Chain-length dependent organisation in mixtures of hydrogenous and fluorous ionic liquids.

As part of an ongoing study of the structure and properties of mixtures of ionic liquids in which one component has a hydrocarbon chain and the other a semiperfluorocarbon chain, we now report a study of the mixtures [C8MIM]1-x[C10MIM-F17]x[Tf2N], [C10MIM]1-x[C8MIM-F13]x[Tf2N] and [C10MIM]1-x[C10MIM-F17]x[Tf2N], where [C8MIM][Tf2N] is 1-methyl-3-octylimidazolium bis(trifluoromethylsulfonyl)imide, [C10MIM][Tf2N] is 1-decyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C8MIM-F13][Tf2N] is 1-(1H,1H,2H,2H-perfluorooctyl)-3-methylimidizolium bis(trifluoromethylsulfonyl)imide and [C10MIM-F17][Tf2N] is 1-(1H,1H,2H,2H-perfluorodecyl)-3-methylimidizolium bis(trifluoromethylsulfonyl)imide. The mixtures were investigated using small-angle X-ray (SAXS) and neutron (SANS) scattering complemented by molecular dynamics simulations (with viscosity and surface tension measurements also possible for the mixtures [C10MIM]1-x[C8MIM-F13]x[Tf2N]). Unlike previous studies of [C8MIM]1-x[C8MIM-F13]x[Tf2N], where no strong evidence of alkyl/fluoroalkyl chain segregation or triphilic behaviour was seen (Elstone et al., J. Phys. Chem. B, 2023, 127, 7394-7407), these new mixtures show the formation of small aggregates of varying sizes of each component, even though all were co-miscible across the full range of compositions. Thus, while a clear polar non-polar peak (PNPP) was observed at large or small values of x, at intermediate compositions the small-angle neutron scattering at low q was dominated by scattering from these small aggregates, while at other compositions, there was little or no evidence of the PNPP. The origins of this behaviour are discussed in terms of inter-chain interactions.

Structure and inhibition of SARS-CoV-2 spike refolding in membranes.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the receptor angiotensin converting enzyme 2 (ACE2) and drives virus-host membrane fusion through refolding of its S2 domain. Whereas the S1 domain contains high sequence variability, the S2 domain is conserved and is a promising pan-betacoronavirus vaccine target. We applied cryo-electron tomography to capture intermediates of S2 refolding and understand inhibition by antibodies to the S2 stem-helix. Subtomogram averaging revealed ACE2 dimers cross-linking spikes before transitioning into S2 intermediates, which were captured at various stages of refolding. Pan-betacoronavirus neutralizing antibodies targeting the S2 stem-helix bound to and inhibited refolding of spike prehairpin intermediates. Combined with molecular dynamics simulations, these structures elucidate the process of SARS-CoV-2 entry and reveal how pan-betacoronavirus S2-targeting antibodies neutralize infectivity by arresting prehairpin intermediates.

Pulmonary Calcifying Fibrous Tumor in a Pediatric Patient: A Case Report.

A calcifying fibrous tumor (CFT), also known as calcifying fibrous pseudotumor, is an uncommon non-cancerous neoplasm usually located in the gastrointestinal tract. Its location in the lung is extremely rare, and only a few case reports have been published. This case report describes our diagnostic approach in a 9-year-old male patient with an incidental pulmonary mass. The mass was initially misdiagnosed, requiring multiple imaging tests and interventions to obtain the definitive diagnosis of pulmonary CFT. This paper aims to contribute to the limited information available on pulmonary CFT by presenting detailed findings from computed tomography and magnetic resonance imaging.

Deployment and validation of a smart bed architecture for untethered patients with wireless biomonitoring stickers.

Conventional patient monitoring in healthcare has limitations such as delayed identification of deteriorating conditions, disruptions to patient routines, and discomfort due to extensive wiring for bed-bound patients. To address these, we have recently developed an innovative IoT-based healthcare system for real-time wireless patient monitoring. This system includes a flexible epidermal patch that collects vital signs using low power electronics and transmits the data to IoT nodes in hospital beds. The nodes connect to a smart gateway that aggregates the information and interfaces with the hospital information system (HIS), facilitating the exchange of electronic health records (EHR) and enhancing access to patient vital signs for healthcare professionals. Our study validates the proposed smart bed architecture in a clinical setting, assessing its ability to meet healthcare personnel needs, patient comfort, and data transmission reliability. Technical performance assessment involves analyzing key performance indicators for communication across various interfaces, including the wearable device and the smart box, and the link between the gateway and the HIS. Also, a comparative analysis is conducted on data from our architecture and traditional hospital equipment. Usability evaluation involves questionnaires completed by patients and healthcare professionals. Results demonstrate the robustness of the architecture proposed, exhibiting reliable and efficient information flow, while offering significant improvements in patient monitoring over conventional wired methods, including unrestricted mobility and improved comfort to enhance healthcare delivery.

Foliar Spraying with ZnSO4 or ZnO of Vitis vinifera cv. Syrah Increases the Synthesis of Photoassimilates and Favors Winemaking.

Zinc enrichment of edible food products, through the soil and/or foliar application of fertilizers, is a strategy that can increase the contents of some nutrients, namely Zn. In this context, a workflow for agronomic enrichment with zinc was carried out on irrigated Vitis vinifera cv. Syrah, aiming to evaluate the mobilization of photoassimilates to the winegrapes and the consequences of this for winemaking. During three productive cycles, foliar applications were performed with ZnSO4 or ZnO, at concentrations ranging between 150 and 1350 g.ha-1. The normal vegetation index as well as some photosynthetic parameters indicated that the threshold of Zn toxicity was not reached; it is even worth noting that with ZnSO4, a significant increase in several cases was observed in net photosynthesis (Pn). At harvest, Zn biofortification reached a 1.2 to 2.3-fold increase with ZnSO4 and ZnO, respectively (being significant relative to the control, in two consecutive years, with ZnO at a concentration of 1350 g.ha-1). Total soluble sugars revealed higher values with grapes submitted to ZnSO4 and ZnO foliar applications, which can be advantageous for winemaking. It was concluded that foliar spraying was efficient with ZnO and ZnSO4, showing potential benefits for wine quality without evidencing negative impacts.

Nucleosomes play a dual role in regulating transcription dynamics.

Transcription has a mechanical component, as the translocation of the transcription machinery or RNA polymerase (RNAP) on DNA or chromatin is dynamically coupled to the chromatin torsion. This posits chromatin mechanics as a possible regulator of eukaryotic transcription, however, the modes and mechanisms of this regulation are elusive. Here, we first take a statistical mechanics approach to model the torsional response of topology-constrained chromatin. Our model recapitulates the experimentally observed weaker torsional stiffness of chromatin compared to bare DNA and proposes structural transitions of nucleosomes into chirally distinct states as the driver of the contrasting torsional mechanics. Coupling chromatin mechanics with RNAP translocation in stochastic simulations, we reveal a complex interplay of DNA supercoiling and nucleosome dynamics in governing RNAP velocity. Nucleosomes play a dual role in controlling the transcription dynamics. The steric barrier aspect of nucleosomes in the gene body counteracts transcription via hindering RNAP motion, whereas the chiral transitions facilitate RNAP motion via driving a low restoring torque upon twisting the DNA. While nucleosomes with low dissociation rates are typically transcriptionally repressive, highly dynamic nucleosomes offer less of a steric barrier and enhance the transcription elongation dynamics of weakly transcribed genes via buffering DNA twist. We use the model to predict transcription-dependent levels of DNA supercoiling in segments of the budding yeast genome that are in accord with available experimental data. The model unveils a paradigm of DNA supercoiling-mediated interaction between genes and makes testable predictions that will guide experimental design.

Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling.

We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.

Machine learning in biological physics: From biomolecular prediction to design.

Machine learning has been proposed as an alternative to theoretical modeling when dealing with complex problems in biological physics. However, in this perspective, we argue that a more successful approach is a proper combination of these two methodologies. We discuss how ideas coming from physical modeling neuronal processing led to early formulations of computational neural networks, e.g., Hopfield networks. We then show how modern learning approaches like Potts models, Boltzmann machines, and the transformer architecture are related to each other, specifically, through a shared energy representation. We summarize recent efforts to establish these connections and provide examples on how each of these formulations integrating physical modeling and machine learning have been successful in tackling recent problems in biomolecular structure, dynamics, function, evolution, and design. Instances include protein structure prediction; improvement in computational complexity and accuracy of molecular dynamics simulations; better inference of the effects of mutations in proteins leading to improved evolutionary modeling and finally how machine learning is revolutionizing protein engineering and design. Going beyond naturally existing protein sequences, a connection to protein design is discussed where synthetic sequences are able to fold to naturally occurring motifs driven by a model rooted in physical principles. We show that this model is "learnable" and propose its future use in the generation of unique sequences that can fold into a target structure.

The presence of a deep lateral femoral notch sign in ACL-injured patients is associated with a 2.7° steeper posterior tibial slope and a 19% higher frequency of lateral meniscal injuries.

PURPOSE: The purpose of this study was to study the relationship between the presence of a deep lateral femoral notch sign (DLFNS) in anterior cruciate ligament (ACL)-injured patients and a higher posterior lateral tibial slope (LPTS), a reduced meniscal bone angle (MBA), a higher LPTS/MBA ratio and a higher incidence of concomitant injuries in primary ACL tears. METHODS: A retrospective case-control study was performed in patients submitted to primary ACL reconstruction with an available preoperative magnetic resonance imaging (MRI) scan. Patients with ACL tears and a femoral impactation with a depth ≥2 mm were assorted to the DLFNS group and patients with ACL tear and without a DLFNS to the control group. LPTS and MBA were measured in MRI. The presence of concomitant injuries (meniscal, posterior cruciate ligament, medial collateral ligament, lateral collateral ligament and bone injuries) was assessed in MRI. Quantitative data are presented in the median ± interquartile range (IQR). RESULTS: There were 206 patients included in the study, with 46 patients assorted to the DLFNS group and 160 patients to the control group. In the DLFNS group, the median LPTS was 6.7° (IQR: 4.0-8.2) versus 4.0° in the control group (IQR: 2.2-6.5) (p = 0.003). The LPTS/MBA ratio was significantly higher in the DLFNS group, with a median of 0.32 (IQR: 0.19-0.44), in comparison to the control group, with a median of 0.19 (IQR: 0.11-0.31) (p < 0.001). The multivariable logistic regression analysis showed that the LPTS is an independent risk factor to having a DLFNS (odds ratio [OR] = 1.161; 95% confidence interval [CI]: 1.042-1.293, p = 0.007). There was a higher incidence of concomitant lateral meniscal injuries in the DLFNS group (67% vs. 48%, p = 0.017). CONCLUSIONS: In patients with ACL tears, the presence of a DLFNS is associated with a steeper lateral posterior tibial slope, as well as a higher incidence of concomitant lateral meniscal injuries. LEVEL OF EVIDENCE: Level III.

Magnesium ions mitigate metastable states in the regulatory landscape of mRNA elements.

Residing in the 5' untranslated region of the mRNA, the 2'-deoxyguanosine (2'-dG) riboswitch mRNA element adopts an alternative structure upon binding of the 2'-dG molecule, which terminates transcription. RNA conformations are generally strongly affected by positively charged metal ions (especially Mg2+). We have quantitatively explored the combined effect of ligand (2'-dG) and Mg2+ binding on the energy landscape of the aptamer domain of the 2'-dG riboswitch with both explicit solvent all-atom molecular dynamics simulations (99 µsec aggregate sampling for the study) and selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) experiments. We show that both ligand and Mg2+ are required for the stabilization of the aptamer domain; however, the two factors act with different modalities. The addition of Mg2+ remodels the energy landscape and reduces its frustration by the formation of additional contacts. In contrast, the binding of 2'-dG eliminates the metastable states by nucleating a compact core for the aptamer domain. Mg2+ ions and ligand binding are required to stabilize the least stable helix, P1 (which needs to unfold to activate the transcription platform), and the riboswitch core formed by the backbone of the P2 and P3 helices. Mg2+ and ligand also facilitate a more compact structure in the three-way junction region.

RACER-m leverages structural features for sparse T cell specificity prediction.

Reliable prediction of T cell specificity against antigenic signatures is a formidable task, complicated by the immense diversity of T cell receptor and antigen sequence space and the resulting limited availability of training sets for inferential models. Recent modeling efforts have demonstrated the advantage of incorporating structural information to overcome the need for extensive training sequence data, yet disentangling the heterogeneous TCR-antigen interface to accurately predict MHC-allele-restricted TCR-peptide interactions has remained challenging. Here, we present RACER-m, a coarse-grained structural model leveraging key biophysical information from the diversity of publicly available TCR-antigen crystal structures. Explicit inclusion of structural content substantially reduces the required number of training examples and maintains reliable predictions of TCR-recognition specificity and sensitivity across diverse biological contexts. Our model capably identifies biophysically meaningful point-mutant peptides that affect binding affinity, distinguishing its ability in predicting TCR specificity of point-mutants from alternative sequence-based methods. Its application is broadly applicable to studies involving both closely related and structurally diverse TCR-peptide pairs.

CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance.

Mitochondria play a central role in muscle metabolism and function. A unique family of iron-sulfur proteins, termed CDGSH Iron Sulfur Domain-containing (CISD/NEET) proteins, support mitochondrial function in skeletal muscles. The abundance of these proteins declines during aging leading to muscle degeneration. Although the function of the outer mitochondrial CISD/NEET proteins, CISD1/mitoNEET and CISD2/NAF-1, has been defined in skeletal muscle cells, the role of the inner mitochondrial CISD protein, CISD3/MiNT, is currently unknown. Here, we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne muscular dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscles, as well as their mitochondria, and that CISD3 interacts with, and donates its [2Fe-2S] clusters to, complex I respiratory chain subunit NADH Ubiquinone Oxidoreductase Core Subunit V2 (NDUFV2). Using coevolutionary and structural computational tools, we model a CISD3-NDUFV2 complex with proximal coevolving residue interactions conducive of [2Fe-2S] cluster transfer reactions, placing the clusters of the two proteins 10 to 16 Å apart. Taken together, our findings reveal that CISD3/MiNT is important for supporting the biogenesis and function of complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact different muscle degeneration syndromes, aging, and related conditions.

Pulmonary and Urologic Sarcoidosis as a Cause of Intermittent Fever of Unknown Origin.

Diagnosing fever of unknown origin (FUO) presents a substantial challenge due to its potential association with various diseases affecting different organs. In 1961, Petersdorf and Beeson initially defined FUO as a condition characterized by a temperature exceeding 38.3 °C on at least three occasions over a minimum three-week period. Despite a week of inpatient investigation, a definitive diagnosis remains unclear.  Sarcoidosis, a granulomatous disease impacting multiple systems, is among the causes of FUO. While the lungs are commonly affected, any organ can be involved, leading to diverse manifestations and clinical courses. Diagnosis relies on clinicopathologic findings and the exclusion of alternative causes of granulomatous disease. The hallmark of sarcoidosis is the development of granulomas in affected organs. Here, we present the case of a 61-year-old man with a history of recurrent spontaneous periurethral abscesses who underwent multiple urological interventions. He developed FUO during hospitalization following treatment for the infectious condition.

Molecular Interactions between Ionic Liquid Lubricants and Silica Surfaces: An MD Simulation Study.

The unique physicochemical properties of ionic liquids (ILs) attracted interest in their application as lubricants of micro/nano-electromechanical systems. This work evaluates the feasibility of using the protic ionic liquids [4-picH][HSO4], [4-picH][CH3SO3], [MIMH][HSO4], and [MIMH][CH3SO3] and the aprotic ILs [C6mim][HSO4] and [C6mim][CH3SO3] as additives to model lubricant poly(ethylene glycol) (PEG200) to lubricate silicon surfaces. Additives based on the cation [4-picH]+ exhibited the best tribological performance, with the optimal value for 2% [4-picH][HSO4] in PEG200 (w/w). Molecular dynamics (MD) simulations of the first stages of adsorption of the ILs at the glass surface were performed to portray the molecular behavior of the ILs added to PEG200 and their interaction with the silica substrate. For the pure ILs at the solid substrates, the MD results indicated that weak specific interactions of the cation with the glass interface are lost to accommodate the larger anion in the first contact layer. For the PEG200 + 2% [4-picH][HSO4] system, the formation of a more compact protective film adsorbed at the glass surface is revealed by a larger trans population of the dihedral angle -O(R)-C-C-O(R)- in PEG200, in comparison to the same distribution for the pure model lubricant. Our findings suggest that the enhanced lubrication performance of PEG200 with [4-picH][HSO4] arises from synergistic interactions between the protic IL and PEG200 at the adsorbed layer.

Spatial-temporal order-disorder transition in angiogenic NOTCH signaling controls cell fate specification.

Angiogenesis is a morphogenic process resulting in the formation of new blood vessels from pre-existing ones, usually in hypoxic micro-environments. The initial steps of angiogenesis depend on robust differentiation of oligopotent endothelial cells into the Tip and Stalk phenotypic cell fates, controlled by NOTCH-dependent cell-cell communication. The dynamics of spatial patterning of this cell fate specification are only partially understood. Here, by combining a controlled experimental angiogenesis model with mathematical and computational analyses, we find that the regular spatial Tip-Stalk cell patterning can undergo an order-disorder transition at a relatively high input level of a pro-angiogenic factor VEGF. The resulting differentiation is robust but temporally unstable for most cells, with only a subset of presumptive Tip cells leading sprout extensions. We further find that sprouts form in a manner maximizing their mutual distance, consistent with a Turing-like model that may depend on local enrichment and depletion of fibronectin. Together, our data suggest that NOTCH signaling mediates a robust way of cell differentiation enabling but not instructing subsequent steps in angiogenic morphogenesis, which may require additional cues and self-organization mechanisms. This analysis can assist in further understanding of cell plasticity underlying angiogenesis and other complex morphogenic processes.

Blood vessels are vital for transporting blood containing oxygen, nutrients and waste around the body. To maintain this function, new blood vessels are continually formed through a process called angiogenesis. Often triggered in areas requiring oxygen, new blood vessels form from existing vessels as 'sprouts' in response to elevated levels of a signaling molecule called vascular endothelial growth factor (or VEGF for short). For 'sprouting' to occur, endothelial cells lining the parental blood vessel must become either 'Tip' or 'Stalk' cells. Tip cells lead the extension of the blood vessel sprouts, while Stalk cells proliferate rapidly, ensuring the growth of the sprout. Correct spatial arrangement of these different cell types is crucial for the development of functional blood vessels. Previous work has shown that VEGF promotes differentiation of endothelial cells lining blood vessels into different cell types. In neighboring cells, a signaling pathway known as NOTCH is activated due to interactions between adjacent cells, promoting differentiation of Tip cells and Stalk cells. Ideally, Tip cells are spaced out by intervals of Stalk cells to allow separate sprouts to form. Throughout this process, a single cell can receive contradictory signals, with VEGF promoting Tip cell formation and NOTCH signaling promoting Stalk cell differentiation. It remained unclear how the right cells are formed in the right places when surrounded by these conflicting inputs. To better understand these dynamics Kang, Bocci et al. combined a laboratory model of angiogenesis with mathematical modelling. Experiments using these approaches showed that the overall pattern of cell type specification induced by VEGF and NOTCH signaling is consistent with so-called order-disorder transition, commonly observed in crystals in other ordered structures. For blood vessel cells, this transition means that they can still robustly take on either the Tip or Stalk cell identities, but this fate selection is not stable in time. Additionally, the overall pattern is much more sensitive to additional cues and self-organization mechanisms. Further analysis revealed that one such cue can be local fluctuations the density of fibronectin, a key pro-angiogenic extracellular component, leading to formation of sprouts that tend to distance themselves as much as possible from other fully formed sprouts. These findings provide a framework for understanding NOTCH-mediated patterning processes in the context of responding to a variety of environmental cues. This sensitivity in cell type specification is important for determining the dynamic nature of the initial steps of angiogenesis and may be crucial for understanding growth of new blood vessels in damaged organs, cancer and other diseases.

Residue coevolution and mutational landscape for OmpR and NarL response regulator subfamilies.

DNA-binding response regulators (DBRRs) are a broad class of proteins that operate in tandem with their partner kinase proteins to form two-component signal transduction systems in bacteria. Typical DBRRs are composed of two domains where the conserved N-terminal domain accepts transduced signals and the evolutionarily diverse C-terminal domain binds to DNA. These domains are assumed to be functionally independent, and hence recombination of the two domains should yield novel DBRRs of arbitrary input/output response, which can be used as biosensors. This idea has been proved to be successful in some cases; yet, the error rate is not trivial. Improvement of the success rate of this technique requires a deeper understanding of the linker-domain and inter-domain residue interactions, which have not yet been thoroughly examined. Here, we studied residue coevolution of DBRRs of the two main subfamilies (OmpR and NarL) using large collections of bacterial amino acid sequences to extensively investigate the evolutionary signatures of linker-domain and inter-domain residue interactions. Coevolutionary analysis uncovered evolutionarily selected linker-domain and inter-domain residue interactions of known experimental structures, as well as previously unknown inter-domain residue interactions. We examined the possibility of these inter-domain residue interactions as contacts that stabilize an inactive conformation of the DBRR where DNA binding is inhibited for both subfamilies. The newly gained insights on linker-domain/inter-domain residue interactions and shared inactivation mechanisms improve the understanding of the functional mechanism of DBRRs, providing clues to efficiently create functional DBRR-based biosensors. Additionally, we show the feasibility of applying coevolutionary landscape models to predict the functionality of domain-swapped DBRR proteins. The presented result demonstrates that sequence information can be used to filter out bioengineered DBRR proteins that are predicted to be nonfunctional due to a high negative predictive value.

Secondary Analysis of a Dataset to Estimate the Prevalence of Vertebral Subluxation and Its Implications for Health Promotion and Prevention.

Background Vertebral subluxation (VS) is a clinical entity defined as a misalignment of the spine affecting biomechanical and neurological function. The identification and correction of VS is the primary focus of the chiropractic profession. The purpose of this study is to estimate VS prevalence using a sample of individuals presenting for chiropractic care and explore the preventative public health implications of VS through the promotion of overall health and function. Methodology A brief review of the literature was conducted to support an operational definition for VS that incorporated neurologic and kinesiologic exam components. A retrospective, quantitative analysis of a multi-clinic dataset was then performed using this operational definition. Descriptive statistics on patient demographic data included age, gender, and past health history characteristics. In addition to calculating estimates of the overall prevalence of VS, age- and gender-stratified estimates in the different clinics were calculated to allow for potential variations. Results A total of 1,851 patient records from seven chiropractic clinics in four states were obtained. The mean age of patients was 43.48 (SD = 16.8, range = 18-91 years). There were more females (n = 927, 64.6%) than males who presented for chiropractic care. Patients reported various reasons for seeking chiropractic care, including, spinal or extremity pain, numbness, or tingling; headaches; ear, nose, and throat-related issues; or visceral issues. Mental health concerns, neurocognitive issues, and concerns about general health were also noted as reasons for care. The overall prevalence of VS was 78.55% (95% CI = 76.68-80.42). Female and male prevalence of VS was 77.17% and 80.15%, respectively; notably, all per-clinic, age, or gender-stratified prevalences were ≥50%. Conclusions To date, this is the first study of its magnitude and application of an operational definition to estimate the prevalence of VS. Albeit nonrandom, the sample had a broad geographic distribution. The results of this study suggest a high rate of prevalence of VS in a sample of individuals who sought chiropractic care. Concerns about general health and wellness were represented in the sample and suggest chiropractic may serve a primary prevention function in the absence of disease or injury. Further investigation into the epidemiology of VS and its role in health promotion and prevention is recommended.

Acute-on-Chronic Aortic Dissection: Management and Outcomes of the Unstable "Triple-Lumen" Aorta.

BACKGROUND: The impact of acute aortic dissection of the chronically dissected distal aorta is unknown. This study sought to describe the incidence and characteristics of the triple-lumen aortic dissection and its impact on survival. METHODS: From 2010 to 2021, a query of a single-institution aortic database identified 1149 patients with chronic distal aortic dissection. Thirty-three (2.9%) patients with at least 3 distinct lumens and 2 separate "primary" intimal tears were identified by analysis of contrast-enhanced cross-sectional imaging. Triple-lumen patients were exactly matched with a cohort of double-lumen patients on a 1:1 ratio using 5 preoperative variables, and outcomes between the groups were assessed. RESULTS: The median age at time of initial dissection in patients with a triple-lumen dissection was 46 years. Initial dissection was a type A in 33% and a type B in 67% of patients. The median time from initial dissection to triple-lumen diagnosis was 4.2 years. On diagnosis of the triple-lumen aorta, 85% of patients required urgent aortic repair for rapid growth (36%), aortic diameter ≥55 mm (30%), malperfusion (6%), intractable pain (6%), and rupture/type A (6%). Thirty-day mortality after triple lumen dissection was 12%. CONCLUSIONS: Acute-on-chronic distal dissection resulting in a triple-lumen aorta should be classified as a "complicated" type B dissection as these patients typically have large aneurysms and a high incidence of rapid false lumen expansion requiring urgent surgical repair.

Optimal Therapeutic Strategy for PD-L1 Negative Metastatic Non-Small Cell Lung Cancer: A Decision-Making Guide Based on Clinicopathological and Molecular Features.

OPINION STATEMENT: Strategies using immune checkpoint inhibitors (ICI), which can enhance antitumor immune responses, have revolutionized the lung cancer therapeutic landscape. The ICI mechanism of action involves the blockade of regulatory cell surface molecules using antibodies against the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) (ipilimumab, tremelimumab); the programmed death receptor-1 (PD-1; nivolumab, pembrolizumab); or the PD ligand-1 (PD-L1; atezolizumab, durvalumab). Notably, anti-PD-1 demonstrated long-term survival benefits, durable objective responses, and a manageable safety profile in patients with non-small cell lung cancer (NSCLC). The combination of anti-PD1 or anti-PD-L1 and platinum chemotherapy achieved better survival outcomes than chemotherapy alone, which was observed irrespective of PD-L1 expression on cancer cells. Although promising results have been reported from large clinical trials, especially for patients with high PD-L1 expression, the optimal treatment approach for patients with PD-L1-negative NSCLC has yet to be defined. We propose a guide for clinicians in the therapeutic decision-making process based on the latest data available about treatments, prognostic factors, predictive biomarkers, and real-world evidence in PD-L1-negative NSCLC patients.

Calciphylaxis Secondary to Vitamin D Supplementation.

Calciphylaxis is a rare cutaneous disease consisting of purpuric and necrotic lesions, and it affects mostly patients with renal failure. More rarely, it can be observed in patients with preserved renal function, acquiring the name of non-uremic calciphylaxis (NUC). Although its pathophysiology is under uncertainty, many etiological factors have been implicated. This report describes a patient who developed NUC, possibly triggered by vitamin D supplementation.