Understanding the development, pathogenesis, and injury response of meningeal lymphatic networks through the use of animal models.

Meningeal lymphatic vessels (MLVs) help maintain central nervous system (CNS) homeostasis via their ability to facilitate macromolecule waste clearance and neuroimmune trafficking. Although these vessels were overlooked for centuries, they have now been characterized in humans, non-human primates, and rodents. Recent studies in mice have explored the stereotyped growth and expansion of MLVs in dura mater, the various transcriptional, signaling, and environmental factors regulating their development and long-term maintenance, and the pathological changes these vessels undergo in injury, disease, or with aging. Key insights gained from these studies have also been leveraged to develop therapeutic approaches that help augment or restore MLV functions to improve brain health and cognition. Here, we review fundamental processes that control the development of peripheral lymphatic networks and how these might apply to the growth and expansion of MLVs in their unique meningeal environment. We also emphasize key findings in injury and disease models that may reveal additional insights into the plasticity of these vessels throughout the lifespan. Finally, we highlight unanswered questions and future areas of study that can further reveal the exciting therapeutic potential of meningeal lymphatics.

ICOR: improving codon optimization with recurrent neural networks.

BACKGROUND: In protein sequences-as there are 61 sense codons but only 20 standard amino acids-most amino acids are encoded by more than one codon. Although such synonymous codons do not alter the encoded amino acid sequence, their selection can dramatically affect the expression of the resulting protein. Codon optimization of synthetic DNA sequences is important for heterologous expression. However, existing solutions are primarily based on choosing high-frequency codons only, neglecting the important effects of rare codons. In this paper, we propose a novel recurrent-neural-network based codon optimization tool, ICOR, that aims to learn codon usage bias on a genomic dataset of Escherichia coli. We compile a dataset of over 7,000 non-redundant, high-expression, robust genes which are used for deep learning. The model uses a bidirectional long short-term memory-based architecture, allowing for the sequential context of codon usage in genes to be learned. Our tool can predict synonymous codons for synthetic genes toward optimal expression in Escherichia coli. RESULTS: We demonstrate that sequential context achieved via RNN may yield codon selection that is more similar to the host genome. Based on computational metrics that predict protein expression, ICOR theoretically optimizes protein expression more than frequency-based approaches. ICOR is evaluated on 1,481 Escherichia coli genes as well as a benchmark set of 40 select DNA sequences whose heterologous expression has been previously characterized. ICOR's performance is measured across five metrics: the Codon Adaptation Index, GC-content, negative repeat elements, negative cis-regulatory elements, and codon frequency distribution. CONCLUSIONS: The results, based on in silico metrics, indicate that ICOR codon optimization is theoretically more effective in enhancing recombinant expression of proteins over other established codon optimization techniques. Our tool is provided as an open-source software package that includes the benchmark set of sequences used in this study.

Impact of piflufolastat F-18 PSMA PET imaging on clinical decision-making in prostate cancer across disease states: A retrospective review.

INTRODUCTION: Piflufolastat F-18 (18F-DCFPyL) prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging is approved by the US food and drug administration for initial staging of high-risk prostate cancer, biochemical recurrence (BCR), and restaging of metastatic prostate cancer. Here, we sought to assess how its integration into clinical care may have impacted the management of patients. METHODS: We identified 235 consecutive patients who underwent an 18F-DCFPyL PET scan from August 2021 to June 2022. The median prostate-specific antigen at the time of imaging was 1.8 ng/mL (Range: 0-3740 ng/mL). Descriptive statistics were used to analyze its impact on clinical care for a subset of 157 patients with available treatment information: 22 for initial staging, 109 with BCR, and 26 patients with known metastatic disease. RESULTS: PSMA-avid lesions were detected in 154/235 (65.5% of) patients. In patients undergoing initial staging, 18/39 (46.2% of) patients had extra-prostatic metastatic lesions; 15/39 (38.5% of) scans were negative and 6/39 (15.4%) had equivocal results. 12/22 (54.5% of) patients had a change in their treatment plan post-PSMA PET scan while 10/22 (45.5%) had no change in their treatment plan. In the BCR cohort, 93/150 (62.0%) had a local recurrence or metastatic lesions. Equivocal and negative scans accounted for 11/150 (7.3%) and 46/150 (30.7%) of scans, respectively. 37/109 (33.9% of) patients had a change in their treatment plan, while treatment was not altered in 72/109 (66.1% of) cases. In patients with metastatic disease, 43/46 (93.5%) had PSMA-avid lesions identified; equivocal and negative scans accounted for 2/46 (4.3%) and 1/46 (2.2%) of scan results, respectively. 6/26 (23.1%) had their tentative treatment plan adjusted after the PSMA PET scan. No change in the treatment plan was observed in 20/26 (76.9% of) cases. CONCLUSION: Integration of F-18 PSMA PET imaging impacted clinical decision-making and subsequent management across all stages of prostate cancer. It remains to be seen whether this translates into superior survival outcomes.

Nonlinear association between body mass index and overall survival in advanced NSCLC patients treated with immune checkpoint blockade.

BACKGROUND: We investigated the association of body mass index (BMI) modeled as a continuous variable with survival outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). METHODS: We performed a single-institution retrospective analysis of consecutively diagnosed locally advanced or metastatic NSCLC patients treated with single-agent ICI in the first line or recurrent setting. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and objective response rate (ORR). BMI was modeled using a four-knot restricted cubic spline. Multiple Cox regression was used for survival analysis. RESULTS: Two hundred patients were included (female 54%; never smoker 12%). Adenocarcinoma was the most common histology (61%). Median age was 67 years, median BMI was 25.9 kg/m2, and 65% of patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. On multivariable analysis, only BMI and ECOG PS were independently associated with OS (p < 0.01). Mortality risk decreased as the BMI increased from 20 to 30 kg/m2 (HR 0.49, 95% CI 0.28-0.84); however, it was reversed as the BMI surpassed ~ 30 kg/m2. Compared to ECOG PS ≥ 2, patients with ECOG PS of 0-1 had a longer OS (HR 0.42, 95% CI 0.28-0.63). Similar trends were observed with PFS and ORR, but the strength of the association was weaker. CONCLUSION: We observed a nonlinear association between BMI and OS following treatment with ICI in advanced NSCLC. Risk of death increases at both extremes of BMI with a nadir that exists around 30 kg/m2.

Ipsilateral femoral neck and shaft fractures: case series from a single Level-I trauma centre and review of literature.

INTRODUCTION: Uncommon but increasingly diagnosed, ipsilateral femoral neck and shaft fracture represents a complex injury pattern with challenging management. The conundrum involves optimal diagnostic modality, timing of surgery, sequence of fixation, and the choice of implant. METHODOLOGY: A retrospective review was conducted at a Level-I trauma centre to assess the outcome of concomitant femoral neck and shaft fractures managed with various implants and attempt to provide solutions to the aforementioned queries. The time between injury and definitive surgery, choice of implant, sequence of fixation, time to fracture union, and complications were documented and analyzed. RESULTS: A total of 46 patients were included in the study wherein associated neck fracture was identified preoperatively in 93.5% of patients. In patients with isolated limb fractures, the mean time to surgery was 16.7 ± 5 h whereas patients with polytrauma witnessed an average delay of 4.6 days before fracture fixation. 72% of patients were managed by dual implants and in the remaining both the fractures were addressed using a single implant with no union time difference amongst implants. The mean time to the union for neck fracture was 21.7 weeks and 24.2 weeks for shaft femur fracture. 21.7% patients developed delayed union of fracture shaft femur and infection complicated 11% shaft fractures. CONCLUSION: Although, 6% neck fractures were missed in the series, we advocate that careful pre/intra/post-operative fluoroscopic evaluation of the femoral neck along with a low threshold for a pre-operative CT scan remains the optimal diagnostic modality while avoiding universal employment of computed tomography (CT). With fracture union being unaffected by implant choice, authors suggest that anatomical fixation of the femoral neck is of paramount importance followed by restoration of the length, alignment and rotation of the femoral shaft, and the implant selection primarily depends on surgeon's experience and the pattern of injury.

Delayed Kinetics of IgG, but Not IgA, Antispike Antibodies in Transplant Recipients following SARS-CoV-2 Infection.

BACKGROUND: Kidney transplant recipients are at increased risk of severe outcomes during COVID-19. Antibodies against the virus are thought to offer protection, but a thorough characterization of anti-SARS-CoV-2 immune globulin isotypes in kidney transplant recipients following SARS-CoV-2 infection has not been reported. METHODS: We performed a cross-sectional study of 49 kidney transplant recipients and 42 immunocompetent controls at early (≤14 days) or late (>14 days) time points after documented SARS-CoV-2 infection. Using a validated semiquantitative Luminex-based multiplex assay, we determined the abundances of IgM, IgG, IgG1-4, and IgA antibodies against five distinct viral epitopes. RESULTS: Kidney transplant recipients showed lower levels of total IgG antitrimeric spike (S), S1, S2, and receptor binding domain (RBD) but not nucleocapsid (NC) at early versus late time points after SARS-CoV-2 infection. Early levels of IgG antispike protein epitopes were also lower than in immunocompetent controls. Anti-SARS-CoV-2 antibodies were predominantly IgG1 and IgG3, with modest class switching to IgG2 or IgG4 in either cohort. Later levels of IgG antispike, S1, S2, RBD, and NC did not significantly differ between cohorts. There was no significant difference in the kinetics of either IgM or IgA antispike, S1, RBD, or S2 on the basis of timing after diagnosis or transplant status. CONCLUSIONS: Kidney transplant recipients mount early anti-SARS-CoV-2 IgA and IgM responses, whereas IgG responses are delayed compared with immunocompetent individuals. These findings might explain the poor outcomes in transplant recipients with COVID-19. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/JASN/2021_11_23_briggsgriffin112321.mp3.

Bipolar clavicular dislocation treated with biological anatomical repair and reconstruction: A case report with a literature review of management options.

Bipolar clavicular dislocation is rare, and therefore its management is contentious. With an increase of patient's physical demand and a near-normal shoulder function, there has been a shift in the paradigm of its management from a conservative one to a stabilized one of anatomical open reduction. Proposed methods of fixation have also evolved with the advent of more biological fixation devices, which elude implant or fixation related complications. This case report highlights the salient features of this rare case and details the management options along with the benefits of biological anatomical repair and reconstruction.

Intracapsular fracture of the proximal femur in a bilateral above-knee amputee: A case report with technical tips for intraoperative positioning and literature review.

Intracapsular fractures of the proximal femur are one of the most common fractures of the lower limbs. Most cases require osteosynthesis with suitable implants, and intraoperative positioning of the patient on the fracture table is a prerequisite to facilitate fracture manipulation, traction, reduction and fluoroscopy assessment. However, positioning the limbs of bilateral above-knee amputees for internal fixation of related proximal femoral fractures is a difficult task, which requires customized inventory for effective limb positioning and fracture manipulation. This study reported a rare case following a crush injury of bilateral lower limb in a road traffic accident, and described some technical tips of acute femoral neck fractures in bilateral above-knee amputation. The patient was managed with immediate guillotine amputation and later secondary wound closure followed by internal fixation of the right-sided femoral neck fracture with multiple cancellous cannulated screws.

Multiplexed Relative Quantitation with Isobaric Tagging Mass Spectrometry Reveals Class I Major Histocompatibility Complex Ligand Dynamics in Response to Doxorubicin.

MHC-I peptides are intracellular-cleaved peptides, usually 8-11 amino acids in length, which are presented on the cell surface and facilitate CD8+ T cell responses. Despite the appreciation of CD8+ T-cell antitumor immune responses toward improvement in patient outcomes, the MHC-I peptide ligands that facilitate the response are poorly described. Along these same lines, although many therapies have been recognized for their ability to reinvigorate antitumor CD8+ T-cell responses, whether these therapies alter the MHC-I peptide repertoire has not been fully assessed due to the lack of quantitative strategies. We develop a multiplexing platform for screening therapy-induced MHC-I ligands by employing tandem mass tags (TMTs). We applied this approach to measuring responses to doxorubicin, which is known to promote antitumor CD8+ T-cell responses during its therapeutic administration in cancer patients. Using both in vitro and in vivo systems, we show successful relative quantitation of MHC-I ligands using TMT-based multiplexing and demonstrate that doxorubicin induces MHC-I peptide ligands that are largely derived from mitotic progression and cell-cycle proteins. This high-throughput MHC-I ligand discovery approach may enable further explorations to understand how small molecules and other therapies alter MHC-I ligand presentation that may be harnessed for CD8+ T-cell-based immunotherapies.

Facile Synthesis of Semiconducting Ultrathin Layer of Molybdenum Disulfide.

In this paper, we have reported a simple and efficient method for the synthesis of uniform, highly conducting single or few layer molybdenum disulfide (MoS2) on large scale. Scanning Electron Microscopy (SEM) and High Resolution Transmission Electron Microscopy (HRTEM) have been used for the confirmation of mono or few layered nature of the as-synthesized MoS2 sheets. X-ray Photoelectron Spectroscopy (XPS), X-Ray Diffraction (XRD) and Raman Spectroscopy have also been used to study the elemental, phase, and molecular composition of the sample. Optical properties of as-synthesized sample have been probed by measuring absorption and photoluminescence spectra which also compliment the formation of mono and few layers MoS2 Current-voltage (I-V ) characteristics of as-synthesized sample in the pellet form reveal that MoS2 sheets have an ohmic character and found to be highly conducting. Besides characterizing the as-synthesized sample, we have also proposed the mechanism and factors which play a decisive role in formation of high quality MoS2 sheets.

On thin ice: barriers to adoption of surveillance for patients with stage I testicular seminoma. Survey of US radiation oncologists.

PURPOSE: Most men with stage I testicular seminoma are cured with surgery alone, which is a preferred strategy per national guidelines. The current pattern of practice among US radiation oncologists (ROs) is unknown. MATERIALS AND METHODS: We surveyed practicing US ROs via an online questionnaire. Respondent's characteristics, self-rated knowledge, perceived patient compliance rates with observation were analyzed for association with treatment recommendations. RESULTS: We received 353 responses from ROs, of whom 23% considered themselves experts. A vast majority (84%) recommend observation as a default strategy, however this rate drops to 3% if the patient is believed to be noncompliant. 33% of respondents believe that survival is jeopardized in case of disease recurrence, and among these respondents only 5% support observation. 22% of respondents over-estimate the likelihood of noncompliance with observation to be in the 50-80% range. Responders with a higher perceived noncompliance rate are more likely to recommend adjuvant therapy (Fisher's exact p<0.01). Only 7% of respondents recommend observation for stage IS seminoma and 45% administer adjuvant RT in patients with elevated pre-orchiectomy alpha-fetal protein levels. CONCLUSIONS: Many US ROs over-estimate the likelihood that stage I testicular seminoma patients will be noncompliant with surveillance and incorrectly believe that overall survival is jeopardized if disease recurs on surveillance. Observation is quickly dismissed for patients who are not deemed to be compliant with observation, and is generally not accepted for patients with stage IS disease. There is clearly an opportunity for improved physician education on evidence-based management of stage I testicular seminoma.

Forward bias operation of silicon photonic Mach Zehnder modulators for RF applications.

In this paper, we demonstrate that forward bias (+0.9V) of a high-speed silicon (Si) optical Mach-Zehnder modulator (MZM) increases the radio-frequency (RF) link gain by 30 dB when compared to reverse bias operation (-8V). RF applications require tunable, narrowband electro-optic conversion with high gain to mitigate noise of the optical receiver and realize high RF spur-free dynamic range. Compared to reverse bias, the forward bias gain rolls off more rapidly but offers higher RF link gain improvement of more than 13.2 dB at 20 GHz. Furthermore, forward bias is shown to result in comparable spurious-free dynamic range (SFDR: 104.5 dB.Hz2/3). We demonstrate through an analytical dc transfer curve the existence of simultaneous high gain and OIP3 and verify the theoretical results with measurement under forward bias at a bias point of around +0.9 V.

Novel Lasers Based on Resonant Dark States.

The route to miniaturization of laser systems has so far led to the utilization of diverse materials and techniques for reaching the desired laser oscillation at small scales. Unfortunately, at some point all approaches encounter a trade-off between the system dimensions and the Q factor, especially when going subwavelength, mostly because the radiation damping is inherent to the oscillating mode and can thus not be controlled separately. Here, we propose a metamaterial laser system that overcomes this trade-off and offers radiation damping tunability, along with many other features, such as directionality, subwavelength integration, and simple layer-by-layer fabrication.

Effect of parameter mismatch on the dynamics of strongly coupled self sustained oscillators.

In this paper, we present an experimental setup and an associated mathematical model to study the synchronization of two self-sustained, strongly coupled, mechanical oscillators (metronomes). The effects of a small detuning in the internal parameters, namely, damping and frequency, have been studied. Our experimental system is a pair of spring wound mechanical metronomes; coupled by placing them on a common base, free to move along a horizontal direction. We designed a photodiode array based non-contact, non-magnetic position detection system driven by a microcontroller to record the instantaneous angular displacement of each oscillator and the small linear displacement of the base, coupling the two. In our system, the mass of the oscillating pendula forms a significant fraction of the total mass of the system, leading to strong coupling of the oscillators. We modified the internal mechanism of the spring-wound "clockwork" slightly, such that the natural frequency and the internal damping could be independently tuned. Stable synchronized and anti-synchronized states were observed as the difference in the parameters was varied in the experiments. The simulation results showed a rapid increase in the phase difference between the two oscillators beyond a certain threshold of parameter mismatch. Our simple model of the escapement mechanism did not reproduce a complete 180° out of phase state. However, the numerical simulations show that increased mismatch in parameters leads to a synchronized state with a large phase difference.

Large quality factor in sheet metamaterials made from dark dielectric meta-atoms.

Metamaterials--or artificial electromagnetic materials--can create media with properties unattainable in nature, but mitigating dissipation is a key challenge for their further development. Here, we demonstrate a low-loss metamaterial by exploiting dark bound states in dielectric inclusions coupled to the external waves by small nonresonant metallic antennas. We experimentally demonstrate a dispersion-engineered metamaterial based on a meta-atom made from alumina, and we show that its resonance has a much larger quality factor than metal-based meta-atoms. Finally, we show that our dielectric meta-atom can be used to create sheet metamaterials with negative permittivity or permeability.

Determinants and normal values of ascending aortic diameter by age, gender, and race/ethnicity in the Multi-Ethnic Study of Atherosclerosis (MESA).

PURPOSE: To determine the normal size and wall thickness of the ascending thoracic aorta (AA) and its relationship with cardiovascular risk factors in a large population-based study. MATERIALS AND METHODS: The mean AA luminal diameter was measured in 3573 Multi-Ethnic Study of Atherosclerosis (MESA) participants (age: 45-84 years), using gradient echo phase contrast cine MRI. Multiple linear regression models were used to evaluate the associations between risk factors and AA diameter. The median and upper normal limit (95th percentile) was defined in a "healthy" subgroup as well as AA wall thickness. RESULTS: The upper limits of body surface area indexed AA luminal diameter for age categories of 45-54, 55-64, 65-74, and 75-84 years are 21, 22, 22, and 28 mm/m(2) in women and 20, 21, 22, 23 mm/m(2) in men, respectively. The mean AA wall thickness was 2.8 mm. Age, gender, and body surface area were major determinants of AA luminal diameter (∼+1 mm/10 years; ∼+1.9 mm in men than women; ∼+1 mm/ 0.23 m(2) ; P < 0.001). The AA diameter in hypertensive subjects was +0.9 mm larger than in normotensives (P < 0.001). CONCLUSION: AA diameter increases gradually with aging for both genders among all race/ethnicities. The normal value of AA diameter is provided.

Revolutionizing Wound Healing: Unleashing Nanostructured Lipid Carriers Embodied with Herbal Medicinal Plant.

Wound healing is crucial for maintaining skin integrity and preventing complications from external threats. Various plants, such as Achillea millefolium, Aloe vera, Curcuma longa, Calendula officinalis, Camellia sinensis, Azadirachta indica, and Plantago, have demonstrated wound healing capabilities and have been used in herbal medicine for wound care. NLCs are second-generation lipid nanoparticles, blending solid and liquid lipids to improve medication loading and limit leakage. NLCs have been used in various applications, including cosmeceuticals, chemotherapy, gene therapy, and brain targeting. Wound healing is divided into four stages: hemostasis, inflammatory response, proliferation, and remodeling. Factors such as age, gender, chronic disorders, and local agents like infections can affect recovery. These plants' antiinflammatory, antioxidant, and antibacterial activities have demonstrated potential in wound healing. Combining herbal medicinal plants and nanostructured lipid carriers (NLCs) can revolutionise wound treatment and improve overall healthcare outcomes.

Convergence of Crisis: A Case Report of Diabetic Ketoacidosis Masking an Impending Thyroid Storm and Periodic Paralysis.

Diabetic ketoacidosis (DKA) is an extreme complication of diabetes mellitus characterized by hyperglycemia, metabolic acidosis, and ketonemia. Thyroid storm, a potentially life-threatening manifestation of thyrotoxicosis, presents with a multitude of symptoms, including hyperthermia, tachycardia, and altered mental status. Periodic paralysis can be precipitated by different metabolic disturbances, including thyrotoxicosis, and may lead to extreme episodes of muscle weakness and paralysis. We present a case of a 41-year-old female with a history of type 1 diabetes mellitus and hyperthyroidism, who presented with DKA complicated by an impending thyroid storm and likely periodic paralysis exacerbated due to hypokalemia. Prompt recognition and aggressive management of each component of this triad were essential for a positive patient outcome. This case highlights the importance of a broad and comprehensive approach to managing complex metabolic emergencies, particularly in patients with multiple comorbidities. Our patient presented to the emergency department with symptoms of severe vomiting, shortness of breath, and altered mental status. Laboratory investigations revealed metabolic derangements consistent with DKA, alongside impending thyrotoxicosis and hypokalemia-induced periodic paralysis. Management involved aggressive fluid resuscitation, insulin therapy, anti-thyroid medications, and potassium supplementation, with a multidisciplinary approach to stabilize the patient's condition.

Exploring the Microbial Landscape of Neonatal Skin Flora: A Comprehensive Review.

This comprehensive review explores the intricate landscape of the neonatal skin microbiome, shedding light on its dynamic composition, developmental nuances, and influential factors. The neonatal period represents a critical window during which microbial colonization significantly impacts local skin health and the foundational development of the immune system. Factors such as mode of delivery and gestational age underscore the vulnerability of neonates to disruptions in microbial establishment. Key findings emphasize the broader systemic implications of the neonatal skin microbiome, extending beyond immediate health outcomes to influence susceptibility to infections, allergies, and immune-related disorders. This review advocates for a paradigm shift in neonatal care, proposing strategies to preserve and promote a healthy skin microbiome for long-term health benefits. The implications of this research extend to public health, where interventions targeting the neonatal skin microbiome could potentially mitigate diseases originating in early life. As we navigate the intersection of research and practical applications, bridging the gap between knowledge and implementation becomes imperative for translating these findings into evidence-based practices and improving neonatal well-being on a broader scale.

Weyers Acrofacial Dysostosis: A Case Report.

Weyers acrofacial dysostosis (WAD) is a rare skeletal dysplasia, which is autosomal-dominant, and the clinical symptoms are presented as dental anomalies, polydactyly, nail dystrophy, and short physical stature. It is also termed "Curry­Hall syndrome" and reported to be linked to genetic mutations mapped on chromosome 4p16, the region reported being commonly associated with a similar genetic syndrome, Ellis-van Creveld (EVC) syndrome. Most individuals with EVC have congenital heart abnormalities, most often atrial septal defects, unlike WAD. In this case, a 15­year­old girl presented with onychodystrophy and polydactyly observed in the hands and feet, microdontia, or agenesis of teeth, which were conical in shape, with a short stature. The patient had dystrophy of nails since birth, and physical growth in terms of height did not match the normal growth parameters with respect to age. The patient also had abnormal dentation with conical-shaped teeth, with the rest of the clinical presentations suggestive of WAD.