Longitudinal outcomes of trismus release with free-flap reconstruction in primary and secondary oral submucous fibrosis-related trismus.

BACKGROUND: Oral submucous fibrosis is a global health concern associated with betel quid use and results in trismus, which can be either primary or secondary in origin. Severe cases often require trismus release with free-flap reconstruction. This study examined longitudinal outcome trends following trismus release and compared the outcomes of patients with primary and secondary oral submucous fibrosis-related trismus. METHODS: We conducted a retrospective cohort study by including patients who underwent trismus release between 2013 and 2022. All procedures were performed by a single surgical team to ensure technique standardisation. We measured the maximum mouth opening, the interincisal distance, perioperatively and 1, 2, 3, 4, 6 and 12 months post-operatively. Data were analysed using generalised estimating equations. RESULTS: A total of 35 patients were included in the study, 17 with primary and 18 with secondary oral submucous fibrosis-related trismus. Initially, patients with primary oral submucous fibrosis-related trismus had greater interincisal distance gains than those with secondary oral submucous fibrosis-related trismus (p = 0.015 and p = 0.025 at 3 and 4 months post-operatively, respectively). However, after 12 months, this initial advantage faded, with comparable interincisal distance improvements in patients with primary and secondary disease, despite the more complex surgical procedures required in secondary cases. CONCLUSION: Surgeons should carefully consider the benefits of trismus release procedures for patients with secondary oral submucous fibrosis-related trismus by recognising the changes in post-operative outcomes.

Iterative Reconstruction of Micro Computed Tomography Scans Using Multiple Heterogeneous GPUs.

Graphics processing units (GPUs) facilitate massive parallelism and high-capacity storage, and thus are suitable for the iterative reconstruction of ultrahigh-resolution micro computed tomography (CT) scans by on-the-fly system matrix (OTFSM) calculation using ordered subsets expectation maximization (OSEM). We propose a finite state automaton (FSA) method that facilitates iterative reconstruction using a heterogeneous multi-GPU platform through parallelizing the matrix calculations derived from a ray tracing system of ordered subsets. The FSAs perform flow control for parallel threading of the heterogeneous GPUs, which minimizes the latency of launching ordered-subsets tasks, reduces the data transfer between the main system memory and local GPU memory, and solves the memory-bound of a single GPU. In the experiments, we compared the operation efficiency of OS-MLTR for three reconstruction environments. The heterogeneous multiple GPUs with job queues for high throughput calculation speed is up to five times faster than the single GPU environment, and that speed up is nine times faster than the heterogeneous multiple GPUs with the FIFO queues of the device scheduling control. Eventually, we proposed an event-triggered FSA method for iterative reconstruction using multiple heterogeneous GPUs that solves the memory-bound issue of a single GPU at ultrahigh resolutions, and the routines of the proposed method were successfully executed on each GPU simultaneously.

A bi-criterion sequence-dependent scheduling problem with order deliveries.

The manufacturing sector faces unprecedented challenges, including intense competition, a surge in product varieties, heightened customization demands, and shorter product life cycles. These challenges underscore the critical need to optimize manufacturing systems. Among the most enduring and complex challenges within this domain is production scheduling. In practical scenarios, setup time is whenever a machine transitions from processing one product to another. Job scheduling with setup times or associated costs has garnered significant attention in both manufacturing and service environments, prompting extensive research efforts. While previous studies on customer order scheduling primarily focused on orders or jobs to be processed across multiple machines, they often overlooked the crucial factor of setup time. This study addresses a sequence-dependent bi-criterion scheduling problem, incorporating order delivery considerations. The primary objective is to minimize the linear combination of the makespan and the sum of weighted completion times of each order. To tackle this intricate challenge, we propose pertinent dominance rules and a lower bound, which are integral components of a branch-and-bound methodology employed to obtain an exact solution. Additionally, we introduce a heuristic approach tailored to the problem's unique characteristics, along with three refined variants designed to yield high-quality approximate solutions. Subsequently, these three refined approaches serve as seeds to generate three distinct populations or chromosomes, each independently employed in a genetic algorithm to yield a robust approximate solution. Ultimately, we meticulously assess the efficacy of each proposed algorithm through comprehensive simulation trials.

Assessment of Cement Leakage in Decompressed Percutaneous Kyphoplasty.

Symptomatic osteoporotic compression fractures are commonly addressed through vertebroplasty and kyphoplasty. However, cement leakage poses a significant risk of neurological damage. We introduced "aspiration percutaneous kyphoplasty", also known as "decompressed kyphoplasty", as a method to mitigate cement leakage and conducted a comparative analysis with high viscosity cement vertebroplasty. We conducted a retrospective study that included 136 patients with single-level osteoporotic compression fractures. Among them, 70 patients underwent high viscosity cement vertebroplasty, while 66 patients received decompressed percutaneous kyphoplasty with low-viscosity cement. Comparison parameters included cement leakage rates, kyphotic angle alterations, and the occurrence of adjacent segment fractures. The overall cement leakage rate favored the decompressed kyphoplasty group (9.1% vs. 18.6%), although statistical significance was not achieved (p = 0.111). Nonetheless, the risk of intradiscal leakage significantly reduced in the decompressed kyphoplasty cohort (p = 0.011), which was particularly evident in cases lacking the preoperative cleft sign on X-rays. Kyphotic angle changes and the risk of adjacent segment collapse exhibited similar outcomes (p = 0.739 and 0.522, respectively). We concluded that decompressed kyphoplasty demonstrates efficacy in reducing intradiscal cement leakage, particularly benefiting patients without the preoperative cleft sign on X-rays by preventing intradiscal leakage.

The Implementation of a Gesture Recognition System with a Millimeter Wave and Thermal Imager.

During the COVID-19 pandemic, the number of cases continued to rise. As a result, there was a growing demand for alternative control methods to traditional buttons or touch screens. However, most current gesture recognition technologies rely on machine vision methods. However, this method can lead to suboptimal recognition results, especially in situations where the camera is operating in low-light conditions or encounters complex backgrounds. This study introduces an innovative gesture recognition system for large movements that uses a combination of millimeter wave radar and a thermal imager, where the multi-color conversion algorithm is used to improve palm recognition on the thermal imager together with deep learning approaches to improve its accuracy. While the user performs gestures, the mmWave radar captures point cloud information, which is then analyzed through neural network model inference. It also integrates thermal imaging and palm recognition to effectively track and monitor hand movements on the screen. The results suggest that this combined method significantly improves accuracy, reaching a rate of over 80%.

Biophysical and biochemical characterization of a recombinant Lyme disease vaccine antigen, CspZ-YA.

Lyme disease, caused by Lyme Borrelia spirochetes, is the most common vector-borne illness in the United States. Despite its global significance, with an estimated 14.5 % seroprevalence, there is currently no licensed vaccine. Previously, we demonstrated that CspZ-YA protein conferred protection against Lyme Borrelia infection, making it a promising vaccine candidate. However, such a protein was tagged with hexahistidine, and thus not preferred for vaccine development; furthermore, the formulation to stabilize the protein was understudied. In this work, we developed a two-step purification process for tag-free E. coli-expressed recombinant CspZ-YA. We further utilized various bioassays to analyze the protein and determine the suitable buffer system for long-term storage and formulation as a vaccine immunogen. The results indicated that a buffer with a pH between 6.5 and 8.5 stabilized CspZ-YA by reducing its surface hydrophobicity and colloidal interactions. Additionally, low pH values induced a change in local spatial conformation and resulted in a decrease in α-helix content. Lastly, an optimal salinity of 22-400 mM at pH 7.5 was found to be important for its stability. Collectively, this study provides a fundamental biochemical and biophysical understanding and insights into the ideal stabilizing conditions to produce CspZ-YA recombinant protein for use in vaccine formulation and development.

The antioxidant and anti-inflammatory activities of avasopasem manganese in age-associated, cisplatin-induced renal injury.

PURPOSE: Cisplatin contributes to acute kidney injury (AKI) and chronic kidney disease (CKD) that occurs with greater frequency and severity in older patients. Age-associated cisplatin sensitivity in human fibroblasts involves increased mitochondrial superoxide produced by older donor cells. EXPERIMENTAL DESIGN: Young and old C57BL/6 J murine models of cisplatin-induced AKI and CKD were treated with the SOD mimetic avasopasem manganese to investigate the potential antioxidant and anti-inflammatory effects. Adverse event reporting from a phase 2 and a phase 3 randomized clinical trial (NCT02508389 and NCT03689712) conducted in patients treated with cisplatin and AVA was determined to have established the incidence and severity of AKI. RESULTS: Cisplatin-induced AKI and CKD occurred in all mice, however, was more pronounced in older mice. AVA reduced cisplatin-induced mortality, AKI, and CKD, in older animals. AVA also alleviated cisplatin-induced alterations in mitochondrial electron transport chain (ETC) complex activities and NADPH Oxidase 4 (NOX4) and inhibited the increased levels of the inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1. Analysis of age-stratified subjects treated with cisplatin from clinical trials (NCT02508389, NCT03689712) also supported that the incidence of AKI increased with age and AVA reduced age-associated therapy-induced adverse events (AE), including hypomagnesemia, increased creatinine, and AKI. CONCLUSIONS: Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation.

Tubular mitochondrial pyruvate carrier disruption elicits redox adaptations that protect from acute kidney injury.

OBJECTIVE: Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity. METHODS: We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal 13C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI. RESULTS: MPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival. CONCLUSIONS: Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity.

A Recombinant Protein XBB.1.5 RBD/Alum/CpG Vaccine Elicits High Neutralizing Antibody Titers against Omicron Subvariants of SARS-CoV-2.

(1) Background: We previously reported the development of a recombinant protein SARS-CoV-2 vaccine, consisting of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, adjuvanted with aluminum hydroxide (alum) and CpG oligonucleotides. In mice and non-human primates, our wild-type (WT) RBD vaccine induced high neutralizing antibody titers against the WT isolate of the virus, and, with partners in India and Indonesia, it was later developed into two closely resembling human vaccines, Corbevax and Indovac. Here, we describe the development and characterization of a next-generation vaccine adapted to the recently emerging XBB variants of SARS-CoV-2. (2) Methods: We conducted preclinical studies in mice using a novel yeast-produced SARS-CoV-2 XBB.1.5 RBD subunit vaccine candidate formulated with alum and CpG. We examined the neutralization profile of sera obtained from mice vaccinated twice intramuscularly at a 21-day interval with the XBB.1.5-based RBD vaccine, against WT, Beta, Delta, BA.4, BQ.1.1, BA.2.75.2, XBB.1.16, XBB.1.5, and EG.5.1 SARS-CoV-2 pseudoviruses. (3) Results: The XBB.1.5 RBD/CpG/alum vaccine elicited a robust antibody response in mice. Furthermore, the serum from vaccinated mice demonstrated potent neutralization against the XBB.1.5 pseudovirus as well as several other Omicron pseudoviruses. However, regardless of the high antibody cross-reactivity with ELISA, the anti-XBB.1.5 RBD antigen serum showed low neutralizing titers against the WT and Delta virus variants. (4) Conclusions: Whereas we observed modest cross-neutralization against Omicron subvariants with the sera from mice vaccinated with the WT RBD/CpG/Alum vaccine or with the BA.4/5-based vaccine, the sera raised against the XBB.1.5 RBD showed robust cross-neutralization. These findings underscore the imminent opportunity for an updated vaccine formulation utilizing the XBB.1.5 RBD antigen.

Metabolite Variations in the Hippocampus and Corpus Callosum of Patients with Mild Cognitive Impairment Using Magnetic Resonance Spectroscopy with Three-Dimensional Chemical Shift Images.

This study compared the metabolites in the brain regions of hippocampus and corpus callosum between patients with mild cognitive impairment (MCI) and healthy controls using no-radiation and high-sensitivity magnetic resonance spectroscopy (MRS) with three-dimensional chemical shift images (3D-CSI). Twenty volunteers (seven patients with MCI and 13 healthy controls) aged 50-71 years were recruited for this prospective study. MRS with 3D-CSI images of a variety of metabolites was collected from the hippocampus and corpus callosum. Sex and weight showed no significant differences between the two groups. The metabolite levels in the hippocampus and corpus callosum of the MCI group were generally lower than in those of the healthy group, especially for creatine (p < 0.001 in the hippocampus and p = 0.020 in the corpus callosum) and N-acetyl aspartate/creatine (p < 0.001 in the hippocampus and p = 0.020 in the corpus callosum); however, choline/creatine showed a significant difference (p < 0.001) only in the hippocampus, and myo-inositol/creatine showed a significant difference (p < 0.001) only in the corpus callosum. Our study demonstrated that MRS with 3D-CSI can be used to measure these metabolite levels to determine the differences between patients with MCI and healthy individuals. This would aid early diagnosis of MCI in clinical practice, and patients could receive prompt intervention to improve their quality of life.

Effects of early aquatic exercise intervention on trunk strength and functional recovery of patients with lumbar fusion: a randomized controlled trial.

This study investigated the effectiveness of an early aquatic exercise program on trunk muscle function and functional recovery of patients with lumbar fusion. Twenty-eight subjects were divided into two equal groups. Patients in the aquatic group performed two 60-min aquatic exercise sessions and three 60-min home exercise sessions per week for 6 weeks, whereas those in the control group performed five sessions of 60-min home exercises per week for 6 weeks. The primary outcomes were the Numerical Pain Rating Scale (NPRS) and Oswestry Disability Index (ODI), and the secondary outcomes were Timed Up and Go Test (TUGT), trunk flexor and extensor muscle strength, lumbopelvic stability, and lumbar multifidus muscle thickness measured pre- and post-intervention. Compared with participants in the control group, those in the experimental group showed significant improvement in NPRS, ODI, trunk extensor strength, lumbopelvic control, lumbar multifidus muscle thickness, and relative change in multifidus muscle thickness (significant time by group interactions, P < 0.05). Participants in both groups showed significant time effects (P < 0.001) for TUGT and trunk flexor strength outcome. Aquatic exercise combined with home exercise was superior to home exercise alone in reducing pain, disability and improving muscle strength, lumbopelvic stability, and lumbar multifidus muscle thickness.

From concept to delivery: a yeast-expressed recombinant protein-based COVID-19 vaccine technology suitable for global access.

INTRODUCTION: The development of a yeast-expressed recombinant protein-based vaccine technology co-developed with LMIC vaccine producers and suitable as a COVID-19 vaccine for global access is described. The proof-of-concept for developing a SARS-CoV-2 spike protein receptor-binding domain (RBD) antigen as a yeast-derived recombinant protein vaccine technology is described. AREAS COVERED: Genetic Engineering: The strategy is presented for the design and genetic modification used during cloning and expression in the yeast system. Process and Assay Development: A summary is presented of how a scalable, reproducible, and robust production process for the recombinant protein COVID-19 vaccine antigen was developed. Formulation and Pre-clinical Strategy: We report on the pre-clinical and formulation strategy used for the proof-of-concept evaluation of the SARS-CoV-2 RBD vaccine antigen. Technology Transfer and Partnerships: The process used for the technology transfer and co-development with LMIC vaccine producers is described. Clinical Development and Delivery: The approach used by LMIC developers to establish the industrial process, clinical development, and deployment is described. EXPERT OPINION: Highlighted is an alternative model for developing new vaccines for emerging infectious diseases of pandemic importance starting with an academic institution directly transferring their technology to LMIC vaccine producers without the involvement of multinational pharma companies.

Tubular Mitochondrial Pyruvate Carrier Disruption Elicits Redox Adaptations that Protect from Acute Kidney Injury.

Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Tubular metabolism changes markedly following acute kidney injury (AKI), but which changes are adaptive versus maladaptive remain poorly understood. In publicly available data sets, we noticed a consistent downregulation of the mitochondrial pyruvate carrier (MPC) after AKI, which we experimentally confirmed. To test the functional consequences of MPC downregulation, we generated novel tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice. 13C-glucose tracing, steady-state metabolomic profiling, and enzymatic activity assays revealed that MPC TubKO coordinately increased activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, MPC TubKO decreased markers of kidney injury and oxidative damage and strikingly increased survival. Our findings suggest that decreased mitochondrial pyruvate uptake is a central adaptive response following AKI and raise the possibility of therapeutically modulating the MPC to attenuate AKI severity.

Neuronal deletion of CaV1.2 is associated with sex-specific behavioral phenotypes in mice.

The gene CACNA1C, which encodes the pore forming subunit of the L-type calcium channel CaV1.2, is associated with increased risk for neuropsychiatric disorders including schizophrenia, autism spectrum disorder, major depression, and bipolar disorder. Previous rodent work identified that loss or reduction of CaV1.2 results in cognitive, affective, and motor deficits. Most previous work has either included non-neuronal cell populations (haploinsufficient and Nestin-Cre) or investigated a discrete neuronal cell population (e.g. CaMKII-Cre, Drd1-Cre), but few studies have examined the effects of more broad neuron-specific deletion of CaV1.2. Additionally, most of these studies did not evaluate for sex-specific effects or used only male animals. Here, we sought to clarify whether there are sex-specific behavioral consequences of neuron-specific deletion of CaV1.2 (neuronal CaV1.2 cKO) using Syn1-Cre-mediated conditional deletion. We found that neuronal CaV1.2 cKO mice have normal baseline locomotor function but female cKO mice display impaired motor performance learning. Male neuronal CaV1.2 cKO display impaired startle response with intact pre-pulse inhibition. Male neuronal CaV1.2 cKO mice did not display normal social preference, whereas female neuronal CaV1.2 cKO mice did. Neuronal CaV1.2 cKO mice displayed impaired associative learning in both sexes, as well as normal anxiety-like behavior and hedonic capacity. We conclude that deletion of neuronal CaV1.2 alters motor performance, acoustic startle reflex, and social behaviors in a sex-specific manner, while associative learning deficits generalize across sexes. Our data provide evidence for both sex-specific and sex-independent phenotypes related to neuronal expression of CaV1.2.

A novel multi-epitope recombinant protein elicits an antigen-specific CD8+ T cells response in Trypanosoma cruzi-infected mice.

About 6.5 million people worldwide are afflicted by Chagas disease, which is caused by the protozoan parasite Trypanosoma cruzi. The development of a therapeutic vaccine to prevent the progression of Chagasic cardiomyopathy has been proposed as an alternative for antiparasitic chemotherapy. Bioinformatics tools can predict MHC class I CD8 + epitopes for inclusion in a single recombinant protein with the goal to develop a multivalent vaccine. We expressed a novel recombinant protein Tc24-C4.10E harboring ten nonameric CD8 + epitopes and using Tc24-C4 protein as scaffold to evaluate the therapeutic effect in acute T. cruzi infection. T. cruzi-infected mice were immunized with Tc24-C4.10E or Tc24-C4 in a 50-day model of acute infection. Tc24-C4.10E-treated mice showed a decreased parasitemia compared to the Tc24-C4 (non-adjuvant) immunized mice or control group. Moreover, Tc24-C4.10E induced a higher stimulation index of CD8 + T cells producing IFNγ and IL-4 cytokines. These results suggest that the addition of the MHC Class I epitopes to Tc24-C4 can synergize the antigen-specific cellular immune responses, providing proof-of-concept that this approach could lead to the development of a promising vaccine candidate for Chagas disease.

Skewed X-Chromosome Inactivation and Parental Gonadal Mosaicism Are Implicated in X-Linked Recessive Female Hemophilia Patients.

BACKGROUND: Hemophilia A (HA) and B (HB) are X-linked recessive disorders that mainly affect males born from a mother carrier. Females are rarely affected but a number of mechanisms have been suggested in symptomatic females, such as skewed X-chromosome inactivation (XCI), chromosomal rearrangements, and hermaphrodites. Different methodologies are required to elucidate the underlying causes of such diseases in female patients. METHODS: Three families with female hemophilia patients, including two HA and one HB, were enrolled for genetic analyses. Cytogenetics, molecular examinations on F8 and F9 genes, XCI assay, and linkage analysis were performed. RESULTS: All three female patients are demonstrated to be heterozygous for an F8, or F9 mutation: one patient is inherited from her unaffected mother and the other two are sporadic cases. All three patients exhibit skewed XCI. The inherited patient is found to be unmethylated in the maternal X chromosome, which increases the potential for the expression of the mutant allele. The two sporadic cases are hypomethylated or unmethylated in the paternal X chromosome, suggesting that paternal gonadal mosaicism may exist in these families. CONCLUSIONS: In addition to screening for coagulation function, different genetic analyses are mandatory to explore the nature of mechanisms responsible for the X-linked recessive disorders in female patients as shown in this study. Our results confirm that skewed XCI is responsible for hemophilia in heterozygous female patients. Likewise, our results implicate that parental gonadal mosaicism, followed by skewed XCI, contributes to hemophilia in "sporadic" female patients.

Benefits and risks of low molecular weight heparin use on reproductive outcomes: A retrospective cohort study.

OBJECTIVE: Low molecular weight heparin (LMWH) has been given to reproductive-age women with various indications. This study aims to assess the benefits and risks of such use. MATERIALS AND METHODS: We retrospectively reviewed data (n = 204) between Jan 2016 and May 2019. Logistic regression analysis was conducted to evaluate the correlation between indications and reproductive outcomes. RESULTS: LMWH use had higher odds of live birth in women less than 30 years of age (OR: 4.98; 95% CI = 1.13-21.98; p = 0.034) and with protein S deficiency (OR: 3.90; 95% CI = 1.77-8.59; p = 0.001). For the subgroup of recurrent pregnant loss, LMWH use was only advantageous to women with protein S deficiency (OR: 2.45; 95%:1.01-5.97; p = 0.048). Risks such as preterm delivery, small-for-gestational-age, placental abruption, antepartum/postpartum hemorrhage were not significantly increased among subgroups. Women treated with LMWH and who had successful live births (n = 171) had a slightly increased risk of postpartum hemorrhage compared to controls (n = 8058) during this period in our institution (2.9% vs 1.2%, p < 0.001). CONCLUSION: LMWH administration produces a higher chance of live-birth to women younger than 30 years of age or with protein S deficiency. However, risk of postpartum hemorrhage is increased.

Proposal for Practical Approach in Prenatal Diagnosis of Beckwith-Wiedemann Syndrome and Review of the Literature.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a phenotypically and genetically heterogeneous disorder associated with epigenetic/genetic aberrations on chromosome 11p15.4p15.5. There is no consensus criterion for prenatal diagnosis of BWS. METHODS: Three BWS patients with their clinical histories, prenatal ultrasonographic features, and results of molecular diagnosis were presented. Likewise, by incorporating the findings of our cases and literature review, the phenotypic spectrum and genotype-phenotype correlations of fetal BWS were summarized, and a practical approach in prenatal diagnosis of BWS was proposed. RESULTS: A total of 166 BWS cases with prenatal features were included for analysis. Common fetal features include abdominal wall defects (42.8%), polyhydramnios (33.1%), and macrosomia (32.5%). Molecular pathologies include methylation changes in imprinting control region 1 and 2 (ICR1 and ICR2), paternal uniparental disomy of chromosome 11p15.5, copy number change involving 11p15, etc. Some genotype-phenotype correlations were observed. However, the broad phenotypic spectrum but limited features manifested by affected fetuses rendering ultrasonographic diagnosis not easy. CONCLUSIONS: Molecular tests are used for prenatal diagnosis of BWS suspected by ultrasonography. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is recommended as the first-line molecular tool because it simultaneously detects ICR1/ICR2 methylation statuses and copy numbers that solve the majority of clinical cases in the prenatal scenario.

Past, present, and future of Lyme disease vaccines: antigen engineering approaches and mechanistic insights.

INTRODUCTION: Transmitted by ticks, Lyme disease is the most common vector-borne disease in the Northern hemisphere. Despite the geographical expansion of human Lyme disease cases, no effective preventive strategies are currently available. Developing an efficacious and safe vaccine is therefore urgently needed. Efforts have previously been taken to identify vaccine targets in the causative pathogen (Borrelia burgdorferi sensu lato) and arthropod vector (Ixodes spp.). However, progress was impeded due to a lack of consumer confidence caused by the myth of undesired off-target responses, low immune responses, a limited breadth of immune reactivity, as well as by the complexities of the vaccine process development. AREA COVERED: In this review, we summarize the antigen engineering approaches that have been applied to overcome those challenges and the underlying mechanisms that can be exploited to improve both safety and efficacy of future Lyme disease vaccines. EXPERT OPINION: Over the past two decades, several new genetically redesigned Lyme disease vaccine candidates have shown success in both preclinical and clinical settings and built a solid foundation for further development. These studies have greatly informed the protective mechanisms of reducing Lyme disease burdens and ending the endemic of this disease.

CspZ FH-Binding Sites as Epitopes Promote Antibody-Mediated Lyme Borreliae Clearance.

Transmitted by ticks, the bacterium Borrelia burgdorferi sensu lato is the causative agent of Lyme disease (LD), the most common vector-borne disease in the Northern hemisphere. No effective vaccines are currently available. B. burgdorferi sensu lato produces the CspZ protein that binds to the complement inhibitor, factor H (FH), promoting evasion of the host complement system. We previously showed that while vaccination with CspZ did not protect mice from B. burgdorferi infection, mice can be protected after immunization with CspZ-Y207A/Y211A (CspZ-YA), a CspZ mutant protein without FH-binding activity. To further study the mechanism of this protection, herein we evaluated both poly- and monoclonal antibodies recognizing CspZ FH-binding or non-FH-binding sites. We found that the anti-CspZ antibodies that recognize the FH-binding sites (i.e., block FH-binding activity) eliminate B. burgdorferi sensu lato in vitro more efficiently than those that bind to the non-FH-binding sites, and passive inoculation with anti-FH-binding site antibodies eradicated B. burgdorferi sensu lato in vivo. Antibodies against non-FH-binding sites did not have the same effect. These results emphasize the importance of CspZ FH-binding sites in triggering a protective antibody response against B. burgdorferi sensu lato in future LD vaccines.