Pre-challenge gut microbial signature predicts RhCMV/SIV vaccine efficacy in rhesus macaques.

Background: RhCMV/SIV vaccines protect ∼59% of vaccinated rhesus macaques against repeated limiting-dose intra-rectal exposure with highly pathogenic SIVmac239M, but the exact mechanism responsible for the vaccine efficacy is not known. It is becoming evident that complex interactions exist between gut microbiota and the host immune system. Here we aimed to investigate if the rhesus gut microbiome impacts RhCMV/SIV vaccine-induced protection. Methods: Three groups of 15 rhesus macaques naturally pre-exposed to RhCMV were vaccinated with RhCMV/SIV vaccines. Rectal swabs were collected longitudinally both before SIV challenge (after vaccination) and post challenge and were profiled using 16S rRNA based microbiome analysis. Results: We identified ∼2,400 16S rRNA amplicon sequence variants (ASVs), representing potential bacterial species/strains. Global gut microbial profiles were strongly associated with each of the three vaccination groups, and all animals tended to maintain consistent profiles throughout the pre-challenge phase. Despite vaccination group differences, using newly developed compositional data analysis techniques we identified a common gut microbial signature predictive of vaccine protection outcome across the three vaccination groups. Part of this microbial signature persisted even after SIV challenge. We also observed a strong correlation between this microbial signature and an early signature derived from whole blood transcriptomes in the same animals. Conclusions: Our findings indicate that changes in gut microbiomes are associated with RhCMV/SIV vaccine-induced protection and early host response to vaccination in rhesus macaques.

An In Silico Analysis of PCR-Based Monkeypox Virus Detection Assays: A Case Study for Ongoing Clinical Surveillance.

The 2022 global Mpox outbreak swiftly introduced unforeseen diversity in the monkeypox virus (MPXV) population, resulting in numerous Clade IIb sublineages. This propagation of new MPXV mutations warrants the thorough re-investigation of previously recommended or validated primers designed to target MPXV genomes. In this study, we explored 18 PCR primer sets and examined their binding specificity against 5210 MPXV genomes, representing all the established MPXV lineages. Our results indicated that only five primer sets resulted in almost all perfect matches against the targeted MPXV lineages, and the remaining primer sets all contained 1-2 mismatches against almost all the MPXV lineages. We further investigated the mismatched primer-genome pairs and discovered that some of the primers overlapped with poorly sequenced and assembled regions of the MPXV genomes, which are consistent across multiple lineages. However, we identified 173 99% genome-wide conserved regions across all 5210 MPXV genomes, representing 30 lineages/clades with at least 80% lineage-specific consensus for future primer development and primer binding evaluation. This exercise is crucial to ensure that the current detection schemes are robust and serve as a framework for primer evaluation in clinical testing development for other infectious diseases.

Reducing the risk of criminal exploitation using multi-systemic therapy (the RESET Study): study protocol for a feasibility study and process evaluation.

BACKGROUND: Child criminal exploitation is a form of child abuse that poses a serious risk to the welfare, safety, and wellbeing of young people. Multisystemic therapy (MST) is an intensive family and community-based intervention for young people with anti-social behavioral problems, many of whom will be at risk of criminal exploitation. This protocol describes a pilot feasibility study and process evaluation, designed to examine MST for children at risk of criminal exploitation. METHODS: This pilot feasibility study and process evaluation involves two phases with associated subphases: phase 1.1 involved the collaborative refinement of the logic model adapting MST for children at risk of criminal exploitation; phase 1.2 involved pre-pilot interviews with MST therapists, families, and young people; phase 2.1 is a pilot modeling study of MST for children at risk of criminal exploitation, and; Phase 2.2 is a process evaluation that will involve interviewing stakeholders, MST therapists and employees, families, and young people. The dataset for the process evaluation will include questionnaires completed by parents and young people at baseline, mid-treatment, end of treatment, and 6 months after treatment. We will supplement these data with participant-level data linkage from MST sites and services. RESULTS: Accrual to the pilot stage of this project opened on 6th August 2021 and is due to close on 31st May 2022. We aim to publish the results of this feasibility study and process evaluation in 2023. CONCLUSIONS: The results of this feasibility study and process evaluation will inform the decision as to whether it is advisable to progress to a pilot clinical trial of MST for children at risk of criminal exploitation. TRIAL REGISTRATION: Trial registration: ISRCTN registry, ISRCTN16164816 on 25th January 2021- https://doi.org/10.1186/ISRCTN16164816 .

Development and initial psychometric properties of the Warwick-Edinburgh Mental Wellbeing Scale-Intellectual Disability version.

BACKGROUND: The Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS; Tennant et al., 2007) is yet to be validated in the intellectual disability (ID) population. The aim of this study was to report the development process and assess the psychometric properties of a newly adapted version of the WEMWBS and the Short WEMWBS for individuals with mild to moderate IDs (WEMWBS-ID/SWEMWBS-ID). METHOD: The WEMWBS item wordings and response options were revised by clinicians and researchers expert in the field of ID, and a visual aid was added to the scale. The adapted version was reviewed by 10 individuals with IDs. The measure was administered by researchers online using screenshare, to individuals aged 16+ years with mild to moderate IDs. Data from three UK samples were collated to evaluate the WEMWBS-ID (n = 96). A subsample (n = 22) completed the measure again 1 to 2 weeks later to assess test-retest reliability, and 95 participants additionally completed an adapted version of the adapted Rosenberg Self-Esteem Scale to examine convergent validity. Additional data from a Canadian sample (n = 27) were used to evaluate the SWEMWBS-ID (n = 123). RESULTS: The WEMWBS-ID demonstrated good internal consistency (ω = 0.77-0.87), excellent test-retest reliability [intraclass correlation coefficient (ICC) = .88] and good convergent validity with the self-esteem scale (r = .48-.60) across samples. A confirmatory factor analysis for a single factor model demonstrated an adequate fit. The SWEMWBS-ID showed poor to good internal consistency (ω = 0.36-0.74), moderate test-retest reliability (ICC = .67) and good convergent validity (r = .48-.60) across samples, and a confirmatory factor analysis indicated good model fit for a single factor structure. CONCLUSIONS: The WEMWBS-ID and short version demonstrated promising psychometric properties, when administered virtually by a researcher. Further exploration of the scales with larger, representative samples is warranted.

Behavioural adjustment of children with intellectual disability and their sibling is associated with their sibling relationship quality.

BACKGROUND: Understanding sibling relationship quality is important, as it is associated with mental health outcomes in both childhood and adulthood. Arguably, these relationships are even more important for individuals with intellectual disability, as siblings can be important sources of care, support, advocacy and friendship for one another. The intellectual disability field, however, has a tendency to assume that the relationship lacks reciprocity, and that it is the sibling with intellectual disability who affects the sibling, and that this effect is somehow 'negative'. METHODS: We examined whether the behaviour problems and prosocial behaviour of 500 child sibling pairs, where one child has an intellectual disability, were associated with their sibling relationship quality. Measures included the Strengths and Difficulties Questionnaires and the Sibling Relationship Questionnaire. Family poverty, the gender of both children, birth order and whether the child with intellectual disability had autism or Down syndrome were also included in the analyses. RESULTS: Confirmatory factor analysis indicated an adequate model fit for the latent variables measuring sibling relationships. The final structural model found that the prosocial behaviour and internalising problems of the children with intellectual disability, their typically developing siblings' prosocial behaviours and sibling birth order were associated with intimacy-companionship in the sibling relationship. The internalising, externalising and prosocial behaviours of the children with intellectual disability, their siblings' externalising behaviours and sibling birth order were associated with antagonism-quarrelling in the sibling relationship. CONCLUSIONS: We found that the behaviours of both the child with intellectual disability and their sibling were associated with both 'positive' and 'negative' dimensions of their sibling relationship. This indicates a bidirectional and reciprocal effect.

Single-Cell-Based High-Throughput Ig and TCR Repertoire Sequencing Analysis in Rhesus Macaques.

Recent advancements in microfluidics and high-throughput sequencing technologies have enabled recovery of paired H and L chains of Igs and VDJ and VJ chains of TCRs from thousands of single cells simultaneously in humans and mice. Despite rhesus macaques being one of the most well-studied model organisms for the human adaptive immune response, high-throughput single-cell immune repertoire sequencing assays are not yet available due to the complexity of these polyclonal receptors. We used custom primers that capture all known rhesus macaque Ig and TCR isotypes and chains that are fully compatible with a commercial solution for single-cell immune repertoire profiling. Using these rhesus-specific assays, we sequenced Ig and TCR repertoires in >60,000 cells from cryopreserved rhesus PBMCs, splenocytes, and FACS-sorted B and T cells. We were able to recover every Ig isotype and TCR chain, measure clonal expansion in proliferating T cells, and pair Ig and TCR repertoires with gene expression profiles of the same single cells. Our results establish the ability to perform high-throughput immune repertoire analysis in rhesus macaques at the single-cell level.

Parkland Trauma Index of Mortality: Real-Time Predictive Model for Trauma Patients.

OBJECTIVE: Vital signs and laboratory values are used to guide decisions to use damage control techniques in lieu of early definitive fracture fixation. Previous models attempted to predict mortality risk but have limited utility. There is a need for a dynamic model that captures evolving physiologic changes during a trauma patient's hospital course. METHODS: The Parkland Trauma Index of Mortality (PTIM) is a machine learning algorithm that uses electronic medical record data to predict mortality within 48 hours during the first 3 days of hospitalization. It updates every hour, recalculating as physiology changes. The model was developed using 1935 trauma patient encounters from 2009 to 2014 and validated on 516 patient encounters from 2015 to 2016. Model performance was evaluated statistically. Data were collected retrospectively on its performance after 1 year of clinical use. RESULTS: In the validation data set, PTIM accurately predicted 52 of the sixty-three 12-hour time intervals within 48 hours of mortality, for sensitivity of 82.5% [95% confidence interval (CI), 73.1%-91.9%]. The specificity was 93.6% (95% CI, 92.5%-94.8%), and the positive predictive value (PPV) was 32.5% (95% CI, 25.2%-39.7%). PTIM predicted survival for 1608 time intervals and was incorrect only 11 times, yielding a negative predictive value of 99.3% (95% CI, 98.9%-99.7%). The area under the curve of the receiver operating characteristic curve was 0.94.During the first year of clinical use, when used in 776 patients, the last PTIM score accurately predicted 20 of the twenty-three 12-hour time intervals within 48 hours of mortality, for sensitivity of 86.9% (95% CI, 73%-100%). The specificity was 94.7% (95% CI, 93%-96%), and the positive predictive value was 33.3% (95% CI, 21.4%-45%). The model predicted survival for 716 time intervals and was incorrect 3 times, yielding a negative predictive value of 99.6% (95% CI, 99.1%-100%). The area under the curve of the receiver operating characteristic curve was 0.97. CONCLUSIONS: By adapting with the patient's physiologic response to trauma and relying on electronic medical record data alone, the PTIM overcomes many of the limitations of previous models. It may help inform decision-making for trauma patients early in their hospitalization. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

The effect of age on risk of retear after rotator cuff repair: a systematic review and meta-analysis.

HYPOTHESIS: The purpose of this study was to perform a systematic review and meta-analysis to determine the effect of age on rotator cuff repair failure. The hypothesis of this study was that increased patient age would lead to a higher rate of retears and/or repair failures after rotator cuff repair. METHODS: We conducted a systematic review and meta-analysis of level I and II studies evaluating patients undergoing rotator cuff repair that also included an imaging assessment of the structural integrity of the repair. Univariate and multivariate meta-regression was performed to assess the dependence of the retear rate on the mean age of the cohort, imaging modality, time to imaging, and publication year. RESULTS: The meta-regression included 38 studies with a total of 3072 patients. Significant heterogeneity in retear rates was found among the studies (Q = 209.53, I 2 = 82.34, P < .001). By use of a random-effects model, the retear rate point estimate was 22.1% (95% confidence interval [CI], 18.6%-26.0%). On univariate analysis, type of imaging modality did not significantly influence the retear rate (P = .188). On univariate analysis, mean age (odds ratio [OR], 1.05 [95% CI, 1.01-1.09]; P = .027) and mean time to imaging (OR, 1.04 [95% CI, 1.01-1.08]; P = .006) were associated with the retear rate. Publication year (OR, 0.94 [95% CI, 0.88-1.01]; P = .083) demonstrated a trend toward significance. On multivariate analysis, increased age was associated with a 5%/yr increased odds of retear (OR, 1.05 [95% CI, 1.01-1.08]; P = .025). The risk of retear doubled from 15% at age 50 years to >30% at age 70 years. Time to imaging demonstrated a trend toward increased odds of retear (OR, 1.03 [95% CI, 1.00-1.07]; P = .056). Publication year was not associated with the retear rate on multivariate analysis (OR, 0.96 [95% CI, 0.90-1.02]; P = .195). CONCLUSION: The risk of retear after rotator cuff repair is associated with increased age and doubles between the ages of 50 and 70 years.

Staged vs Concurrent Hardware Removal During Conversion Total Knee Arthroplasty.

BACKGROUND: Conversion total knee arthroplasty (TKA) in the presence of periarticular hardware can be associated with increased resource utilization, complications, and revisions. However, little guidance exists on the optimal approach to hardware removal. The purpose of this study is to compare outcomes of conversion TKA with hardware removal performed in either a staged or concurrent manner. METHODS: This is a retrospective study of 155 TKA operations performed with staged (45) or concurrent (110) removal of hardware at the time of TKA. Differences in patient data, case data, complications, reoperations, and revisions were evaluated. Subgroup comparisons of cases involving major hardware (plates, nails, rods), minor hardware (screws, buttons, wires), and tibial plates were performed. RESULTS: There were no differences in age, sex, body mass index, or comorbidities between patients who underwent staged or concurrent hardware removal. Rates of complications, reoperations, and revisions did not differ at multiple time points (90 days, 1 year, 2 years, 4 years). Patients who underwent staged hardware removal were more likely to have had prior surgery for fracture reconstruction (68% vs 33%, P < .001), to have had major hardware removed (84% vs 59%, P = .03), and were less likely to have had hardware removal performed through a single incision with TKA (50% vs 92%, P < .001). Subgroup analysis of major and minor hardware cases demonstrated comparable outcomes. CONCLUSION: There remains no established benefit to either a staged or concurrent approach to hardware removal at the time of TKA. This is true regardless of hardware burden. At this time, a case-by-case approach should be taken to conversion TKA in the presence of periarticular hardware.

Systematic Profiling of Full-Length Ig and TCR Repertoire Diversity in Rhesus Macaque through Long Read Transcriptome Sequencing.

The diversity of Ig and TCR repertoires is a focal point of immunological studies. Rhesus macaques (Macaca mulatta) are key for modeling human immune responses, placing critical importance on the accurate annotation and quantification of their Ig and TCR repertoires. However, because of incomplete reference resources, the coverage and accuracy of the traditional targeted amplification strategies for profiling rhesus Ig and TCR repertoires are largely unknown. In this study, using long read sequencing, we sequenced four Indian-origin rhesus macaque tissues and obtained high-quality, full-length sequences for over 6000 unique Ig and TCR transcripts, without the need for sequence assembly. We constructed, to our knowledge, the first complete reference set for the constant regions of all known isotypes and chain types of rhesus Ig and TCR repertoires. We show that sequence diversity exists across the entire variable regions of rhesus Ig and TCR transcripts. Consequently, existing strategies using targeted amplification of rearranged variable regions comprised of V(D)J gene segments miss a significant fraction (27-53% and 42-49%) of rhesus Ig/TCR diversity. To overcome these limitations, we designed new rhesus-specific assays that remove the need for primers conventionally targeting variable regions and allow single cell level Ig and TCR repertoire analysis. Our improved approach will enable future studies to fully capture rhesus Ig and TCR repertoire diversity and is applicable for improving annotations in any model organism.

In Vivo analysis of spinopelvic kinematics and peak head-cup contact in total hip arthroplasty patients with lumbar degenerative disc disease.

Anterior instability after total hip arthroplasty (THA) has been described in patients with thoracolumbar kyphotic deformity. Although compensatory posterior pelvic tilt with subsequent increased functional anteversion has been described as the mechanism, there is a paucity of in vivo data. The purpose of our study was to compare pelvic tilt, anteversion, inclination, and position of head-cup contact points in patients with lumbar degenerative disc disease (DDD) and a matched patient cohort without DDD. A total of 50 THA, 18 hips with lumbar DDD and 32 hips without DDD, underwent CT imaging for 3D hip reconstruction. Component orientations and in vivo hip gait kinematics was quantified using a validated dual fluoroscopic imaging system. Hip kinematics and head-cup contact points were compared. Patients with lumbar DDD demonstrated decreased maximum (5.9° ± 4.2° vs. 9.3° ± 5.4°, p = 0.02) and minimum (2.4° ± 4.1° vs. 6.2° ± 5.6°, p = 0.01) anterior pelvic tilt, and increased maximum cup anteversion (29.3° ± 8.7° vs. 25.1° ± 8.1°, p = 0.05). The peak head-cup contact points were shifted closer to the anterior edge of the polyethylene (7.8 ± 1.7 mm vs. 9.6 ± 2.2 mm, p = 0.02). Patients with lumbar degenerative disc disease demonstrated increased posterior pelvic tilt, functional acetabular anteversion, inclination as well as shifting of the peak head-cup contact pattern significantly closer to an anterior edge, suggesting sagittal spinopelvic deformity may predispose to anterior instability in THA patients during upright activities. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Venous Thromboembolism Prophylaxis after Total Knee Arthroplasty.

Venous thromboembolic disease (VTED) is a major cause of morbidity and mortality after total knee arthroplasty (TKA). Current VTED prophylaxis protocols consist of early mobilization, mechanical compression devices, and pharmacologic agents. Venous phasic flow-regulated below-knee devices are generally favored, but the optimal duration and method of mechanical prophylaxis is unknown. Risk stratification models have been developed to guide pharmacologic prophylaxis. For patients with standard VTED risk profile, aspirin has become increasingly popular. Recent studies have validated the efficacy, relatively low bleeding risks, and cost-effectiveness of aspirin in the patients with standard risk profile. Current evidence suggests that the newer oral anticoagulants, including the factor Xa and the direct thrombin inhibitors, are effective for the reduction of postoperative VTED but may be associated with increased bleeding and wound complication rates.

Tranexamic acid administration for anatomic and reverse total shoulder arthroplasty: a systematic review and meta-analysis.

BACKGROUND: Tranexamic acid (TXA) has been shown to reduce perioperative blood loss and risk of blood transfusion. Evidence establishing its efficacy in total shoulder arthroplasty (TSA) is limited. The current study evaluated the effect of TXA on perioperative blood loss and transfusion risk after TSA. METHODS: A systematic review and meta-analysis of TXA administration for TSA was performed, and 6 studies with a total of 680 patients were found. Data on change in hemoglobin, drain output, total blood loss, and transfusion were extracted. Meta-analysis was performed with stratification into reverse and anatomic TSA subgroups. RESULTS: TXA administration was associated with decreased change in hemoglobin (-0.63 g/dL; 95% CI, -0.87 to -0.39 g/dL; P < .00001), drain output (-112.05 mL; 95% CI, -182.29 to -41.81 mL; P < .0001), and total blood loss (-231.87 mL; 95% CI, -334.23 to -129.48 mL; P < .00001) after reverse TSA. There was a trend toward reduction in transfusion rate after reverse TSA (-4%; 95% CI, -8% to 0%; P = .06). TXA administration was associated with reduced drain output after anatomic TSA (-123.07 mL; 95% CI, -163.93 to -82.20 mL; P < 0.00001). TXA administration was not associated with decreased transfusion rate after anatomic TSA. Data to evaluate the effect of TXA on change in hemoglobin and total blood loss after anatomic TSA were insufficient. CONCLUSIONS: Routine administration of TXA reduces perioperative blood loss and may reduce the risk of transfusion after reverse TSA. Future studies are needed to further characterize its effect on the risk of transfusion after reverse TSA and efficacy in anatomic TSA.

Elucidating the Role of Host Long Non-Coding RNA during Viral Infection: Challenges and Paths Forward.

Research over the past decade has clearly shown that long non-coding RNAs (lncRNAs) are functional. Many lncRNAs can be related to immunity and the host response to viral infection, but their specific functions remain largely elusive. The vast majority of lncRNAs are annotated with extremely limited knowledge and tend to be expressed at low levels, making ad hoc experimentation difficult. Changes to lncRNA expression during infection can be systematically profiled using deep sequencing; however, this often produces an intractable number of candidate lncRNAs, leaving no clear path forward. For these reasons, it is especially important to prioritize lncRNAs into high-confidence "hits" by utilizing multiple methodologies. Large scale perturbation studies may be used to screen lncRNAs involved in phenotypes of interest, such as resistance to viral infection. Single cell transcriptome sequencing quantifies cell-type specific lncRNAs that are less abundant in a mixture. When coupled with iterative experimental validations, new computational strategies for efficiently integrating orthogonal high-throughput data will likely be the driver for elucidating the functional role of lncRNAs during viral infection. This review highlights new high-throughput technologies and discusses the potential for integrative computational analysis to streamline the identification of infection-related lncRNAs and unveil novel targets for antiviral therapeutics.

Characterization and removal of DNAPL from sand and clay layered media.

Important characterization and remediation techniques (e.g. partitioning tracer tests (PTT), cosolvent and surfactant flushing) have been developed over the years to deal with dense nonaqueous phase liquid (DNAPL) sources in the saturated zone. Unfortunately, subsurface media layering and heterogeneity pose a major challenge to the efficiency of these and other techniques that rely on flushing fluids through porous media. Using laboratory column experiments with both single media and layered-media columns and computer modeling of tracer breakthrough results, we examined the difficulty that layering poses to subsurface remediation and characterization techniques. Quantifying tetrachloroethylene (PCE) saturation in layered media was determined using PTT and effluent mass determinations. Conservative tracer breakthrough curves were used to determine permeability and the flow through layers before and after PCE contamination. The removal efficiency of alcohol flushing in the layered systems was also determined. Results showed that even a relatively simple layering with less than an order magnitude difference in permeability leads to difficulty in characterization and remediation using flushing technologies. These results suggest that much greater volumes of flushing solutions will be needed in heterogeneous environments to ensure adequate flushing of lower permeable lenses and layers.

Changes in outflow to respiratory pump muscles produced by natural vestibular stimulation.

1. Activity was recorded from abdominal (expiratory) and phrenic (inspiratory) nerves during natural vestibular stimulation in multiple vertical planes and the horizontal plane in decerebrate cats. Vestibular stimulation was produced by rotating the head in animals whose upper cervical dorsal roots were transected to remove inputs from neck receptors; the upper airway and carotid sinus were denervated, and the vagus nerves were transected to assure that the head rotations did not elicit visceral or pulmonary inputs. 2. The plane of head rotation that produced maximal modulation of respiratory nerve activity (response vector orientation) was measured at one or more frequencies between 0.05 and 0.5 Hz. The dynamics of the response were then studied with sinusoidal (0.05-2 Hz) stimuli aligned with this orientation. In some animals, sinusoidal horizontal rotations of the head at 0.5 and 1 Hz or static head tilts in the pitch and roll planes were also delivered. 3. Typically, maximal modulation of abdominal nerve outflow was elicited by head rotations in a plane near pitch; nose-up rotations produced increased outflow, and nose-down rotations reduced nerve discharges. The gains of the responses (relative to stimulus position) remained relatively constant across stimulus frequencies, and the phases were consistently near stimulus position, like regularly firing otolith afferents. Static nose-up tilt produced elevated abdominal nerve activity throughout the stimulus period, providing further evidence that pitch-sensitive otolith receptors contribute to the response. Horizontal head rotations had little influence on abdominal nerve discharges. 4. The abdominal nerve responses to head rotation were abolished by chemical or aspiration lesions of the medial and inferior vestibular nuclei, which is concordant with the responses resulting from activation of vestibular receptors. Transections of axons arising from bulbospinal neurons in the ventral respiratory group, which are known to be the predominant source of expiratory signals to the spinal cord, reduced but did not abolish the vestibuloabdominal reflex. Thus it is likely that nonrespiratory neurons also participate in generating this response. 5. Nose-up pitch of the head; and in particular large (50 degrees) static tilts, produced small increases in phrenic nerve activity. Ear-down tilt and horizontal rotation of the head produced no responses in the phrenic nerve. 6. The existence of vestibular inputs to some respiratory motoneurons suggests that the vestibular system has influences on muscles in addition to those typically considered to have antigravity roles, and participates globally in adjusting muscle activity during movement and changes in posture.

Oral malignant acanthosis nigricans.

Awareness of a possible association of late-onset oral acanthosis nigricans with internal malignant disorders is important for early detection and treatment of the underlying cancer. A classic case of malignant oral acanthosis nigricans is reported here, and its possible etiologic factors and pathogenetic mechanisms are discussed.