Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome.

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril's effects on the GI following TBI (60Co 1.79 or 1.80 Gy, 0.42-0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

Comparative study of retrograde intramedullary nailing versus locking extramedullary plating in complete articular fractures with metaphyseal comminution of the distal femur.

INTRODUCTION: Fractures of the distal femur with metaphyseal comminution and complete intra-articular involvement (AO/OTA classifications 33C2 and 33C3) present challenges for reduction and fixation. However, an optimal fixation method remains unknown. This study aimed to compare the clinical and radiographic outcomes of locking extramedullary plating (LEP) and retrograde intramedullary nailing (RIN) for complete distal femoral intra-articular fractures with metaphyseal comminution. MATERIALS AND METHODS: Between January 2016 and May 2022, 80 patients (45 men and 35 women; average age, 56.7 years) diagnosed with AO/OTA 33C2 and 33C3 were treated with either LEP or RIN and followed up for at least one year. Post-operative evaluations included radiographic assessments of bone union rate, timing, and alignment. Clinically, the knee joint range of motion (ROM), lower extremity functional scale (LEFS), and Kellgren and Lawrence (KL) grade were analyzed. The complications were also compared. RESULTS: 36 underwent LEP and 44 underwent RIN. Bone union was observed in 69.4% and 63.6% of the patients in the LEP and RIN groups, respectively (p = 0.64). The average union time was 6.9 months for the LEP group and 6.6 months for the RIN group (p = 0.51). A tendency toward varus deformity was observed in the RIN group, although the difference was not statistically significant. No significant differences were observed in knee ROM, LEFS, or KL grade. Complications included non-union (33.8%; RIN, 11; LEP, 16), varus deformity (5%; RIN, 4; LEP, 0), infection (1.3%; RIN, 0; LEP, 1), heterotrophic ossification (1.3%; RIN, 0; LEP, 1), and wound dehiscence (2.5%; RIN, 2; LEP, 0). CONCLUSIONS: The surgical fixation methods, RIN and LEP, for complete distal femoral intra-articular fractures with metaphyseal comminution showed similar clinical and radiological outcomes. However, regardless of the type of fixation device used, there was a reduced rate of bone union owing to high energy and a less favorable prognosis.

Exercise affects high-fat diet-stimulated breast cancer metastasis through irisin secretion by altering cancer stem cell properties.

Background: Regular physical activities reduce the growth of breast cancer, but research on the effects of steady exercise on metastasis and its mechanisms is limited. In this study, the effects of steady exercise on breast cancer metastasis and its possible mechanism were demonstrated. Methods: Experimental metastasis was induced after 8 weeks of steady exercise using a mouse model. Furthermore, one of the myokines, irisin, was studied to elucidate the effects of metastasis-regulating protein expression, and colony and sphere formation, which are cancer stem cell properties. Results: Low- and moderate-intensity exercise significantly reduced the number and volume of metastasized tumors. Among myokines, only irisin was significantly increased by steady exercise but decreased by a high-fat diet. In vitro studies, irisin significantly decreased the number of colonies and sphere formation. Irisin also inhibited cell migration and invasion and suppressed the malignancy of breast cancer cells by reducing the expression of vimentin, MMP-2, MMP-9, and HIF-1 and by increasing the expression of TIMP-1 and TIMP-2. Conclusion: Steady exercise modulates myokine secretions and among them, irisin suppresses breast cancer metastasis by decreasing self-renewal properties and invasion regulating protein expressions. Thus, regular exercise may be beneficial in the prevention of breast tumor metastasis.

Relationships between the Spinal Dural Pulsations and the Short-Term Efficacy of Lumbar Epidural Steroid Injection.

Background: Lumbar spinal stenosis (LSS) causes low back pain, leg pain, numbness in the leg, and neurogenic intermittent claudication. Epidural steroid injection (ESI) has been used for treating spinal stenosis symptoms. We hypothesized that dural pulsation was variable for lumbar spinal stenosis. In cases of the presence of dural pulsation, the pain relief after the ESI was better than in the absence of dural pulsation. This study aimed at investigating the relationships between the presence or absence of spinal dural pulsations and the efficacy of ESI. Methods: A total of 71 patients were enrolled in this prospective study. Prior to the ESI, the dural pulsation was measured using a 5-1 MHz array ultrasound transducer. The visual analogue scale (VAS) score was measured pre-ESI and 2 weeks post-ESI and 4 weeks post-ESI. At 4 weeks post-ESI, dural pulsation was rechecked. Results: The VAS scores improved after the ESI procedure regardless of the presence or absence of dural pulsation. There was a correlation between the pulsation of the dura and post-ESI VAS scores. However, VAS was not significantly different for different grades of stenosis. Conclusion: The ESI was effective in patients with spinal stenosis in short-term follow-up. Dural pulsation of the spinal cord was a positive predictive factor for the ESI effect, but the grade of spinal stenosis severity had no effect on the effectiveness of ESI.

Histopathological studies of nonhuman primates exposed to supralethal doses of total- or partial-body radiation: influence of a medical countermeasure, gamma-tocotrienol.

Despite remarkable scientific progress over the past six decades within the medical arts and in radiobiology in general, limited radiation medical countermeasures (MCMs) have been approved by the United States Food and Drug Administration for the acute radiation syndrome (ARS). Additional effort is needed to develop large animal models for improving the prediction of clinical safety and effectiveness of MCMs for acute and delayed effects of radiation in humans. Nonhuman primates (NHPs) are considered the animal models that reproduce the most appropriate representation of human disease and are considered the gold standard for drug development and regulatory approval. The clinical and histopathological effects of supralethal, total- or partial-body irradiations (12 Gy) of NHPs were assessed, along with possible protective actions of a promising radiation MCM, gamma-tocotrienol (GT3). Results show that these supralethal radiation exposures induce severe injuries that manifest both clinically as well as pathologically, as evidenced by the noted functionally crippling lesions within various major organ systems of experimental NHPs. The MCM, GT3, has limited radioprotective efficacy against such supralethal radiation doses.

Minimally Invasive Surgery Transpedicular Intrabody Cage Technique for the Management of Kummell Disease.

BACKGROUND: The treatment of Kummell disease remains controversial, with a wide variety of options proposed in the literature. This study aims to introduce a unique and minimally invasive approach for the treatment of Kummell disease and present the clinical results of this technique. METHODS: Twenty patients underwent surgery using the minimally invasive surgery transpedicular intrabody cage (MISTIC) technique from 2014 to 2016. Postoperatively, patients were seen at 3, 6, and 12 months after surgery. Visual analog scale and Oswestry Disability Index scores were collected, and patient outcomes were graded according to the modified MacNab's criteria. Radiological outcomes were assessed through measurements of the anterior vertebral height (AH), mean vertebral body height (BH), and segmental angle (SA) on standing lateral radiographs pre- and postoperatively. RESULTS: There was significant improvement in the SA, AH, and BH postoperatively. The SA improved from 15.2 ± 8.7° of kyphosis to 1.2 ± 5.2° (P < 0.01) in the immediate postoperative period. The AH increased from 13.3 ± 14.6 to 22.6 ± 12.2 mm (P < 0.01), and at the final follow-up, it was 21.9 ± 12.6 mm (P < 0.01). Similarly, the BH increased from 18.5 ± 6.8 to 25.6 ± 7.6 mm (P < 0.01) postsurgery, and at the final follow-up, it was 23.6 ± 4.4 mm (P < 0.01). CONCLUSIONS: The MISTIC technique offers significant correction of kyphosis and restoration of the vertebral anatomy following surgery. These results were maintained at 12 months postoperation, with a 100% union rate of the fractures. Additionally, patients experienced significant pain relief and improvement in their ODI scores that were maintained at 12 months.

Acute hospitalizations after proton therapy versus intensity-modulated radiotherapy for locally advanced non-small cell lung cancer in the durvalumab era.

INTRODUCTION: It was hypothesized that use of proton beam therapy (PBT) in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiation and consolidative immune checkpoint inhibition is associated with fewer unplanned hospitalizations compared with intensity-modulated radiotherapy (IMRT). METHODS: Patients with locally advanced non-small cell lung cancer treated between October 2017 and December 2021 with concurrent chemoradiation with either IMRT or PBT ± consolidative immune checkpoint inhibition were retrospectively identified. Logistic regression was used to assess the association of radiation therapy technique with 90-day hospitalization and grade 3 (G3+) lymphopenia. Competing risk regression was used to compare G3+ pneumonitis, G3+ esophagitis, and G3+ cardiac events. Kaplan-Meier method was used for progression-free survival and overall survival. Inverse probability treatment weighting was applied to adjust for differences in PBT and IMRT groups. RESULTS: Of 316 patients, 117 (37%) received PBT and 199 (63%) received IMRT. The PBT group was older (p < .001) and had higher Charlson Comorbidity Index scores (p = .02). The PBT group received a lower mean heart dose (p < .0001), left anterior descending artery V15 Gy (p = .001), mean lung dose (p = .008), and effective dose to immune circulating cells (p < .001). On inverse probability treatment weighting analysis, PBT was associated with fewer unplanned hospitalizations (adjusted odds ratio, 0.55; 95% CI, 0.38-0.81; p = .002) and less G3+ lymphopenia (adjusted odds ratio, 0.55; 95% CI, 0.37-0.81; p = .003). There was no difference in other G3+ toxicities, progression-free survival, or overall survival. CONCLUSIONS: PBT is associated with fewer unplanned hospitalizations, lower effective dose to immune circulating cells and less G3+ lymphopenia compared with IMRT. Minimizing dose to lymphocytes may be warranted, but prospective data are needed.

Pneumonitis Rates Before and After Adoption of Immunotherapy Consolidation in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation.

PURPOSE: We hypothesized that after adoption of immune checkpoint inhibitor (ICI) consolidation for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy (cCRT), rates of symptomatic pneumonitis would increase, thereby supporting efforts to reduce lung radiation dose. METHODS AND MATERIALS: This single institution, multisite retrospective study included 783 patients with LA-NSCLC treated with definitive cCRT either before introduction of ICI consolidation (pre-ICI era cohort [January 2011-September 2017]; N = 448) or afterward (ICI era cohort [October 2017-December 2021]; N = 335). Primary endpoint was grade ≥2 pneumonitis (G2P) and secondary endpoint was grade ≥3 pneumonitis (G3P), per Common Terminology Criteria for Adverse Events v5.0. Pneumonitis was compared between pre-ICI era and ICI era cohorts using the cumulative incidence function and Gray's test. Inverse probability of treatment weighting (IPTW)-adjusted Fine-Gray models were generated. Logistic models were developed to predict the 1-year probability of G2P as a function of lung dosimetry. RESULTS: G2P was higher in the ICI era than in the pre-ICI era (1-year cumulative incidence 31.4% vs 20.1%; P < .001; IPTW-adjusted multivariable subdistribution hazard ratio, 2.03; 95% confidence interval, 1.53-2.70; P < .001). There was no significant interaction between ICI era treatment and either lung volume receiving ≥20 Gy (V20) or mean lung dose in Fine-Gray regression for G2P; however, the predicted probability of G2P was higher in the ICI era at clinically relevant values of lung V20 (≥24%) and mean lung dose (≥14 Gy). Cut-point analysis revealed a lung V20 threshold of 28% in the ICI era (1-year G2P rate 46.0% above vs 19.8% below; P < .001). Among patients receiving ICI consolidation, lung V5 was not associated with G2P. G3P was not higher in the ICI era (1-year cumulative incidence 7.5% vs 6.0%; P = .39; IPTW-adjusted multivariable subdistribution hazard ratio, 1.12; 95% confidence interval, 0.63-2.01; P = .70). CONCLUSIONS: In patients with LA-NSCLC treated with cCRT, the adoption of ICI consolidation was associated with an increase in G2P but not G3P. With ICI consolidation, stricter lung dose constraints may be warranted.

Patterns of Failure, Low-Volume Relapse, and Subsequent Ablative Management in Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation and Consolidation Immune Checkpoint Inhibitors.

PURPOSE: The objective of this study was to describe the patterns of failure, frequency of low-volume relapse (LVR), and candidacy for ablative therapy at time of disease progression (PD) after chemoradiation and consolidative immunotherapy (CRT + ICI) in patients with stage III non-small cell lung cancer. METHODS AND MATERIALS: We identified 229 consecutive patients with stage III non-small cell lung cancer treated with CRT + ICI between October 2017 and December 2021 at a single institution. PD was classified as isolated locoregional failure (LRF), isolated distant failure (DF), or synchronous LRF + DF. Any LRF was subclassified as in-field failure, marginal failure, or out-of-field failure. LVR was defined as 3 or fewer sites of PD in any number of organs. Ablative candidates were defined as having 5 or fewer sites of PD radiographically amenable to high-dose radiation or surgery. Time-to-event data were calculated using cumulative incidence analysis and Kaplan-Meier methods. Multivariable Cox modeling was used to examine the correlations between characteristics of relapse and postprogression survival. RESULTS: Of the 229 patients, 119 (52%) had PD. Of these 119 patients, 20 (21%) had isolated LRF, 28 (24%) had synchronous LRF + DF, and 71 (60%) had isolated DF. Of the 48 patients with any LRF, 28 (58%) had in-field failure, 10 (21%) marginal failure, and 10 (21%) out-of-field failure. The cumulative incidence of LRF and DF was 13% (95% CI, 9.2%-18%) and 32% (95% CI, 26%-38%) at 1 year and 19% (95% CI, 14%-24%) and 39% (95% CI, 33%-46%) at 2 years, respectively. Overall, 64 patients (54%) were considered to have LVR. At time of PD, 60 patients (50%) were eligible for ablative therapy. Patients with LVR had longer median survival versus with high-volume relapse (37.4 vs 15.2 months, P < .001). On multivariable analysis, LVR (hazard ratio, 0.32; 95% CI, 0.18-0.56; P < .001) was associated with improved postprogression survival. CONCLUSIONS: After CRT + ICI, approximately half of patients experience LVR at time of PD and are candidates for ablative therapies. Prospective trials are needed to validate the optimal treatment strategy for LVR.

The effective radiation dose to immune cells predicts lymphopenia and inferior cancer control in locally advanced NSCLC.

PURPOSE: To explore the association of the effective dose to immune cells (EDIC) with disease control, lymphopenia, and toxicity in patients with non-small cell lung cancer (NSCLC) and identify methods to reduce EDIC. METHODS: We abstracted data from all patients with locally advanced NSCLC treated with chemoradiation with or without consolidative immunotherapy over a ten-year period. Associations between EDIC and progression-free survival (PFS) and overall survival (OS) were modeled with Cox proportional hazards and Kaplan-Meier method. Logistic regression was used to model predictors of lymphopenia and higher EDIC. Analyses were performed with EDIC as a continuous and categorical variable. Lymphopenia was graded per CTCAE v5.0. RESULTS: Overall, 786 patients were included (228 of which received consolidative immunotherapy); median EDIC was 4.7 Gy. Patients with EDIC < 4.7 Gy had a longer median PFS (15.3 vs. 9.0 months; p < 0.001) and OS (34.2 vs. 22.4 months; p < 0.001). On multivariable modeling, EDIC correlated with inferior PFS (HR 1.08, 95 % CI 1.01-1.14, p = 0.014) and OS (HR 1.10, 95 % CI 1.04-1.18, p = 0.002). EDIC was predictive of grade 4 lymphopenia (OR 1.16, 95 % CI 1.02-1.33, p = 0.026). EDIC ≥ 4.7 Gy was associated with increased grade 2 + pneumonitis (6-month incidence: 26 % vs 20 %, p = 0.04) and unplanned hospitalizations (90-day incidence: 40 % vs 30 %, p = 0.002). Compared to protons, photon therapy was associated with EDIC ≥ 4.7 Gy (OR 5.26, 95 % CI 3.71-7.69, p < 0.001) in multivariable modeling. CONCLUSIONS: EDIC is associated with inferior disease outcomes, treatment-related toxicity, and the development of severe lymphopenia. Proton therapy is associated with lower EDIC. Further investigations to limit radiation dose to the immune system appear warranted.

DW71177: A novel [1,2,4]triazolo[4,3-a]quinoxaline-based potent and BD1-Selective BET inhibitor for the treatment of acute myeloid leukemia.

The bromodomain and extraterminal domain (BET) family proteins recognize acetyl-lysine (Kac) at the histone tail through two tandem bromodomains, i.e., BD1 and BD2, to regulate gene expression. BET proteins are attractive therapeutic targets in cancer due to their involvement in oncogenic transcriptional activation, and bromodomains have defined Kac-binding pockets. Here, we present DW-71177, a potent BET inhibitor that selectively interacts with BD1 and exhibits strong antileukemic activity. X-ray crystallography, isothermal titration calorimetry, and molecular dynamic studies have revealed the robust and specific binding of DW-71177 to the Kac-binding pocket of BD1. DW-71177 effectively inhibits oncogenes comparable to the pan-BET inhibitor OTX-015, but with a milder impact on housekeeping genes. It efficiently blocks cancer-associated transcriptional changes by targeting genes that are highly enriched with BRD4 and histone acetylation marks, suggesting that BD1-selective targeting could be an effective and safe therapeutic strategy against leukemia.

Iron Deposition in the Bone Marrow and Spleen of Nonhuman Primates with Acute Radiation Syndrome.

The risk of exposure to high levels of ionizing radiation from nuclear weapons or radiological accidents is an increasing world concern. Partial- or total-body exposure to high doses of radiation is potentially lethal through the induction of acute radiation syndrome (ARS). Hematopoietic cells are sensitive to radiation exposure; white blood cells primarily undergo apoptosis while red blood cells (RBCs) undergo hemolysis. Several laboratories demonstrated that the rapid hemolysis of RBCs results in the release of acellular iron into the blood. We recently demonstrated using a murine model of ARS after total-body irradiation (TBI) and the loss of RBCs, iron accumulated in the bone marrow and spleen, notably between 4-21 days postirradiation. Here, we investigated iron accumulation in the bone marrow and spleens from TBI nonhuman primates (NHPs) using histological stains. We observed trends in increased intracellular and extracellular brown pigmentation in the bone marrow after various doses of radiation, especially after 4-15 days postirradiation, but these differences did not reach significance. We observed a significant increase in Prussian blue-staining intracellular iron deposition in the spleen 13-15 days after 5.8-8.5 Gy of TBI. We observed trends of increased iron in the spleen after 30-60 days postirradiation, with varying doses of radiation, but these differences did not reach significance. The NHP model of ARS confirms our earlier findings in the murine model, showing iron deposition in the bone marrow and spleen after TBI.

Cardiovascular Substructure Dose and Cardiac Events following Proton- and Photon-Based Chemoradiotherapy for Non-Small Cell Lung Cancer.

Purpose: Radiation therapy (RT) plays a critical role in treating locally advanced non-small cell lung cancer but has been associated with deleterious cardiac effects. We hypothesized that RT dose to certain cardiovascular substructures may be higher among those who experience post-chemoradiation (CRT) cardiac events, and that dose to specific substructures-the great vessels, atria, ventricles, and left anterior descending coronary artery-may be lower with proton- versus photon-based RT. Methods and Materials: In this retrospective review, we selected 26 patients who experienced cardiac events after CRT for locally advanced non-small cell lung cancer and matched them to 26 patients who did not experience cardiac events after CRT. Matching was done based on RT technique (protons vs photons), age, sex, and cardiovascular comorbidity. For each patient, the whole heart and 10 cardiovascular substructures on the RT planning computerized tomography scan were manually contoured. Dosimetric comparisons were made between those who did and did not experience cardiac events and between the proton and photon groups. Results: There was no significant difference in heart or any cardiovascular substructure dose between those patients who experienced post-treatment cardiac events and those who did not (P > .05 for all). The mean heart dose in the patients receiving proton therapy was significantly lower than the mean heart dose in the patients receiving photon therapy (P = .032). The left ventricle, right ventricle, and the left anterior descending artery also had significantly lower doses (by multiple measures) when treated with protons (P = .0004, P < .0001, and P = .0002, respectively). Conclusions: Proton therapy may have a significant effect on decreasing dose to individual cardiovascular substructures compared with photon therapy. There was no significant difference in heart dose or dose to any cardiovascular substructure between patients who did and did not experience post-treatment cardiac events. Further research should be done to assess the association between cardiovascular substructure dose and post-treatment cardiac events.

Fermented Sprouts of Codonopsis lanceolata Suppress LPS-Induced Inflammatory Responses by Inhibiting NF-κB Signaling Pathway in RAW 264.7 Macrophages and CD1 Mice.

The interest in bioconversion through fermentation of sprouts produced in smart farms is increasing due to their potential health benefits. Codonopsis lanceolata (CL) is reported to alleviate inflammatory conditions, but much research is still needed to determine which types and parts of CL are most effective. This study investigated the anti-inflammatory effects of a fermented extract of CL sprouts' aerial part (F-CSA) against LPS-stimulated RAW 264.7 macrophages and mice. In the screening test, F-CSA showed the most substantial anti-inflammatory effect among several samples, containing the highest total flavonoids, tannins, and polyphenols. UPLC-ESI-Q/TOF-MS and HPLC analysis revealed that F-CSA had the highest amount of luteolin among all the CL samples analyzed. F-CSA reduced the release of inflammatory cytokines and mediators such as NO and PGE2 by inhibiting the expression levels of iNOS and COX-2 in LPS-stimulated macrophages. Further, we found that the anti-inflammatory effects of F-CSA were mediated by inhibiting the JNK/NF-κB signaling pathway. Moreover, F-CSA improved survival rates and reduced plasma levels of NO and IL-6 in CD1 mice stimulated with LPS. These findings suggest that F-CSA, which contains luteolin, can alleviate inflammation in LPS-induced RAW 264.7 cells and a CD1 mouse model by inhibiting the JNK/NF-κB signaling pathways.

Discordant renal progression of Fabry disease in male monozygotic twins: a case report.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the GLA gene that encodes α-galactosidase A (α-GAL). Clinical phenotypes tend to vary in monozygotic female twins because mutations are located on the X-chromosome, whereas similar phenotypes are found in male monozygotic twins. Here we report the case of male monozygotic twins with FD presenting with distinguishable renal phenotypes. Case: A 49-year-old male patient who visited the hospital with proteinuria 14 years prior was readmitted for the same issue. His monozygotic twin brother had started hemodialysis 6 months prior due to renal failure of unknown origin. The patient's renal function was within the normal range, while his spot urine protein-to-creatinine ratio was 557 mg/g. Echocardiography revealed left ventricular hypertrophy (LVH). The findings of a renal biopsy were consistent with FD. Genetic testing identified a c.656T>C mutation in the GLA gene, and α-GAL activity was significantly decreased. Genetic screening of his family clarified that his mother, older sister, twin brother, and his daughter had the same genetic mutations. The patient received enzyme replacement therapy 34 times. Subsequently, migalastat was initiated that continues today. Renal function and proteinuria remain stable, and the LVH has mildly improved. Conclusion: This is the first case of male monozygotic twins expressing different progressions of FD. Our findings demonstrate the possibility that environmental or epigenetic factors may critically influence genotype-phenotype discordance.

Interpretable Machine Learning for Choosing Radiation Dose-volume Constraints on Cardio-pulmonary Substructures Associated with Overall Survival in NRG Oncology RTOG 0617.

PURPOSE: Our objective was to use interpretable machine learning for choosing dose-volume constraints on cardiopulmonary substructures (CPSs) associated with overall survival (OS) in radiation therapy for locally advanced non-small cell lung cancer. METHODS AND MATERIALS: A total of 428 patients with non-small cell lung cancer were randomly divided into training/validation/test subsets (n = 230/149/49) in Radiation Therapy Oncology Group 0617. Manual or automated contouring was performed to segment CPSs, including heart, atria, ventricles, aorta, left/right ventricle/atrium (LV+RV+LA+RA), inferior/superior vena cava, pulmonary artery, and pericardium. Peri (pericardium-heart), rest (heart-[LV+RV+LA+RA]), clinical target volume (CTV), and lungs-CTV contours were also obtained. Dose-volume histogram features were extracted, including minimum/mean dose to the hottest x% volume (Dx%[Gy]/MOHx%[Gy]), minimum/mean/maximum dose, percent volume receiving at least xGy (VxGy[%]), and overlapping volume of each CPS with planning target volume (PTV_Voverlap[%]). Clinical parameters were collected from the National Clinical Trials Network/Community oncology research program data archive. Feature selection was performed using a series of multiblock sparse partial least squares regression, stability selection supervised principal component analysis, and Boruta. Explainable boosting machine (EBM) was trained using a conditional survival distribution-based approach for imputing censored data, treating survival analysis as a regression problem. Harrell's C-index was used to evaluate OS discrimination performance of EBM, Cox proportional hazards (CPH), random survival forest, extreme gradient boosting survival embeddings, and CPH deep neural network (DeepSurv) models in the test set. Dose-volume constraints were selected using the binary change point detection algorithm in Shapley additive explanations-based partial dependence functions. RESULTS: Selected features included LA_V60Gy(%), pericardium_D30%(Gy), lungs-CTV_PTV_Voverlap(%), RA_V55Gy(%), and received_cons_chemo. All models ranked LA_V60Gy(%) as the most important feature. EBM achieved the best performance for predicting OS, followed by extreme gradient boosting survival embeddings, random survival forest, DeepSurv, and CPH (C-index = 0.653, 0.646, 0.642, 0.638, and 0.632). EBM global explanations suggested that LA_V60Gy(%) < 25.6, lungs-CTV_PTV_Voverlap(%) < 1.1, pericardium_D30%(Gy) < 18.9, RA_V55Gy(%) < 19.5, and received_cons_chemo = 'Yes' for improved OS. CONCLUSIONS: EBM can be used to discriminate OS while also guiding dose-volume constraint selection for optimal management of cardiac toxicity in lung cancer radiation therapy.

Uniportal full endoscopic spinous process-preserving laminectomy for bilateral decompression in cervical stenotic myelopathy: patient series.

BACKGROUND: Endoscopic decompression for cervical stenotic myelopathy has several advantages over conventional open surgery. However, sometimes performing bilateral decompression, especially contralateral decompression, can be dangerous. The cervical spine has specific characteristics, including a shallower lamina angle and thinner lamina than the lumbar or thoracic lamina. These characteristics may cause cord compression when instruments approach the contralateral side of the lamina. This article introduces a novel surgical technique that can overcome the specificities of the cervical spine and discusses the efficacy and safety of uniportal full endoscopy for cervical decompression. OBSERVATIONS: Fourteen patients underwent uniportal full endoscopic spinous process-preserving laminectomy (ESP-L) for bilateral decompression of multilevel cervical stenotic myelopathy. The mean follow-up period was 13.44 months (range: 4-17 months). The preoperative and postoperative cervical spine angle and cervical range of motion did not differ significantly. The Japanese Orthopaedic Association score significantly improved postoperatively. The numeric rating scale scores significantly improved postoperatively. The mean duration of postoperative hospitalization was 2.3 days. LESSONS: ESP-L is a new, safe, effective, and noninvasive technique that can achieve complete decompression of multilevel cervical stenotic myelopathy.

Discovery of cellular and genetic signatures of immune tolerance in kidney transplant recipients through single cell RNA sequencing analysis.

The objective of this study was to uncover distinct cellular and genetic signatures of transplant operational tolerance (TOT) in kidney transplant recipients (KTRs) through single cell RNA sequencing (scRNA-seq) using peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 12 KTRs, including those with TOT (TOT, n = 4), stable allograft function on maintenance immunosuppression (STA, n = 4) and biopsy-proven allograft rejection (BPAR, n = 4). ScRNA-seq of PBMCs was analyzed using 20 cell surface marker antibody sequencing to annotate clusters and 399 immune response panel to identify gene expression. Differences in cellular distribution and gene expression were compared among the three groups. Heatmap hierarchical clustering showed that overall cellular distribution pattern was distinct in TOT in comparison with those in the other two groups, with the proportion of B cells being higher in TOT, attributed to immature B cell fraction (TOT vs. STA vs. BPAR: 4.61% vs. 1.27% vs. 2.53%, p = 0.01). Transcript analysis of B cells revealed that genes involved in allo-immune pathway were downregulated in TOT. In T cell subset analysis, the proportion of naïve T cells and regulatory T cells (Tregs) was increased. In transcript analysis, genes associated with inflammation were decreased, while expression levels of CCR6 in Tregs were increased in TOT. Proportions of NKT and NK cells were increased in TOT than in the other two groups. This study showed that TOT has distinct cellular and genetic signatures such as increases of immature B cells, naïve T cells and Tregs and high expression levels of CCR6 in Tregs.

Risk factors for ninety-day readmissions following full-endoscopic transforaminal lumbar discectomy for 1542 patients in the biggest spine institutes in Korea.

INTRODUCTION: Endoscopic techniques are becoming popular among spine surgeons because of their advantages. Though the advantages of endoscopic spine surgery are evident and patients can be discharged home within hours of surgery, readmissions can be sought for incomplete relief of leg pain, recurrent disc herniation, and recurrent leg pain. We aim to find out the factors related to the readmission of patients treated for lumbar pathologies. MATERIALS AND METHODS: This is a retrospective analysis of the data between the time duration of 2012 and 2022. Patients in the age group of 18-85 years, with lumbar disc herniation treated by transforaminal endoscopic lumbar procedures, were included. The patients who were readmitted within 90 days were included in the R Group and those who were not were included in the NR group. Univariable and multivariable logistic regression analyses were used to find the risk factors for 90-day readmission. RESULTS: There were a total of 1542 patients enrolled in this study. Sex, number of episodes before admission, hypertension, smoking, BMI, migration, disc height, disc height index, spondylolisthesis, instability, pelvic tilt (PT), and disc cross-sectional area (CSA) were found significant on univariable analysis. Age, spondylolisthesis, instability and muscle CSA were the only variables that were found to be statistically significant on multivariable analysis. CONCLUSIONS: This study shows that the elderly age group, presence of spondylolisthesis, segmental instability and decreased muscle cross-sectional area are independent risk factors for 90-day hospital readmissions. Patients having the above risk factors should be carefully counseled regarding the possibility of readmission in the future.

High physical activity alleviates the adverse effect of higher sedentary time on the incidence of chronic kidney disease.

BACKGROUND: Low physical activity (PA) increases the prevalence of chronic kidney disease (CKD). This study aimed to investigate the effects of PA and sedentary time (ST) on the changes in renal function and the development of CKD in the middle-aged Korean population. METHODS: From the Korean Genome and Epidemiology Study Database, 7988 participants in their 40s and 60s were identified and stratified by (1) PA: high-PA (>24 MET-h/day), moderate-PA (9-24 MET-h/day) and low-PA (<9 MET-h/day); and (2) ST: high-ST (>6 h/day), moderate-ST (3-6 h/day) and low-ST (<3 h/day). Incident CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 following the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: The mean age of the participants was 52.0 years. The overall incidence of CKD was 16.8 per 1000 person-years over a median of 12 years. The lower the PA and the higher the ST, the lower the baseline eGFR. Relative to the high-PA, the coefficients of the annual eGFR decline were -0.12 (95% confidence interval [CI]: -0.26 to 0.001, P = 0.081) and -0.13 (95% CI: -0.27 to 0.01, P = 0.078) in the moderate- and low-PA groups, respectively. Similarly, relative to the low-ST, the coefficients of annual eGFR decline were -0.07 (59% CI: -0.19 to 0.05, P = 0.236) and -0.14 (95% CI: -0.28 to -0.01, P = 0.039) in the moderate- and high-ST groups, respectively. Incident CKD was higher with lower PA (hazard ratio: high-PA 1.00, moderate-PA 1.13 [1.00, 1.28, P = 0.056] and low-PA 1.25 [1.11, 1.24, P < 0.001]) and higher ST (hazard ratio: low-ST 1.00, moderate-ST 1.04 [0.94, 1.16, P = 0.440] and high-ST 1.19 [1.05, 1.34, P = 0.007]). The high-PA reduced the risk for the CKD development irrespective of the amount of ST. CONCLUSIONS: Low-PA and high-ST are risk factors for the development of CKD in the middle-aged Korean population. High-PA recovers high-ST, inducing a harmful effect on the occurrence of CKD.