Reverse Engineering of a Pathogenic Antibody Reveals the Molecular Mechanism of Vaccine-Induced Immune Thrombotic Thrombocytopenia.

The massive COVID-19 vaccine roll-out campaign illuminated a range of rare side effects, the most dangerous of which─vaccine-induced immune thrombotic thrombocytopenia (VITT)─is caused by adenoviral (Ad)-vectored vaccines. VITT occurrence had been linked to the production of pathogenic antibodies that recognize an endogenous chemokine, platelet factor 4 (PF4). Mass spectrometry (MS)-based evaluation of the ensemble of anti-PF4 antibodies obtained from a VITT patient's blood indicates that the major component is a monoclonal antibody. Structural characterization of this antibody reveals several unusual characteristics, such as the presence of an N-glycan in the Fab segment and high density of acidic amino acid residues in the complementarity-determining regions. A recombinant version of this antibody (RVT1) was generated by transient expression in mammalian cells based on the newly determined sequence. It captures the key properties of VITT antibodies such as their ability to activate platelets in a PF4 concentration-dependent fashion. Homology modeling of the Fab segment reveals a well-defined polyanionic paratope, and the docking studies indicate that the polycationic segment of PF4 readily accommodates two Fab segments, cross-linking the antibodies to yield polymerized immune complexes. Their existence was verified with native MS by detecting assemblies as large as (RVT1)3(PF4)2, pointing out at FcγRIIa-mediated platelet activation as the molecular mechanism underlying VITT clinical manifestations. In addition to the high PF4 affinity, RVT1 readily binds other polycationic targets, indicating a polyreactive nature of this antibody. This surprising promiscuity not only sheds light on VITT etiology but also opens up a range of opportunities to manage this pathology.

Differences in cardiometabolic risk profiles between Chinese and Finnish older adults with glucose impairment and central obesity.

BACKGROUND: Obesity and ethnicity play important roles in cardiovascular complications in patients with type 2 diabetes mellitus (T2DM). This study aimed to compare cardiometabolic risk profiles between Chinese and Finnish older adults of central obesity with prediabetes or T2DM. METHODS: Study subjects were 60-74 years old and originated from two population samples. The Finnish subjects came from the Kuopio Ischemic Heart Disease (KIHD) study (n = 1089), and the Chinese subjects came from the Shanghai High-risk Diabetic Screen (SHiDS) study (n = 818). The KIHD and SHiDS studies used similar questionnaires to determine participants' baseline characteristics regarding the history of medication use and diseases and lifestyle factors. All study subjects participated in glucose tolerance tests and anthropometry assessments, including waist circumference measurements. RESULTS: Among study subjects of central obesity with prediabetes (n = 298), fasting and 2-h glucose, and fasting insulin and insulin resistance were significantly higher in Chinese than in Finnish (p < 0.0001-0.016). In addition, triglyceride (TG) level was higher and the low-density lipoprotein cholesterol (LDL) and LDL to high-density lipoprotein cholesterol (HDL) ratio were lower in Chinese than in Finnish (p < 0.0001-0.003). Among subjects of central obesity with T2DM (n = 251), Chinese subjects had significantly less proportions of antihypertensive, glycaemic control medication, and statin users as well as lower level of physical activity (p < 0.0001 for all), while higher blood pressure (p = 0.002 for systolic blood pressure and p < 0.0001 for diastolic blood pressure), TG levels (p < 0.05) and HDL (p = 0.002) than the Finnish counterparts. There were no differences in ß-cell function (HOMA-ß) between Chinese and Finnish both in prediabetes and T2DM. CONCLUSIONS: Our results indicated that Chinese and Finnish older adults of central obesity with prediabetes and T2DM had similar ß-cell function. However, Chinese individuals with prediabetes are prone to insulin resistance. Meanwhile, lipid metabolism dysfunction is also different between Chinese and Finnish. Chinese older adults of central obesity with prediabetes showed higher TG, but Finnish showed higher LDL and LDL/HDL. Strategic for T2DM prevention and treatment should be ethnically specific.

Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

Immune profiling of lupus miliaris disseminatus faciei and successful management with anti-tumour necrosis factor therapy.

Lupus miliaris disseminatus faciei (LMDF) is a chronic inflammatory dermatosis of unknown aetiology, most often seen in young adults. Although many treatments for LMDF exist, treatment guidelines have not been developed, and response to therapy is generally unpredictable. We present the results of transcriptomic analysis of LMDF lesional skin, which revealed a variety of differentially expressed genes linking LMDF to alterations in innate and adaptive T helper 1 immunity. Immunohistochemical analysis was also performed, identifying similar changes in T-cell immune responses. Given evidence for increased tumour necrosis factor (TNF) pathway activity, our patient, who had previously been refractory to multiple treatments, was initiated on TNF inhibitor therapy with excellent response. This characterization of the LMDF immune response may lead to improved treatment of this condition.

Rhizoma Atractylodis macrocephalae: a review of photochemistry, pharmacokinetics and pharmacology.

Rhizoma Atractylodis macrocephalae is commonly used in Traditional Chinese Medicine. Its traditional functions include treating hypofunction of the spleen with the loss of appetite, abdominal distension diarrhea, phlegm drink dizziness palpitation, edema, fetal movement restless. A literature search was conducted by systematic searching multiple electronic databases including Web of Science, PubMed, CNKI and Google Scholar. Chemical composition analysis of RAM showed that the main compositions were volatile oil, lactones, polysaccharides, amino acids, vitamins and resins. Pharmacological studies indicated that RAM possessed antitumor activities, neuroprotective effect, anti-hepatotoxicity, immune and anti-inflammatory activity, etc. This review gives a detailed description of the chemical constituents, pharmacology and pharmacokinetics of RAM and provides reliable basis for clinical development and application.

[Difficulties in dental health care for the disabled]. / Difficultés de prise en charge de la santé bucco-dentaire des personnes en situation de handicap.

Upper Normandy has several disadvantages in terms of access to dental health care for disabled people: an insufficient medical population, a lack of dental schools and dental care networks.A cross-sectional epidemiological investigation, using a questionnaire form, was carried out between November 2014 and February 2015 with a cohort of dentists in this region.The topics on this form focused firstly on accessibility and compliance with standards of dental offices and the influencing factors which are hampering their accessibility implementation, and secondly on the oral care of disabled patients by practitioners of this region : the impact of incentives, influencing factors which are complicating the dental care and the usage of private and public structures.If the care of disability concerns most practitioners, an apprehension is observed in the adaptation of these doctors' treatment protocols for these specific patients. The expectations of dentists concerning disability are multiple : the creation of specific care networks, better coordination of medical and social actors, and specific training programs concerning the dental care of disabled patients.

Modeling washoff of total suspended solids in the tropics.

Washoff behavior in the tropics is expected to behave differently from temperate areas due to differences in rainfall characteristics. In this study, rainfall, runoff and total suspended solids (TSS) were monitored from 9 catchments distinguished by different types of land use, in Singapore. The catchments ranged in size from 5.7ha to 85.2ha. Over 120 rain events were studied and more than 1000 storm samples were collected and analyzed. Monte Carlo analysis was applied to obtain the best fit values of the washoff model parameters consisting the washoff coefficient c3, washoff exponent c4 and initial mass on surface Bini. The exponent c4 was found to be approximately unity for all the events monitored, in agreement with other studies. The values of c3 and Bini were found to vary between events. Among all the rainfall and runoff characteristics studied, rainfall depth of the current event (d) was found to be the single parameter that significantly influenced the values of c3 and Bini. Contrary to expectations, Bini did not correlate well with antecedent dry period or with rainfall depth of the prior storm event. The results show that the common modeling practice where Bini is assumed to vary with antecedent dry period and previous rainfall depth should be reassessed when applied to catchments in the tropics. ANCOVA analysis showed that land use was not significant, but rather the variation of c3 and Bini with d was found to correlate well with the catchment area.

Transmission performance improvement using random DFB laser based Raman amplification and bidirectional second-order pumping.

We demonstrate that a distributed Raman amplification scheme based on random distributed feedback (DFB) fiber laser enables bidirectional second-order Raman pumping without increasing relative intensity noise (RIN) of the signal. This extends the reach of 10 × 116 Gb/s DP-QPSK WDM transmission up to 7915 km, compared with conventional Raman amplification schemes. Moreover, this scheme gives the longest maximum transmission distance among all the Raman amplification schemes presented in this paper, whilst maintaining relatively uniform and symmetric signal power distribution, and is also adjustable in order to be highly compatible with different nonlinearity compensation techniques, including mid-link optical phase conjugation (OPC) and nonlinear Fourier transform (NFT).

Dual-polarization multi-band optical OFDM transmission and transceiver limitations for up to 500 Gb/s uncompensated long-haul links.

A number of critical issues for dual-polarization single- and multi-band optical orthogonal-frequency division multiplexing (DP-SB/MB-OFDM) signals are analyzed in dispersion compensation fiber (DCF)-free long-haul links. For the first time, different DP crosstalk removal techniques are compared, the maximum transmission-reach is investigated, and the impact of subcarrier number and high-level modulation formats are explored thoroughly. It is shown, for a bit-error-rate (BER) of 10(-3), 2000 km of quaternary phase-shift keying (QPSK) DP-MB-OFDM transmission is feasible. At high launched optical powers (LOP), maximum-likelihood decoding can extend the LOP of 40 Gb/s QPSK DP-SB-OFDM at 2000 km by 1.5 dB compared to zero-forcing. For a 100 Gb/s DP-MB-OFDM system, a high number of subcarriers contribute to improved BER but at the cost of digital signal processing computational complexity, whilst by adapting the cyclic prefix length the BER can be improved for a low number of subcarriers. In addition, when 16-quadrature amplitude modulation (16QAM) is employed the digital-to-analogue/analogue-to-digital converter (DAC/ADC) bandwidth is relaxed with a degraded BER; while the 'circular' 8QAM is slightly superior to its 'rectangular' form. Finally, the transmission of wavelength-division multiplexing DP-MB-OFDM and single-carrier DP-QPSK is experimentally compared for up to 500 Gb/s showing great potential and similar performance at 1000 km DCF-free G.652 line.

Janus structures of the C 2h polymorph of gallium monochalcogenides: first-principles examination of Ga2XY (X/Y = S, Se, Te) monolayers.

Group III monochalcogenide compounds can exist in different polymorphs, including the conventional D 3h and C 2h phases. Since the bulk form of the C 2h-group III monochalcogenides has been successfully synthesized [Phys. Rev. B: Condens. Matter Mater. Phys. 73 (2006) 235202], prospects for research on their corresponding monolayers have also been opened. In this study, we design and systematically consider a series of Janus structures formed from the two-dimensional C 2h phase of gallium monochalcogenide Ga2XY (X/Y = S, Se, Te) using first-principles simulations. It is demonstrated that the Janus Ga2XY monolayers are structurally stable and energetically favorable. Ga2XY monolayers exhibit high anisotropic mechanical features due to their anisotropic lattice structure. All Janus Ga2XY are indirect semiconductors with energy gap values in the range from 1.93 to 2.67 eV. Due to the asymmetrical structure, we can observe distinct vacuum level differences between the two surfaces of the examined Janus structures. Ga2XY monolayers have high electron mobility and their carrier mobilities are also highly directionally anisotropic. It is worth noting that the Ga2SSe monolayer possesses superior electron mobility, up to 3.22 × 103 cm2 V-1 s-1, making it an excellent candidate for potential applications in nanoelectronics and nanooptoelectronics.

New C 2h phase of group III monochalcogenide monolayers AlX (X = S, Se, and Te) with anisotropic crystal structure: first-principles study.

In this paper, we introduce a new phase of two-dimensional aluminum monochalcogenide, namely C 2h-AlX (X = S, Se, and Te). With the C 2h space group, C 2h-AlX possesses a large unit cell containing 8 atoms. The C 2h phase of AlX monolayers is found to be dynamically and elastically stable based on the evaluation of its phonon dispersions and elastic constants. The anisotropic atomic structure of C 2h-AlX leads to a strong anisotropy in its mechanical properties with Young's modulus and Poisson's ratio strongly dependent on the directions examined in the two-dimensional plane. All three monolayers of C 2h-AlX are found to be direct band gap semiconductors, which are compared with the indirect band gap semiconductors of available D 3h-AlX. Particularly, the transition from direct to indirect band gap is observed in C 2h-AlX when a compressive biaxial strain is applied. Our calculated results indicate that C 2h-AlX exhibits anisotropic optical characteristics and its absorption coefficient is high. Our findings suggest that C 2h-AlX monolayers are suitable for applications in next-generation electro-mechanical and anisotropic opto-electronic nanodevices.

Regional pulmonary blood flow in the lung of the chicken.

It is known that alterations in respiratory gases in birds can cause a nonhomogenous redistribution of pulmonary blood flow between the 2 separate gas-exchanging regions of the avian lung, the paleopulmo (PALEO) and neopulmo (NEO); however, the effect of alterations in respired gas content on the distribution of pulmonary blood flow in birds, such as the chicken, that possess a highly developed NEO is not known. This study used a colorimetric microsphere method to determine the effects of hypoxia and hypercapnia on the relative distribution of pulmonary blood flow in anesthetized chickens (Gallus domesticus) during control (normoxic) and experimental (hypoxic or hypercapnic) conditions, where the relative regional distribution of blood flow in the lung is expressed as the ratio NEO/PALEO. Administration of a hypoxic gas mixture (16.0% O(2)) produced a 13.4% increase in NEO/PALEO, and, administration of a hypercapnic gas mixture (5.0% CO(2)) resulted in a 27.8% increase in NEO/PALEO. Our results are consistent with a mechanism in which the regional redistribution of pulmonary blood flow is mediated by local intrapulmonary factors.

[Mutational spectrum and its prognostic significance in childhood acute lymphoblastic leukemia based on next-generation sequencing technology].

Objective: This study analyzed the correlation between genetic mutation and prognostic significance in childhood acute lymphoblastic leukemia (ALL) . Methods: Targeted exome by next-generation sequencing (NGS) technology was used to carry out molecular profiling of untreated 141 children with ALL in Fujian Medical University Union Hospital from November 2016 to December 2019. Correlation of genetic features and clinical features and outcomes was analyzed. Results: Among the 141 pediatric patients with ALL, 160 somatic mutations were detected in 83 patients (58.9% ) , including 37 grade Ⅰ mutations and 123 grade Ⅱ mutations. Single nucleotide variation was the most common type of mutation. KRAS was the most common mutant gene (12.5% ) , followed by NOTCH1 (11.9% ) , and NRAS (10.6% ) . RAS pathway (KRAS, FLT3, PTPN11) , PAX5 and TP53 mutations were only detected, and NRAS mutations was mainly found in B-ALL while FBXW7 and PTEN mutations were only found, and NOTCH1 mutation was mainly detected in T-ALL. The average number of mutations detected in each child with T-ALL was significantly higher than in children with B-ALL (4.16±1.33 vs 2.04±0.92, P=0.004) . The children were divided into mutation and non-mutation groups according to the presence or absence of genetic variation. There were no statistically significant differences in sex, age, newly diagnosed white blood cell count, minimal or measurable residual disease monitoring results, expected 3-year event-free survival (EFS) and overall survival (OS) between the two groups (P>0.05) . On the other hand, the proportion of T-ALL and fusion gene negative children in the mutant group was significantly higher than the non-mutation group (P=0.021 and 0.000, respectively) . Among the patients without fusion gene, the EFS of children with grade I mutation was significantly lower than children without grade I mutation (85.5% vs 100.0% , P=0.039) . Among children with B-ALL, the EFS of those with TP53 mutation was significantly lower than those without TP53 mutation (37.5% vs 91.2% , P<0.001) . Conclusion: Genetic variation is more common in childhood ALL and has a certain correlation with clinical phenotype and prognosis. Therefore, targeted exome by NGS can be used as an important supplement to the traditional morphology, immunology, cytogenetics, and molecular biology classification.

Gene expression profile of the fibrotic response in the peritoneal cavity.

The cellular response to materials implanted in the peritoneal cavity has been utilised to produce tissue for grafting to hollow smooth muscle organs (blood vessels, bladder, uterus and vas deferens). To gain insight into the regulatory mechanisms involved in encapsulation of a foreign object, and subsequent differentiation of encapsulating cells, the present study used microarray technology and real-time RT-PCR to identify the temporal changes in gene expression associated with tissue development. Immunohistochemical analysis showed that 3-7 days post-implantation of foreign objects (cubes of boiled egg white) into rats, they were encapsulated by tissue comprised primarily of haemopoietic (CD45(+)) cells, mainly macrophages (CD68(+), CCR1(+)). By day 14, tissue capsule cells no longer expressed CD68, but were positive for myofibroblast markers alpha-smooth muscle (SM) actin and SM22. In accordance with these results, gene expression data showed that early capsule (days 3-7) development was dominated by the expression of monocyte/macrophage-specific genes (CD14, CSF-1, CSF-1R, MCP-1) and pro-inflammatory mediators such as transforming growth factor (TGF-beta). As tissue capsule development progressed (days 14-21), myofibroblast-associated and pro-fibrotic genes (associated with TGF-beta and Wnt/beta-catenin signalling pathways, including Wnt 4, TGFbetaRII, connective tissue growth factor (CTGF), SMADs-1, -2, -4 and collagen-1 subunits) were significantly up-regulated. The up-regulation of genes associated with Cardiovascular and Skeletal and Muscular System Development at later time-points suggests the capacity of cells within the tissue capsule for further differentiation to smooth muscle, and possibly other cell types. The identification of key regulatory pathways and molecules associated with the fibrotic response to implanted materials has important applications not only for optimising tissue engineering strategies, but also to control deleterious fibrotic responses.

Impact ionization-induced bistability in CMOS transistors at cryogenic temperatures for capacitorless memory applications.

Cryogenic operation of complementary metal oxide semiconductor (CMOS) silicon transistors is crucial for quantum information science, but it brings deviations from standard transistor operation. Here, we report on sharp current jumps and stable hysteretic loops in the drain current as a function of gate voltage V G for both n- and p-type commercial-foundry 180-nm-process CMOS transistors when operated at voltages exceeding 1.3 V at cryogenic temperatures. The physical mechanism responsible for the device bistability is impact ionization charging of the transistor body, which leads to effective back-gating of the inversion channel. This mechanism is verified by independent measurements of the body potential. The hysteretic loops, which have a >107 ratio of high to low drain current states at the same V G, can be used for a compact capacitorless single-transistor memory at cryogenic temperatures with long retention times.

Relationship between preoperative dental anxiety and short-term inflammatory response following oral surgery.

BACKGROUND: The relationship between dental anxiety and mucosal wound healing, especially the inflammatory response, has not been well studied. This study aimed to examine the relationship between anxiety prior to dental treatment and short-term inflammation following impacted mandibular third molar (IMTM) surgery. METHODS: Fifty-nine patients who required IMTM surgery were recruited for this study. Sample demographics (gender, age) and surgical extent (Pederson classification, duration) were collected. Psychological stress towards surgery was assessed by the Dental Fear Survey (DFS). All surgeries were conducted according to an identical surgical protocol and all patients were given the same medical prescription. Correlations between short-term inflammation (swelling and trismus after 2 days) and DFS, demographics and surgical extent were statistically analysed. RESULTS: The results showed that patients with a higher DFS score demonstrated more severe swelling (ß = 0.36, P = 0.016) and trismus (ß = 0.37, P = 0.008) 2 days after surgery. In addition, more severe trismus occurred following more difficult surgery (ß = 0.29, P = 0.016) or that with a longer duration (ß = 0.21, P = 0.081). Neither gender nor age showed any significant relationship with swelling or trismus. CONCLUSION: Short-term inflammatory response following IMTM surgery correlated with the preoperative dental anxiety and this correlation was independent of gender and surgical extent.

[Clinical features and prognosis of ETV6-RUNX1-positive childhood B-precursor acute lymphocyte leukemia].

Objective: To investigate the clinical features and prognosis of ETV6-RUNX1-positive childhood B-precursor acute lymphocyte leukemia (B-ALL) . Methods: The clinical data of 927 newly diagnosed children with B-ALL admitted to the Fujian Medical University Union Hospital from April 2011 to May 2020 were retrospectively analyzed. According to the results of ETV6-RUNX1 gene, the patients were divided into ETV6-RUNX1(+) and ETV6-RUNX1(-) groups. The clinical features and prognosis between the two groups were compared. Among the 182 children with ETV6-RUNX1(+), 144 patients received the Chinese Childhood Leukemia Collaborative Group (CCLG) -ALL 2008 protocol (CCLG-ALL 2008 group) and 38 received the China Childhood Cancer Collaborative Group (CCCG) -ALL2015 protocol (CCCG-ALL 2015 group) . The efficacy, serious adverse effects (SAE) incidence, and treatment-related mortality (TRM) of the two groups were also compared. Results: Of the 927 B-ALL patients, 189 (20.4% ) were ETV6-RUNX1(+). The proportion of patients with risk factors (age ≥10 years or <1 year, white blood cell count ≥50×10(9)/L) in the ETV6-RUNX1(+) group was significantly lower than that in the ETV6-RUNX1(-) group (P=0.000, 0.001, respectively) , while the proportion of patients with good early response (good response to prednisone, d15 or d19 MRD <1% , and d33 or d46 MRD<0.01% in induction chemotherapy) in the ETV6-RUNX1(+) group was significantly higher than that in the ETV6-RUNX1(-) group (P=0.028, 0.004, respectively) . The 5-year EFS and OS of the ETV6-RUNX1(+) group were significantly higher than those of the ETV6-RUNX1(-) group (EFS: 89.8% vs 83.2% , P=0.003; OS: 90.2% vs 86.3% , P=0.030) . The incidence of infection-related SAE and TRM was significantly higher than that of CCCG-ALL 2015 group. A statistical difference was observed between the incidence of infection-related SAE of the two groups (27.1% vs 5.3% , P=0.004) , but no difference in TRM (4.9% vs 0, P=0.348) . Conclusion: ETV6-RUNX1(+)B-ALL children have fewer risk factors at diagnosis, better early response, lower recurrence rate, and good prognosis than that of ETV6-RUNX1(-)B-ALL children. Reducing the intensity of chemotherapy appropriately can lower the infection-related SAE and TRM and improve the long-term survival in this subtype.

Primary cytomegalovirus ileitis complicated by massive gastrointestinal haemorrhage in a patient with steroid refractory Crohn's disease.

A young man with known steroid refractory terminal ileal Crohn's disease developed torrential gastrointestinal bleeding necessitating an emergency ileal resection. Serology was indicative of primary cytomegalovirus (CMV) infection and this was confirmed with histopathology of the resected ileum. We highlight the difficulty in clinical practice of distinguishing between CMV infection and CMV disease as well as the different investigations available to aid in the diagnosis of pathogenic CMV disease.