included women aged 15~79 with cervical cancer or precancerous lesions in 18 countries from 1989 to 2021. On the one hand, there were 40 studies on therapeutic vaccines for cervical precancerous lesions (22 867 participants), involving 21 kinds of vaccines in 6 categories. Results showed 3 marketed vaccines (Cervarix, Gardasil, Gardasil 9) as adjuvant immunotherapies were significant effective in preventing the recurrence of precancerous lesions compared with the conization only. In addition, MVA E2 vaccine had been in phase Ⅲ clinical trials as a specific therapeutic vaccine, with relative literature showing it could eliminate most high-grade precancerous lesions. Therapeutic vaccines for precancerous lesions all showed good safety. On the other hand, there were 31 studies on therapeutic vaccines for cervical cancer (781 participants), involving 19 kinds of vaccines in 7categories, with none had been marketed. 25 studies were with no control group, showing the vaccines could effectively eliminate solid tumors, prevent recurrence, and prolong the median survival time. However, the vaccines effectiveness couldn't be statistically calculated due to the lack of a control group. As for the safety of therapeutic vaccines for cervical cancer, 9 studies showed that patients experienced serious adverse events after treatments, where 7 studies reported that serious adverse events occurred in patients couldn't be ruled out as the results of therapeutic vaccines. Conclusions: The literature review shows that the literature evidence for the therapeutic vaccines for cervical precancerous lesions is relatively mature compared with the therapeutic vaccines for cervical cancer. The four kinds of vaccines on the market are all therapeutic vaccines for precancerous lesions, but they are generally used as vaginal infection treatments or adjuvant immunotherapies for cervical precancerous lesions, not used for the specific treatments of cervical precancerous lesions. Other specific therapeutic vaccines are in the early stage of clinical trials, mainly phase Ⅰ/Ⅱ clinical trials with small sample size. The effectiveness and safety data are limited, and further research is still needed.

[Design and application of three-dimensional printing guide plate for oral and maxillofacial surgery].

Objective: To explore the application of three-dimensional (3D) printing technology in oral and maxillofacial surgery, so as to optimize and standardize its design and application. Methods: From January 2010 to December 2020, 40 cases of mandibular tumor surgery (20 cases of conventional group and 20 cases of guide plate group), 20 cases of temporomandibular joint replacement surgery (10 cases of conventional group and 10 cases of guide plate group), 20 cases of malocclusion surgery (10 cases of conventional group and 10 cases of guide plate group), 20 cases of radioactive particle implantation surgery (10 cases of CT guided group and 10 cases of guide plate group) were analyzed. All patients in the guide plate group were scanned with spiral CT, and the 3D models of the jaw and the donor bone area were reconstruction. According to the purpose of surgical guide, the design and clinical application of osteotomy guide, in place forming guide and puncture positioning guide were analyzed respectively. The design time of guide plate, the performance and printing time of guide material, the sterilization method of guide and its influence on accuracy, and the influence of guide application on operation time and accuracy were analyzed. Results: The design time of orthognathic guide plate was (2.9±1.8) d, and the design time of mandibular transplantation guide plate was (2.8±1.8) d, that of the temporomandibular joint replacement guide plate and the puncture guide plate was (2.2±0.3) and (0.9±0.3) d. The average printing time of the 40 maxilla model was (11.1±1.6) h, and that of the 40 mandible models was (2.6±0.4) h. The average printing time of the 40 sets of osteotomy and positioning guide plate was (2.5±0.8) h, and that of the 10 puncture positioning guide plate (1.1±0.4) h. The operation time of the conventional group was (6.99±1.10) and (6.02±0.55) h. In the CT guided group, the operation time was (1.91±0.55) h and (0.89±0.15). The operation time of mandible tumor operation and radioactive particle implantation in the guide plate group was less than that in the control group (P<0.05), and there was no significant difference in the operation time of orthognathic surgery and joint replacement between the two groups (P>0.05). The displacement distance of the mark points in the TMJ replacement and mandibular tumor operation guide group was less than that in the control group (P<0.05), and the error of the guide plate in orthognathic operation and particle implantation operation was basically less than 1 mm. Conclusions: The application of the surgical guide plate made by 3D printing technology helps to complete the operation more safely, accurately and quickly, But its design, manufacture and disinfection still need to be further standardized and improved.

[Clinicopathological analysis of anti-mitochondrial antibody negative primary biliary cholangitis-autoimmune hepatitis overlap syndrome].

Objective: To explore the clinicopathological features of anti-mitochondrial antibody (AMA) negative and positive patients with primary biliary cholangitis-autoimmune hepatitis overlap syndrome (PBC-AIH OS). Methods: Seventy-four cases diagnosed as PBC-AIH OS from June 2017 to April 2018 were enrolled in this study. Among them, forty cases were AMA negative (negative group) and thirty-four cases were AMA positive (positive group). The clinical manifestations, serum biochemical indexes, immunological indexes and histological data of the negative group were compared with the positive group. Mann-Whitney U test and theχ (2)test were used for statistical analysis. Results: There was no significant difference in sex, age, clinical manifestations and major liver function indexes (ALT, AST, ALP, GGT, TB, DB) between the negative group and positive group (P> 0.05). The level of IgM in the negative group (1.68 ± 0.87) was significantly lower than positive group (3.77 ± 2.88)(P< 0.05). The positive rates of antinuclear antibodies (ANA) and gp-210 antibodies was lower than positive group (P< 0.05). There were no significant differences in the stages of inflammation and fibrosis between the two groups (P> 0.05), and the bile duct injury was more significant in the negative than positive group (P< 0.05). Conclusion: The serum IgM level of AMA-negative PBC-AIH OS is low, and immunological antibody is often negative, which makes bile duct injury apparent in liver histology. A liver biopsy should be carried out as soon as possible for early diagnosis and treatment.

[Application of three-dimensional printing personalized acetabular wing-plate in treatment of complex acetabular fractures via lateral-rectus approach].

Objective: To investigate reduction and fixation of complex acetabular fractures using three-dimensional (3D) printing technique and personalized acetabular wing-plate via lateral-rectus approach. Methods: From March to July 2016, 8 patients with complex acetabular fractures were surgically managed through 3D printing personalized acetabular wing-plate via lateral-rectus approach at Department of Orthopedics, the Third Affiliated Hospital of Southern Medical University. There were 4 male patients and 4 female patients, with an average age of 57 years (ranging from 31 to 76 years). According to Letournel-Judet classification, there were 2 anterior+ posterior hemitransverse fractures and 6 both-column fractures, without posterior wall fracture or contralateral pelvic fracture. The CT data files of acetabular fracture were imported into the computer and 3D printing technique was used to print the fractures models after reduction by digital orthopedic technique. The acetabular wing-plate was designed and printed with titanium. All fractures were treated via the lateral-rectus approach in a horizontal position after general anesthesia. The anterior column and the quadrilateral surface fractures were fixed by 3D printing personalized acetabular wing-plate, and the posterior column fractures were reduction and fixed by antegrade lag screws under direct vision. Results: All the 8 cases underwent the operation successfully. Postoperative X-ray and CT examination showed excellent or good reduction of anterior and posterior column, without any operation complications. Only 1 case with 75 years old was found screw loosening in the pubic bone with osteoporosis after 1 month's follow-up, who didn't accept any treatment because the patient didn't feel discomfort. According to the Matta radiological evaluation, the reduction of the acetabular fracture was rated as excellent in 3 cases, good in 4 cases and fair in 1 case. All patients were followed up for 3 to 6 months and all patients had achieved bone union. According to the modified Merle D'Aubigné and Postel scoring system, 5 cases were excellent, 2 cases were good, 1 case was fair. Conclusions: Surgical management of complex acetabular fracture via lateral-rectus approach combine with 3D printing personalized acetabular wing-plate can effectively improve reduction quality and fixation effect. It will be truly accurate, personalized and minimally invasive.

Ketamine-induced ventricular structural, sympathetic and electrophysiological remodelling: pathological consequences and protective effects of metoprolol.

BACKGROUND AND PURPOSE: Growing evidence suggests that long-term abuse of ketamine does harm the heart and increases the risk of sudden death. The present study was performed to explore the cardiotoxicity of ketamine and the protective effects of metoprolol. EXPERIMENTAL APPROACH: Rats and rabbits were divided into control, ketamine, metoprolol alone and ketamine plus metoprolol groups. Ketamine (40 mg·kg(-1) ·day(-1), i.p.) and metoprolol (20 mg·kg(-1) ·day(-1), p.o.) were administered continuously for 12 weeks in rats and 8 weeks in rabbits. Cardiac function, electrophysiological disturbances, cardiac collagen, cardiomyocte apoptosis and the remodelling-related proteins were evaluated. KEY RESULTS: Rabbits treated with ketamine showed decreased left ventricular ejection fraction, slowed ventricular conduction velocity and increased susceptibility to ventricular arrhythmia. Metoprolol prevented these pathophysiological alterations. In ketamine-treated rats, cardiac collagen volume fraction and apoptotic cell number were higher than those of control animals; these effects were prevented by co-administration of metoprolol. Consistently, the expressions of poly (ADP-ribose) polymerases-1, apoptosis-inducing factor and NF-κB-light-chain-enhancer of activated B cells were all increased after ketamine treatment and sharply reduced after metoprolol administration. Moreover, ketamine enhanced sympathetic sprouting, manifested as increased growth-associated protein 43 and tyrosine TH expression. These effects of ketamine were prevented by metoprolol. CONCLUSIONS AND IMPLICATIONS: Chronic treatment with ketamine caused significant ventricular myocardial apoptosis, fibrosis and sympathetic sprouting, which altered the electrophysiological properties of the heart and increased its susceptibility to malignant arrhythmia that may lead to sudden cardiac death. Metoprolol prevented the cardiotoxicity of ketamine, indicating a promising new therapeutic strategy.

[Effects of nitroprusside and vibration on peritoneal transport of solutes in continuous ambulatory peritoneal dialysis patients].

To explore the relationship between peritoneal transport of solutes and permeability of the peritoneum capillary as well as peritoneal stagnant fluid layer within dwell time, we observed the effects of nitroprusside and vibration on peritoneal transport of solutes in continuous ambulatory peritoneal dialysis(CAPD) patients. Twelve stable, routine CAPD patients were involved, who had no peritonitis for at least 4 weeks before the test. Standard peritoneal equilibrium tests(PETs) were performed, and mass transfer area coefficiency(MTAC) were calculated after adding nitroprusside to the dialysate or vibrating the patients's peritoneum. The concentrations of total protein, albumin and immunity globulin G in total drained dialysate were examined, and total drained volumes were recorded. Compared with the control, the MTACs value of BUN, Creatinine(Cr) increased significantly both in the nitroprusside group and vibration group(P < 0.05); the concentration of immunoglobin G in the total drained fluid was higher in the nitroprusside group than that in the control(P < 0.05); However, there was no significant difference in the total drained volume among the three groups. We conclude that nitroprusside and vibration can increase the peritoneal transport of small molecular solutes, and vibration has less influence on the loss of protein in CAPD. It suggests that moderated movement may improve the removal of the small molecules in CAPD patients.

A humanized, bispecific immunoadhesin-antibody that retargets CD3+ effectors to kill HIV-1-infected cells.

We have developed a humanized, bispecific immunoadhesin-antibody (BsIAb) that targets and kills HIV-infected cells. Comprised of CD4-IgG and humanized anti-CD3-IgG, this BsIAb is bifunctional. First, in targeting, it exploits the natural affinity of CD4 for gp120 to target the BsIAb to HIV-infected cells, and second, it recruits and activates, through its anti-CD3 moiety, cytotoxic T lymphocytes (CTL) to lyse target cells in a non-MHC restricted manner. To produce purified BsIAb from supernantants of transfected mammalian cells, we designed a three-step recovery scheme based on the structural elements of this heterotrimeric protein. The ability of purified BsIAb to specifically lyse HIV-infected target cells was demonstrated using CTL from two different sources: whole peripheral blood lymphocyte (PBL) fractions and pure CTL preparations. In contrast, a human anti-gp120 antibody mediated lysis of HIV-infected target cells only with PBL fractions and not with purified CTL. Moreover, lysis observed in the presence of the human anti-gp120 antibody was completely blocked in the presence of human serum (which competes for Fc gamma receptor binding), whereas BsIAb-mediated lysis of target cells was not affected. We measured the monovalent affinities of BsIAb for HIV-gp120 on infected cells and for CD3 epsilon on CTL. Relative to the bivalent parent molecules, CD4/gp120 affinity in the BsIAb is unchanged, whereas anti-CD3/CD3 is substantially decreased. We further demonstrated by fluorescence microscopy that physical association of CD3+ cells with gp120-expressing cells occurs only in the presence of BsIAb. Thus, the cytocidal activity of BsIAb in the presence of serum reflects its unique ability to recruit CTL as effector cells and highlights a potentially important advantage of this type of construct over antibodies for HIV-directed therapy.

A humanized, bispecific immunoadhesin-antibody that retargets CD3+ effectors to kill HIV-1-infected cells.

HIV infection depletes the immune system of the coordinating functions of CD4+ T cells and APCs, whereas the population of CD8+ CTLs remains largely intact: functional but undirected. We have developed a humanized bispecific immunoadhesin-antibody (BIA) that redirects these remaining T cells to kill HIV-infected cells. This BIA expresses effector cell retargeting via a targeting activity that exploits the natural affinity of CD4 for gp120, and a recruiting activity that employs an anti-CD3 moiety to engage CTLs. The resultant molecule is 97% human in origin. In functional tests, this BIA mediated killing of HIV-infected cells using either pure CTL preparations, or whole PBL fractions that additionally include Fc gamma receptor-bearing large granular lymphocyte effectors. In contrast, a human anti-gp120 Ab induced target lysis via Ab-dependent cellular cytotoxicity (ADCC) only with large granular lymphocyte-containing fractions and not with CTLs. ADCC with this Ab was blocked in human serum, whereas BIA-mediated effector cell retargeting lysis of HIV-infected cells by CTLs was preserved. The affinity of the BIA for HIV-gp120 on infected cells and for CD3 epsilon on CTLs was derived in a flow cytometric Scatchard procedure. Relative to the bivalent parent molecules, CD4/gp120 affinity on cells was unchanged in the BIA (Ka 7 x 10(7) M-1), whereas the anti-CD3 affinity was diminished 50-fold (Ka 2 x 10(6) M-1 vs 1 x 10(8) M-1). Physical association of CD3+ effectors and gp120-expressing targets was confirmed by fluorescence microscopy and was dependent upon the presence of BIA and expression of target gp120. The unimpaired cytocidal activity of the BIA in the presence of serum highlights a potentially important advantage of this type of construct over native Abs for HIV-directed therapy.

[Analysis of complication following blepharoptosis operation].

The complications following various operative procedures of blepharoptosis are analysed in 60 cases, including 85 eyes, treated in Hangzhou Plastic Surgery Hospital since 1984. The reasons underlying the complications are discussed. Some of the complications are avoidable, and measures which can be taken to prevent or correct them are illustrated. Some others are intrinsically related to the degree of severity of the ptosis and are bound to occur after the elected operative methods. They are therefore, inevitable, hence can not be corrected. The authors emphasizes that this fact should be explained to the patients before operations, in order to obtain their understanding and cooperation.

A new approach to the treatment of malignant effusion.

Lymphocytes isolated from malignant effusion were induced to become LAK cells after in vitro culture with rIL-2. 28 patients with malignant effusion were treated by i.p. or intrapleural administration of autologous LAK cells combined with rIL-2 or by rIL-2 alone. The effusion disappeared in 13 patients and significantly decreased in another 13. Two patients did not respond to the treatment. Tumor cells in effusion disappeared or significantly decreased and lymphocytes significantly increased in all responses. Except for transient fever in 9 patients, no serious side effects were found.