Nevin Manimala

EJNMMI Res. 2022 Nov 8;12(1):71. doi: 10.1186/s13550-022-00944-5.

ABSTRACT

BACKGROUND: Antiepileptic drugs, levetiracetam (LEV) and brivaracetam (BRV), bind to synaptic vesicle glycoprotein 2A (SV2A). In their anti-seizure activity, speed of brain entry may be an important factor. BRV showed faster entry into the human and non-human primate brain, based on more rapid displacement of SV2A tracer ¹¹C-UCB-J. To extract additional information from previous human studies, we developed a nonlinear model that accounted for drug entry into the brain and binding to SV2A using brain ¹¹C-UCB-J positron emission tomography (PET) data and the time-varying plasma drug concentration, to assess the kinetic parameter K₁ (brain entry rate) of the drugs.

METHOD: Displacement (LEV or BRV p.i. 60 min post-tracer injection) and post-dose scans were conducted in five healthy subjects. Blood samples were collected for measurement of drug concentration and the tracer arterial input function. Fitting of nonlinear differential equations was applied simultaneously to time-activity curves (TACs) from displacement and post-dose scans to estimate 5 parameters: K₁ (drug), K₁(¹¹C-UCB-J, displacement), K₁(¹¹C-UCB-J, post-dose), free fraction of ¹¹C-UCB-J in brain (f_ND(¹¹C-UCB-J)), and distribution volume of ¹¹C-UCB-J (V_T(UCB-J)). Other parameters (K_D(drug), K_D(¹¹C-UCB-J), f_P(drug), f_P(¹¹C-UCB-J, displacement), f_P(¹¹C-UCB-J, post-dose), f_ND(drug), k_off(drug), k_off(¹¹C-UCB-J)) were fixed to literature or measured values.

RESULTS: The proposed model described well the TACs in all subjects; however, estimates of drug K₁ were unstable in comparison with ¹¹C-UCB-J K₁ estimation. To provide a conservative estimate of the relative speed of brain entry for BRV vs. LEV, we determined a lower bound on the ratio BRV K₁/LEV K₁, by finding the lowest BRV K₁ or highest LEV K₁ that were statistically consistent with the data. Specifically, we used the F test to compare the residual sum of squares with fixed BRV K₁ to that with floating BRV K₁ to obtain the lowest possible BRV K₁; the same analysis was performed to find the highest LEV K₁. The lower bound of the ratio BRV K₁/LEV K₁ was ~ 7.

CONCLUSIONS: Under appropriate conditions, this advanced nonlinear model can directly estimate entry rates of drugs into tissue by analysis of PET TACs. Using a conservative statistical cutoff, BRV enters the brain at least sevenfold faster than LEV.

PMID:36346513 | DOI:10.1186/s13550-022-00944-5

Dig Dis Sci. 2022 Nov 8. doi: 10.1007/s10620-022-07734-y. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Several studies showed muscularis macrophages (MMφ) are associated with GI motility disorders. The purpose of this study was to preliminary explore the association between MMφ and achalasia.

METHODS: Tissue samples of the lower esophageal sphincter (LES) high-pressure zone were obtained from 27 achalasia patients and 10 controls. Immunohistochemistry for MMφ, interstitial cells of Cajal (ICC), neuronal nitric oxide synthase (nNOS), and glial cells were conducted. Histological characteristics were compared between groups, and correlation analysis was performed.

RESULTS: Fewer ICC was found in achalasia compared with controls (P = 0.018), and the level of M1 macrophages was higher than that in controls no matter in terms of the number or the proportion of M1(P = 0.026 for M1 and 0.037 for M1/MMφ). Statistical differences were found between two groups in terms of proportion of M2 and ratio of M1 to M2 (P = 0.048 for M2/ MMφ and < 0.001 for M1/M2). For the correlation analysis, significant correlations were detected between levels of nNOS, ICC, and glial cells in patients with achalasia (P = 0.026 for nNOS and ICC, 0.001 for nNOS and glial cells, 0.019 for ICC and glial cells). There were significant correlations between M2/MMφ and levels of ICC (P = 0.019), glial cells (P = 0.004), and nNOS (P = 0.135).

CONCLUSION: Patients with achalasia had a higher level of M1/M2 ratio in LES and significant correlations were found between M2/MMφ and numbers of ICC and glial cells, which suggested that MMφ were probably associated with occurrence and development of achalasia.

PMID:36346489 | DOI:10.1007/s10620-022-07734-y

Breast Cancer Res Treat. 2022 Nov 8. doi: 10.1007/s10549-022-06781-3. Online ahead of print.

ABSTRACT

PURPOSE: The status of human epidermal growth factor receptor 2 (HER2) is important for treatment decision-making of breast cancer and was commonly determined by core needle biopsy (CNB). The concordance of CNB with surgical excision biopsy (SEB) has been verified, but remain unclear according to the newly developed classification of HER2 status. Our study aimed to re-evaluate the diagnostic value of CNB for determining HER2 status in breast cancer, especially in the HER2-low population.

METHODS: Eligible breast cancer patients in West China Hospital between January 1, 2007 and December 31, 2021 were enrolled consecutively and data were extracted from the Hospital Information System. The agreement of HER2 status between CNB and SEB was calculated by concordance rate and κ statistics, as well as the sensitivity, specificity, positive, and negative predictive values (PPV & NPV). Logistic models were used to explore potential factors associated with the discordance between both tests.

RESULTS: Of 1829 eligible patients, 1097 (60.0%) and 1358 (74.2%) were consistent between CNB and SEB by pathological and clinical classifications, respectively, with κ value being 0.46 (0.43-0.49) and 0.57 (0.53-0.60). The sensitivity (50.9%-52.7%) and PPV (50.5%-55.2%) of CNB were especially low among IHC 1+ and 2+/ISH – subgroups by pathological classifications; however, it showed the highest sensitivity (77.5%) and the lowest specificity (73.9%) in HER2-low population by clinical classifications. Advanced N stages might be a stable indicator for the discordance between both tests.

CONCLUSION: The diagnostic value of CNB was limited for determining HER2 status in breast cancer, especially in HER2-low population.

PMID:36346486 | DOI:10.1007/s10549-022-06781-3

Eur J Clin Microbiol Infect Dis. 2022 Nov 8. doi: 10.1007/s10096-022-04516-2. Online ahead of print.

ABSTRACT

The accuracy of contemporary risk scores in predicting perioperative mortality in infective endocarditis (IE) remains controversial. The aim is to evaluate the performance of existent mortality risk scores for cardiovascular surgery in IE and the impact on operability at high-risk thresholds. A single-center retrospective review of adult patients diagnosed with acute left-sided IE undergoing surgery from May 2014 to August 2019 (n = 142) was done. Individualized risk calculation was obtained according to the available mortality risk scores: EuroScore I and II, PALSUSE, Risk-E, Costa, De Feo-Cotrufo, AEPEI, STS-risk, STS-IE, APORTEI, and ICE-PCS scores. A cross-validation analysis was performed on the score with the best area under the curve (AUC). The 30-day survival was 96.5% (95%CI 91-98%). The score with worse area under the curve (AUC = 0.6) was the STS-IE score, while the higher was for the RISK-E score (AUC = 0.89). The AUC of the majority of risk scores suggested acceptable performance; however, statistically significant differences in expected versus observed mortalities were common. The cross-validation analysis showed that a large number of survivors (> 75%) would not have been operated if arbitrary high-risk threshold estimates had been used to deny surgery. The observed mortality in our cohort is significantly lower than is predicted by contemporary risk scores. Despite the reasonable numeric performance of the analyzed scores, their utility in judging the operability of a given patient remains questionable, as demonstrated in the cross-validation analysis. Future guidelines may advise that denial of surgery should only follow a highly experienced Endocarditis Team evaluation.

PMID:36346471 | DOI:10.1007/s10096-022-04516-2

Rheumatol Int. 2022 Nov 8. doi: 10.1007/s00296-022-05222-0. Online ahead of print.

ABSTRACT

Febuxostat is the drug used to treat hyperuricemia in patients with gout. Recently, the usage of Febuxostat has been controversial over the side effects in cardiovascular. The study aimed to comparatively analyze the risk of cardiovascular disease associated with febuxostat and allopurinol use in Korean patients with gout. A cohort study was conducted using national insurance claim data from the Health Insurance Review and Assessment Service (HIRA). Adult patients who were diagnosed with gout and prescribed febuxostat or allopurinol more than once from July 1, 2015, to June 30, 2018 were studied. The outcome was cardiovascular disease. Analysis was performed using Cox’s proportional hazard model following 1:1 propensity score matching to estimate the hazard ratio with a 95% confidence interval. In total, 90,590 patients were defined as the final study cohort who had an average follow-up of 467 days, including 28,732 and 61,858 patients in the febuxostat and allopurinol groups, respectively. After the 1:1 propensity score matching, the risk of cardiovascular disease in the febuxostat group was significantly higher than in the allopurinol group (HR: 1.17; 95% CI: 1.10-1.24). In the sensitivity analysis, the risk of cardiovascular disease in the febuxostat group was significantly higher than in the allopurinol group (HR: 1.09; 95% CI: 1.04-1.15). However, further sensitivity analysis showed no statistically significant difference between the febuxostat group and allopurinol group after adjusting for cardiovascular disease history before the index date. Similarly, no statistically significant difference was found between the two drugs in the subgroup analysis. Febuxostat was not associated with a significantly increased risk of cardiovascular disease.

PMID:36346443 | DOI:10.1007/s00296-022-05222-0

Eur Radiol. 2022 Nov 8. doi: 10.1007/s00330-022-09188-2. Online ahead of print.

ABSTRACT

OBJECTIVES: To investigate the incidence, risk factors, and clinical outcomes of pleuroparenchymal fibroelastosis (PPFE) in pediatric hematopoietic stem cell transplantation (HSCT) recipients.

METHODS: This single-center, retrospective, case-control study included 738 consecutive patients who underwent chest CT more than 3 months after HSCT. We identified patients who fulfilled the diagnostic criteria for PPFE and assessed their clinical characteristics and radiologic findings. Propensity score-matched analysis was performed using four covariates (age, sex, HSCT type, and primary disease). The risk factors and clinical outcomes of PPFE were analyzed using the Fine and Gray regression model and stratified log-rank test in the matched groups.

RESULTS: PPFE was identified in 4% (31/738, 8.3 ± 3.1 years, 15 males) of the pediatric HSCT recipients with a median time of 2.7 years after HSCT, and it occurred following allogeneic (5%, 15/317), autologous (4%, 15/379), or both (2%, 1/42). Matching yielded 30 and 130 cases in the PPFE and control groups, respectively. The PPFE group showed more frequent late-onset noninfectious pulmonary complications (LONIPCs) and pneumonia more than 3 months after HSCT (p < 0.05). Multivariable analysis showed a significantly higher risk of PPFE in HSCT recipients who had pneumonia more than 3 months after HSCT (hazard ratio = 10.78 [95% confidence interval: 4.29, 27.13], p < 0.001). The PPFE group showed higher mortality (73%, 22/30) and poorer median overall survival (6.8 years [95% confidence interval: 4.1, 9.5]) than the control group (p < 0.001).

CONCLUSIONS: PPFE represents a severe type of LONIPC after HSCT. HSCT recipients with pneumonia after HSCT may have an increased risk of PPFE.

KEY POINTS: • The incidence of pleuroparenchymal fibroelastosis is not negligible (4%), and it can occur after either allogeneic or autologous hematopoietic stem cell transplantation. • Pleuroparenchymal fibroelastosis after hematopoietic stem cell transplantation showed poor outcome with a high mortality rate of 73% and median overall survival of 6.8 years. • After hematopoietic stem cell transplantation, pneumonia may increase the risk of pleuroparenchymal fibroelastosis development in children. • Lung biopsy should not be indicated in patients with pleuroparenchymal fibroelastosis findings on chest CT as it can cause refractory pneumothorax without helping the diagnosis.

PMID:36346442 | DOI:10.1007/s00330-022-09188-2

CA Cancer J Clin. 2022 Nov 8. doi: 10.3322/caac.21757. Online ahead of print.

ABSTRACT

American Indian and Alaska Native (AIAN) individuals are diverse culturally and geographically but share a high prevalence of chronic illness, largely because of obstacles to high-quality health care. The authors comprehensively examined cancer incidence and mortality among non-Hispanic AIAN individuals, compared with non-Hispanic White individuals for context, using population-based data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries. Overall cancer rates among AIAN individuals were 2% higher than among White individuals for incidence (2014 through 2018, confined to Purchased/Referred Care Delivery Area counties to reduce racial misclassification) but 18% higher for mortality (2015 through 2019). However, disparities varied widely by cancer type and geographic region. For example, breast and prostate cancer mortality rates are 8% and 31% higher, respectively, in AIAN individuals than in White individuals despite lower incidence and the availability of early detection tests for these cancers. The burden among AIAN individuals is highest for infection-related cancers (liver, stomach, and cervix), for kidney cancer, and for colorectal cancer among indigenous Alaskans (91.3 vs. 35.5 cases per 100,000 for White Alaskans), who have the highest rates in the world. Steep increases for early onset colorectal cancer, from 18.8 cases per 100,000 Native Alaskans aged 20-49 years during 1998 through 2002 to 34.8 cases per 100,000 during 2014 through 2018, exacerbated this disparity. Death rates for infection-related cancers (liver, stomach, and cervix), as well as kidney cancer, were approximately two-fold higher among AIAN individuals compared with White individuals. These findings highlight the need for more effective strategies to reduce the prevalence of chronic oncogenic infections and improve access to high-quality cancer screening and treatment for AIAN individuals. Mitigating the disparate burden will require expanded financial support of tribal health care as well as increased collaboration and engagement with this marginalized population.

PMID:36346402 | DOI:10.3322/caac.21757

J Adhes Dent. 2022 Nov 8;24(1):395-406. doi: 10.3290/j.jad.b3559027.

ABSTRACT

PURPOSE: To evaluate the microtensile bond strength (μTBS) and silver nitrate uptake (SNU) of three universal adhesives used in etch-and-rinse (ER) and self-etch (SE) modes on dry, wet, and oversaturated dentin surfaces after 24 h and 1 year of water storage. The morphology of the hybrid layer (MHL) and the degree of conversion (DC) were also evaluated.

MATERIALS AND METHODS: Human molars were divided into 36 groups according to combinations of the following variables: (i) universal adhesives (Ambar Universal APS [AMB], Prime&Bond Active [PBA], Scotchbond Universal Adhesive [SBU]), (ii) adhesive strategies (ER or SE), (iii) moisture level (dry, wet, or oversaturated dentin surface), and (iv) storage time (24 h or 1 year). After restoration, the specimens were sectioned into resin-dentin sticks and tested for μTBS and SNU according to storage time. For MHL, the specimens were sectioned and evaluated after 24 h using SEM. DC was evaluated using FTIR. ANOVA and Tukey’s test were used for statistical analyses (5%).

RESULTS: When 24-h vs 1-year data were compared, there was a significant decrease in μTBS and an increase in SNU values for the majority of experimental groups (p < 0.0001). On dry (ER) and oversaturated (ER and SE) dentin, AMB showed higher μTBS than did PBA (p < 0.00001). No significant decrease in μTBS was observed when universal adhesives were applied in the SE mode to dry dentin (p > 0.05). Regarding SNU, at all moisture levels, AMB showed lower SNU values than SBU (p < 0.001). Regarding MHL, SBU showed several imperfections when applied to oversaturated dentin in comparison with AMB and PBA. Regarding DC, when dentin was kept dry or was oversaturated, AMB showed a higher DC than PBA (p < 0.0001).

CONCLUSION: The behavior of the different universal adhesives evaluated did not vary when applied to wet or dry dentin. However, the results with oversaturated dentin were dependent on the universal adhesive. Independent of the moisture level and the universal adhesive evaluated, significant degradation of the bonding properties occurred after 1 year of water storage, with the exception of universal adhesives applied to dry dentin in the SE strategy.

PMID:36346400 | DOI:10.3290/j.jad.b3559027

Expert Rev Mol Diagn. 2022 Nov 8. doi: 10.1080/14737159.2022.2144235. Online ahead of print.

ABSTRACT

BACKGROUND: Suppressor of variegation, Enhancer of Zeste, Trithorax (SET) and Myeloid-Nervy-DEAF1 (MYND) domain-containing protein (SMYD) family with methyltransferase activity is involved in cancer progression. This novel meta-analysis aimed to evaluate the association of SMYD family with the clinical and survival outcomes in solid cancer patients.

METHODS: We systematically searched Embase, PubMed, Scopus and Web of Science to select relevant articles. Hazard ratios (HRs), odds ratios (ORs) and 95% confidence intervals were extracted. Heterogeneity was evaluated by chi-square-based Q and I² tests, while publication bias by funnel plots and Egger’s test. Seven subcategories were used to perform subgroup analyses.

RESULTS: 32 articles (4,826 patients) met inclusion criteria. SMYD2/3 overexpression was statistically associated with poor overall survival (HR=1.794, P<0.001), disease/relapse/progression-free survival (HR=2.114, P<0.001), disease/cancer-specific survival (HR=3.220, 95%CI:1.498-6.921, P=0.003), larger tumor size (OR=1.963, P<0.001), advanced TNM stage (OR=2.066, P<0.001), lymph node metastasis (OR=2.054, P<0.001), and distant metastasis (OR=1.978, P=0.004). Subgroup analysis showed more significant association between SMYD2 overexpression and reduced survival outcomes than that in SMYD3. Conversely, the relationship between SMYD3 and various clinicopathologic factors was stronger compared to SMYD2.

CONCLUSION: Enhanced SMYD2/3 expression may be an unfavorable clinical prognostic factor in different solid cancer types, being linked to tumor development, poor survival outcomes and high likelihood of metastasis.

PMID:36346387 | DOI:10.1080/14737159.2022.2144235

J Exp Med. 2023 Jan 2;220(1):e20220829. doi: 10.1084/jem.20220829. Epub 2022 Nov 8.

ABSTRACT

Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon-driven inflammatory diseases. In these pathophysiological conditions, activation of the DNA sensor cGAS and IFN production are linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here, we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to a DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling in Samhd1-deficient mice and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.

PMID:36346347 | DOI:10.1084/jem.20220829