History of biological, mechanistic, and clinical understanding of concussion.

The history behind the biological, mechanistic, and clinical insights into concussion provides awareness of the current understanding and future areas for study. Although the initial description of concussion appeared in the 10th century, the potential long-term structural consequences were first defined by Harrison Martland, M.D., who performed a postmortem study of former boxers in 1928. He found evidence of perivascular microhemorrhage that he believed eventually evolved into a "replacement gliosis" underlying a clinical syndrome that he named "punch drunk," which was characterized by acute confusion with chronic cognitive and physical symptoms developing in those with prolonged exposure. Further research into the potential long-term consequences of repetitive concussions, particularly in athletics and the military, led to an understanding of chronic traumatic encephalopathy. To ameliorate possible long-term risks, research has been focused on preventative and therapeutic measures for concussion. In this review article, the authors present the history of concussion and the long-term sequelae of repeated head injury. Specifically, they consider how the understanding of concussion has evolved from antiquity into the modern era, and how this change in understanding of head injury has led to an appreciation of the fact that its long-term implications sometimes manifest as the clinical and histopathological entity of chronic traumatic encephalopathy.

The Association Between Meeting Physical Activity Guidelines and Mental Health Among High-School Students in the United States During the COVID-19 Pandemic.

PURPOSE: Physical activity (PA) is associated with mental health outcomes in high-school students, yet many students do not meet the recommended PA levels. Furthermore, both PA levels and mental health were severely impacted by the COVID-19 pandemic. The aim of this study was to assess whether the number of PA recommendations students met during the COVID-19 pandemic was associated with their self-reported mental health (including their experiences with stress, anxiety, and depression) during the COVID-19 pandemic. METHODS: Students completed the Adolescent Behaviors and Experiences Survey, where they reported PA behaviors, mental health, and COVID-19-related experiences (as control variables) during the pandemic. RESULTS: Each PA recommendation that was met was associated with a 17% decrease in the odds of students self-reporting that they experienced stress, anxiety, or depression most of the time or always during the COVID-19 pandemic. DISCUSSION: Students should be provided with opportunities to participate in PA to obtain the physical and mental health benefits, especially in the event of a crisis like the pandemic.

Crimean-Congo hemorrhagic fever survivors elicit protective non-neutralizing antibodies that target 11 overlapping regions on glycoprotein GP38.

Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, exclusive to Nairoviridae, is a target of protective antibodies and is a key antigen in preclinical vaccine candidates. Here, we isolate 188 GP38-specific antibodies from human survivors of infection. Competition experiments show that these antibodies bind across 5 distinct antigenic sites, encompassing 11 overlapping regions. Additionally, we show structures of GP38 bound with 9 of these antibodies targeting different antigenic sites. Although these GP38-specific antibodies are non-neutralizing, several display protective efficacy equal to or better than murine antibody 13G8 in two highly stringent rodent models of infection. Together, these data expand our understanding regarding this important viral protein and may inform the development of broadly effective CCHFV antibody therapeutics.

Protozoan communities serve as a strong indicator of water quality in the Nile River.

The relationship between the protozoan communities and environmental variables was studied in the Nile River to evaluate their potential as water quality indicators. Protozoans were sampled monthly at six sampling sites in the Nile's Damietta Branch across a spatial gradient of environmental conditions during a 1-year cycle (February 2016-January 2017). The Protozoa community was comprised of 54 species belonging to six main heterotrophic Protozoa phyla. The abundance (average, 1089 ± 576.18 individuals L-1) and biomass (average, 86.60 ± 106.13 µg L-1) were comparable between sites. Ciliates comprised the majority of protozoan species richness (30 species), abundance (79.72%), and biomass (82.90%). Cluster analysis resulted in the distribution of protozoan species into three groups, with the most dominant species being the omnivorous ciliate Paradileptus elephantinus. Aluminium, fluoride, and turbidity negatively affected abundance and biomass, while dissolved oxygen and potassium positively impacted biomass. Of the dominant species recorded over the study area, the amoebozoa Centropyxis aculeata was associated with runoff variables, while the bacterivorous ciliates Colpidium colpoda, Glaucoma scintillans, and Vorticella convallaria were related to the abundance of heterotrophic bacteria, phytoplankton biomass, and total organic carbon. Total dissolved salts, PO4, NH3, NO2, dissolved oxygen, and total organic carbon were the strongest causative factors for protozoa distribution. The α-Mesosaprobic environment at site VI confirmed a high load of agricultural runoffs compared to other sites. This study demonstrates that protozoans can be a potential bioindicator of water quality status in this subtropical freshwater river system.

Child and mother characteristics associated with 6-month weight gain for infants and toddlers during 6 to 36 months.

BACKGROUND: The prevalence of childhood obesity in the U.S. has increased, likely due to decreased physical activity, increased sedentary behaviour and unhealthy diets. Little is known about the relationships between these factors and weight gain in those under the age of three. OBJECTIVES: This study aimed to understand the longitudinal associations of weight gain over 6-month intervals with child and parent characteristics as children develop from 6 to 36 months. METHODS: Mother and infant data were collected at 6-month intervals from 6 to 36 months. Weight (kg) was the primary outcome variable, and potential explanatory variables included child and parent characteristics, physical activity, motor development, diet and sleep. Structural equation modelling was used to assess associations between explanatory variables and 6-month weight gain. RESULTS: Weight increased ~1 kg per 6-month interval (p < 0.001) from 6 to 36 months. Childcare outside of the home at 12 months was associated with 0.272 kg (p = 0.002) greater weight gain at 18 months, while children's physical activity was associated with 0.228 kg (per 2 SD, p = 0.051) less weight gain during the same time period. Mother's TV and screen media use (0.102 kg per hour/day, p = 0.046) and child's intake of high-energy beverages at 18 months (0.387 kg, p = 0.037) were both associated with greater weight gain at 24 months. CONCLUSION: Childcare, physical activity, screen media use and high-energy beverage consumption might affect weight gain at different time points in early childhood. These insights can inform efforts to prevent excessive weight gain and childhood obesity effectively.

Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.

Lynch syndrome (LS) is defined by inherited mutations in DNA mismatch repair genes, including MSH2, and carries 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, specific mechanisms for LS-associated endometrial carcinogenesis are not well understood. Here, we assessed the effects of MSH2 loss on EC pathogenesis using a novel mouse model (PR-Cre Msh2 flox/flox , abbreviated Msh2KO), primary cell lines established from this model, human tissues, and human EC cell lines with isogenic MSH2 knockdown. Beginning at eight months of age, 30% of Msh2KO mice exhibited endometrial atypical hyperplasia (AH), a precancerous lesion. At 12 to 16 months of age, 47% of Msh2KO mice exhibited either AH or ECs with histologic features similar to human LS-related ECs. Transcriptomic profiling of EC from Msh2KO mice revealed a transcriptomic signature for mitochondrial dysfunction. Studies in vitro and in vivo revealed mitochondrial dysfunction based upon two mechanisms: marked mitochondrial content reduction, along with pronounced disruptions to the integrity of retained mitochondria. Human LS-related ECs also exhibited mitochondrial content reduction compared with non-LS-related ECs. Functional studies revealed metabolic reprogramming of MSH2-deficient EC cells in vitro , including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. We are the first to identify mitochondrial dysfunction and metabolic disruption as a consequence of MSH2 deficiency-related EC. Mitochondrial and metabolic aberrations should be evaluated as novel biomarkers for endometrial carcinogenesis or risk stratification and could serve as targets for cancer interception in women with LS. Significance: This is the first study to report mitochondrial dysfunction contributing to MSH2-deficient endometrial cancer development, identifying a noncanonical pathway for MSH2 deficient carcinogenesis, which also imparts vulnerability to metabolic targeting.

Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen transmitted by tick bites, with no vaccines or specific therapeutics approved to date. Severe disease manifestations include hemorrhage, endothelial dysfunction, and multiorgan failure. Infected cells secrete the viral glycoprotein GP38, whose extracellular function is presently unknown. GP38 is considered an important target for vaccine and therapeutic design as GP38-specific antibodies can protect against severe disease in animal models, albeit through a currently unknown mechanism of action. Here, we show that GP38 induces endothelial barrier dysfunction in vitro, and that CCHFV infection, and GP38 alone, can trigger vascular leak in a mouse model. Protective antibodies that recognize specific antigenic sites on GP38, but not a protective neutralizing antibody binding the structural protein Gc, potently inhibit endothelial hyperpermeability in vitro and vascular leak in vivo during CCHFV infection. This work uncovers a function of the secreted viral protein GP38 as a viral toxin in CCHFV pathogenesis and elucidates the mode of action of non-neutralizing GP38-specific antibodies.

Children's physical activity in family child care homes: Influence of quality status, environment and policy features, and child characteristics.

BACKGROUND: About half of preschool-age children are not meeting recommendations of 15 min/h of physical activity (PA), and nearly one out of seven children between the ages of 2-5 years are living with obesity. Furthermore, children attending family child care homes (FCCHs), compared with larger child care centers, engage in lower levels of PA and appear to be at a higher risk of obesity. Therefore, examining PA and multi-level factors that influence PA in children who attend FCCHs is essential. METHODS: The Childcare Home Eating and Exercise Study (CHEER) examined PA behaviors of 184 children enrolled in 56 FCCHs and FCCH quality status, environment and policy features, and child characteristics. PA was assessed by accelerometer, and FCCH environment and policy was assessed via structured observation. Multiple linear regression was used to model associations between school day total PA and FCCH quality status, environment and policy features, and child characteristics. RESULTS: Child participants were on average 3.1 years old; participants were non-Hispanic Black (47.3%), Non-Hispanic White (42.9%), other race/ethnicity (7.1%), and Hispanic/Latin (2.7%). Children in FCCH settings participated in 11.2 min/h of total PA, which is below the recommended 15 min per hour. The PA environment and policy observation yielded a score of 11.8 out of a possible 30, which is not supportive of child PA. There were no associations between total child PA and FCCH quality status, environment and policy features, and child characteristics in these FCCH settings. CONCLUSIONS: This study was unique in its examination of PA and a comprehensive set of factors that may influence PA at the individual, organizational, environmental, and policy levels in a diverse sample of children attending FCCHs in South Carolina. Additional research is needed to better understand how to increase children's physical activity while they are in the FCCH setting. This research should use multi-level frameworks and apply longitudinal study designs.

Syrian Hamsters Model Does Not Reflect Human-like Disease after Aerosol Exposure to Encephalitic Alphaviruses.

Venezuelan (VEE), eastern (EEE), and western (WEE) equine encephalitis viruses are encephalitic New World alphaviruses that cause periodic epizootic and epidemic outbreaks in horses and humans that may cause severe morbidity and mortality. Currently there are no FDA-licensed vaccines or effective antiviral therapies. Each year, there are a limited number of human cases of encephalitic alphaviruses; thus, licensure of a vaccine or therapeutic would require approval under the FDA animal rule. Approval under the FDA animal rule requires the disease observed in the animal model to recapitulate what is observed in humans. Currently, initial testing of vaccines and therapeutics is performed in the mouse model. Unfortunately, alphavirus disease manifestations in a mouse do not faithfully recapitulate human disease; the VEEV mouse model is lethal whereas in humans VEEV is rarely lethal. In an effort to identify a more appropriate small animal model, we evaluated hamsters in an aerosol exposure model of encephalitic alphavirus infection. The pathology, lethality, and viremia observed in the infected hamsters was inconsistent with what is observed in NHP models and humans. These data suggest that hamsters are not an appropriate model for encephalitic alphaviruses to test vaccines or potential antiviral therapies.

Allergen-Encapsulating Nanoparticles Reprogram Pathogenic Allergen-Specific Th2 Cells to Suppress Food Allergy.

Food allergy is a prevalent, potentially deadly disease caused by inadvertent sensitization to benign food antigens. Pathogenic Th2 cells are a major driver for disease, and allergen-specific immunotherapies (AIT) aim to increase the allergen threshold required to elicit severe allergic symptoms. However, the majority of AIT approaches require lengthy treatments and convey transient disease suppression, likely due to insufficient targeting of pathogenic Th2 responses. Here, the ability of allergen-encapsulating nanoparticles to directly suppress pathogenic Th2 responses and reactivity is investigated in a mouse model of food allergy. NPs associate with pro-tolerogenic antigen presenting cells, provoking accumulation of antigen-specific, functionally suppressive regulatory T cells in the small intestine lamina propria. Two intravenous doses of allergen encapsulated in poly(lactide-co-glycolide) nanoparticles (NPs) significantly reduces oral food challenge (OFC)-induced anaphylaxis. Importantly, NP treatment alters the fates of pathogenic allergen-specific Th2 cells, reprogramming these cells toward CD25+FoxP3+ regulatory and CD73+FR4+ anergic phenotypes. NP-mediated reductions in the frequency of effector cells in the gut and mast cell degranulation following OFC are also demonstrated. These studies reveal mechanisms by which an allergen-encapsulating NP therapy and, more broadly, allergen-specific immunotherapies, can rapidly attenuate allergic responses by targeting pathogenic Th2 cells.

Biomarkers from subcutaneous engineered tissues predict acute rejection of organ allografts.

Invasive graft biopsies assess the efficacy of immunosuppression through lagging indicators of transplant rejection. We report on a microporous scaffold implant as a minimally invasive immunological niche to assay rejection before graft injury. Adoptive transfer of T cells into Rag2-/- mice with mismatched allografts induced acute cellular allograft rejection (ACAR), with subsequent validation in wild-type animals. Following murine heart or skin transplantation, scaffold implants accumulate predominantly innate immune cells. The scaffold enables frequent biopsy, and gene expression analyses identified biomarkers of ACAR before clinical signs of graft injury. This gene signature distinguishes ACAR and immunodeficient respiratory infection before injury onset, indicating the specificity of the biomarkers to differentiate ACAR from other inflammatory insult. Overall, this implantable scaffold enables remote evaluation of the early risk of rejection, which could potentially be used to reduce the frequency of routine graft biopsy, reduce toxicities by personalizing immunosuppression, and prolong transplant life.

Persistent GDNF Expression 45 Months after Putaminal Infusion of AAV2-GDNF in a Patient with Parkinson's Disease.

OBJECTIVE: Gene therapy by convection-enhanced delivery of type 2 adeno-associated virus-glial cell derived neurotrophic factor (AAV2-GDNF) to the bilateral putamina seeks to increase GDNF gene expression and treat Parkinson's disease (PD). METHODS: A 63-year-old man with advanced PD received AAV2-GDNF in a clinical trial. He died from pneumonia after anterior cervical discectomy and fusion 45 months later. An autopsy included brain examination for GDNF transgene expression. Putaminal catecholamine concentrations were compared to in vivo 18F-Fluorodopa (18F-FDOPA) positron emission tomography (PET) scanning results before and 18 months after AAV2-GDNF infusion. RESULTS: Parkinsonian progression stabilized clinically. Postmortem neuropathology confirmed PD. Bilateral putaminal regions previously infused with AAV2-GDNF expressed the GDNF gene. Total putaminal dopamine was 1% of control, confirming the striatal dopaminergic deficiency suggested by baseline 18F-DOPA-PET scanning. Putaminal regions responded as expected to AAV2-GDNF. CONCLUSION: After AAV2-GDNF infusion, infused putaminal regions showed increased GDNF gene expression, tyrosine hydroxylase immunoreactive sprouting, catechol levels, and 18F-FDOPA-PET signal, suggesting the regenerative potential of AAV2-GDNF in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Congenital Dislocation of the Knee in the Delivery Room.

BACKGROUND Congenital dislocation of the knee (CDK) is rare and can cause significant distress in the delivery room to parents and to healthcare providers, especially if the latter are unaware of this condition. It may not be detected by prenatal ultrasound and can be either an isolated finding or associated with other anomalies such as developmental hip dysplasia and genetic syndromes such as Larsen syndrome. Because of the risk of development of contractures, immediate referral to a specialized provider is needed. Poor prognostic factors include an association with a genetic syndrome, limited knee flexion related to severe quadriceps retraction, and absence of anterior skin grooves. A satisfactory outcome can be anticipated in isolated cases with easy reducibility of the knee. CASE REPORT A term baby presented unexpectedly with left knee dislocation after delivery. The providers, unaware of the condition, immediately consulted the orthopedic service, who assisted in the diagnosis, and appropriate management was initiated. The baby had serial casting of the leg, which was applied for almost 3 months, with excellent results on the clinical examination. CONCLUSIONS CDK is a rare finding. The diagnosis is primarily clinical and radiographs are used to confirm and assess the degree of the dislocation. The degree of dislocation is important for management and prognosis. Interventions ranging from serial casting to surgery are required as soon as possible. As the CDK can be associated with genetic syndromes or other dysplasias such as developmental dysplasia of the hip and talipes equinovarus, further evaluation for these conditions is warranted.

Immune Checkpoint Inhibitor-induced Polymyalgia Rheumatica.

Polymyalgia rheumatica (PMR) immune-related adverse events (ICI-PMRs) represent a novel, distinct entity, despite many clinical, laboratory, and imaging similarities to classical PMR. Important questions remain in differentiating ICI-PMR from classical PMR, as well as other immune-related adverse events and PMR mimics. Despite this, ICI-PMR currently takes treatment cues from classical PMR, albeit with considerations relevant to cancer immunotherapy. Comparisons between ICI-PMR and classical PMR may provide further bidirectional insights, especially given that important questions remain unanswered about both diseases. The cause of classical PMR remains poorly understood, and ICI-PMR may represent a model of induced PMR, with important therapeutic implications.

Validation of SeptiCyte RAPID to Discriminate Sepsis from Non-Infectious Systemic Inflammation.

(1) Background: SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and for estimating sepsis probabilities. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospectively banked and prospectively collected patient samples. (2) Methods: The cartridge-based SeptiCyte RAPID test accepts a PAXgene blood RNA sample and provides sample-to-answer processing in ~1 h. The test output (SeptiScore, range 0-15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (N = 356) and prospective (N = 63) samples were tested from adult patients in ICU who either had the systemic inflammatory response syndrome (SIRS), or were suspected of having/diagnosed with sepsis. Patients were clinically evaluated by a panel of three expert physicians blinded to the SeptiCyte test results. Results were interpreted under either the Sepsis-2 or Sepsis-3 framework. (3) Results: Under the Sepsis-2 framework, SeptiCyte RAPID performance for the combined retrospective and prospective cohorts had Areas Under the ROC Curve (AUCs) ranging from 0.82 to 0.85, a negative predictive value of 0.91 (sensitivity 0.94) for SeptiScore Band 1 (score range 0.1-5.0; lowest risk of sepsis), and a positive predictive value of 0.81 (specificity 0.90) for SeptiScore Band 4 (score range 7.4-15; highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86-0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in Bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. A comparable performance was obtained for the majority of patients reanalyzed under the Sepsis-3 definition, although a subgroup of 16 patients was identified that was called septic under Sepsis-2 but not under Sepsis-3. (4) Conclusions: This study validates SeptiCyte RAPID for estimating sepsis probability, under both the Sepsis-2 and Sepsis-3 frameworks, for hospitalized patients on their first day of ICU admission.

Engineering, structure, and immunogenicity of a Crimean-Congo hemorrhagic fever virus pre-fusion heterotrimeric glycoprotein complex.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that can cause severe disease in humans with case fatality rates of 10-40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we used structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-GnH-DS-Gc). A cryo-EM structure of this complex provides the molecular basis for GP38's association on the viral surface, reveals the structure of Gn, and demonstrates that GP38-Gn restrains the Gc fusion loops in the prefusion conformation, facilitated by an N-linked glycan attached to Gn. Immunization with GP38-GnH-DS-Gc conferred 40% protection against lethal IbAr10200 challenge in mice. These data define the architecture of a GP38-Gn-Gc protomer and provide a template for structure-guided vaccine antigen development.

Crimean-Congo Hemorrhagic Fever Survivors Elicit Protective Non-Neutralizing Antibodies that Target 11 Overlapping Regions on Viral Glycoprotein GP38.

Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, unique to Nairoviridae, is a target of protective antibodies, but extensive mapping of the human antibody response to GP38 has not been previously performed. Here, we isolated 188 GP38-specific antibodies from human survivors of infection. Competition experiments showed that these antibodies bind across five distinct antigenic sites, encompassing eleven overlapping regions. Additionally, we reveal structures of GP38 bound with nine of these antibodies targeting different antigenic sites. Although GP38-specific antibodies were non-neutralizing, several antibodies were found to have protection equal to or better than murine antibody 13G8 in two highly stringent rodent models of infection. Together, these data expand our understanding regarding this important viral protein and inform the development of broadly effective CCHFV antibody therapeutics.

Preoperative prescription opioid use as an independent predictor of 90-day mortality and adverse events in craniotomy and craniectomy patients.

OBJECTIVE: A growing body of literature suggests that preoperative opioid exposure is an independent predictor of poor outcomes in surgical patients. No outcomes data exist on preoperative opioid use and craniotomies/craniectomies. The objective of this study was to determine the impact of preoperative opioid use on 90-day adverse events after craniotomy or craniectomy. METHODS: A single-center retrospective cohort study of 2445 patients undergoing a craniotomy/craniectomy between January 1, 2013, and October 1, 2018, was conducted. Baseline demographics, pre- and postoperative opioid use (morphine milligram equivalents [MMEs]), and surgical metrics were recorded. Patients were categorized based on whether they took prescription opioids preoperatively, defined as within 1 month of surgery, or were opioid naive. The outcomes were mortality and adverse events 90 days after craniotomy/craniectomy. RESULTS: Overall, 26.6% of patients composed the preoperative opioid group. The median daily MME intake among this group was 34.6 (IQR 14.1-90) MMEs. Lower employment rates (p < 0.001), uninsured status (p = 0.016), and intravenous drug use (p = 0.006) were associated with preoperative opioid use. Preoperative opioid use was associated with increased venous thromboembolism (p = 0.001), acute kidney injury (p = 0.002), acute respiratory failure (p < 0.001), myocardial infarction (p = 0.002), delirium (p < 0.001), and infection (p < 0.001). Preoperative opioid use was an independent predictor of overall 90-day adverse events (OR 1.643, 95% CI 1.289-2.095; p < 0.001) and 90-day mortality (OR 1.690, 95% CI 1.254-2.277; p < 0.001). CONCLUSIONS: Preoperative opioid use was independently associated with 90-day postoperative adverse events and mortality. Opioid use increases vulnerability in craniotomy/craniectomy patients and necessitates close monitoring to improve outcomes.

A statistical approach to system suitability testing for mass spectrometry imaging.

RATIONALE: Mass spectrometry imaging (MSI) elevates the power of conventional mass spectrometry (MS) to multidimensional space, elucidating both chemical composition and localization. However, the field lacks any robust quality control (QC) and/or system suitability testing (SST) protocols to monitor inconsistencies during data acquisition, both of which are integral to ensure the validity of experimental results. To satisfy this demand in the community, we propose an adaptable QC/SST approach with five analyte options amendable to various ionization MSI platforms (e.g., desorption electrospray ionization, matrix-assisted laser desorption/ionization [MALDI], MALDI-2, and infrared matrix-assisted laser desorption electrospray ionization [IR-MALDESI]). METHODS: A novel QC mix was sprayed across glass slides to collect QC/SST regions-of-interest (ROIs). Data were collected under optimal conditions and on a compromised instrument to construct and refine the principal component analysis (PCA) model in R. Metrics, including mass measurement accuracy and spectral accuracy, were evaluated, yielding an individual suitability score for each compound. The average of these scores is utilized to inform if troubleshooting is necessary. RESULTS: The PCA-based SST model was applied to data collected when the instrument was compromised. The resultant SST scores were used to determine a statistically significant threshold, which was defined as 0.93 for IR-MALDESI-MSI analyses. This minimizes the type-I error rate, where the QC/SST would report the platform to be in working condition when cleaning is actually necessary. Further, data scored after a partial cleaning demonstrate the importance of QC and frequent full instrument cleaning. CONCLUSIONS: This study is the starting point for addressing an important issue and will undergo future development to improve the efficiency of the protocol. Ultimately, this work is the first of its kind and proposes this approach as a proof of concept to develop and implement universal QC/SST protocols for a variety of MSI platforms.