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Background: Previous research on spinal alignment and postoperative outcomes after cervical and upper thoracic fixation has suggested that clinical and patient-reported outcomes are improved when certain anatomical parameters are maintained. These parameters include the cervical sagittal vertical axis (cSVA), C2 and T1 slopes, and cervical lordosis (CL). For patients with primary and metastatic tumors involving the subaxial cervical and/or upper thoracic spine, there is minimal guidance on how to apply these parameters. Surgeons must make critical decisions when designing the optimal construct, considering patient life expectancy, bone quality, oncology goals and deformity. This study aims to evaluate the impact of cervical spine alignment parameters on postoperative hardware failure in spine tumor patients and highlight instances of complications in patients with instrumentation crossing the cervicothoracic junction (CTJ). Methods: A retrospective review of a single institutional spine tumor database identified seventeen patients who underwent spinal fusion crossing the CTJ from 2015 to 2023. All patients had postoperative neutral standing radiographs with measurable cSVA, C2 and T1 slopes, and/or CL. The primary endpoint was instrumentation failure, defined as hardware pull out or breakage, and secondary endpoints included other complications including wound infection and spinal fluid leak. Results: The number of instrumented levels ranged from 3 to 15 segments with a mean of 7.47. Surgical approaches included anterior (n=3), posterior (n=12), and simultaneous anterior and posterior (n=2). The mean cSVA was 3.39±1.02 cm (range 1.59–4.9 cm). Fourteen patients had measurable C2 slopes with a mean of 25.03±9.16° (range 8.7 - 38.6°). Ten patients had measurable T1 slopes with a mean of 31.5±11.54° (range 18.4–59.6°). Thirteen patients had a measurable CL with a mean of 9.13±9.93° (range 0–37.5°). No cases of instrumentation failure were noted. Four patients experienced other postoperative complications (24%), but rates did not vary with increasing deviation from ideal parameters for cSVA, C2 and T1 slope, or CL. Conclusions: Although there was wide variability in alignment parameters in this cohort, there were no instances of hardware failure with crossing the CTJ at a mean follow-up of 41 months. The overall complication rate was high at 24%. Despite common concerns about the impact of exaggerated slope and SVA on instrumentation failure these results suggest that cervical and upper thoracic tumor patients may still have a satisfactory result following CTJ fixation, even with unfavorable alignment parameters. Larger prospective studies are needed.

Abstract Aluminum alloy AlSi10Mg is a widely used engineering material that offers a very high strength‐to‐weight ratio and easy processing. It is common in the aerospace, medical, and automotive industries and has excellent machining and casting properties, as well as being easily made into fine powder. In recent years, it has become one of the most common light‐weight materials for additive manufacturing (AM). Its chemical composition and stability in powder form make it particularly ideal for laser powder bed fusion (LPBF) applications. It is one of the few available aluminum alloys that can be reliably processed using AM. Numerous studies have been dedicated to mechanical properties and design strategies, but much less attention has been given to corrosion behavior. This article reviews the corrosion behavior and the correlation between the microstructure and corrosion for AlSi10Mg when fabricated using an LPBF process. Specific topics reviewed include corrosion performance, corrosion issues (pores, surface roughness, and residual stresses), and passive film formation mechanisms and compare these to conventionally‐manufactured counterparts. In addition, this review discusses available methods for mitigating and avoiding corrosion in LPBF‐processed AlSi10Mg parts, including relevant post‐processing methods.

Abstract Despite the importance of informed consent in healthcare, the readability and specificity of consent forms often impede patients’ comprehension. This study investigates the use of GPT-4 to simplify surgical consent forms and introduces an AI-human expert collaborative approach to validate content appropriateness. Consent forms from multiple institutions were assessed for readability and simplified using GPT-4, with pre- and post-simplification readability metrics compared using nonparametric tests. Independent reviews by medical authors and a malpractice defense attorney were conducted. Finally, GPT-4’s potential for generating de novo procedure-specific consent forms was assessed, with forms evaluated using a validated 8-item rubric and expert subspecialty surgeon review. Analysis of 15 academic medical centers’ consent forms revealed significant reductions in average reading time, word rarity, and passive sentence frequency (all P

Carbon-carbon composites are advanced materials known for their high strength, high-temperature stability, and superior thermal conductivity. Mechanical properties such as tensile strength, flexural strength, and compressive strength are examined, as well as thermal properties like the coefficient of thermal expansion and thermal conductivity, to understand the characteristics of the composite. Carbon-carbon composites are ideal for the aerospace industry’s need for lightweight and high-performance materials. Tribological and surface properties are relevant to this discussion, given the use case of carbon-carbon composites in extreme conditions, the effect of exposing the composite to different fluids and the change in friction and wear properties. Coatings can protect the composite from environmental factors such as UV radiation, oxidation, and erosion. Self-healing composites that can repair themselves can increase the lifespan of structures while reducing maintenance costs. These have been used in aerospace applications such as airplane braking systems, rocket nozzles, and re-entry vehicle heat shields. Furthermore, researchers have recently addressed the problem of finishing and drilling without delamination and loss of properties, and this study looks into unconventional methods that can be adopted for the same. This study aims to provide an overview of the current state of carbon-carbon composite materials and their applications.

Chronic inflammatory enteropathies (CIEs) are an important group of diseases in dogs and involve complex pathogenetic aspects. Endoscopy and histopathology are vital for documenting the disease but are less useful for subclassifying CIEs and predicting the response to treatment. However, healing of the mucosal disease process (deep remission) and ultrastructural evaluation of the mucosa have received little attention in canine CIE. Given that canine CIE shares many similarities with inflammatory bowel diseases (IBDs) in human patients—and presents a good spontaneous disease model for human IBD—this perspective article evaluates the literature on ultrastructural lesions in canine CIE and human IBD and offers future directions for the study of ultrastructural mucosal lesions in canine CIE. Such lesions might have a higher sensitivity of detection than structural changes revealed upon light microscopy and may even precede or remain after the resolution of the clinical signs and histologic lesions.

Abstract The Herpes simplex virus (HSV)-based platform for production of recombinant adeno-associated viral vectors (rAAVs) yields higher titers and increased percentage of full capsids when compared to the triple transient transfection (TTT) method. However, this platform currently faces two major challenges. The first challenge is the reliance on commercial media, sometimes supplemented with serum, leading to costly manufacturing and a high risk for introduction of adventitious agents. The second challenge is that the production of HSV-1 relies on adherent complementing Vero cells (V27), making it difficult to scale up. We engineered serum-free-adapted CHO cells expressing key HSV-1 entry receptors, HVEM and/or Nectin-1 to address the first challenge. Using high-throughput cloning methods, we successfully selected a HVEM receptor-expressing clone (CHO–HV–C1) that yields 1.62 × 109, 2.51 × 109, and 4.07 × 109 viral genome copies/mL with rAAV6.2-GFP, rAAV8-GFP, and rAAV9-GFP vectors respectively, within 24 h post rHSV-1 co-infection. Moreover, CHO–HV–C1-derived rAAVs had comparable in vitro transduction, infectivity, and biodistribution titers to those produced by TTT. The second challenge was addressed via engineering CHO–HV–C1 cells to express HSV-1 CP27. These cells successfully produced rHSV-1 vectors, but with significantly lower titers than V27 cells. Taken together, the CHO/HSV system provides a novel, scalable, reduced cost, serum-free AAV manufacturing platform.

The changing notion of “companion animals” and their increasing global status as family members underscores the dynamic interaction between gut microbiota and host health. This review provides a comprehensive understanding of the intricate microbial ecology within companion animals required to maintain overall health and prevent disease. Exploration of specific diseases and syndromes linked to gut microbiome alterations (dysbiosis), such as inflammatory bowel disease, obesity, and neurological conditions like epilepsy, are highlighted. In addition, this review provides an analysis of the various factors that impact the abundance of the gut microbiome like age, breed, habitual diet, and microbe-targeted interventions, such as probiotics. Detection methods including PCR-based algorithms, fluorescence in situ hybridisation, and 16S rRNA gene sequencing are reviewed, along with their limitations and the need for future advancements. Prospects for longitudinal investigations, functional dynamics exploration, and accurate identification of microbial signatures associated with specific health problems offer promising directions for future research. In summary, it is an attempt to provide a deeper insight into the orchestration of multiple microbial species shaping the health of companion animals and possible species-specific differences.

Sepsis is a potentially fatal condition characterized by organ dysfunction caused by an imbalanced immune response to infection. Although an increased inflammatory response significantly contributes to the pathogenesis of sepsis, several molecular mechanisms underlying the progression of sepsis are associated with increased cellular reactive oxygen species (ROS) generation and exhausted antioxidant pathways. This review article provides a comprehensive overview of the involvement of ROS in the pathophysiology of sepsis and the potential application of antioxidants with antimicrobial properties as an adjunct to primary therapies (fluid and antibiotic therapies) against sepsis. This article delves into the advantages and disadvantages associated with the utilization of antioxidants in the therapeutic approach to sepsis, which has been explored in a variety of animal models and clinical trials. While the application of antioxidants has been suggested as a potential therapy to suppress the immune response in cases where an intensified inflammatory reaction occurs, the use of multiple antioxidant agents can be beneficial as they can act additively or synergistically on different pathways, thereby enhancing the antioxidant defense. Furthermore, the utilization of immunoadjuvant therapy, specifically in septic patients displaying immunosuppressive tendencies, represents a promising advancement in sepsis therapy.

Abstract Organoids are three-dimensional structures of self-assembled cell aggregates that mimic anatomical features of in vivo organs and can serve as in vitro miniaturized organ models for drug testing. The most efficient way of studying drug toxicity and efficacy requires high-resolution imaging of a large number of organoids acquired in the least amount of time. Currently missing are suitable platforms capable of fast-paced high-content imaging of organoids. To address this knowledge gap, we present the OrganoidChip, a microfluidic imaging platform that incorporates a unique design to immobilize organoids for endpoint, fast imaging. The chip contains six parallel trapping areas, each having a staging and immobilization chamber, that receives organoids transferred from their native culture plates and anchors them, respectively. We first demonstrate that the OrganoidChip can efficiently immobilize intestinal and cardiac organoids without compromising their viability and functionality. Next, we show the capability of our device in assessing the dose-dependent responses of organoids’ viability and spontaneous contraction properties to Doxorubicin treatment and obtaining results that are similar to off-chip experiments. Importantly, the chip enables organoid imaging at speeds that are an order of magnitude faster than conventional imaging platforms and prevents the acquisition of blurry images caused by organoid drifting, swimming, and fast stage movements. Taken together, the OrganoidChip is a promising microfluidic platform that can serve as a building block for a multiwell plate format that can provide high-throughput and high-resolution imaging of organoids in the future.

Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2–5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or understood. In this study, using a candidate gene approach, we performed a genetic variant analysis of retinoic acid (RA) metabolic and developmental signaling pathway genes on whole exome sequencing data of 23 FASD-diagnosed individuals. We found risk and resilience alleles in ADH and ALDH genes known to normally be involved in alcohol detoxification at the expense of RA production, causing RA deficiency, following PAE. Risk and resilience variants were also identified in RA-regulated developmental pathway genes, especially in SHH and WNT pathways. Notably, we also identified significant variants in the causative genes of rare neurodevelopmental disorders sharing comorbidities with FASD, including STRA6 (Matthew–Wood), SOX9 (Campomelic Dysplasia), FDG1 (Aarskog), and 22q11.2 deletion syndrome (TBX1). Although this is a small exploratory study, the findings support PAE-induced RA deficiency as a major etiology underlying FASD and suggest risk and resilience variants may be suitable biomarkers to determine the risk of FASD outcomes following PAE.

Sexual minority men (SMM) and transgender women in South Africa engage in HIV care at lower rates than other persons living with HIV and may experience population-specific barriers to HIV treatment and viral suppression (VS). As part of a pilot trial of an SMM-tailored peer navigation (PN) intervention in Ehlanzeni district, South Africa, we assessed factors associated with ART use and VS among SMM at trial enrolment. A total of 103 HIV-positive SMM and transgender women enrolled in the pilot trial. Data on clinical visits and ART adherence were self-reported. VS status was verified through laboratory analysis (

Summary: Muscle stem cells (MuSCs) are the building blocks for regenerating skeletal muscle after trauma. If we intend to maximize the therapeutic potential of MuSCs, we must further study their molecular and functional properties. Here, we present a protocol for the isolation of mouse MuSCs via a two-step enzymatic and mechanical dissociation of skeletal muscle coupled with fluorescence-activated cell sorting (FACS). FACS-isolated MuSCs can be used for various downstream applications including cell culture, cell transduction, immunofluorescence, and gene expression assays.For complete details on the use and execution of this protocol, please refer to Almada et al. (2021).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Biofilm has been implicated in multi-drug resistant organism outbreaks following endoscopic procedures. Automated Endoscope Reprocessors (AER) are devices validated to clean and disinfect endoscopes per applicable standards. The ISO 15883 part 4 standard guides performance testing validation of AERs, including cleaning performance using a biofilm test soil. The standard recommends assessment of biofilm reduction using protein or carbohydrate quantification methods. The aim of this study was to assess the suitability of various quantification methods using the ISO biofilm model.The ISO 15883 part 5 biofilm test soil method was used to grow biofilm within lumens representative of endoscopes channels. The biofilm was then quantified using five methods: Crystal Violet (CV), Colony Forming Units (CFU), Total Organic Carbon (TOC), protein assay with Orthophtalaldehyde (OPA), and protein assay by micro bicinchoninic acid (μBCA). The five methods were statistically analyzed for their ability to assess biofilm reduction on samples accurately and precisely. In addition, the quantification methods were compared to demonstrate statistical equivalency, and thus their suitability for assessing biofilm cleaning performance testing of AERs.

Abstract Background A panel of IgA‐based serologic assays might aid in the diagnosis of chronic enteropathy (CE) in dogs, a syndrome encompassing conditions such as food‐responsive enteropathy, immunosuppressant‐responsive enteropathy, and inflammatory bowel disease (also referred to as chronic inflammatory enteropathy). However, it is unclear whether these biomarkers discriminate between CE and other types of primary intestinal disorders. Objectives To evaluate a diagnostic panel that measures serum concentrations of IgA directed against OmpC (ACA), canine calprotectin (ACNA), and gliadin‐derived peptides (AGA) in dogs with well‐characterized intestinal diseases. Animals Fifty‐five dogs with primary intestinal disease. Methods Serum ACA, ACNA, and AGA concentrations were measured in 30 dogs with CE and 25 dogs with other intestinal diseases (non‐CE population), including histoplasmosis, parasitism, E. coli‐associated granulomatous colitis, and lymphoma. Serum IgA concentrations were compared among populations, and sensitivities and specificities were calculated using laboratory‐provided cut‐points. Results Twenty‐six of 30 (87%) CE dogs and 21 of 25 (84%) non‐CE dogs had abnormal concentrations (intermediate or high) of at least 2 markers; these proportions were not significantly different (P = .99). A serum ACA concentration ≥15 EU/mL was 86.7% (95% confidence interval [CI], 69.3%‐96.2%) sensitive and 24.0% (95% CI, 9.4%‐45.1%) specific for CE diagnosis. High AGA concentrations were observed in 16 of 25 (64%) non‐CE dogs. Conclusions and Clinical Importance The evaluated serologic markers were poorly specific for CE diagnosis, which raises concerns that their use in clinical practice might lead to misdiagnoses and delayed or even detrimental treatments in dogs with non‐CE intestinal diseases.

Sweet syndrome (SS), or acute febrile neutrophilic dermatosis, is a rare painful skin condition that is characterized by hyperpyrexia, peripheral blood and skin neutrophilia, and edematous skin lesions. Necrotizing SS (NSS) is a severe and locally aggressive condition that histopathologically resembles a necrotizing soft tissue infection. As opposed to necrotizing soft tissue infections, NSS responds to systemic steroids. SS is divided into three subtypes: classical SS, malignancy-associated SS, and drug-induced SS. Within the malignancy-associated SS subtype, both solid tumor and hematologic malignancies have been precursors to developing SS. Here, we present a case of acute myeloid leukemia-associated NSS.

ABSTRACT Antibody responses to variant surface antigens (VSAs) produced by the malaria parasite Plasmodium falciparum may contribute to age-related natural immunity to severe malaria. One VSA family, P. falciparum erythrocyte membrane protein-1 (PfEMP1), includes a subset of proteins that binds endothelial protein C receptor (EPCR) in human hosts and potentially disrupts the regulation of inflammatory responses, which may lead to the development of severe malaria. We probed peptide microarrays containing segments spanning five PfEMP1 EPCR-binding domain variants with sera from 10 Malian adults and 10 children to determine the differences between adult and pediatric immune responses. We defined serorecognized peptides and amino acid residues as those that elicited a significantly higher antibody response than malaria-naïve controls. We aimed to identify regions consistently serorecognized among adults but not among children across PfEMP1 variants, potentially indicating regions that drive the development of immunity to severe malaria. Adult sera consistently demonstrated broader and more intense serologic responses to constitutive PfEMP1 peptides than pediatric sera, including peptides in EPCR-binding domains. Both adults and children serorecognized a significantly higher proportion of EPCR-binding peptides than peptides that do not directly participate in receptor binding, indicating a preferential development of serologic responses at functional residues. Over the course of a single malaria transmission season, pediatric serological responses increased between the start and the peak of the season, but waned as the transmission season ended. IMPORTANCE Severe malaria and death related to malaria disproportionately affect sub-Saharan children under 5 years of age, commonly manifesting as cerebral malaria and/or severe malarial anemia. In contrast, adults in malaria-endemic regions tend to experience asymptomatic or mild disease. Our findings indicate that natural immunity to malaria targets specific regions within the EPCR-binding domain, particularly peptides containing EPCR-binding residues. Epitopes containing these residues may be promising targets for vaccines or therapeutics directed against severe malaria. Our approach provides insight into the development of natural immunity to a binding target linked to severe malaria by characterizing an “adult-like” response as recognizing a proportion of epitopes within the PfEMP1 protein, particularly regions that mediate EPCR binding. This “adult-like” response likely requires multiple years of malaria exposure, as increases in pediatric serologic response over a single malaria transmission season do not appear significant.

Abstract. Endoscopic spine surgery (ESS) is an innovative technique allowing for minimally invasive, direct visualization of spinal abnormalities. The growth of ESS in the United States has been stunted by high start-up costs, low reimbursement rates, and the steep learning curve associated with mastering endoscopic techniques. Hergrae, we describe the current state and future direction of ESS and provide key action items for ESS program implementation.

Inflammatory bowel disease (IBD) is a chronic, relapsing gastrointestinal (GI) disorder characterized by intestinal inflammation. The etiology of IBD is multifactorial and results from a complex interplay between mucosal immunity, environmental factors, and host genetics. Future therapeutics for GI disorders, including IBD, that are driven by oxidative stress require a greater understanding of the cellular and molecular mechanisms mediated by reactive oxygen species (ROS). In the GI tract, oxidative stressors include infections and pro-inflammatory responses, which boost ROS generation by promoting the production of pro-inflammatory cytokines. Nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2–related factor 2 (Nrf2) represent two important signaling pathways in intestinal immune cells that regulate numerous physiological processes, including anti-inflammatory and antioxidant activities. Natural antioxidant compounds exhibit ROS scavenging and increase antioxidant defense capacity to inhibit pro-oxidative enzymes, which may be useful in IBD treatment. In this review, we discuss various polyphenolic substances (such as resveratrol, curcumin, quercetin, green tea flavonoids, caffeic acid phenethyl ester, luteolin, xanthohumol, genistein, alpinetin, proanthocyanidins, anthocyanins, silymarin), phenolic compounds including thymol, alkaloids such as berberine, storage polysaccharides such as tamarind xyloglucan, and other phytochemicals represented by isothiocyanate sulforaphane and food/spices (such as ginger, flaxseed oil), as well as antioxidant hormones like melatonin that target cellular signaling pathways to reduce intestinal inflammation occurring with IBD.

Abstract Background The AP-1 transcription factor, FBJ osteosarcoma oncogene (FOS), is induced in adult muscle satellite cells (SCs) within hours following muscle damage and is required for effective stem cell activation and muscle repair. However, why FOS is rapidly downregulated before SCs enter cell cycle as progenitor cells (i.e., transiently expressed) remains unclear. Further, whether boosting FOS levels in the proliferating progeny of SCs can enhance their myogenic properties needs further evaluation. Methods We established an inducible, FOS expression system to evaluate the impact of persistent FOS activity in muscle progenitor cells ex vivo. We performed various assays to measure cellular proliferation and differentiation, as well as uncover changes in RNA levels and three-dimensional (3D) chromatin interactions. Results Persistent FOS activity in primary muscle progenitor cells severely antagonizes their ability to differentiate and form myotubes within the first 2 weeks in culture. RNA-seq analysis revealed that ectopic FOS activity in muscle progenitor cells suppressed a global pro-myogenic transcriptional program, while activating a stress-induced, mitogen-activated protein kinase (MAPK) transcriptional signature. Additionally, we observed various FOS-dependent, chromosomal re-organization events in A/B compartments, topologically associated domains (TADs), and genomic loops near FOS-regulated genes. Conclusions Our results suggest that elevated FOS activity in recently activated muscle progenitor cells perturbs cellular differentiation by altering the 3D chromosome organization near critical pro-myogenic genes. This work highlights the crucial importance of tightly controlling FOS expression in the muscle lineage and suggests that in states of chronic stress or disease, persistent FOS activity in muscle precursor cells may disrupt the muscle-forming process.

Although it is well-recognized within the endoscopic spine community that a learning curve exists for percutaneous endoscopic lumbar discectomy (PELD), it is less well understood how the learning curve impacts PELD clinical outcomes. This systematic literature review serves as the most comprehensive and up-to-date resource on this topic. Following a focused literature search, 21 articles on the learning curve for PELD were found, and from those articles, 21 unique clinical outcome metrics were identified. Operative time was the most commonly reported clinical outcome metric in this cohort, appearing in 17 studies. There were unanimous findings among the relevant studies that the following clinical outcomes are not affected by the learning curve for PELD: Oswestry Disability Index and herniation rate. Additionally, there were unanimous findings that the following clinical results are affected by the learning curve for PELD: cannula placement time, postoperative dural sac cross-sectional area; fluoroscopy time; and operative time. The purpose of this collection of findings in this systematic review is to positively inform current and future surgeons and trainees embarking on the learning curve for PELD.

Reported Legionnaires’ disease (LD) cases began increasing in the United States in 2003 after relatively stable numbers for >10 years; reasons for the rise are unclear. We compared epidemiologic patterns associated with cases reported to the Centers for Disease Control and Prevention before and during the rise. The age-standardized average incidence was 0.48 cases/100,000 population during 1992–2002 compared with 2.71 cases/100,000 in 2018. Reported LD incidence increased in nearly every demographic, but increases tended to be larger in demographic groups with higher incidence. During both periods, the largest number of cases occurred among White persons, but the highest incidence was in Black or African American persons. Incidence and increases in incidence were generally largest in the East North Central, Middle Atlantic, and New England divisions. Seasonality was more pronounced during 2003–2018, especially in the Northeast and Midwest. Rising incidence was most notably associated with increasing racial disparities, geographic focus, and seasonality.

Abstract Background Screening methods for detecting Ultra High Risk status (UHR) or psychosis should be improved, especially in adolescent samples. We therefore tested whether the Child Behavior Checklist (CBCL) and the Youth Self Report (YSR) add value to the Prodromal Questionnaire-16 items version (PQ-16) for detecting UHR status or psychosis. Methods We included help-seeking adolescents who had completed the PQ-16, YSR, CBCL, and a Comprehensive Assessment of an At Risk Mental States (CAARMS) interview, and used independent samples t-tests and binary logistic regression analyses to determine the scales contributing to the prediction of UHR status or of having reached the psychosis threshold (PT). Cutoff scores were determined using ROC analyses. Results Our sample comprised 270 help-seeking adolescents (mean age 14.67; SD 1.56, range 12–17); 67.8% were girls and 66.3% were of Dutch origin. The Thought Problems syndrome scales of both the YSR and the CBCL best predicted UHR or PT, and had screening values comparable to the PQ-16. Other syndrome scales did not improve screening values. Although combining measures reduced the number of false negatives, it also increased the number of adolescents to be interviewed. The best choice was to combine the YSR Thought Problems scale and the PQ-16 as a first-step screener. Conclusions Combining measures improves the detection of UHR or PT in help-seeking adolescents. The Thought Problems subscales of the YSR and CBCL can both be used as a first-step screener in the detection of UHR and/or psychosis. Trial registration Permission was asked according to the rules of the Ethics Committee at Leiden. This study is registered as NL.44180.058.13

Abstract High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31–0.66) and a median PFS of 7.6 months (90% CI: 3.4–12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.

The mechanical behavior of thermoplastic materials processed via material extrusion additive manufacturing (MEAM) is a topic of great interest in several disciplines. Most of the material behavior characterization that has been done on the materials produced by material extrusion has been on macro-scale (“bulk”) parts. In order to better model and understand the process effects and take advantage of these during design, it is necessary to study the meso-scale material elements extruded by the process used to build the part geometry. While modeled effectively in previous works, full mechanical characterization at the meso-scale is yet to be accomplished. At this level, the essential material elements are known as “beads” or “roads”, the sum of which comprise each layer of the part. These elements are approximately uniform in cross-section and are defined by their dimensions, length, and placement angle. Therefore, they are effectively fibers and a set of them together constitute a layer, which can be built as a film (usually but not always flat). To further progress on this topic, this article explored the manufacturing and testing of these elements (fibers) and layers (films) at the meso-scale. The dimensional consistency was measured for each case in order to determine the process repeatability, followed by tensile tests on the fibers and films made from three common thermoplastic materials: Acrylonitrile butadiene styrene (ABS), polylactic acid (PLA), and polycarbonate (PC). For the fibers, both extruded (round, as produced) and deposited (rectangular, after printing on a surface) fibers were tested. Films were tested in single- and double-layer configurations with several different element layout patterns. The results and potential process sensitivities were discussed in detail, providing recommendations for use and future development of design rules when using these materials. These results will be useful in driving design decisions (for both macro-scale products and structured materials) and providing characterization data for further modeling and simulation of the MEAM process. These results will also help ensure the manufacturability of designed parts and materials built of these deposited thermoplastic fibers and films. This article also introduced and described mechanical testing methods that are useful for thermoplastic MEAM parts and have not yet been utilized elsewhere.

The coronavirus disease 2019 (COVID-19) pandemic challenges our collective understanding of transmission, prevention, complications, and clinical management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Risk factors for severe infection, morbidity, and mortality are associated with age, environment, socioeconomic status, comorbidities, and interventional timing. Clinical investigations report an intriguing association of COVID-19 with diabetes mellitus and malnutrition but incompletely describe the triphasic relationship, its mechanistic pathways, and potential therapeutic approaches to address each malady and their underlying metabolic disorders. This narrative review highlights common chronic disease states that interact epidemiologically and mechanistically with the COVID-19 to create a syndromic phenotype—the COVID-Related Cardiometabolic Syndrome—linking cardiometabolic-based chronic disease drivers with pre-, acute, and chronic/post-COVID-19 disease stages. Since the association of nutritional disorders with COVID-19 and cardiometabolic risk factors is well established, a syndromic triad of COVID-19, type 2 diabetes, and malnutrition is hypothesized that can direct, inform, and optimize care. In this review, each of the three edges of this network is uniquely summarized, nutritional therapies discussed, and a structure for early preventive care proposed. Concerted efforts to identify malnutrition in patients with COVID-19 and elevated metabolic risks are needed and can be followed by improved dietary management while simultaneously addressing dysglycemia-based chronic disease and malnutrition-based chronic disease.

Abstract Background RIFINs and STEVORs are variant surface antigens expressed by P. falciparum that play roles in severe malaria pathogenesis and immune evasion. These two highly diverse multigene families feature multiple paralogs, making their classification challenging using traditional bioinformatic methods. Results STRIDE (STevor and RIfin iDEntifier) is an HMM-based, command-line program that automates the identification and classification of RIFIN and STEVOR protein sequences in the malaria parasite Plasmodium falciparum. STRIDE is more sensitive in detecting RIFINs and STEVORs than available PFAM and TIGRFAM tools and reports RIFIN subtypes and the number of sequences with a FHEYDER amino acid motif, which has been associated with severe malaria pathogenesis. Conclusions STRIDE will be beneficial to malaria research groups analyzing genome sequences and transcripts of clinical field isolates, providing insight into parasite biology and virulence.

Respiratory disorders may be one of the adverse effects of sedentary lifestyle. This study investigated respiratory functions (FEV1, FVC and PEFR) and anthropometric parameters (body weight and body mass index) of healthy young males and females participating in moderate aerobic exercise. Forty young healthy untrained non-athletes, twenty males and twenty females (age, 25 ± 5.6 years; body weight, 65 ± 4.0 kg; body height, 176.9 ± 2.5 cm) volunteered to participate in this study. The exercise regimen was of moderate intensity lasting for 20 min daily on a treadmill consistently at the speed of 13 km/h for 14 days. The weight and height of participants were measured using medical scale and wall-mounted stadiometer respectively. The forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR) were assessed using digital spirometer. The results showed a significant (p

Minimally invasive approaches to spinal pathology have progressed through the advent of navigation and high-definition endoscopes. Endoscopic spine surgery affords key advantages for operative visualization and is associated with reduced tissue trauma and complication rates relative to open surgery. The excellent functional outcomes and expedient postoperative recovery afforded by endoscopic approaches is of great benefit to children and adolescents, whose quality of life can be drastically impacted by postoperative complications and revision surgeries. In this chapter, we discuss the applications and advantages of pediatric endoscopic spine surgery and detail our experiences with two case examples: (1) transforaminal endoscopic discectomy for pediatric lumbar disc herniation and (2) endoscopic approaches for thoracic spinal tumor resection.

Background: In the context of increased attention afforded to hospital efficiency and improved but safe patient throughput, decreasing unnecessary hospital length of stay (LOS) is imperative. Given that lumbar spine procedures may be among a hospital's most profitable services, identifying patients at risk of increased healthcare resource utilization prior to surgery is a valuable opportunity to develop targeted pre- and peri-operative intervention and quality improvement initiatives. The purpose of the present investigation was to examine patient factors that predict prolonged LOS as well as discharge disposition following elective, posterior, lumbar spine surgery. Methods: We employed a retrospective cohort analysis on 779 consecutive patients treated with lumbar surgery without fusion. Our primary outcome measures were extended LOS (three or more midnights) and discharge disposition. Patient sociodemographic, procedural, and discharge characteristics were adjusted for in our analysis. Sociodemographic variables included Area of Deprivation Index (ADI), a comprehensive metric of socioeconomic status, utilizing income, education, employment, and housing quality based on patient zip code. Multivariable logistic regression and ordinal logistic regression analyses were performed to assess whether covariates were independently predictive of extended LOS and discharge disposition, respectively. Results: 779 patients were studied, with a median age of 66 years (±15) and a median LOS of 1 midnight (range, 1-10 midnights). Patients in the most disadvantaged ADI quintile (adjusted odds ratio, aOR 2.48 95% CI 1.15-5.47), those who underwent a minimally-invasive or tubular retractor surgery (aOR 3.03 95% CI 1.02-8.56), those who had an intra-operative drain placed (aOR 4.46 95% CI 2.53-7.26), who had a cerebrospinal fluid leak (aOR 3.46 95% CI 1.55-7.58), who were discharged anywhere but home (aOR 17.11 95% CI 9.24-33.00), and those who were evaluated by physical therapy (aOR 7.23 95% CI 2.13-45.30) or OT (aOR 2.20 95% CI 1.13-4.22) had a significantly increased chance of an extended LOS. Preoperative opioid use was not associated with an increased LOS following surgery (aOR 1.12 95% CI 0.56-1.46). Extended LOS was not associated with post-discharge emergency department representation or unplanned readmission within 90 days following discharge (p=0.148). Patients who were older (aOR 1.99 95% CI 1.62-2.48), in higher quintiles on ADI (3rd quintile; aOR 1.90 95% CI 1.12-3.23, 4th quintile; aOR 1.79, 95% CI 1.05-3.05, 5th quintile; aOR 2.16 95% CI 1.26-3.75), who had a CSF leak (aOR 2.18 95% CI 1.22-3.86), or who had a longer procedure duration (aOR 1.38 95% CI 1.17-1.62) were more likely to require additional services or be sent to a subacute facility upon discharge. Conclusions: Patient sociodemographics, along with procedural factors, and discharge disposition were all associated with an increased likelihood of prolonged LOS and resource intensive discharges following elective lumbar spine surgery. Several of these factors could be reliably identified pre-operatively and may be amenable to targeted preoperative intervention. Improving discharge disposition planning in the peri-operative period may allow for more efficient use of hospitalization and inpatient and post-acute resources.

Background: Discharge to acute rehabilitation is strongly correlated with functional recovery after traumatic injury, including spinal cord injury (SCI). However, services such as acute care rehabilitation and Skilled Nursing Facilities (SNF) are expensive. Our objective was to understand if high-cost, resource-intensive post-discharge rehabilitation or alternative care facilities are utilized at disparate rates across socioeconomic groups after SCI. Methods: We performed a cohort analysis using the National Trauma Data Bank® tabulated from 2012-2016. Eligible patients had a diagnosis of cervical or thoracic spine fracture with spinal cord injury (SCI) and were treated surgically. We evaluated associations of sociodemographic and psychosocial variables with non-home discharge (e.g., discharge to SNF, other healthcare facility, or intermediate care facility) via multivariable logistic regression while correcting for injury severity and hospital characteristics. Results: We identified 3933 eligible patients. Patients who were older, male (OR=1.29 95% Confidence Interval [1.07-1.56], p=.007), insured by Medicare (OR=1.45 [1.08-1.96], p=.015), diagnosed with a major psychiatric disorder (OR=1.40 [1.03-1.90], p=.034), had a higher Injury Severity Score (OR=5.21 [2.96-9.18], p

Background: Lateral lumbar interbody fusion (LLIF) is a minimally invasive fusion procedure that may be performed with or without supplemental instrumentation. However, there is a paucity of evidence on the effect of supplemental instrumentation technique on perioperative morbidity and fusion rate in LLIF. Methods: A single-institutional retrospective review of patients who underwent LLIF for lumbar spondylosis was conducted. Patients were grouped according to supplemental instrumentation technique: stand-alone LLIF, LLIF with laterally placed instrumentation, or LLIF with posterior percutaneous pedicle screw fixation (PPSF). Outcomes included fusion rates, peri-operative complication, and reoperation; estimated blood loss (EBL); surgery duration; length of stay; and length of follow-up. Results: 82 patients underwent LLIF at 114 levels. 35 patients (42.7%) received supplemental lateral instrumentation, 30 (36.6%) received supplemental PPSF, and 17 (20.7%) underwent stand-alone LLIF. More patients in the lateral instrumentation group had prior lumbar fusion at adjacent levels (23/35, 65.71%) versus stand-alone (3/17, 17.6%) or PPSF (2/30, 6.67%) groups (p = 0.003). 4/17 patients (23.5%) with stand-alone LLIF and 4/35 patients (11.42%) with lateral instrumentation underwent reoperation, versus 0/30 with PPSF (p = 0.030). There was no difference in fusion rates between groups (p = 0.717). Operation duration was longer in patients with PPSF (p

Temperature extremes vary across Africa. A continent-wide examination of the impacts of heat on health in Africa, and a synthesis of Africa-informed evidence is, however, lacking. A systematic review of articles published in peer-reviewed journals between January 1992 and April 2019 was conducted. To be eligible, articles had to be Africa-specific, in English, and focused on how heatwaves and high ambient temperatures affect morbidity and mortality. A secondary systematic analysis on policies and interventions comprising 17 studies was also conducted, and the findings synthesised together with those of the 20 primary studies. Eleven studies showed that high ambient temperatures and heat waves are linked with increased mortality rates in Africa. These linkages are characterised by complex, linear and non-linear (J or U) relationships. Eight of the nine primary studies of morbidity outcome reported that an increase in temperature was accompanied by raised disease incidence. Children and the elderly were the population groups most vulnerable to extreme heat exposure. Location-specific interventions and policy suggestions include developing early warning systems, creating heat-health plans, changing housing conditions and implementing heat-health awareness campaigns. In summary, this review demonstrates that, while heat-health relationships in Africa are complex, extreme temperatures are associated with high mortality and morbidity, especially amongst vulnerable populations. As temperatures increase across Africa, there is an urgent need to develop heat-health plans and implement interventions. Future studies must document intervention effectiveness and quantify the costs of action and inaction on extreme heatrelated mortality and morbidity. Significance: • Empirical evidence shows that the relationship between heat and human health is complex in the African This complexity has implications for the development of interventions and policies for heathealth on the continent. • This review is important for African policymakers, practitioners and others who support Africa’s adaptation to climate change. Through this review, a compendium of Africa-specific and relevant empirical information is aggregated and made readily available to various interested and affected parties.

Abstract The goal of this research is to design, fabricate, and test an amplifier circuit which minimizes the input bias current over the input direct current operating point of the amplifier. A biasing scheme to set the drain‐source voltage (Vds) to null the net gate leakage current of the input transistor is shown. The desired Vds bias is obtained by replicating the Vds of a reference transistor that operates at the same current density as the input transistor and has its gate terminal open‐circuited so that the drain‐gate leakage and the gate‐source leakage must cancel. An implementation of this scheme as a cascode amplifier is described. Measurement results are presented showing > 20× reduced drift rate of a track‐and‐hold circuit when the output buffer amplifier uses the new approach as compared with a conventional buffer amplifier.

DNA shotgun sequencing is an untargeted approach for identifying changes in relative abundances, while qPCR allows reproducible quantification of specific bacteria. The canine dysbiosis index (DI) assesses the canine fecal microbiota by using a mathematical algorithm based on qPCR results. We evaluated the correlation between qPCR and shotgun sequencing using fecal samples from 296 dogs with different clinical phenotypes. While significant correlations were found between qPCR and sequencing, certain taxa were only detectable by qPCR and not by sequencing. Based on sequencing, less than 2% of bacterial species (17/1190) were consistently present in all healthy dogs (n = 76). Dogs with an abnormal DI had lower alpha-diversity compared to dogs with normal DI. Increases in the DI correctly predicted the gradual shifts in microbiota observed by sequencing: minor changes (R = 0.19, DI < 0 with any targeted taxa outside the reference interval, RI), mild-moderate changes (R = 0.24, 0 < DI < 2), and significant dysbiosis (R = 0.54, 0.73, and 0.91 for DI > 2, DI > 5, and DI > 8, respectively), compared to dogs with a normal DI (DI < 0, all targets within the RI), as higher R-values indicated larger dissimilarities. In conclusion, the qPCR-based DI is an effective indicator of overall microbiota shifts observed by shotgun sequencing in dogs.

Leptomeningeal metastases from solid tumors are a rare complication with a very poor prognosis. Here the authors report the efficacy and safety of combined ipilimumab and nivolumab in patients with leptomeningeal carcinomatosis.

Leptomeningeal disease (LMD) is a serious complication of metastatic solid tumors with a poor prognosis. Here, by using single-cell RNA sequencing of cerebrospinal fluid, the authors report genomic and immune correlates of response to immunotherapy in two cohorts of patients with LMD treated with immune checkpoint inhibitors.

OBJECTIVES/GOALS: Recent in vitro evidence suggests that diverse parasite protein families called RIFINs and STEVORs are displayed on the surface of infected red blood cells and may have a role in severe malaria, but they remain sparsely studied in natural infections. We measured the RNA expression of these antigens in Malian children with severe or mild malaria illness. METHODS/STUDY POPULATION: We collected blood samples from Malian children aged six months to five years, including 14 with cerebral malaria, 10 with severe malarial anemia, and demographic-matched controls with mild, uncomplicated malaria. We extracted total RNA from each patient and used a custom capture array to selectively enrich Plasmodium falciparum parasite RNA. We then performed Illumina next-generation RNA sequencing and reconstructed parasite transcriptomes using reference-free de novo assembly. We identified RNA encoding RIFINs and STEVORs using an in-house classifier, then measured the diversity and abundance of gene expression for each infection. Expression diversity was defined as the number of unique variants transcribed. Expression abundance was calculated as transcripts per million (TPM). RESULTS/ANTICIPATED RESULTS: Cerebral malaria cases, but not severe malarial anemia cases, had higher diversity and abundance of RIFIN expression compared to mild infections. Type A RIFINs predominated over Type B RIFINs, and the same two RIFINs were predominantly expressed in all disease phenotypes. We anticipate that predominantly expressed RIFINs share high sequence homology with variants previously shown to bind blood antigens or immune inhibitory receptors. STEVOR expression was also higher in cerebral malaria compared to mild malaria, but STEVOR transcripts were sparse overall. DISCUSSION/SIGNIFICANCE: Elevated RIFIN expression in cerebral malaria over mild malaria supports a role for these antigens in pathogenesis. Severe malarial anemia may progress through a different pathogenic mechanism. Predominantly expressed RIFIN variants may be promising targets for vaccines and therapeutics to protect children against cerebral malaria.

Over the last decade, chronic inflammatory enteropathies (CIE) in dogs have received great attention in the basic and clinical research arena. The 2010 ACVIM Consensus Statement, including guidelines for the diagnostic criteria for canine and feline CIE, was an important milestone to a more standardized approach to patients suspected of a CIE diagnosis. Great strides have been made since understanding the pathogenesis and classification of CIE in dogs, and novel diagnostic and treatment options have evolved. New concepts in the microbiome-host-interaction, metabolic pathways, crosstalk within the mucosal immune system, and extension to the gut-brain axis have emerged. Novel diagnostics have been developed, the clinical utility of which remains to be critically evaluated in the next coming years. New directions are also expected to lead to a larger spectrum of treatment options tailored to the individual patient. This review offers insights into emerging concepts and future directions proposed for further CIE research in dogs for the next decade to come.

Spinal cord injury (SCI) is a debilitating neurologic disorder that can result in significant morbidity and mortality, as well as long term disability. Pediatric spinal cord injuries account for only 5% of all spinal cord injuries. Understanding differences in anatomic and epidemiologic characteristics between pediatric and adult SCI is paramount to the accurate evaluation, diagnosis, and treatment of this potentially debilitating pathology. Standardized neurological examination and dedicated spine imaging guide optimal management. For both adult and pediatric populations, medical optimization and surgical decompression, stabilization, and/or fusion in select patient groups comprise the foundation of high-quality SCI care. Research into novel therapeutics, however, may afford improved functional outcomes. In the present review, we discuss differences between pediatric and adult patients with spinal cord injury as they pertain to patient anatomy, evaluation, management, and medical complications.

Abstract Microtiter plate methods are commonly used for biofilm assessment. However, results obtained with these methods have often been difficult to reproduce. Hence, it is important to obtain a better understanding of the repeatability and reproducibility of these methods. An interlaboratory study was performed in five different laboratories to evaluate the reproducibility and responsiveness of three methods to quantify Staphylococcus aureus biofilm formation in 96-well microtiter plates: crystal violet, resazurin, and plate counts. An inter-lab protocol was developed for the study. The protocol was separated into three steps: biofilm growth, biofilm challenge, biofilm assessment. For control experiments participants performed the growth and assessment steps only. For treatment experiments, all three steps were performed and the efficacy of sodium hypochlorite (NaOCl) in killing S. aureus biofilms was evaluated. In control experiments, on the log10-scale, the reproducibility SD (SR) was 0.44 for crystal violet, 0.53 for resazurin, and 0.92 for the plate counts. In the treatment experiments, plate counts had the best responsiveness to different levels of efficacy and also the best reproducibility with respect to responsiveness (Slope/SR = 1.02), making it the more reliable method to use in an antimicrobial efficacy test. This study showed that the microtiter plate is a versatile and easy-to-use biofilm reactor, which exhibits good repeatability and reproducibility for different types of assessment methods, as long as a suitable experimental design and statistical analysis is applied.

In January 2020, Santa Clara County, California, USA, began identifying laboratory-confirmed coronavirus disease among residents. County staff conducted case and contact investigations focused on households and collected detailed case demographic, occupation, exposure, and outcome information. We describe the first 200 test-positive cases during January 31–March 20, 2020, to inform future case and contact investigations. Probable infection sources included community transmission (104 cases), known close contact with a confirmed case-patient (66 cases), and travel (30 cases). Disease patterns across race and ethnicity, occupational, and household factors suggested multiple infection risk factors. Disproportionately high percentages of case-patients from racial and ethnic subgroups worked outside the home (Hispanic [86%] and Filipino [100%]); household transmission was more common among persons from Vietnam (53%). Even with the few initial cases, detailed case and contact investigations of household contacts capturing occupational and disaggregated race and ethnicity data helped identify at-risk groups and focused solutions for disease control.

A complex heterogeneous intracellular environment seems to affect enzymatic catalysis by changing the mobility of biomolecules, their stability, and their conformational states, as well as by facilitating or hindering continuously occurring interactions. The evaluation and description of the influence of the cytoplasmic matrix components on enzymatic activity are problems that remain unsolved. In this work, we aimed to determine the mechanisms of action of two-component media with cosolvents of various molecular sizes on the complex multi-stage bioluminescent reaction catalyzed by bacterial luciferase. Kinetic and structural effects of ethylene glycol, glycerol, sorbitol, glucose, sucrose, dextran, and polyethylene glycol on bacterial luciferase were studied using stopped-flow and fluorescence spectroscopy techniques and molecular dynamics simulations. We have found that diffusion limitations in the presence of cosolvents promote the stabilization of flavin substrate and peroxyflavin intermediate of the reaction, but do not provide any advantages in bioluminescence quantum yield, because substrate binding is slowed down as well. The catalytic constant of bacterial luciferase has been found to be viscosity-independent and correlated with parameters of water–cosolvent interactions (Norrish constant, van der Waals interaction energies). Crowding agents, in contrast to low-molecular-weight cosolvents, had little effect on peroxyflavin intermediate decay and enzyme catalytic constant. We attributed specific kinetic effects to the preferential interaction of the cosolvents with enzyme surface and their penetration into the active site.

Background: Lateral lumbar interbody fusion (LLIF) is a minimally invasive surgical option for treating symptomatic degenerative lumbar spinal stenosis (DLSS) in select patients. However, the efficacy of LLIF for indirectly decompressing the lumbar spine in DLSS, as well as the best radiographic metrics for evaluating such changes, are incompletely understood. Methods: A single-institutional cohort of patients who underwent LLIF for DLSS between 5/2015 – 12/2019 was retrospectively reviewed. Diameter, area, and stenosis grades were measured for the central canal (CC) and neural foramina (NF) at each LLIF level based on preoperative and postoperative T2-weighted MRI. Baseline facet joint (FJ) space, degree of FJ osteoarthritis, presence of spondylolisthesis, interbody graft position, and posterior disc height were analyzed as potential predictors of radiographic outcomes. Changes to all metrics after LLIF were analyzed and compared across lumbar levels. Preoperative and intraoperative predictors of decompression were then assessed using multivariate linear regression. Results: A total of 102 patients comprising 153 fused levels were analyzed. Pairwise linear regression of stenosis grade to diameter and area revealed significant correlations for both the CC and NF. All metrics except CC area were significantly improved after LLIF (p < 0.05, 2-tailed t-test). Worse FJ osteoarthritis ipsilateral to the surgical approach was predictive of greater post-operative CC and NF stenosis grade (p < 0.05, univariate and multivariate ordinary least squares linear regression). Lumbar levels L3-5 had significantly higher absolute postoperative CC stenosis grades while relative change in CC stenosis at the L2-3 was significantly greater than other lumbar levels (p < 0.05, one-way ANOVA). There were no baseline or postoperative differences in NF stenosis grade across lumbar levels. Conclusions: Radiographically, LLIF is effective at indirect compression of the CC and NF at all lumbar levels, though worse FJ osteoarthritis predicted higher degrees of post-operative stenosis.