Real-world adherence to toxicity management guidelines for immune checkpoint inhibitor-induced diabetes mellitus.

Objective: Immune checkpoint inhibitors(ICIs) have improved survival and are increasingly used for cancer. However, ICIs use may be limited by immune-related adverse events (irAEs), such as ICI-induced diabetes mellitus(ICI-DM). The objective of the present study was to characterize ICI-DM patients and real-world adherence to guidelines. Research design and methods: The present study was a retrospective review of electronic records of ICI-DM patients at the First Affiliated Hospital of Nanjing Medical University between July 2018 and October 2022. Results: 34.8% (8/23)patients monitored blood glucose in every treatment cycle. The proportion of patients with severe diabetic ketoacidosis(DKA) was lower in the tight glycemic monitoring group than the non-tight glycemic monitoring group (16.7% vs. 55.6%, p = 0.049). 78.3%(18/23) patients with hyperglycemia visited a non-endocrinologist first, but 95.7% of patients were then referred to an endocrinologist. Twenty patients were tested for distinguishing the etiology of hyperglycemia and 20% patients with positive glutamic acid decarboxylase antibody(GADA), 55% with C-peptide <3.33pmol/L. High screening rates for other ICI-induced endocrinopathies were observed and half of the patients with ICI-DM developed other endocrine gland irAEs, with the most common being thyroiditis. Moreover, five patients developed non-endocrine serious adverse events(SAEs). Twelve (52.2%) patients were withdrawn from ICI due to ICI-DM. The time to progression of tumor in ICI-DM patients in the continue and interruption group was longer than in the withdrawal group (333.5 ± 82.5 days vs. 183.1 ± 62.4 days, p = 0.161). Only 17.4% of ICI-DM patients were completely managed according to guidelines. Thus, the present study proposed a screening, diagnosis, and management algorithm for ICI-DM in real-world practice. Conclusion: The present study reported the largest number of ICI-DM cases described in a single institute, providing insight into real-world ICI-DM management guideline adherence and highlighting the clinical challenges in ICI-DM management.

Growth differentiation factor-15/adiponectin ratio as a potential biomarker for metabolic syndrome in Han Chinese.

Aims: Growth differentiation factor-15 (GDF-15) and adiponectin are adipokines that regulate metabolism. This study aimed to evaluate the roles of GDF-15, adiponectin, and GDF-15/adiponectin ratio (G/A ratio) as biomarkers for detecting metabolic syndrome (MS). Materials and methods: This cross-sectional study included 676 participants aged 20-70 years in Jurong, China. The participants were divided into four groups based on sex and age (<40 and ≥40 years). MS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria. Receiver operating characteristic curves were used to evaluate the performance of GDF-15, adiponectin, and the G/A ratio in predicting MS. Results: The prevalence of MS was 22.0% (149/676). Logistic regression analysis indicated that the G/A ratio and adiponectin levels, but not GDF-15 levels, were correlated with MS [odds ratio; 95% CI 1.010 (1.006-1.013) and 0.798 (0.735-0.865), respectively] after adjusting for confounding factors. The G/A ratio displayed a significant relationship with MS in each subgroup and with each MS component in both men and women; however, adiponectin concentrations were significantly associated with MS and all its components only in men (all P <0.05). The area under the curve (AUC) of the G/A ratio and the adiponectin level for MS was 0.758 and 0.748, respectively. The highest AUC was 0.757 for the adiponectin level in men and 0.724 for the G/A ratio in women. Conclusions: This study suggests that the G/A ratio and adiponectin are potential biomarkers for detecting MS in women and men, respectively.

Heterogeneity of circulating CXCR5-PD-1hiTph cells in patients of type 2 and type 1 diabetes in Chinese population.

AIMS: Circulating peripheral helper T (Tph) cells are shown to promote the progression of autoimmune diseases. However, the role of Tph cells in inflammatory diseases such as type 2 diabetes mellitus (T2DM) and the differences between T2DM and autoimmune diabetes remain unclear. METHODS: We recruited 92 T2DM patients, 106 type 1 diabetes mellitus (T1DM) patients and 84 healthy control individuals. Peripheral blood mononucleated cells were isolated and examined by multicolor flow cytometry. We further evaluated the correlations between circulating Tph cells and clinical biochemical parameters, islet function, disease progression and islet autoantibodies. RESULTS: Circulating Tph cells were significantly higher in both T2DM and T1DM patients than in healthy control individuals. A significant positive correlation was observed between Tph cells and B cells in T1DM patients and overweight T2DM patients. Furthermore, Tph cells were negatively correlated with the area under the C-peptide curve (C-PAUC), and Tph cells were significantly positively correlated with fasting glucose and glycated hemoglobin levels in T2DM patients. However, no correlation was found between Tph cells and the above clinical indicators in T1DM patients. The frequency of Tph cells positively correlated with the titer of GAD autoantibodies and duration of disease in T1DM patients. In addition, we demonstrated that the frequency of Tph cells was decreased after rituximab therapy in T1DM patients. CONCLUSIONS: Circulating Tph cells are associated with blood glucose levels and islet function in T2DM patients. In T1DM patients, circulating Tph cells are associated with B cells and islet autoantibodies. This may suggest that Tph cells have different pathogenic mechanisms in the two types of diabetes. CLINICAL TRIAL INFORMATION: http://ClinicalTrials.gov NCT01280682 (registered July, 2010).

Investigation on the knowledge level of the rational application of antimicrobial drugs among pharmacists in medical institutions in Shanxi Province.

OBJECTIVE: To investigate the knowledge of the rational use of antibiotics among pharmacists in medical institutions in Shanxi Province, People's Republic of China, in order to determine the problems and provide support for the correct management of antibiotics. METHODS: A questionnaire survey was conducted, which included the basic information of the respondents, the basic knowledge of antimicrobial management, and the related knowledge of antimicrobial drugs. RESULTS: 462 pharmacists were investigated. The average score of the knowledge related to the rational use of antibiotics was 10.49±4.05. It showed that the hospital type, grade, pharmacist's education, professional title and working years all had an effect on the pharmacist's mastery of antimicrobial-related knowledge (p<0.05). Multivariate logistic regression analysis showed that hospital grade and pharmacist's education were the main influencing factors (p<0.05). CONCLUSION: Pharmacists have insufficient knowledge about the rational application of antibacterial drugs. It is essential to strengthen the training of management regulations and the application of antibacterial drugs.

Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-ß1 positive feedback loop.

BACKGROUND: Radiation-induced bystander effect (RIBE) can promote tumor metastasis contributing to the failure of radiotherapy for esophageal squamous cell carcinoma (ESCC). Aberrant expression of DJ-1 has been identified in ESCC; however, the relationship between DJ-1 and RIBE in ESCC remains unknown. METHODS: We detected DJ-1 in the serum and cell supernatants by enzyme-linked immunosorbent assay (ELISA) and evaluated tumor metastasis by phenotypic experiments in vivo and in vitro. RNA-seq, mass spectrometry, western blot (WB), immunoprecipitation (IP), and dual-luciferase reporter assays were performed to explore the underlying mechanisms. RESULTS: DJ-1 was highly expressed in the serum of patients with ESCC receiving radiotherapy and was significantly overexpressed in the medium of ESCC cells receiving irradiation. DJ-1 promoted tumor metastasis via the TGF-ß1 pathway. Mechanistic studies revealed that DJ-1 bound to HSC70 to promote Smad3 phosphorylation and nuclear aggregation in a protein-interaction manner, which activated the transcription of Thrombospondin-1 (TSP1). Subsequently, the activation of TGF-ß1 by TSP1 re-promoted Smad3 phosphorylation and nuclear aggregation, constituting a positive feedback loop to strengthen the metastasis of ESCC cells, which was effectively blocked by LY2109761 and LSKL. Moreover, higher levels of serum DJ-1 in patients with ESCC were related to a poorer prognosis of radiotherapy. CONCLUSIONS: Irradiation can induce ESCC cells secreting DJ-1. Secreted DJ-1 enters bystander cells to initiate activation of the TGF-ß1 pathway via the DJ-1/HSC70/Smad3 signaling axis. The TSP1/TGF-ß1/Smad3 positive feedback pathway constitutes the core pathway that promotes ESCC metastasis. DJ-1 is a useful biomarker for predicting the efficacy of radiotherapy and a potential therapeutic target for reversing RIBE in ESCC. Schematic diagram showing the underlying mechanism that irradiation-induced secretion of DJ-1 accelerates the metastasis of bystander ESCC cells.

Guideline for the management of pediatric off-label use of drugs in China (2021).

BACKGROUND: The "Law on Doctors of the People's Republic of China," which was officially implemented on March 1, 2022, emphasizes the requirements for rational drug use and the necessity for appropriate management of off-label drug use. The safety and ethical considerations related to off-label drug use are different in children than in adults. There is so far no management guideline for pediatric off-label use of drugs in China, and the applicability of foreign guidelines is limited. Establishing a localized evidence-based management guideline for pediatric off-label use of drugs to support the national legislation and clinical practice is of critical importance. METHODS: We established a guideline working group, including experts from a broad range of disciplines and developed recommendations following the guidance of the World Health Organization Handbook and the Chinese Medical Association. The following themes were identified by questionnaires and expert interviews to be of great concern in the management of off-label drug use in children: general principles and characteristics of management of pediatric off-label drug use; establishment of expert committees; evidence evaluation; risk-benefit assessment; informed consent; monitoring and assessment of the risk; and monitoring and patient education. Two rounds of Delphi surveys were organized to determine the final recommendations of this guideline. We graded the recommendations based on the body of evidence, referring to the evaluation tool of the Evidence-based management (EBMgt) and the Oxford Center for Evidence-Based Medicine: Level of Evidence (March 2009). RESULTS: We developed the first guideline for the management of pediatric off-label use of drugs in China. CONCLUSIONS: The guideline is to offer guidance for pediatricians, pharmacists, medical managers, policymakers, and primary care physicians on how to manage off-label drug use in pediatrics and to provide recommendations for Chinese healthcare policy in the future.

lncRNA XIST knockdown suppresses cell proliferation and promotes apoptosis in diabetic cataracts through the miR­34a/SMAD2 axis.

According to emerging evidence, long non­coding RNAs (lncRNAs) play critical roles in diabetes. The aim of the present study was to investigate the role and mechanism of X­inactive specific transcript (XIST) in cell proliferation, migration and apoptosis in diabetic cataracts (DC). SRA01/04 lens epithelial cells were treated with high glucose (HG). The levels of XIST, microRNA (miR)­34a and SMAD family member 2 (SMAD2) were examined via reverse transcription­quantitative PCR. MTT, Transwell, wound healing and TUNEL assays were performed to examine cell proliferation, invasion, migration and apoptosis, respectively. The interaction between miR­34a and XIST or SMAD2 was verified by luciferase reporter assay. It was found that the expression of XIST was increased and that of miR­34a was decreased in DC tissues and HG­treated SRA01/04 cells. XIST knockdown or miR­34a overexpression attenuated cell proliferation and migration, and induced apoptosis in HG­treated SRA01/04 cells. XIST targeted miR­34a and regulated DC progression through miR­34a. SMAD2 was identified as a target gene of miR­34a and was positively modulated by XIST. XIST knockdown inhibited cell proliferation and migration, and accelerated apoptosis in HG­stimulated SRA01/04 cells, and these effects were abrogated by SMAD2 overexpression. In conclusion, XIST promoted cell proliferation, migration and invasion, and inhibited apoptosis, through the miR­34a/SMAD2 axis in DC.

Occurrence of Phytoplasma Belonging to 16SrII Group Associated with Witches'-broom Symptoms in Emilia sonchifolia in Hainan Island of China.

Emilia sonchifolia is a medical plant belonging to the family of Asteraceae, mainly used as a traditional Chinese medicine with the function of anti-inflammatory, analgesic, antibacterial and so on. During October to November 2020, the plants showing abnormal symptoms including witches'-broom, internode shortening, leaf chlorosis and leaflet were found in Hainan province, a tropical island of China. The total DNA of the plant samples were extracted using 0.10 g fresh plant leaves using CTAB method. PCR reactions were performed using primers R16mF2/R16mR1 and secAfor1/secArev3 specific for phytoplasma 16S rRNA and secA gene fragments. The target productions of the two gene fragments of phytoplasma were detected in the DNA from three symptomatic plant samples whereas not in the DNA from the symptomless plant samples. The two gene fragments of the DNA extracted from the symptomatic plant samples were all identical, with the length of 1324 bp 16S rRNA and 760 bp secA gene sequence fragments, putatively encoding 253 (secA) amino acids sequence. The phytoplasma strain was named as Emilia sonchifolia witches'-broom (EsWB) phytoplasma, EsWB-hnda strain. To our knowledge, this was the first report that Emilia sonchifolia witches'-broom disease was caused by the phytoplasma belonging to16SrII-V subgroup in Hainan island of China, with close relationship to 16SrII peanut witches'-broom group phytoplasma strains infecting the plants like peanut, Desmodium ovalifolium and cleome from the same island of China and cassava from Viet Nam.

Temporal metabolic and transcriptomic characteristics crossing islets and liver reveal dynamic pathophysiology in diet-induced diabetes.

To investigate the molecular mechanisms underlying islet dysfunction and insulin resistance in diet-induced diabetes, we conducted temporal RNA sequencing of tissues responsible for insulin secretion (islets) and action (liver) every 4 weeks in mice on high-fat (HFD) or chow diet for 24 weeks, linking to longitudinal profile of metabolic characteristics. The diverse responses of α, ß, and δ cells to glucose and palmitate indicated HFD-induced dynamic deterioration of islet function from dysregulation to failure. Insulin resistance developed with variable time course in different tissues. Weighted gene co-expression network analysis and Ingenuity Pathway Analysis implicated islets and liver jointly programmed ß-cell compensatory adaption via cell proliferation at early phase and irreversible islet dysfunction by inappropriate immune response at later stage, and identified interconnected molecules including growth differentiation factor 15. Frequencies of T cell subpopulation showed an early decrement in Tregs followed by increases in Th1 and Th17 cells during progression to diabetes.

Hybrid dual-gain tunable integrated InP-Si3N4 external cavity laser.

We present a hybrid dual-gain integrated external cavity laser with full C-band wavelength tunability. Two parallel reflective semiconductor optical amplifier gain channels are combined by a Y-branch in the Si3N4 photonic circuit to increase the optical gain. A Vernier ring filter is integrated in the Si3N4 photonic circuit to select a single longitudinal mode and meanwhile reduce the laser linewidth. The side-mode suppression ratio is ∼67 dB with a pump current of 75 mA. The linewidth of the unpackaged laser is 6.6 kHz under on-chip output power of 23.5 mW. The dual-gain operation of the laser gives higher output power and narrower linewidth compared to the single gain operation. It is promising for applications in optical communications and light detection and ranging systems.

Tephrosia purpurea Represents a New Host of 16SrII-V Subgroup Phytoplasma Associated with Witches'-Broom Disease in China.

Tephrosia purpurea is a medical plant with excellent insecticidal activity belonging to the family of Leguminosae distributed throughout southern of China (Pei et al., 2013). During January to February 2021, the plants showing abnormal symptoms including witches'-broom, internode shortening, leaf chlorosis and leaflet formation, as shown in Fig.1, were found in Ledong County of Hainan Province, a tropical island in China, with about 60 % incidence. The Tephrosia purpurea disease symptoms were suspected to be induced by phytoplasma, a phloem-limited prokaryotic pathogen which can not be cultured in vitro and which causes severe financial loss and ecological damage to the island. Total DNA from the symptomatic and asymptomatic samples of Tephrosia purpurea were extracted using 0.10 g fresh plant leaves and branches by CTAB method (Doyle and Doyle, 1990). 16S rRNA and secA gene sequence fragments of phytoplasma were detected through PCR amplification using primers R16mF2/R16mR1 (Gundersen and Lee, 1996) and secAfor1/secArev3 (Hodgetts et al., 2008). The two gene sequence fragments of phytoplasma were obtained from the DNA of six symptomatic plant samples whereas not from the DNA of six asymptomatic plant samples. These amplified products were sequenced and the data were deposited in GenBank. The two gene sequence fragments of the DNA obtained from the diseased plant samples were all identical, with a length of 1335 bp for the 16S rRNA (GenBank accession: MW616560) and 729 bp for the secA gene (MW603929). The secA gene fragment putatively encodes for 242 amino acids. The phytoplasma strain was named as Tephrosia purpurea witches'-broom (TpWB) phytoplasma, TpWB-hnld strain. 16S rRNA gene sequence fragment of TpWB-hnld was analyzed by online tool iPhyClassifier (Wei et al., 2007), indicating that the pathogen strain was a member of subgroup 16SrII-V and a 'Candidatus Phytoplasma aurantifolia'-related strain. Blast analysis based on the 16S rRNA gene sequence fragment of TpWB-hnld showed 100 % sequence identity with that of peanut witches'-broom group members (16SrII group), such as Cassava witches'-broom phytoplasma (KM280679) and Cleome sp. phytoplasma (KM280677); Blast analysis based on the secA gene sequence fragment of TpWB-hnld showed 100 % sequence identity with that of peanut witches'-broom group members (16SrII group), such as sesame phyllody phytoplasma (JN977044). Homology and phylogeny were analyzed using the software of DNAMAN 5.0 and MEGA 7.0, indicating that TpWB-hnld and other subgroup 16SrII-V phytoplasma strains, including Cassava witches'-broom phytoplasma, Cleome sp. phytoplasma, Crotalaria witches'-broom phytoplasma (EU650181) and Desmodium ovalifolium witches'-broom phytoplasma (GU113152), were clustered into one clade with 98 % bootstrap value based on the 16S rRNA gene sequence fragments; TpWB-hnld and sesame phyllody phytoplasma were clustered into one clade based on the secA gene sequence fragments. Multiple alignment based on the 16S rRNA gene sequence fragment showed that the TpWB-hnld phytoplasma strain showed 98 % sequence identity with TpWB phytoplasma strain (HG792252) belonging to 16SrII-M subgroup reported in India (Yadav et al., 2014). To our knowledge, this was the first time that 16SrII-V subgroup phytoplasma associated with Tephrosia purpurea witches'-broom disease was identified in China. Molecular analysis based on the 16S rRNA and secA gene sequence fragments indicated that TpWB-hnld phytoplasma was a member of subgroup 16SrII-V and a 'Candidatus Phytoplasma aurantifolia'-related strain.

Effects of Sevoflurane versus Propofol on Endogenous Nitric Oxide Metabolism during Laparoscopic Surgery.

For laparoscopic surgery, it is very difficult to assess the effect of different medicines used in the surgical procedure on the surgical results. In the past, doctors could use sevoflurane to numb and calm patients. For decades, this type of treatment has been fairly reliable and effective, but for laparoscopic surgery, the use of sevoflurane can lead to a wide range of blood glucose changes, so in recent years, sevoflurane compared to propofol in laparoscopic surgery on endogenous and nitrogen oxide metabolism has been studied more and more. In this paper, a variety of research methods were used to study the phenomenon of shock and excessive anesthesia encountered by patients in the treatment process. Through observation and drug experiment of patients in different treatment courses and treatment stages, patients were asked to use sevoflurane and propofol to conduct double-blind experiments on their own drug effects. At the same time, through the long-term observation of patients with different diseases and patients who need laparoscopic surgery, the nitrogen oxide metabolism in patients with sevoflurane compared with propofol endogenous was studied and analyzed. Through three groups of different conditions, the experimental group, the blind test group, and the control group were studied. To conclude, in laparoscopic surgery, the use of sevoflurane compared with propofol can have a good impact on the endogenous drug and nitrogen oxide metabolism. It can achieve a good effect on the anesthesia effect of surgery, the maintenance of patient's physical signs and heart rate, which is very beneficial to the operation. Conclusion. Sevoflurane compared with propofol has a good effect on endogenous nitrogen oxide metabolism in laparoscopic surgery.

Waltheria indica is a New Host of Phytoplasma Belongs to 16SrI-B Subgroup Associated with Virescence Symptoms in China.

Waltheria indica L. is a kind of medicinal plants belonging to the family of Sterculiaceae distributed in China, which extracts with many active compounds used for treatment of rheumatism and sore pains (Hua et al., 2019). During September to November 2020, the plants showing abnormal symptoms including floral virescence, leaf chlorosis and leaflet, as shown in Fig.1, were found in Dingan county of Hainan province, China, with about 70% incidence. The disease symptoms which were suspected to be infected by the phytoplasma, a phloem-limited cell-wall-less prokaryotic pathogen could not be cultured in vitro, severely impacted Waltheria indica growth resulting in financial loss and ecological damage in the location. For identification of the causal pathogen, the total DNA of symptom or symptomless Waltheria indica samples were extracted using 0.10 g fresh plant tissues using CTAB method. PCR reactions were performed using primers R16mF2/R16mR1 (Lee et al., 1993) and AYgroelF/AYgroelR (Mitrovic et al., 2011) specific for phytoplasma 16S rRNA and groEL gene fragments. The target productions of the two gene fragments of phytoplasma were detected in the DNA from four symptomatic plant samples whereas not in the DNA from the symptomless plant samples. The PCR productions were sequenced and the data were deposited in GenBank. The two gene fragments of the DNA extracted from the symptom plant samples were all identical, with the length of 1340 bp 16S rRNA (GenBank accession: MW353909) and 1312 bp groEL (MW353709) gene sequence fragments, putatively encoding 437 (groEL) amino acids sequence. The phytoplasma strain was named as Waltheria indica virescence (WiV) phytoplasma, WiV-hnda strain. A Blast search based on the 16S rRNA gene fragment of WiV-hnda phytoplasma strain revealed the highest level of sequence identities (99.85%) with that of 16SrI aster yellows group members (16SrI-B subgroup), such as Onion yellows phytoplasma strain OY-M (AP006628) from Japan (Oshima et al., 2004); Periwinkle virescence phytoplasma strain PeV-hnhk (KP662136), Chinaberry witches'-broom phytoplasma strain CWB-hnsy1 (KP662119) and CWB-hnsy2 (KP662120), all the strains from Hainan island of China (Yu et al., 2017). A Blast search based on the groEL gene sequence fragment of WiV-hnda indicated 99.92% sequence identity with that of 16SrI aster yellows group members (16SrI-B subgroup) such as Onion yellows phytoplasma strain OY-M (AP006628). Homology and phylogenetic analysis by DNAMAN 5.0 and MEGA 7.0 software indicated that the phytoplasma strains of WiV-hnda, OY-M, PeV-hnhk, CWB-hnsy1 and CWB-hnsy2 were clustered into one clade based on the 16S rRNA gene fragments. WiV-hnda, OY-M and Aster yellow witches'-broom (AYWB) (CP000061) phytoplasma strains were clustered into one clade based on the groEL gene fragments. To our knowledge, this was the first time that Waltheria indica virescence disease induced by 16SrI-B subgroup phytoplasma strain was reported in China. Genetic analysis showed that WiV-hnda was closely related to the phytoplasma strains causing Onion yellows in Japan, Periwinkle virescence and Chinaberry witches'-broom disease in China.

Geographical disparities in access to hospital care in Ontario, Canada: a spatial coverage modelling approach.

OBJECTIVES: Previous studies on geographical disparities in healthcare access have been limited by not accounting for the healthcare provider's capacity, a key determinant of supply and demand relationships. DESIGN: This study proposed a spatial coverage modelling approach to evaluate disparities in hospital care access using Canadian Institute for Health Information data in 2007. SETTING: This study focusses on accessibility of inpatient and emergency cares at both levels of individual hospital and the administrative regions of Local Health Integration Network (LHIN) levels. MEASURES: We integrated a set of traffic and geographical data to precisely estimate travel time as a measure of the level of accessibility to the nearest hospital by three scenarios: walking, driving and a combination of the both. We estimated population coverage rates, using hospital capacities and population in the catchments, as a measure of the level of the healthcare availability. Hospital capacities were calculated based on numbers of medical staff and beds, occupation rates and annual working hours of healthcare providers. RESULTS: We observed significant disparities in hospital capacity, travel time and population coverage rate across the LHINs. This study included 25 teaching and 148 community hospitals. The teaching hospitals had stronger capacities with 489 209 inpatient and 130 773 emergency patients served in the year, while the population served in community hospitals were 2.64 times higher. Compared with north Ontario, more locations in the south could reach to hospitals within 30 min irrespective of the travel mode. Additionally, Northern Ontario has higher population coverage rates, for example, with 42.6~46.9% for inpatient and 15.7~44% for emergency cares, compared with 2.4~34.7% and 0.35~14.6% in Southern Ontario, within a 30 min catchment by driving. CONCLUSION: Creating a comprehensive, flexible and integrated healthcare system should be considered as an effective approach to improve equity in access to care.

First report of phytoplasma belongs to 16SrXXXII group associated with witches'-broom symptoms in Trema tomentosa in China.

Trema tomentosa (Roxb.) Hara belonging to Ulmaceae displayed abnormal symptoms including witches'-broom, internode shortening, leaf chlorosis and leaflet that affected seriously their growth causing financial loss and ecological damage in China. During August through September 2020, these plants with the symptoms were first found and collected in Dingan and Qinghai counties of Hainan province, China. PCR were performed using the primers R16mF2/R16mR1 and secAfor1/secArev3 specific for phytoplasma 16S rRNA and secA gene fragments. The two gene fragments of the DNA extracted from the four disease samples were identical, with length of 1303 bp 16S rRNA and 587 bp secA gene fragments. The phytoplasma strain was named as Trema tomentosa witches'-broom (TtWB) phytoplasma, TtWB-hn strain. Phylogenetic and computer-simulated RFLP analyses based on the nearly full-length 16S rRNA gene sequence indicated that the TtWB phytoplasma strain is more closely related to the 16SrXXXII-A subgroup than to the other subgroups within 16SrXXXII group. It may represent a new subgroup, designed as 16SrXXXII-D subgroup, which is distinct from the other phytoplasma subgroups within the 16SrXXXII group. To our knowledge, this is the first report showing the occurrence of the phytoplasma strain belongs to 16SrXXXII-D subgroup associated with witches'-broom disease in Trema tomentosa in China. Genetic analysis indicated that the TtWB strain was closely related to the phytoplasma strains infecting periwinkle, oil palm, coconut palm in Malyasian, Camptotheca acuminate in Yunnan province of China and Elaeocarpus zollingeri in Japan.

First report of 16SrI-B subgroup related phytoplasma associated with witches'-broom symptoms in Pericampylus glaucus in China.

Pericampylus glaucus is an important medicinal plant resource containing active components with potential antitumor activity in China (Zhao & Cui, 2009). During July through August 2020, plants displayed disease symptoms including "witches' broom", leaf chlorosis, leaflet and internode shortening that impacted their growth (Fig. 1). These plants were first found in Dingan county of Hainan province, China. Total DNA from 12 plants were extracted using 0.10 g fresh plant leaves based on CTAB method. After amplification using primers specific for phytoplasma 16S rRNA, tuf and secA gene targets, R16mF2R16mR1 (Lee et al, 1993), fTuf1/rTuf1 (Schneider et al., 1997) and secAfor1/secArev3 (Hodgetts et al., 2008), the target bands of the three gene fragments of phytoplasma were detected in the disease sample DNA from six disease plants, and not in the healthy sample DNA from six healthy plants. Nucleotide sequences of the three genes were obtained from the PCR products sequencing and analyzed by DNAMAN 5.0 software. The three gene fragments of the DNA extracted from the disease samples were identical, with length of 1334 bp 16S rRNA (GenBank accession: MT872515), 989 bp tuf (MT755960) and 750 bp secA (MT755961) gene fragments, putatively encoding 329 (tuf) and 249 (secA) amino acids sequence separately. The phytoplasma strain was named as Pericampylus glaucus witches'-broom (PgWB) phytoplasma, PgWB-hnda strain, belonging to 16SrI-B subgroup by iPhyClassifier analysis. Homology and phylogenetic analysis indicated that based on 16S rRNA gene fragments, PgWB-hnda, pepper yellow crinkle phytoplasma PYC-hnhk (MT760793), chinaberry witches'-broom phytoplasma CWB-hnsy1 (KP662119) and CWB-hn (EF990733), periwinkle virescence phytoplasma PeV-hnhk (KP662136), with 100.0 % identity value, arecanut yellow leaf phytoplasma AYL-hnwn (FJ998269) and AYL-hn (FJ694685), with 99.8 % identity value, were clustered into one clade. Based on the analysis of tuf gene sequence fragments, PgWB was closely related to PYC-hnhk (MT755960), CWB-hnsy1 (KP662155), PeV-hnhk (KP662172) with 99.9 % identity value. Based on the analysis of secA gene sequence fragments, PgWB was closely related to CWB-hnsy1 (KP662173) with 99.7 % identity value, PYC-hnhk (MT755961), PeV-hnhk (KP662190) with 99.4 % identity value. To our knowledge, this is the first time that Pericampylus glaucus witches'-broom disease caused by 16SrI-B subgroup phytoplasma strain was found in China. Multilocus sequence analysis showed that PgWB was closely related to the phytoplasma strains causing pepper yellow crinkle, chinaberry witches'-broom, periwinkle virescence and areca palm yellow leaf diseases, all occurred in Hainan Island of China.

ICPis-Induced Autoimmune Polyendocrine Syndrome Type 2: A Review of the Literature and a Protocol for Optimal Management.

CONTEXT: Immune checkpoint inhibitors (ICPis) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) are now approved to treat a variety of cancers. However, ICPis therapy is associated with a risk of immune-related adverse events (irAEs). Autoimmune polyendocrine syndrome type 2 (APS-2) is a rare endocrine irAE. EVIDENCE ACQUISITION: Several databases (PubMed, Web of Science, Cochrane Central Registry of Controlled Trials, ClinicalTrials.gov, and Scopus) were searched up to February 18, 2020, for case reports on endocrine irAEs and ICPis. The reported side effects and adverse events of the ICPis therapy in the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) adverse events pharmacovigilance registries are also included. EVIDENCE SYNTHESIS: Here, we provide an overview of all published and reported cases (n = 30) of ICPis-induced APS-2. We summarize the clinical characteristics, autoantibodies, human leukocyte antigen (HLA) genotypes, and therapies and propose an APS-2 screening strategy. CONCLUSIONS: Given the life-threatening risks of endocrine dysfunction if it is not promptly recognized (such as diabetic ketoacidosis and acute adrenal crisis), physicians (especially endocrinologists and oncologists) should be familiar with APS-2. After diagnosis of an autoimmune disease induced by ICPis (especially PD-1 inhibitors), patients with a high-risk HLA allele (HLA-DR4) require close monitoring for the development of APS-2.

Follicular Regulatory T Cells Are Associated With ß-Cell Autoimmunity and the Development of Type 1 Diabetes.

OBJECTIVE: Impaired follicular regulatory T (Tfr) cells enhance T follicular helper cells activity, resulting in the expansion of autoreactive B cells and autoantibody production. However, the role of Tfr cells in the pathogenesis of type 1 diabetes (T1D) is unclear. DESIGN: We evaluated the expression and changes in function of circulating Tfr cells by studying patients with T1D alongside those with type 2 diabetes (T2D), first-degree relatives of T1D patients, and healthy controls. We also investigated the effects of Tfr cells on disease development in nonobese diabetic (NOD) mice and in an adoptive transfer model. RESULTS: Tfr cells were significantly decreased in both patient groups. However, they showed different correlations with fasting C-peptide (C-P) and the area under the curve of blood C-P in patients with T1D and T2D. The frequency of Tfr cells was associated with the number of positive autoantibodies and the titer of glutamic acid decarboxylase autoantibody in T1D patients. Furthermore, Tfr cells decreased significantly after 1 year of follow-up. We also observed Tfr cells in four T1D patients treated with rituximab. After rituximab therapy, the frequency of C-X-C motif chemokine receptor 5 (CXCR5)+ programmed death 1+ Tfr cells was decreased and of CXCR5+ inducible costimulator+ Tfr cells was increased in three patients. We also found that Tfr cells were associated with the development of diabetes in NOD mice and an adoptive transfer model. CONCLUSIONS: Tfr cell deficiency could be involved in the pathogenesis of T1D. Therapy with Tfr cells has potential value for T1D. Modulation of these cells may enhance protective immunity to inhibit autoimmune diabetes.

Economic disadvantage and transitional outcomes: a study of young people from low-income families in Hong Kong.

This study draws on data from focus groups involving 50 young people from low-income families in Hong Kong to investigate their school-to-work experiences. In line with the ecological-developmental perspective, our results show that contextual influences, including lower levels of parental involvement and lack of opportunities for further education or skill development, constrain both the formulation and pursuit of educational and career goals. In contrast, service use and supportive interactions with parents and non-family adults were found to help young people find a career direction and foster more adaptive transition. Furthermore, our results indicate a striking difference in intrapersonal agency and coping styles between youths who were attending further education or engaged in jobs with career advancement opportunities and those who were not. We discuss the implications of our findings, both for future research and for policy development to enhance the school-to-work transition of economically disadvantaged young people.