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Primary hypothyroidism can lead to delayed growth and pseudoprecocious puberty in juvenile patients, which was known as Van Wyk-Grumbach's syndrome (VWGS). There have been very few clinical case reports of primary juvenile hypothyroidism presenting with concurrent huge bilateral cystic ovaries. Here, we report the case of a 14-year-old female patient suffering from primary hypothyroidism in combination with bilateral cystic ovaries. Remarkable improvement of symptoms was observed after one month of hormone replacement therapy and an unnecessary surgical treatment was avoided. A comprehensive literature review of VWGS is summarised here to illustrate the presentation, diagnosis, and treatment of VWGS in pediatric patients. The present study aims to improve the current clinical knowledge of VWGS.

The transient hydrodynamic lubrication model of tilting pad journal bearings (TPJBs) was established by the computational fluid dynamics (CFD) method and the self-developed dynamic grid program. The fluid-structure interaction between the flow field and the rotor motion, the pads rotations was realized. The feasibility of the model is proved by comparing with the experimental data. The dynamic response of TPJBs under the various unbalance, the loading modes and the rotating speeds was studied. The dynamic response of TPJBs is further analyzed through a research of the relationships among the shaft whirl orbits, transient force acting on the shaft, rotation angles of the pads and transient oil film force of the pads. With the increase of unbalance, the whirl orbits expand and whirl orbits centers rise continuously. The whirl orbits and orbit center attitude angles of TPJBs are smaller than those of fixed-pad journal bearings. Compare with the load between pads, the whirl orbits are smaller and whirl orbits centers drop slightly under the load on pads. With the increase of rotating speed, the whirl orbits expand nonlinearly, whirl orbit center rises nonlinearly. The transient force acting on the shaft, the rotation angles of the pads and the transient oil film force of the pads change periodically, and the period and frequency of these changes are the same as that of the shaft rotation. The maximum force acting on the shaft appear before the maximum shaft center position (the vertexes of the whirl orbit).

Although electrochemical hydrogen evolution and oxidation are arguably the best-understood reactions in electrocatalysis, the anomalous effect of pH on hydrogen reaction kinetics has defied simple ...

This paper selects fault source models of typical earthquakes across the globe and uses a volume extending 100 km horizontally from each mainshock rupture plane and 50 km vertically as the primary area of earthquake influence for calculation and analysis. A deep neural network is constructed to model the relationship between elastic stress tensor components and aftershock state at multiple timescales, and the model is evaluated. Finally, based on the aftershock hysteresis model, the aftershock hysteresis effect of the Wenchuan earthquake in 2008 and Tohoku earthquake in 2011 is analyzed, and the aftershock hysteresis effect at different depths is compared and analyzed. The correlation between the aftershock hysteresis effect and the Omori formula is also discussed and analyzed. The constructed aftershock hysteresis model has a good fit to the data and can predict the aftershock pattern at multiple timescales after a large earthquake. Compared with the traditional aftershock spatial analysis method, the model is more effective and fully considers the distribution of actual faults, instead of treating the earthquake as a point source. The expansion rate of the aftershock pattern is negatively correlated with time, and the aftershock patterns at all timescales are roughly similar and anisotropic.

Objective We sought to determine the extent of lymphadenectomy that optimizes staging and survival in patients with locally advanced esophageal adenocarcinoma (EAC) treated with neoadjuvant chemoradiotherapy followed by esophagectomy. Summary background data Several studies have found that a more extensive lymphadenectomy leads to better disease-specific survival in patients treated with surgery alone. Few studies, however, have investigated whether this association exists for patients treated with neoadjuvant chemoradiotherapy. Methods We examined our prospective database and identified patients with EAC treated with neoadjuvant chemoradiotherapy followed by esophagectomy between 1995 and 2017. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier methods, and a multivariable Cox proportional hazards model was used to identify independent predictors of OS and DFS. The relationship between the total number of nodes removed and 5-year OS or DFS was plotted using restricted cubic spline functions. Results In total, 778 patients met the inclusion criteria. The median number of excised nodes was 21 (interquartile range, 16-27). A lower number of excised lymph nodes was independently associated with worse OS and DFS (OS: hazard ratio [HR], 0.98; confidence interval [CI], 0.97-1.00; P = 0.013; DFS: HR, 0.99; CI, 0.98-1.00; P = 0.028). Removing 25 to 30 lymph nodes was associated with a 10% risk of missing a positive lymph node. Both OS and DFS improved with up to 20 to 25 lymph nodes removed, regardless of treatment response. Conclusions The optimal extent of lymphadenectomy to enhance both staging and survival following chemoradiotherapy, regardless of treatment response, is approximately 25 lymph nodes.

This article investigates the occurrence and outcomes of corporate tax-related political activity through bribery. Specifically, it examines the extent to which firms bribe government officials through gift-giving, banqueting, and entertaining activities and the extent of payoffs that firms gain from these bribery practices. Using a large hand-collected dataset of Chinese listed firms for the period from 2009 to 2014, I find that firms that spend more on consumption bribery exhibit a significantly lower tax burden. This negative association is mainly driven by small firms, non-state-owned firms, state-owned firms with weak political connections, and firms in competitive industries. Further evidence shows that the tax benefits from bribery are more apparent in more corrupt, less economically developed, and less liberalized regions. Furthermore, the payoffs of tax bribery are mitigated by 45.4% after the implementation of China’s anti-corruption campaign in 2012. These findings have policy implications for governments to optimize investment environments and increase tax revenue by curbing power-for-money deals.

Scheduling an access service team made up of full-time staff and student workers to ensure a consistent coverage of service points is an important but time-consuming task for access service manager...

To analyse the response and recovery characteristics of forest to forest fire, this paper selected the forest fire in the Greater Khingan Mountains (GKM) in China in 1987 and the forest fire in the Yellowstone National Park (YSP) in the United States in 1988. We first used Landsat-5 TM images before and after the fire to extract the burned area and calculate burn severity based on the Differential Normalized Burn Ratio (dNBR). Next, we analysed the response of forest vegetation to forest fire with different burn severity using the anomaly value of Leaf area index (LAI) derived from Global Land Surface Satellite (GLASS) products. And the recovery of forest vegetation after forest fire were revealed using time – series LAI data and MODIS Land cover data. The results showed that the LAI decreased rapidly after the forest fire, and the greater the burn severity, the higher the decreasing amplitude of LAI. The maximum decreasing amplitude of LAI in the burned areas with high burn severity were 1.3–3.8 times higher than that in low burn severity areas. The recovery time of LAI is affected by burn severity and manual interference. The recovery time of LAI in burned areas in the GKM is about 5–10 years, which in the burned areas with high burn severity is 2 times than that with low burn severity. The recovery time of LAI in the burned areas with low burn severity in the YSP is at least 20 years, while that with high burn severity will take longer time to recovery. And the manual interference accelerated the recovery of LAI in the GKM. Our research on the response and recovery of vegetation is helpful for formulating and implementing adaptation and mitigation strategies in response to forest fire.

Custom electrochemical cells are necessary for fundamental in situ characterization experiments and applied transport studies of next-generation batteries. Limited data on the chemical compatibilit...

Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA patients in response to Tocilizumab, and to investigate both molecular and clinical factors influencing response. Clinical and biochemical data for 485 RA patients receiving Tocilizumab in combination with methotrexate were extracted from the LITHE phase III clinical study (NCT00106535), and post-hoc analysis conducted. Latent class mixed models were used to identify statistically distinct trajectories of DAS28 after the initiation of treatment. Biomarker measurements were then analysed cross-sectionally and temporally, to characterise patients by serological biomarkers and clinical factors. We identified three distinct trajectories of drug response: class 1 (n = 85, 17.5%), class 2 (n = 338, 69.7%) and class 3 (n = 62, 12.8%). All groups started with high DAS28 on average (DAS28 > 5.1). Class 1 showed the least reduction in DAS28, with significantly more patients seeking escape therapy (p p

Overlap in metabolism pathways of endogenous female sex hormones and antiretroviral drugs may lead to altered exposure to these compounds. In a family planning clinic in Lilongwe, Malawi, blood, blood cell, and cervicovaginal fluid (CVF) samples from seventy-three HIV positive Malawian women taken in follicular and luteal menstrual phases were assessed for estradiol and progesterone by chemiluminescent immunoassay, and for antiretroviral concentration by liquid chromatography-mass spectrometry. In both follicular and luteal phases, estradiol concentrations were lower in women receiving efavirenz compared with women on non-efavirenz regimens or no antiretroviral therapy (p

Genetic alterations of tumor suppressor genes (TSGs) are frequently observed to have cumulative or cooperative tumorigenic effects. We examined whether the TSGs Rb1, Trp53, Pten and Men1 have cooperative effects in suppressing neuroendocrine tumors (NETs) in mice. We generated pairwise homozygous deletions of these four genes in insulin II gene expressing cells using the Cre-LoxP system. By monitoring growth and examining the histopathology of the pituitary (Pit) and pancreas (Pan) in these mice, we demonstrated that pRB had the strongest cooperative function with PTEN in suppressing PitNETs and had strong cooperative function with Menin and TRP53, respectively, in suppressing PitNETs and PanNETs. TRP53 had weak cooperative function with PTEN in suppressing pituitary lesions. We also found that deletion of Pten singly led to prolactinomas in female mice, and deletion of Rb1 alone led to islet hyperplasia in pancreas. Collectively, our data indicated that pRB and PTEN pathways play significant roles in suppressing PitNETs, while the Menin-mediated pathway plays a significant role in suppressing PanNETs. Understanding the molecular mechanisms of these genes and pathways on NETs will help us understand the molecular mechanisms of neuroendocrine tumorigenesis and develop effective preclinical murine models for NET therapeutics to improve clinical outcomes in humans.

Background/Aims The partograph is a tool used to monitor events during labour and was recently modified by the World Health Organization to improve intrapartum care. However, it is unknown how obstetric care providers in Malawi perceive this modified partograph. This study aimed to evaluate the perceived strengths and challenges regarding the World Health Organization's modified partograph design among obstetric care providers in Malawi. Methods For this qualitative study, data were collected from a sample of 34 obstetric care providers from two purposively-selected urban health facilities through in-depth interviews and focus group discussions. The data were subjected to thematic analysis, with the strengths and challenges of using the modified partograph designated as the two major themes. Results The participants reported that there were more challenges than strengths with utilisation of the modified partograph. Two subthemes emerged among the strengths: the partograph is comprehensive and the partograph is clear. Three subthemes emerged from the challenges: 1) unrealistic fetal monitoring intervals, 2) confusing partograph design regarding documentation of caput and moulding and 3) small font. These challenges made partograph use impractical to complete, particularly in the context of chronic understaffing of the labour ward. Conclusions Until staffing levels are improved in Malawi and other resource-limited settings, it is unlikely that the modified partograph design will significantly improve maternal or neonatal outcomes. However, some improvements can be made to the design to help facilitate its use, and more training on its use is needed to prevent confusion.

Less frequent symptoms include headache, sore throat, fatigue, nausea and vomiting, anosmia and ageustia,1,6 skin rashes,7,8 and Kawasaki-like symptoms in children 9-11 Emerging data suggest that approximately 15% of symptomatic patients progress to acute respiratory distress syndrome (ARDS), which requires hospitalization and intensive care unit (ICU) care 1,12 Although the mortality rate of COVID-19 ranges from 0 1% and 16 4% and varies from country to country,1,5 the overall rate is lower than those of SARS and Middle East respiratory syndrome (MERS) 12 Advanced age and the comorbidities with obesity, hypertension, or diabetes mellitus may predispose patients to an increased risk of severe disease and death 13,14 SARS-CoV-2 invades host cells through binding of its surface spike protein to the cell receptor angiotensinconverting enzyme 2 (ACE2), which is widely expressed in arterial and venous endothelial cells, lung type II alveolar cells, arterial smooth muscle cells in most organs, enterocytes of the small intestine, neural cortex, and brainstem 15,16 The wide distribution of ACE2 receptors may partially explain the broad spectrum of clinical presentations of COVID-19 The study also found that decreased platelet count (severe versus nonsevere, 57 7% [90 of 156] versus 31 6% [225 of 713]) was associated with more severe disease 13 These results were consistent with a meta-analysis of 26 studies including 1374 patients with severe and 4326 with less severe COVID-19, showing that elevated D-dimer levels and decreased platelet count were associated with disease severity, with odds ratio of 3 17 (95% CI, 1 86-5 41) and 2 84 (95% CI, 2 00-4 04), respectively 38 The increase in D-dimer and fluctuation of D-dimer concentration mirror the disease activity 30,36,39 In a cohort of 449 patients, we analyzed the association between coagulation parameters and the mortality rate in patients with severe COVID-19 In particular, the production of IgA antiphospholipid antibodies is likely attributable to mucosal immunity [ ]the presence of these antibodies alone is not necessarily associated with thrombotic events 41 Nevertheless, the clinical relevance of these antibodies remains largely unknown in the setting of COVID-19 The more powerful coagulation activation may be driven by the expression and exposure of tissue factor (TF) from damaged alveolar epithelium, macrophages, and endothelium 47 Histology from minimally invasive autopsies showed edematous and widened blood vessels, with modest infiltration of monocytes, lymphocytes, and thrombi 48 Interstitial infiltration of inflammatory cells was widely observed in the lung dissection of patients with mild, severe, and fatal COVID-19 48-53 The inflammatory exudates and accumulation of fluids in the alveolar spaces result in hypoxia and ventilation perfusion mismatch that further exacerbate endothelial cell disruption, tissue factor expression, and activation of the coagulation cascade, leading to a vicious cycle within pulmonary vasculature with diffuse microthrombi and hemorrhage 54 Pulmonary coagulopathy is believed to be a more localized process, at least initially, with changes in fibrin turnover being restricted to the site of infection 51,55 Initial minimal thrombin, together with coagulation factors in the alveolar spaces, as a result of blood vessel leakage, enables the amplification of coagulation cascades resulting in fibrin deposition in the bronchoalveolar spaces 55 These immune-inflammatory-hemostatic changes correlate with severity of inflammation and ARDS progression

PIK3CA mutations may have prognostic value for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer, representing an important potential target for systemic therapy. Prognostic and predictive values associated with PIK3CA mutations are not well understood. A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and conference abstracts was performed for English-language articles published January 1993 through April 2019. Articles were categorized by treatment arms based on experimental and treatment drug classes. Information on progression-free survival (PFS), hazard ratios, overall survival, response rate, and clinical benefit rate was obtained. A total of 17 studies were included. Among those evaluating non-PI3Ki based therapies, 91% showed numerically shorter median PFS, ranging from 1.5 to 19.2 months and 1.8 to 29.6 months for the mutant versus non-mutant subgroups, respectively. Where reported (n = 13 studies), PFS was shorter between those arms offering endocrine monotherapy (range, 1.6-14.7 months) compared with a corresponding targeted therapy + endocrine monotherapy (range, 3.9-29.6 months). Of 5 PI3Ki-based arms comparing PFS, higher median PFS in PIK3CA mutant versus non-mutant cases was demonstrated. PFS was shorter for patients with PIK3CA mutant (range, 1.6-19.2 months) compared with PIK3CA wild-type (range, 1.8-29.6 months) in 10 (71%) of 14 treatment arms reporting PFS. Studies (n = 4) not reporting PFS reported response rate, but there were no clear directional trends. The presence of PIK3CA mutations may be associated with worse clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Clinical outcomes such as PFS may be improved using a combination of PI3Ki-based therapies and endocrine therapies among this population. However, more research is warranted to fully elucidate this association.

This review article summarizes recent (2014–2019) advances in our understanding of tropical cyclogenesis, stemming from activities at the ninth International Workshop on Tropical Cyclones. Tropical cyclogenesis involves the interaction of dynamic and thermodynamic processes at multiple spatio-temporal scales. Studies have furthered our understanding of how tropical cyclogenesis may be affected by external processes, such as intraseasonal oscillations, monsoon circulations, the intertropical convergence zone, and midlatitude troughs and cutoff lows. Additionally, studies have furthered our understanding of how tropical cyclogenesis may be affected by internal processes, such as the organization of deep convection; the evolution of the “pouch” structure; the role of friction; the development of the moist, warm core; the importance of surface fluxes; and the role of the mid-level vortex. A relatively recent class of idealized, numerical simulations of tropical cyclogenesis in radiative-convective equilibrium have highlighted the potential importance of radiative feedbacks on tropical cyclogenesis. We also offer some recommendations to the community on future directions for tropical cyclogenesis research.

In wheat/alien species hybrids, pairing homoeologous (Ph1) suppresses the pairing and recombination of wheat and alien chromosomes. Ph1b has been found to be the most effective allele in inducing meiotic homoeologous pairing/recombination and is widely used in gene introgression from wild Triticeae species into wheat. However, due to the poor agronomic traits of the ‘Chinese Spring’ ph1b (CS ph1b) mutant, which is more susceptible to disease, the application of CS ph1b is limited. In this study, we transferred the ph1b gene from the CS mutant to a commercial cultivar Shumai 126 (SM126), which has excellent agronomic traits, by crossing and continuous backcrossing. The results showed that the ph1b was present in 11 lines in the BC2F2 generation and was transferred to SM126. Further study indicated that seven homozygous ph1b mutant allele lines were identified from the BC2F3 generation. Two of these lines, SM126ph1b line 1 and 24, are homozygous at loci encoding high molecular weight glutenin subunits (HMW-GS) and the Wx protein, and the line 24 possesses the excellent agronomic traits of SM126. The results of meiotic metaphase I pairing showed that the SM126ph1b pollen mother cells (PMCs) are slightly higher pairing than the level of the original CSph1b stock. A progeny line of wild cross between wheat and Aegilops sharonensis was crossed with CSph1b and line 24 of SM126ph1b, respectively; the results of ND-FISH further proved that SM126ph1b and CSph1b have same effect on inducing homoeologous pairing/recombination, which will facilitate the use of wheat alien chromosome recombinations in wheat improvement.

The ability to tolerate and thrive in diverse environments is paramount to all living organisms, and many organisms spend a large part of their lifetime in starvation. Upon acute glucose starvation, yeast cells undergo drastic physiological and metabolic changes and reestablish a constant—although lower—level of energy production within minutes. The molecules that are rapidly metabolized to fuel energy production under these conditions are unknown. Here, we combine metabolomics and genetics to characterize the cells’ response to acute glucose depletion and identify pathways that ensure survival during starvation. We show that the ability to respire is essential for maintaining the energy status and to ensure viability during starvation. Measuring the cells’ immediate metabolic response, we find that central metabolites drastically deplete and that the intracellular AMP-to-ATP ratio strongly increases within 20 to 30 s. Furthermore, we detect changes in both amino acid and lipid metabolite levels. Consistent with this, both bulk autophagy, a process that frees amino acids, and lipid degradation via β-oxidation contribute in parallel to energy maintenance upon acute starvation. In addition, both these pathways ensure long-term survival during starvation. Thus, our results identify bulk autophagy and β-oxidation as important energy providers during acute glucose starvation.

Polymer electrolyte membrane fuel cell (PEMFC) electrodes with a 0.07 mgPt cm–2 Pt/Vulcan electrocatalyst loading, containing only a sulfonated poly(ionic liquid) block copolymer (SPILBCP) ionomer,...

Objectives:\ud \ud This study aimed to assess the impact of stent optimization by NC‐balloon postdilatation (PD) during primary‐PCI for STEMI with the use of coronary physiology and intracoronary imaging.\ud \ud Methods:\ud \ud This was a prospective observational study (ClinicalTrials.gov:NCT02788396). Optical coherence tomography (OCT) and physiological measurements were performed immediately before and after PD with the operators blinded to all measurements. The index of microcirculatory resistance (IMR), coronary flow reserve (CFR) and fractional flow reserve (FFR) were measured. OCT analysis was performed for assessment of stent expansion, malapposition, in‐stent plaque‐thrombus prolapse (PTP) and stent‐edge dissections (SED). The change in IMR before and after PD as a measure of microvascular injury was the primary objective of the study.\ud \ud Results:\ud \ud Thirty‐two STEMI patients undergoing primary‐PCI had physiological measurements before and after PD. All patients received second‐generation DES (diameter 3.1 ± 0.5 mm, length 29.9 ± 10.7 mm) and postdilatation with NC‐balloons (diameter 3.6 ± 0.6 mm, inflation pressure 19.3 ± 2.0 atm). IMR (44.9 ± 25.6 vs. 48.8 ± 34.2, p = 0.26) and CFR (1.60 ± 0.89 vs. 1.58 ± 0.71, p = 0.87) did not change, while FFR increased after PD (0.91 ± 0.08 vs. 0.93 ± 0.06, p = 0.037). At an individual patient level, IMR increased in half of the cases. PD improved significantly absolute and relative stent expansion, reduced malapposition, and increased PTP. There was no difference in clinically relevant SED.\ud \ud Conclusion:\ud \ud In this exploratory, hypothesis‐generating study, postdilatation during primary‐PCI for STEMI improved stent expansion, apposition and post‐PCI FFR, without a significant effect on coronary microcirculation overall. Nevertheless, IMR increased in a group of patients and larger studies are warranted to explore predictors of microcirculatory response to postdilatation.

Janadolide is a cyclic depsipeptide natural product isolated from the marine cyanobacterium Okeania sp. Herein, we describe the total synthesis of janadolide, along with eight simplified analogues, via an efficient solid-phase strategy. Crucial to the synthesis of the natural product was the construction of a key polyketide fragment via an enantioselective (-)-B-chlorodiisopinocampheylborane-mediated reduction and a B-alkyl Suzuki reaction. Janadolide and the simplified analogues exhibited antitrypanosomal activity against pathogenic Trypanosoma brucei rhodesiense and Trypanosoma cruzi parasites.

Recovering from major earthquakes is a challenge, especially in mountainous environments where postearthquake hazards may cause substantial impacts for prolonged periods of time. Although such impacts were reported in the 1923 Great Kantō earthquake and the 1999 Chi-Chi earthquake, careless reconstruction in hazard-prone areas and consequently huge losses were witnessed following the 2008 Wenchuan earthquake in the Sichuan province of China, as several reconstructed settlements were severely damaged by mass movements and floods. In order to summarize experiences and identify problems in the reconstruction planning, a monitoring of one of the settlements, the town of Longchi, was carried out by image interpretation and field investigation. Seven inventories containing buildings, farmlands, roads and mitigation measures were made to study the dynamics of elements at risk and exposure over a period of 11 years. It was found that the total economic value of the newly reconstructed buildings was several times more than in the preearthquake situation in 2007, because of enormous governmental investment. Postseismic hazards were not sufficiently taken into consideration in the recovery planning before the catastrophic debris flow disaster in 2010. As a result, the direct economic loss from postseismic disasters was slightly more than the loss caused by the Wenchuan earthquake itself. The society showed an impact-adapt pattern, experiencing losses from disasters and then gaining resistance by abandoning buildings in hazard-prone areas and installing mitigation measures. The locations potentially exposed to postearthquake hazards were summarized, and a possible timetable for reconstruction was proposed. Problems might be encountered in hazard assessment, and possible solutions were discussed.

Aims: We sought to compare the efficiency of the novel EuroCTO (CASTLE) score with the commonly used Multicentre CTO registry in Japan (J-CTO) score in predicting procedural success of percutaneous recanalization (PCI) for coronary chronic total occlusions (CTOs). Methods and results: We evaluated 660 consecutive CTO PCIs (mean age: 66±11 years, 84% male). The mean J-CTO and EuroCTO (CASTLE) scores were 1.86 ± 1.2 and 1.74 ± 1.2, respectively. Antegrade wire escalation, antegrade dissection re-entry and retrograde approach were used in 82%, 14% and 37% of cases, respectively. Receiver-operator characteristic analysis demonstrated equal overall discriminatory capacity between the two scores (AUC: 0.698, 95%CI: 0.653-0.742 p

乙型肝炎病毒感染及相关肝硬化少见并发严重的坏死性肌病。本文报道1例58岁男性患者，主诉为HBsAg阳性伴转氨酶异常30年，进行性周身乏力、四肢运动障碍2个月，入院后首先考虑乙型肝炎肝硬化所致周身乏力等症状，并予以抗病毒、保肝及对症支持等治疗，病情未见明显好转。进一步行血清肌炎抗体谱、四肢肌肉磁共振成像及肌肉组织病理学检查，明确诊断为乙型肝炎肝硬化合并坏死性肌病，结合患者2个月前有昆虫叮咬史，考虑为昆虫叮咬所释放毒素诱发了机体异常免疫反应，在抗病毒及保肝治疗基础上，联合应用糖皮质激素及人免疫球蛋白，坏死性肌病逐渐康复，继续应用抗病毒药物。当慢性乙型肝炎病毒感染及肝硬化患者出现进行性周身乏力、运动障碍等肌肉损伤症状时，应进行免疫性肌损伤等相关检查，以明确病因，及时救治。.

1. Melatonin is an indole hormone that, among its myriad biological functions, regulates circadian and seasonal rhythms in animals. The

Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis-pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.

Extracting the seismic deformation field and analyzing the surface deformation after an earthquake occurs are of great significance for explaining earthquake mechanism and earthquake relief. Through the dual polarization mode of the two-pass method D-InSAR technology, this paper extracted the coseismic deformation fields based on two Sentinel-1A SAR images covering the Yulin earthquake area, and analyzed the surface deformation. The results show that the subsidence area obtained by VV and VH polarization modes are consistent. The uplift center areas are located in Tongxin Village in Rong County and Mapo Town in Luchuan County, and the subsidence center area is located in Fuxin Town of Beiliu City in the northeast. In the earthquake area, the maximum uplift derived by the VV mode SAR data is 12.1 cm, and the maximum subsidence is 5.8 cm. the maximum uplift obtained by the VH mode SAR data is 11.2 cm, and the maximum subsidence is 9 cm. The results obtained by the two polarization modes are consistent. D-InSAR technology can accurately obtain the coseismic deformation field, which provides data guarantee for the follow-up study of the inversion of seismic source parameters in the region.

Neoadjuvant therapy is recommended for locally advanced esophageal cancer, but the optimal strategy remains unclear. We aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) vs neoadjuvant chemotherapy (nCT) followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal squamous cell carcinoma (ESCC).Eligible patients staged as cT3-4aN0-1M0 ESCC were randomly assigned (1:1) to the nCRT or nCT group stratified by age, cN stage and centers. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while concurrent radiotherapy added for nCRT group; then MIE was performed. The primary endpoint was 3-year overall survival. This study is registered with ClinicalTrials.gov, NCT03001596.A total of 264 patients were eligible for the intention-to-treat analysis. By November 30, 2021, 121 deaths had occurred. The median follow-up was 43.9 months (interquartile range, 36.6-49.3 months). The overall survival in the intention-to-treat population were comparable between nCRT and nCT strategy (hazard ratio [HR], 0.82; 95% CI, 0.58-1.18; P = 0.28), with a 3-year survival rate of 64.1% (95% CI, 56.4% to 72.9%) vs. 54.9% (95% CI, 47.0% to 64.2%), respectively. There were also no differences in progression-free survival (HR, 0.83; 95% CI, 0.59-1.16; P = 0.27) and recurrence-free survival (HR, 1.07; 95% CI, 0.71-1.60; P = 0.75), although the pathological complete response (pCR) in the nCRT group (27.7%, 31/112) was significantly higher than that in the nCT group (2.9%, 3/104) (P0.001). Besides, a trend of lower risk of recurrence was observed in the nCRT group (P = 0.063), while the recurrence pattern was similar (P = 0.802).NCRT followed by MIE was not associated with significantly better overall survival than nCT among patients with cT3-4aN0-1M0 ESCC. The results underscore the pending issue of the best strategy of neoadjuvant therapy for locally advanced bulky ESCC.

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a writing group to develop a consensus report on the management of type 1 diabetes in adults in September 2021. The writing group has proposed principles of the diagnosis and management of adult patients with type 1 diabetes, and has made suggestions for glycemic control with individualized glycemic targets to avoid hypoglycemia. They have also emphasized the importance of education and support for the self-management of diabetes in the management of type 1 diabetes.美国糖尿病协会（ADA）/欧洲糖尿病研究协会（EASD）的专家小组于2021年9月就成人1型糖尿病（T1DM）患者的管理发布了共识报告，即《成人1型糖尿病管理：ADA/EASD联合共识》。该《共识》提出了针对成年T1DM的诊断流程及管理途径、建议实施个体化的血糖管理并避免发生低血糖，同时强调了糖尿病自我管理教育与支持在T1DM管理中的重要意义。.

Evaluate factors associated with coronavirus 2019 (COVID-19) vaccine hesitancy and clinical trends in primary rhegmatogenous retinal detachments (RRDs) during the first year of vaccine availability.Single-center, clinical cohort study.Consecutive patients from December 14, 2020, to December 12, 2021, presenting vaccinated (Prior-), subsequently vaccinated (Later-), or remaining unvaccinated (Never-Vax). Primary outcome was proportion with macula-off (mac-off) RRD. Secondary outcomes included logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA), primary proliferative vitreoretinopathy (PVR), proportion lost to follow-up, and distance traveled.1047 patients were divided into 391 Prior-, 252 Later-, and 404 Never-Vax cohorts. Significantly greater proportions of Later- and Never-Vax cohorts presented with mac-off RRDs (Prior-Vax = 44.5%; Later-Vax = 54%, P.0001; Never-Vax = 57.9%, P.0001) and primary PVR (Prior-Vax = 4.3%; Later-Vax = 13.6%, P.0001; Never-Vax = 17.1%, P.0001) compared to Prior-Vax cohort. Significantly greater proportion of Never-Vax cohort (7.7%, P.0001) were lost to follow-up compared to Prior- (2.3%) and Later-Vax (2.2%) cohorts. Never-Vax cohort (median = 35 miles) traveled farther compared to Prior- (median = 22.3 miles; P.0001) and Later-Vax cohorts (25.45 miles; P = .0038). Prior-Vax cohort had significantly better (P.05) initial (median = 0.30 logMAR) and final (0.18 logMAR) BCVA compared to Later- (Initial: 0.54 logMAR; Final: 0.30 logMAR) and Never-Vax (Initial: 0.70 logMAR; Final: 0.40 logMAR) cohorts.COVID-19 vaccine hesitancy is associated with worse clinical presentation and outcomes for primary RRD.

To explore the protective immune effect induced by mucosal delivery heparin-binding hemagglutinin (HBHA)-a candidate vaccine antigen of为探讨疫苗候选抗原—结核分枝杆菌肝素结合血凝素（HBHA）通过黏膜接种诱导的保护性免疫效应。动物实验均使用6~8周龄雌性C57BL/6小鼠。30只小鼠接受不同的免疫接种策略，采用随机数字表法分为对照组、早期分泌抗原靶蛋白-6（ESAT-6）滴鼻组、HBHA滴鼻组、BCG初免PBS对照组、BCG初免HBHA加强组，每组6只。通过检测免疫后小鼠血浆白细胞介素17A（IL-17A）等细胞因子水平；肺IL-17A mRNA相对表达量（RQ）；肺三级淋巴结构的形成，及与其形成相关的趋化因子的检测；脾Th1、Th17细胞比例比较，从而分析免疫效应。BCG初免PBS对照组和BCG初免HBHA加强组（每组各30只小鼠），用BCG滴鼻模拟感染。在感染后预设的时间点做肺组织菌落计数，以评估细菌清除效率。多组间比较采用单因素方差分析，事后分析采用

IntroductionTo enhance health and prevent secondary consequences for patients with cardiovascular disease (CVD), maintenance of an active lifestyle following participation in cardiac rehabilitation (CR) is important. However, levels of physical activity often decrease after completion of a structured CR programme. Models that support long-term behaviour change with a sustained level of physical activity are imperative. The aim of this study is to evaluate the feasibility of a mobile health intervention based on the Health Action Process Approach theoretical model of behaviour change in patients with CVD for 3 months after completion of a CR programme.Methods and analysisIn a feasibility trial design, we will recruit 40 participants from CR programmes at Slagelse Hospital, the City of Slagelse (municipality), or Holbæk Hospital. After completing the standard structured CR programme, each participant will create an action plan for physical activity together with a physiotherapist. Following that, participants are sent 2 weekly text messages for 3 months. The first text message prompts physical activity, and the second will check if the action plan has been followed. If requested by participants, a coordinator will call and guide the physical activities behaviour. The feasibility of this maintenance intervention is evaluated based on predefined progression criteria. Physical activity is measured with accelerometers at baseline and at 3 months follow-up.Ethics and disseminationStudy approval was waived (EMN-2021-00020) by the Research Ethics Committee of Region Zealand, Denmark. Study results will be made public and findings disseminated to patients, health professionals, decision-makers, researchers and the public.Trial registration numberNCT05011994.

OBJECTIVE: To investigate the effects of melatonin on the growth and metastasis of MDA-MB-231 breast cancer cells and explore the mechanism. METHODS: MDA-MB-231 cells were treated with 1, 3 or 5 mmol/L melatonin, and the changes in cell proliferation were examined using CCK-8 assay. Colony-forming assay and wound healing assay were used to assess the effects of melatonin treatmnent on colony-forming ability and migration of the cells. Flow cytometry and immunofluoresnce assay were employed to examine apoptosis and positive staining for autophagy-related proteins in the cells treated with 3 mmol/L melatonin. The effects of melatonin treatment alone or in combination with 3-methyladenine (3-MA) on the expressions of the proteins associated with autophagy (LC3, P62 and Beclin1), apoptosis (Bcl2 and Bax) and epithelial-mesenchymal transition (E-cadherin and Snail) were examined with Western blotting. RESULTS: Melatonin treatment significantly inhibited the proliferation of breast cancer cells in a concentration- and time-dependent manner (P < 0.05), suppressed colony-forming ability and migration (P < 0.01), and promoted apoptosis of the cells (P < 0.01). Melatonin treatment alone significantly increased the expressions of Bax (P < 0.05), E-cadherin, LC3-II/LC3-I, and Beclin1 and lowered the expressions of Bcl2 (P < 0.05), Snail, P62 (P < 0.05), and Bcl2/Bax ratio (P < 0.01) in the cells, and caused enhanced positive staining of Beclin1 protein and attenuated staining of P62 protein. Compared with melatonin treatment alone, melatonin treatment combined with 3-MA significantly decreased the expressions of Beclin1 (P < 0.001), LC3-II/LC3-I (P < 0.05), Bax (P < 0.01), and E-cadherin (P < 0.001) and increased the expressions of Bcl2 (P < 0.05), Snail, and Bcl2/Bax ratio (P < 0.01). CONCLUSION: Melatonin can induce autophagy of MDA-MB-231 breast cancer cells to inhibit cell proliferation and metastasis and promote cell apoptosis, and suppressing autophagy can weaken the inhibitory effect of melatonin on the growth and metastasis of breast cancer cells.

We conducted a cluster randomized trial of two models for integrating HPV self-collection into family-planning (FP) services at 16 health facilities in Malawi between March 2020–December 2021. Model 1 involved providing only clinic-based HPV self-collection, whereas Model 2 included both clinic-based and community-based HPV self-collection. An endline household survey was performed in sampled villages and households between October-December 2021 in the catchment areas of the health facilities. We analyzed 7664 surveys from 400 villages. Participants from Model 2 areas were more likely to have ever undergone cervical cancer screening (CCS) than participants from Model 1 areas, after adjusting for district, facility location (urban versus rural), and facility size (hospital versus health center) (adjusted odds ratio = 1.73; 95% CI: 1.29, 2.33). Among participants who had ever undergone CCS, participants from Model 2 were more likely to report having undergone HPV self-collection than participants from Model 1 (50.5% versus 22.8%, p = 0.023). Participants from Model 2 were more likely to be using modern FP (adjusted odds ratio = 1.01; 95% CI: 1.41, 1.98) than Model 1 participants. The integration of FP and HPV self-collection in both the clinic and community increases CCS and modern FP uptake more than integration at the clinic-level alone.

Background: The COVID-19 pandemic affected global access to health services, including contraception We sought to explore effects of the pandemic on family planning (FP) service provision and use in South Africa and Zambia, including on implant and intrauterine device (IUD) users’ desire and ability to obtain removal. Methods: Between August 2020 and April 2021, we conducted surveys with 537 women participating in an ongoing longitudinal contraceptive continuation study. We also carried out in-depth interviews with 39 of the survey participants and 36 key informants involved in FP provision. We conducted descriptive analysis of survey responses and thematic analysis of interviews. Results: Contraceptive use changed minimally in this sample with the emergence of COVID-19. Fewer than half of women (n=220) reported attempting to access FP since the start of the pandemic, the vast majority using short-acting methods. Among those who sought services, 95% obtained their preferred method. The proportion of women not using a method before and after pandemic start did not change in Zambia (31%); in South Africa, the proportion increased from 8% to 10%. Less than 7% of implant or IUD users in either country reported wanting removal. Among those who sought removal (n=22), 91% (n=10) in Zambia and 55% (n=6) in South Africa successfully obtained removal. In qualitative interviews, women with challenges accessing FP services mentioned long queues, deprioritization of contraceptive services, lack of transportation, stock-outs, and fear of contracting COVID-19 at a facility. Key informants reported stock-outs, especially of injectables, and staff shortages as barriers. Conclusions: We did not find a substantial impact of COVID-19 on contraceptive access among this sample; however, providers and others involved in service provision identified risks to continuity of care. As the COVID-19 pandemic wanes, it continues to be important to monitor people’s ability to access their preferred contraceptive methods.

Introduction: The EGFR/K-RAS pathway is a major tumor driver whose hyperactivation is associated with malignant tumor growth, multidrug resistance, early tumor relapse, chemo-resistance, and metastasis. Despite more than 40 years of research, oncogenic K-RAS activation remains an undruggable target in clinical oncology. Seven-In-Absentia (SINA) homologues (SIAH) are conserved E3 ubiquitin ligases that play a critical gatekeeper role downstream of the EGFR/K-RAS pathway. Our prior studies have shown that tumor growth was abolished in human tumor cell lines following SIAH inhibition; however, the underpinning molecular mechanisms that give rise to this anti-EGFR/K-RAS and anticancer phenotype remain unclear. Specific Objectives: to delineate the molecular mechanism(s) of why anti-SIAH2PD targeted therapy is so effective in impeding growth, we conducted reverse-phase protein array (RPPA)-based kinomic analysis to discover how major cancer signaling pathways and K-RAS-dependent signaling networks are remodeled in response to SIAH2 inhibition. Ongoing studies aim to identify and validate dysregulated phospho-proteins identified by RPPA-based kinomic analysis. Methods: 300 proteins/phosphoproteins were quantitatively measured by the RPPA platform to identify new tumor vulnerabilities, actionable targets, and compensatory signaling network alterations in response to anti-SIAH targeted therapies in five cancer cell lines in triplicate. Doxycycline (DOX)-inducible Tet-ON MiaPaCa, MDA-MB-231, MDA-MB-468, HeLa, and A459 cell lines were generated from a single cell, and DOX-induced SIAH2PD expression was confirmed. Reverse Phase Protein Array (RPPA) was conducted to quantify fold-changes of proteins whose expression was significantly (p Results: Supported by statistical analyses, we identified 6 unique proteins that were significantly up-or down-regulated in response to SIAH inhibition. These proteins play a role in controlling and regulating cell growth, cell death, NFκB signaling, stress response, DNA damage, immune function, and cell attachment pathways. Thus, our data provide additional evidence supporting our tumor eradication phenotype observed in these human cancer cell lines lacking functional SIAH. Western Blot and IF validation studies have yielded further supporting evidence to confirm our RPPA results. Conclusion: Validation studies are being conducted to gain insight into pathway alterations and dynamic rewiring in order to uncover SIAH as a major tumor vulnerability in multiple malignant cancers. Our data supports the explanation as to why anti-SIAH targeted therapy works so effectively to shut down malignant tumor growth, as reported in the literature. Citation Format: Andrew Howell, Julia Wulfkhule, Rosa Gallagher, Jonathan Baker, Ashleigh Hannah, Emanuel F. Petricoin, Amy H. Tang. The use of reverse phase protein array (RPPA) to identify new tumor vulnerability and actionable drug targets against human cancer cell lines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5248.