Characterizing white matter connectome abnormalities in patients with temporal lobe epilepsy using threshold-free network-based statistics.

INTRODUCTION: Emerging evidence illustrates that temporal lobe epilepsy (TLE) involves network disruptions represented by hyperexcitability and other seizure-related neural plasticity. However, these associations are not well-characterized. Our study characterizes the whole brain white matter connectome abnormalities in TLE patients compared to healthy controls (HCs) from the prospective Epilepsy Connectome Project study. Furthermore, we assessed whether aberrant white matter connections are differentially related to cognitive impairment and a history of focal-to-bilateral tonic-clonic (FBTC) seizures. METHODS: Multi-shell connectome MRI data were preprocessed using the DESIGNER guidelines. The IIT Destrieux gray matter atlas was used to derive the 162 × 162 structural connectivity matrices (SCMs) using MRTrix3. ComBat data harmonization was applied to harmonize the SCMs from pre- and post-scanner upgrade acquisitions. Threshold-free network-based statistics were used for statistical analysis of the harmonized SCMs. Cognitive impairment status and FBTC seizure status were then correlated with these findings. RESULTS: We employed connectome measurements from 142 subjects, including 92 patients with TLE (36 males, mean age = 40.1 ± 11.7 years) and 50 HCs (25 males, mean age = 32.6 ± 10.2 years). Our analysis revealed overall significant decreases in cross-sectional area (CSA) of the white matter tract in TLE group compared to controls, indicating decreased white matter tract integrity and connectivity abnormalities in addition to apparent differences in graph theoretic measures of connectivity and network-based statistics. Focal and generalized cognitive impaired TLE patients showcased higher trend-level abnormalities in the white matter connectome via decreased CSA than those with no cognitive impairment. Patients with a positive FBTC seizure history also showed trend-level findings of association via decreased CSA. CONCLUSIONS: Widespread global aberrant white matter connectome changes were observed in TLE patients and characterized by seizure history and cognitive impairment, laying a foundation for future studies to expand on and validate the novel biomarkers and further elucidate TLE's impact on brain plasticity.

Impact of multidisciplinary care of diabetic foot infections for inpatients at Campbelltown Hospital.

BACKGROUND: Diabetic foot infection (DFI), including diabetic foot ulcer, is a serious complication of diabetes, particularly in the South Western Sydney (SWS) region where it is a leading cause of diabetes-related hospitalisations. Multidisciplinary team (MDT) involvement is effective at improving the health outcomes of DFI patients. This study investigated the impact of MDT (High Risk Foot Service, HRFS) on the length of stay and surgical outcomes of inpatients with DFI in a Sydney tertiary hospital. METHOD: A retrospective audit of electronic medical records of inpatient admissions for DFI at Campbelltown Hospital between January 2019 - December 2021, was performed. The main outcome of the study was MDT involvement, defined as having two or more specialities involved in the patient's treatment. The other measured variables included length of stay (defined as the total duration from admission to discharge), and surgical outcomes including debridement, minor amputation, and major amputation. RESULTS: Over the three years, 78 participants presented to the hospital for 89 unique DFI admissions. There were 24 admissions in 2019, 28 admissions in 2020, and 37 admissions in 2021, with MDT attendance showing a steady increase at 62.5%, 75.0% and 83.8% respectively. Patients with serious comorbidities such as chronic kidney disease were more likely to have MDT involvement (84.8% vs. 15.2%, P = 0.048). Imaging was more likely to be performed with MDT involvement (78.8% vs. 21.3%, p < 0.05). Comparing patients who received and did not receive MDT care, the mean HbA1c (%) (8.4 ± 2.0 vs. 8.2 ± 2.7, P = 0.701), median length of stay (LOS: 7.8, IQR 15.0 days vs. 4.8 IQR 7.9 days, P = 0.243) and rate of surgical outcomes (74.6% vs. 72.7%, P = 0.262) were similar. Patients who required major amputation had significantly longer LOS (24 days, IQR 21.5 vs. 5.2 days, IQR 13.0, P = 0.004) but similar HbA1c (P = 0.552) compared to those who had conservative intervention. CONCLUSION: Adopting an MDT approach was associated with more thorough investigation of DFI, with similar rates of surgical outcomes. Further research on the impacts of MDT on length of stay and surgical outcomes of DFI patients in other SWS hospitals is needed.

Rhinoviruses A and C elicit long-lasting antibody responses with limited cross-neutralization.

Rhinoviruses (RVs) can cause severe wheezing illnesses in young children and patients with asthma. Vaccine development has been hampered by the multitude of RV types with little information about cross-neutralization. We previously showed that neutralizing antibody (nAb) responses to RV-C are detected twofold to threefold more often than those to RV-A throughout childhood. Based on those findings, we hypothesized that RV-C infections are more likely to induce either cross-neutralizing or longer-lasting antibody responses compared with RV-A infections. We pooled RV diagnostic data from multiple studies of children with respiratory illnesses and compared the expected versus observed frequencies of sequential infections with RV-A or RV-C types using log-linear regression models. We tested longitudinally collected plasma samples from children to compare the duration of RV-A versus RV-C nAb responses. Our models identified limited reciprocal cross-neutralizing relationships for RV-A (A12-A75, A12-A78, A20-A78, and A75-A78) and only one for RV-C (C2-C40). Serologic analysis using reference mouse sera and banked human plasma samples confirmed that C40 infections induced nAb responses with modest heterotypic activity against RV-C2. Mixed-effects regression modeling of longitudinal human plasma samples collected from ages 2 to 18 years demonstrated that RV-A and RV-C illnesses induced nAb responses of similar duration. These results indicate that both RV-A and RV-C nAb responses have only modest cross-reactivity that is limited to genetically similar types. Contrary to our initial hypothesis, RV-C species may include even fewer cross-neutralizing types than RV-A, whereas the duration of nAb responses during childhood is similar between the two species. The modest heterotypic responses suggest that RV vaccines must have a broad representation of prevalent types.

Association of neighborhood deprivation with white matter connectome abnormalities in temporal lobe epilepsy.

OBJECTIVE: Social determinants of health, including the effects of neighborhood disadvantage, impact epilepsy prevalence, treatment, and outcomes. This study characterized the association between aberrant white matter connectivity in temporal lobe epilepsy (TLE) and disadvantage using a US census-based neighborhood disadvantage metric, the Area Deprivation Index (ADI), derived from measures of income, education, employment, and housing quality. METHODS: Participants including 74 TLE patients (47 male, mean age = 39.2 years) and 45 healthy controls (27 male, mean age = 31.9 years) from the Epilepsy Connectome Project were classified into ADI-defined low and high disadvantage groups. Graph theoretic metrics were applied to multishell connectome diffusion-weighted imaging (DWI) measurements to derive 162 × 162 structural connectivity matrices (SCMs). The SCMs were harmonized using neuroCombat to account for interscanner differences. Threshold-free network-based statistics were used for analysis, and findings were correlated with ADI quintile metrics. A decrease in cross-sectional area (CSA) indicates reduced white matter integrity. RESULTS: Sex- and age-adjusted CSA in TLE groups was significantly reduced compared to controls regardless of disadvantage status, revealing discrete aberrant white matter tract connectivity abnormalities in addition to apparent differences in graph measures of connectivity and network-based statistics. When comparing broadly defined disadvantaged TLE groups, differences were at trend level. Sensitivity analyses of ADI quintile extremes revealed significantly lower CSA in the most compared to least disadvantaged TLE group. SIGNIFICANCE: Our findings demonstrate (1) the general impact of TLE on DWI connectome status is larger than the association with neighborhood disadvantage; however, (2) neighborhood disadvantage, indexed by ADI, revealed modest relationships with white matter structure and integrity on sensitivity analysis in TLE. Further studies are needed to explore this relationship and determine whether the white matter relationship with ADI is driven by social drift or environmental influences on brain development. Understanding the etiology and course of the disadvantage-brain integrity relationship may serve to inform care, management, and policy for patients.

Application of data harmonization and tract-based spatial statistics reveals white matter structural abnormalities in pediatric patients with focal cortical dysplasia.

Our study assessed diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) in pediatric subjects with epilepsy secondary to Focal Cortical Dysplasia (FCD) to improve our understanding of structural network changes associated with FCD related epilepsy. We utilized a data harmonization (DH) approach to minimize confounding effects induced by MRI protocol differences. We also assessed correlations between DTI metrics and neurocognitive measures of the fluid reasoning index (FRI), verbal comprehension index (VCI), and visuospatial index (VSI). Data (n = 51) from 23 FCD patients and 28 typically developing controls (TD) scanned clinically on either 1.5T, 3T, or 3T-wide-bore MRI were retrospectively analyzed. Tract-based spatial statistics (TBSS) with threshold-free cluster enhancement and permutation testing with 100,000 permutations were used for statistical analysis. To account for imaging protocol differences, we employed non-parametric data harmonization prior to permutation testing. Our analysis demonstrates that DH effectively removed MRI protocol-based differences typical in clinical acquisitions while preserving group differences in DTI metrics between FCD and TD subjects. Furthermore, DH strengthened the association between DTI metrics and neurocognitive indices. Fractional anisotropy, MD, and RD metrics showed stronger correlation with FRI and VSI than VCI. Our results demonstrate that DH is an integral step to reduce the confounding effect of MRI protocol differences during the analysis of white matter tracts and highlights biological differences between FCD and healthy control subjects. Characterization of white matter changes associated with FCD-related epilepsy may better inform prognosis and treatment approaches.

Combined Tillaux and Bimalleolar Ankle Fracture in a Pediatric Patient: A Case Report.

Adolescents are at risk of unique ankle fracture patterns due to closing physes. Transitional ankle fractures, in particular, are an entity specific to adolescent patients due to the asymmetrically open distal tibia physis. Transitional ankle fractures are rarely seen in combination with bimalleolar ankle fracture patterns. This case is of interest because the combined fracture pattern and the treatment method presented have not been previously reported in the literature to our knowledge. A 15-year-old female presented with right ankle pain after a fall while roller skating. Imaging demonstrated a right Tillaux fracture with ipsilateral displaced medial malleolus fracture and minimally displaced Weber C distal fibula fracture. The Tillaux fracture and medial malleolus fractures were treated with open reduction and internal fixation with partially threaded compression screws. The lateral malleolus remained minimally displaced and did not require operative fixation. The patient healed well with no complications. Transitional injuries of the ankle in adolescents have been reported in the literature; however, combined injuries are uncommon and lack representation in the current literature base. These combined injuries are important to be aware of, as missed injuries can result in long-term pain and disability.

Intra-Articular Corticosteroid Injection After Total Knee Replacement: Is it Safe?

Recalcitrant pain after total knee replacement (TKR) is sometimes treated with intra-articular steroid injections (IASI), with few studies reporting on the risk of subsequent periprosthetic joint infection (PJI). This is a systematic review to evaluate the incidence and risk of PJI after IASI into a total knee replacement. We searched online databases using the keywords "total knee replacement," "total knee arthroplasty," "steroids" and "intra-articular injection." A total of 7386 articles (PubMed - 91, Embase - 70, Web of Science - 57, CINAHL - 8, and Google Scholar - 7160) were retrieved on the initial search. After applying exclusion criteria, four articles were included in this review for evaluation and statistical analysis. There were no level one or two studies. The incidence of infection after IASI at 12 months was 138/6499 or 2.1%, while the incidence of infection rate among controls at 12 months was 158/11256 or 1.4%. A chi-square test showed that the difference in infection rate was significant (p = 0.0002424). A caveat is that simple statistical test results are virtually guaranteed to be statistically significant with large sample size. IASI into a TKR is not a benign procedure and that may be associated with a significantly increased risk of subsequent periprosthetic joint infection. We, therefore, recommend against IASI into a TKR until better studies can be performed to determine their safety and efficacy.

Enhanced Neutralizing Antibody Responses to Rhinovirus C and Age-Dependent Patterns of Infection.

Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing.Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses.Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection.Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (P < 0.001, χ2) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5-27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A; P < 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (P < 0.0001), CDHR3 genotype (P < 0.05), and wheezing illnesses (P < 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time.Conclusions: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.

Targeting macrophage checkpoint inhibitor SIRPα for anticancer therapy.

The CD47/signal regulatory protein α (Cd47/SIRPα)interaction provides a macrophage immune checkpoint pathway that plays a critical role in cancer immune evasion across multiple cancers. Here, we report the engineering of a humanized anti-SIRPα monoclonal antibody (1H9) for antibody target cancer therapy. 1H9 has broad activity across a wide range of SIRPα variants. Binding of 1H9 to SIRPα blocks its interaction with CD47, thereby promoting macrophage-mediated phagocytosis of cancer cells. Preclinical studies in vitro and in vivo demonstrate that 1H9 synergizes with other therapeutic antibodies to promote phagocytosis of tumor cells and inhibit tumor growth in both syngeneic and xenograft tumor models, leading to survival benefit. Thus, 1H9 can potentially act as a universal agent to enhance therapeutic efficacy when used in combination with most tumor-targeting antibodies. We report a comparison of anti-SIRPα and anti-CD47 antibodies in CD47/SIRPα double-humanized mice and found that 1H9 exhibits a substantially reduced antigen sink effect due to the limited tissue distribution of SIRPα expression. Toxicokinetic studies in nonhuman primates show that 1H9 is well tolerated, with no treatment-related adverse effects noted. These data highlight the clinical potential of 1H9 as a pan-therapeutic with the desired properties when used in combination with tumor-targeting antibodies.

Programmed cell removal by calreticulin in tissue homeostasis and cancer.

Macrophage-mediated programmed cell removal (PrCR) is a process essential for the clearance of unwanted (damaged, dysfunctional, aged, or harmful) cells. The detection and recognition of appropriate target cells by macrophages is a critical step for successful PrCR, but its molecular mechanisms have not been delineated. Here using the models of tissue turnover, cancer immunosurveillance, and hematopoietic stem cells, we show that unwanted cells such as aging neutrophils and living cancer cells are susceptible to "labeling" by secreted calreticulin (CRT) from macrophages, enabling their clearance through PrCR. Importantly, we identified asialoglycans on the target cells to which CRT binds to regulate PrCR, and the availability of such CRT-binding sites on cancer cells correlated with the prognosis of patients in various malignancies. Our study reveals a general mechanism of target cell recognition by macrophages, which is the key for the removal of unwanted cells by PrCR in physiological and pathophysiological processes.

Early chemoprophylaxis is associated with decreased venous thromboembolism risk without concomitant increase in intraspinal hematoma expansion after traumatic spinal cord injury.

BACKGROUND: After traumatic spinal cord injury (SCI), there is increased risk of venous thromboembolism (VTE), but chemoprophylaxis (PPX) may cause expansion of intraspinal hematoma (ISH). METHODS: Single-center retrospective study of adult trauma patients from 2012 to 2015 with SCI. EXCLUSION CRITERIA: VTE diagnosis, death, or discharge within 48 hours. Patients were dichotomized based on early (≤48 hours) heparinoid and/or aspirin PPX. Intraspinal hematoma expansion was diagnosed intraoperatively or by follow-up radiology. We used multivariable Cox proportional hazards to estimate the effect of PPX on risk of VTE and ISH expansion controlling for age, injury severity score (ISS), complete SCI, and mechanism as static covariates and operative spine procedure as a time-varying covariate. RESULTS: Five hundred one patients with SCI were dichotomized into early PPX (n = 260 [52%]) and no early PPX (n = 241 [48%]). Early PPX patients were less likely blunt injured (91% vs 97%) and had fewer operative spine interventions (65% vs 80%), but age (median, 43 vs 49 years), ISS (median 24 vs 21), admission ISH (47% vs 44%), and VTE (5% vs 9%) were similar. Cox analysis found that early heparinoids was associated with reduced VTE (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.16-0.84) and reduced pulmonary embolism (PE) (HR, 0.20; 95% CI, 0.06-0.69). The estimated number needed to treat with heparinoids was 10 to prevent one VTE and 13 to prevent one PE at 30 days. Early aspirin was not associated with reduced VTE or PE. Seven patients (1%) had ISH expansion, of which four were on PPX at the time of expansion. Using heparinoid and aspirin as time-varying covariates, neither heparinoids (HR, 1.90; 95% CI, 0.32-11.41) nor aspirin (HR, 3.67; 95% CI, 0.64-20.88) was associated with ISH expansion. CONCLUSION: Early heparinoid therapy was associated with decreased VTE and PE risk in SCI patients without concomitant increase in ISH expansion. LEVEL OF EVIDENCE: Therapeutic, level IV.