Evidence-based expert consensus on clinical management of safety of Bruton's tyrosine kinase inhibitors (2024).

Bruton's tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of B-cell lymphomas. However, safety issues related to the use of BTKis may hinder treatment continuity and further affect clinical efficacy. A comprehensive and systematic expert consensus from a pharmacological perspective is lacking for safety issues associated with BTKi treatment. A multidisciplinary consensus working group was established, comprising 35 members from the fields of hematology, cardiovascular disease, cardio-oncology, clinical pharmacy, and evidence-based medicine. This evidence-based expert consensus was formulated using an evidence-based approach and the Delphi method. The Joanna Briggs Institute Critical Appraisal (JBI) tool and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach were used to rate the quality of evidence and grade the strength of recommendations, respectively. This consensus provides practical recommendations for BTKis medication based on nine aspects within three domains, including the management of common adverse drug events such as bleeding, cardiovascular events, and hematological toxicity, as well as the management of drug-drug interactions and guidance for special populations. This multidisciplinary expert consensus could contribute to promoting a multi-dimensional, comprehensive and standardized management of BTKis.

Protein kinase G2 activation restores Wnt signaling and bone mass in glucocorticoid-induced osteoporosis in mice.

Osteoporotic fractures are a major complication of long-term glucocorticoid therapy. Glucocorticoids transiently increase bone resorption, but they predominantly inhibit bone formation and induce osteocyte apoptosis, leading to bone loss. Current treatments of glucocorticoid-induced osteoporosis aim mainly at reducing bone resorption and are therefore inadequate. We previously showed that signaling via the NO/cGMP/protein kinase G pathway plays a key role in skeletal homeostasis. Here, we show that pharmacological PKG activation with the guanylyl cyclase-1 activator cinaciguat or expression of a constitutively-active, mutant PKG2R242Q restored proliferation, differentiation, and survival of primary mouse osteoblasts exposed to dexamethasone. Cinaciguat treatment of wild type mice or osteoblast-specific expression of PKG2R242Q in transgenic mice prevented dexamethasone-induced loss of cortical bone mass and strength. These effects of cinaciguat and PKG2R242Q expression were due to preserved bone formation parameters and osteocyte survival. The basis for PKG2's effects appeared to be through recovery of Wnt/ß-catenin signaling, which was suppressed by glucocorticoids but is critical for proliferation, differentiation, and survival of osteoblast-lineage cells. Cinaciguat reduced dexamethasone activation of osteoclasts, but this did not occur in the PKG2R242Q transgenic mice, suggesting a minor role in osteoprotection. We propose that existing PKG-targeting drugs could represent a novel therapeutic approach to prevent glucocorticoid-induced osteoporosis.

Increased circulating polymorphonuclear myeloid-derived suppressor cells are associated with prognosis of metastatic castration-resistant prostate cancer.

Introduction: Myeloid-derived suppressor cell (MDSC) exhibits immunosuppressive functions and affects cancer progression, but its relationship with prostate cancer remains unclear. We elucidated the association of polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC) levels of the total peripheral blood mononuclear cells (PBMCs) with prostate cancer progression and evaluated their roles as prognostic indicators. Methods: We enrolled 115 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC, n = 62), metastatic hormone-sensitive prostate cancer (mHSPC, n = 23), and metastatic castration-resistant prostate cancer (mCRPC, n = 30). Subsequently, the proportions of MDSCs in each disease progression were compared. Log-rank tests and multivariate Cox regression analyses were performed to ascertain the associations of overall survival. Results: The patients with mCRPC had significantly higher PMN-MDSC percentage than those with nmHSPC and mHSPC (P = 7.73 × 10-5 and 0.0014). Significantly elevated M-MDSC levels were observed in mCRPC patients aged <70 years (P = 0.016) and with a body mass index (BMI) <25 kg/m2 (P = 0.043). The high PMN-MDSC group had notably shorter median survival duration (159 days) than the low PMN-MDSC group (768 days, log-rank P = 0.018). In the multivariate analysis including age, BMI, and MDSC subset, PMN-MDSC was significantly associated with prognosis (hazard ratios, 3.48; 95% confidence interval: 1.05-11.56, P = 0.042). Discussion: PMN-MDSC levels are significantly associated with mCRPC prognosis. Additionally, we highlight the remarkable associations of age and BMI with M-MDSC levels in mCRPC, offering novel insights into MDSC dynamics in prostate cancer progression.

Changes in aortic root dimensions post aortic root enlargement with Y-incision and modified aortotomy.

Background: Lifetime management in aortic stenosis (AS) can be facilitated by aortic root enlargement (ARE) to improve anatomy for future valve-in-valve (ViV) procedures. A mitral valve-sparing ARE technique ("Y-incision") and sinotubular junction (STJ) enlargement ("roof" patch aortotomy) allow upsizing by 3-4 valve sizes, but quantitative analysis of changes in root anatomy is lacking. Methods: Among 78 patients who underwent ARE by Y-incision technique (± roof aortotomy closure) we identified 45 patients with high-quality pre- and post-operative computed tomography angiography (CTA) scans to allow analysis of change in aortic root dimensions. Detailed measurements of the annulus/basilar ring and sinuses were performed by an expert imager on both pre- and post-operative CTAs. The basal ring was defined as the functional annulus when a bioprosthetic valve was present. Results: Average age was 65±11 years, the majority were female (29, 64%), and 9 (20%) had undergone prior aortic valve replacement (AVR). Valve upsizing was ≥3 sizes in 41 (91%). Post-operative mean basal ring diameter was larger compared to the native annular diameter (26.3 vs. 25.3 mm, P<0.01) and substantially larger than prior prosthetic valve in redo AVR (25.6 vs. 19.3 mm, P<0.001). Diameters of the sinuses at pre-operative computed tomography (CT) increased by +7.7±2.8 [right sinuses of Valsalva (R SVS)], +6.7±3.0 [left sinuses of Valsalva (L SVS)], and +6.6±2.9 mm [non-coronary sinuses of Valsalva (N SVS)]. Mean diameter of the STJ increased to 38.3±3.7 post-operative (+8.1±3.2 mm). Left main (LM) and right coronary artery (RCA) heights decreased by -6.3±3.3 and -3.7±3.4 mm respectively due to the supra-annular position of the valve, however, the post-operative valve-to-coronary (VTC) artery distances were 6.6±2.3 and 4.9±2.0 mm, respectively. Conclusion: The Y-incision root enlargement technique significantly enlarges the sinus and STJ diameters by 6-7 mm while preserving VTC distances despite upsizing by 3-4 valve sizes, resulting in post-operative anatomy that is favorable for future transcatheter aortic valve-in-surgical aortic valve (TAV-in-SAV).

Democratizing FLASH Radiotherapy.

FLASH radiotherapy (RT) is emerging as a potentially revolutionary advancement in cancer treatment, offering the potential to deliver RT at ultra-high dose rates (>40 Gy/s) while significantly reducing damage to healthy tissues. Democratizing FLASH RT by making this cutting-edge approach more accessible and affordable for healthcare systems worldwide would have a substantial impact in global health. Here, we review recent developments in FLASH RT and present perspective on further developments that could facilitate the democratizing of FLASH RT. These include upgrading and validating current technologies that can deliver and measure the FLASH radiation dose with high accuracy and precision, establishing a deeper mechanistic understanding of the FLASH effect, and optimizing dose delivery conditions and parameters for different types of tumors and normal tissues, such as the dose rate, dose fractionation, and beam quality for high efficacy. Furthermore, we examine the potential for democratizing FLASH radioimmunotherapy leveraging evidence that FLASH RT can make the tumor microenvironment more immunogenic, and parallel developments in nanomedicine or use of smart radiotherapy biomaterials for combining RT and immunotherapy. We conclude that the democratization of FLASH radiotherapy represents a major opportunity for concerted cross-disciplinary research collaborations with potential for tremendous impact in reducing radiotherapy disparities and extending the cancer moonshot globally.

Senescent glia link mitochondrial dysfunction and lipid accumulation.

Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.

Real-World Treatment Adherence to Smoking Cessation Medications and Association with Treatment Outcome - 27 Centers, China, 2017-2022.

What is already known about this topic?: Medication non-adherence significantly impedes smoking cessation efforts. While effective smoking cessation medications are accessible in China, real-world adherence and its correlation with treatment outcomes remain largely unexplored. What is added by this report?: From December 2017 to January 2022, 1,120 participants were recruited from 27 centers in all seven geographical regions of China. Results revealed that only 38.2% of smokers adhered to the prescribed 12-week smoking cessation treatment and those with a higher education level were more likely to be adherent. In addition, smokers with good adherence were more likely to successfully quit smoking. What are the implications for public health practice?: The data obtained could enhance our understanding of smoking cessation practices in China. Improving adherence is a crucial strategy to enhance the effectiveness of smoking cessation treatments and management provided to smokers.

Efficacy of Community-Delivered PEERS® for Adolescents: Increases in Social Skills and Decreases in Social Anxiety and Loneliness.

PURPOSE: PEERS® for Adolescents is an evidence-based social skills training program developed for individuals with autism spectrum disorder (ASD), which is now widely implemented by community providers in clinics and schools. However, majority of past efficacy studies on PEERS® were conducted in controlled research settings, with limited information about its effectiveness when delivered in the community. We sought to examine the effects of PEERS® on social functioning and mental health outcomes when delivered in an outpatient autism specialty clinic. METHODS: Clinical data from 45 adolescents with social challenges (age range: 11-18 years old; 31.1% female assigned at birth) were extracted for secondary analyses. Paired t-tests were performed to examine the pre- to post-intervention changes in social and mental health outcomes. Correlations between pre- and post-change scores of outcome measures were examined. RESULTS: Self-reported social skills knowledge, caregiver-reported social skills (measured by the Social Skills Improvement Systems) and the number of get-togethers hosted, increased significantly from pre- to post-intervention. Additionally, caregiver-reported anxiety and self-reported loneliness significantly decreased from pre- to post-intervention. Exploratory analyses showed that increases in caregiver-reported social skills were associated with decreases in self-reported loneliness. CONCLUSIONS: Our findings provide evidence supporting the efficacy of PEERS® for improving social knowledge and skills of adolescents with social challenges when delivered in the community. The current study also showed the potential benefit of PEERS® for improving adolescent mental health.

Tethered balloon system and High-Resolution Mass Spectrometry Reveal Increased Organonitrates Aloft Compared to the Ground Level.

Atmospheric particles play critical roles in climate. However, significant knowledge gaps remain regarding the vertically resolved organic molecular-level composition of atmospheric particles due to aloft sampling challenges. To address this, we use a tethered balloon system at the Southern Great Plains Observatory and high-resolution mass spectrometry to, respectively, collect and characterize organic molecular formulas (MF) in the ground level and aloft (up to 750 m) samples. We show that organic MF uniquely detected aloft were dominated by organonitrates (139 MF; 54% of all uniquely detected aloft MF). Organonitrates that were uniquely detected aloft featured elevated O/C ratios (0.73 ± 0.23) compared to aloft organonitrates that were commonly observed at the ground level (0.63 ± 0.22). Unique aloft organic molecular composition was positively associated with increased cloud coverage, increased aloft relative humidity (∼40% increase compared to ground level), and decreased vertical wind variance. Furthermore, 29% of extremely low volatility organic compounds in the aloft sample were truly unique to the aloft sample compared to the ground level, emphasizing potential oligomer formation at higher altitudes. Overall, this study highlights the importance of considering vertically resolved organic molecular composition (particularly for organonitrates) and hypothesizes that aqueous phase transformations and vertical wind variance may be key variables affecting the molecular composition of aloft organic aerosol.

Development of Putative Bivalent Dicovalent Ligands for the Adenosine A1 Receptor.

Accumulating evidence suggests that G protein-coupled receptors (GPCRs) can exist and function in homodimer and heterodimer forms. The adenosine A1 receptor (A1R) has been shown to form both homodimers and heterodimers, but there is a lack of chemical tools to study these dimeric receptor populations. This work describes the synthesis and pharmacological evaluation of a novel class of bivalent GPCR chemical tools, where each ligand moiety of the bivalent compound contains a sulfonyl fluoride covalent warhead designed to be capable of simultaneously reacting with each A1R of an A1R homodimer. The novel compounds were characterised using radioligand binding assays, including washout assays, and functionally in cAMP assays. The bivalent dicovalent compounds were competitive A1R antagonists and showed evidence of covalent binding and simultaneous binding across an A1R homodimer. Greater selectivity for A1R over the adenosine A3 receptor was observed for bivalent dicovalent over the equivalent monovalent compounds, indicating subtype selectivity can be achieved with dual occupation by a bivalent dicovalent ligand.

Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility.

Hypomyelinating leukodystrophy (HLD) is an autosomal recessive disorder characterized by defective central nervous system myelination. Exome sequencing of two siblings with severe cognitive and motor impairment and progressive hypomyelination characteristic of HLD revealed homozygosity for a missense single-nucleotide variant (SNV) in EPRS1 (c.4444 C > A; p.Pro1482Thr), encoding glutamyl-prolyl-tRNA synthetase, consistent with HLD15. Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA. Variant mRNA exhibits reduced METTL3 methyltransferase-mediated writing of N6-methyladenosine (m6A) and reduced reading by YTHDC1 and YTHDF1/3 required for efficient mRNA nuclear export and translation, respectively. In contrast to current models, the variant does not alter the sequence of m6A target sites, but instead reduces their accessibility for modification. The defect was rescued by antisense morpholinos predicted to expose m6A sites on target EPRS1 mRNA, or by m6A modification of the mRNA by METTL3-dCas13b, a targeted RNA methylation editor. Our bioinformatic analysis predicts widespread occurrence of SNVs associated with human health and disease that similarly alter accessibility of distal mRNA m6A sites. These results reveal a new RNA-dependent etiologic mechanism by which SNVs can influence gene expression and disease, consequently generating opportunities for personalized, RNA-based therapeutics targeting these disorders.

Recurrences after Pulsed Field Ablation of Atrial Fibrillation: Incidence, Mechanisms, Predictors, and Comparison with Thermal Energy.

Pulsed Field Ablation (PFA) is the latest and most intriguing technology for catheter ablation of atrial fibrillation, due to its capability to generate irreversible and cardiomyocytes-selective electroporation of cell membranes by delivering microsecond-lasting high-voltage electrical fields, leading to high expectations. The first trials to assess the clinical success of PFA, reported an arrhythmia-free survival at 1-year of 78.5%, while other trials showed less enthusiastic results: 66.2% in paroxysmal and 55.1% in persistent AF. Nevertheless, real world data are encouraging. The isolation of pulmonary veins with PFA is easily achieved with 100% acute success. Systematic invasive remapping showed a high prevalence of durable pulmonary vein isolation at 75 and 90 days (range 84-96%), which were significatively lower in redo procedures (64.3%). The advent of PFA is prompting a reconsideration of the role of the autonomic nervous system in AF ablation, as PFA-related sparing of the ganglionated plexi could lead to the still undetermined effect on late arrhythmias' recurrences. Moreover, a new concept of a blanking period could be formulated with PFA, according to its different mechanism of myocardial injury, with less inflammation and less chronic fibrosis. Finally, in this review, we also compare PFA with thermal energy.

[Chinese expert consensus on clinical practice of daytime hip arthroplasty].

Daytime hip arthroplasty refers to a medical procedure where a patient undergoes admission, surgery, and discharge all within a single day (24 hours). The establishment of daytime hip arthroplasty centers signifies a significant paradigm shift in the development model of modern hospitals. While numerous nationally accredited large medical institutions are undertaking daytime hip arthroplasty in various forms and scales, there remains a lack of standardized system processes and criteria. In this context, the National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Bone and Joint Specialty Committee of the China Ambulatory Surgery Alliance, Joint Surgery Branch of the Chinese Orthopedic Association, and Osteoarthritis Study Group of the Chinese Association of Orthopedic Surgeons have collaboratively organized experts in the relevant field domestically. Leveraging international experiences in daytime hip arthroplasty and integrating them with the clinical practices of well-established medical institutions conducting daytime surgeries in China, they have arrived at consensus recommendations. These recommendations cover the establishment of daytime hip arthroplasty centers, policies, procedures, and perioperative management. The ultimate goal is to provide reference points and guidance for the standardized implementation of daytime hip arthroplasty.

Drug-Cannabinoid Interactions in Selected Therapeutics for Symptoms Associated with Epilepsy, Autism Spectrum Disorder, Cancer, Multiple Sclerosis, and Pain.

Clinical practice entails a translation of research that assists in the use of scientific data and therapeutic evidence for the benefit of the patient. This review critically summarizes the potential impact of cannabinoids in conjunction with other drugs when associated with treatments for epilepsy, autism spectrum disorder, cancer, multiple sclerosis, and chronic pain. In these associations, potential drug interactions may occur and alter the predicted clinical results. Therefore, the potential for drug interactions must always be assessed to avoid therapeutic failures and/or increased side effects. Some effects may be additive, synergistic, or antagonistic, but changes in absorption, distribution, metabolism, particularly through cytochrome P450 (CYP) isoenzymes (e.g., CYP2C9 and CYP3A4), and excretion may also occur. For example, the combination of cannabis-derived compounds and the antifungal drug ketoconazole, a CYP3A4 inhibitor, increases the plasma concentration of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In contrast, rifampicin, a CYP3A4 inducer, stands out for reducing plasma THC levels by approximately 20-40% and 50% to 60% for CBD. Other CYP3A4 inhibitors and inducers are likely to have a similar effect on plasma concentrations if co-administered. Pharmacokinetic interactions with anticonvulsant medications have also been reported, as have pharmacodynamic interactions between cannabinoids and medications with sympathomimetic effects (e.g., tachycardia, hypertension), central nervous system depressants (e.g., drowsiness, ataxia), and anticholinergics (e.g., tachycardia and somnolence). Although further studies are still pending, there is currently clinical evidence supporting drug interactions with cannabinoids, requiring doctors to evaluate the risk of drug combinations with cannabinoids and vice versa. The tables provided here were designed to facilitate the identification of biorelevant interactions that may compromise therapeutic efficacy and toxicity.

Risk of Pacemaker Implantation After Degenerative Mitral and Concomitant Tricuspid Valve Surgery.

BACKGROUND: A recent multicenter trial showed a reduction in tricuspid regurgitation (TR) progression when tricuspid annuloplasty was performed at the time of surgery for degenerative mitral regurgitation (MR), but with a 14% pacemaker (PPM) rate. We present real-world outcomes at a high-volume center for degenerative MR surgery with/without tricuspid annuloplasty. METHODS: Patients undergoing first-time degenerative mitral surgery between 2011-2021 were identified (n=1,738). After excluding patients undergoing aortic, aortic valve, or tricuspid replacement procedures, patients were stratified into mitral surgery alone (n=1,068) versus mitral surgery plus tricuspid annuloplasty (n=417). Outcomes including operative mortality, new PPM implantation, and postoperative length of stay as well as risk-adjusted overall mortality were compared. RESULTS: Among 1,485 patients in this study, 98% underwent mitral repair. Compared to concomitant tricuspid annuloplasty patients, those undergoing mitral surgery alone were 6 years younger and had lower median STS PROM. Among concomitant tricuspid repair patients, 85% (355/417) had moderate or less preoperative TR, while 15% (61/417) had severe TR. Operative mortality was 1.4%. The incidence of new PPM implantation was 0.7% (7/1,068) in the mitral only group and 5.5% (23/417) in the concomitant tricuspid group (p<0.001). Although unadjusted cumulative survival was lower in the concomitant tricuspid group, after risk adjustment, concomitant tricuspid surgery was not associated with worse overall mortality (HR 0.80 [95% CI, 0.53-1.19], p=0.27). CONCLUSIONS: Concomitant tricuspid annuloplasty is safe, with no difference in mortality and a less than 6% PPM rate at a high-volume mitral center. These data provide real-world context for concomitant tricuspid annuloplasty.

Larger degree of renal function decline in CKD is a favorable factor for the attenuation of eGFR slope worsening by SGLT2 inhibitors: a retrospective observational study.

INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2Is) have beneficial effects on the renal function of chronic kidney disease (CKD) patients, although the types of patients suitable for this treatment remain unclear. METHODS: A retrospective observational study was conducted on CKD patients who were treated with SGLT2I at our department from 2020 to 2023. The estimated glomerular filtration rate (eGFR) just before treatment was defined as the baseline and the difference between pre-and post-treatment eGFR slopes were used to compare the improvement of renal function. Logistic regression analysis was used to evaluate the independent factors for its improvement. RESULTS: A total of 128 patients were analyzed (mean age: 67.2 years; number of women: 28 [22%]). The mean eGFR was 42.1 ml/min/1.73 m2, and urine protein was 0.66 g/gCr. The eGFR slopes of patients with an eGFR < 30 ml/min/1.73 m2 were improved significantly after treatment (-0.28 to -0.14 ml/min/1.73 m2/month, P < 0.001) but were worsened in patients with an eGFR ≥ 30 ml/min/1.73 m2. Logistic analysis for the improvement in eGFR slopes showed that women (odds ratio [OR], 5.63; 95% confidence interval [CI], 1.16 to 27.3; P = 0.03), use of mineral corticoid receptor antagonists (OR, 11.79; 95% CI, 1.05 to 132.67; P = 0.012) and rapid decline of eGFR before treatment (OR, 12.8 per ml/min/1.73 m2/month decrease in eGFR; 95% CI, 3.32 to 49.40; P < 0.001) were significant independent variables. CONCLUSION: SGLT2Is may have beneficial effects especially for rapid decliners of eGFR, including advanced CKD.

XIOSIS: an X-ray-based intra-operative image-guided platform for oncology smart material delivery.

Image-guided interventional oncology procedures can greatly enhance the outcome of cancer treatment. As an enhancing procedure, oncology smart material delivery can increase cancer therapy's quality, effectiveness, and safety. However, the effectiveness of enhancing procedures highly depends on the accuracy of smart material placement procedures. Inaccurate placement of smart materials can lead to adverse side effects and health hazards. Image guidance can considerably improve the safety and robustness of smart material delivery. In this study, we developed a novel generative deep-learning platform that highly prioritizes clinical practicality and provides the most informative intra-operative feedback for image-guided smart material delivery. XIOSIS generates a patient-specific 3D volumetric computed tomography (CT) from three intraoperative radiographs (X-ray images) acquired by a mobile C-arm during the operation. As the first of its kind, XIOSIS (i) synthesizes the CT from small field-of-view radiographs;(ii) reconstructs the intra-operative spacer distribution; (iii) is robust; and (iv) is equipped with a novel soft-contrast cost function. To demonstrate the effectiveness of XIOSIS in providing intra-operative image guidance, we applied XIOSIS to the duodenal hydrogel spacer placement procedure. We evaluated XIOSIS performance in an image-guided virtual spacer placement and actual spacer placement in two cadaver specimens. XIOSIS showed a clinically acceptable performance, reconstructed the 3D intra-operative hydrogel spacer distribution with an average structural similarity of 0.88 and Dice coefficient of 0.63 and with less than 1 cm difference in spacer location relative to the spinal cord.

Nephronophthisis 13 caused by WDR19 variants with pancytopenia: case report.

We present a case of nephronophthisis 13 that resulted from WDR19 variants. The patient, a nine-year-old Japanese boy, had detection of mild proteinuria during a school urine screening. Urinalysis revealed mild proteinuria without hematuria. Blood tests indicated pancytopenia, mild elevation of liver enzymes, and kidney dysfunction. Ultrasound examination disclosed hepatosplenomegaly. Abdominal computed tomography and bone marrow assessments ruled out malignant tumors. Subsequent kidney and liver biopsies suggested nephronophthisis and congenital hepatic fibrosis. Furthermore, comprehensive genetic analysis through next-generation sequencing revealed compound heterozygous variants in WDR19 (NM_025132.4), including the previously reported c.3533G > A, p.(Arg1178Gln), and c.3703G > A, p.(Glu1235Lys) variants, confirming the diagnosis of nephronophthisis 13. There is potential need for liver and kidney transplantation in patients with nephronophthisis and hepatic fibrosis. Early diagnosis is therefore crucial to mitigate delays in treating complications associated with kidney and hepatic insufficiency and to facilitate preparation of transplantation. To achieve early diagnosis of nephronophthisis, it is imperative to consider it as a differential diagnosis when extrarenal symptoms and kidney dysfunction coexist, particularly when mild proteinuria is observed through opportunistic urinalysis. Genetic testing is important because nephronophthisis manifests as diverse symptoms, necessitating an accurate diagnosis. Next-generation sequencing was shown to be invaluable for the genetic diagnosis of nephronophthisis, given the numerous identified causative genes.

Enhancing Image-Guided Radiation Therapy for Pancreatic Cancer: Utilizing Aligned Peak Response Beamforming in Flexible Array Transducers.

To develop ultrasound-guided radiotherapy, we proposed an assistant structure with embedded markers along with a novel alternative method, the Aligned Peak Response (APR) method, to alter the conventional delay-and-sum (DAS) beamformer for reconstructing ultrasound images obtained from a flexible array. We simulated imaging targets in Field-II using point target phantoms with point targets at different locations. In the experimental phantom ultrasound images, image RF data were acquired with a flexible transducer with in-house assistant structures embedded with needle targets for testing the accuracy of the APR method. The lateral full width at half maximum (FWHM) values of the objective point target (OPT) in ground truth ultrasound images, APR-delayed ultrasound images with a flat shape, and images acquired with curved transducer radii of 500 mm and 700 mm were 3.96 mm, 4.95 mm, 4.96 mm, and 4.95 mm. The corresponding axial FWHM values were 1.52 mm, 4.08 mm, 5.84 mm, and 5.92 mm, respectively. These results demonstrate that the proposed assistant structure and the APR method have the potential to construct accurate delay curves without external shape sensing, thereby enabling a flexible ultrasound array for tracking pancreatic tumor targets in real time for radiotherapy.

Clinical characteristics and outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses. METHODS: In this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients. RESULTS: Out of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5-8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15 ml/min/1.73 m2. Patients with C3GN presenting mild to moderate proteinuria (n = 8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up. CONCLUSIONS: Most patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure during the approximately 5-year follow-up. Additionally, patients with C3GN with mild to moderate proteinuria had good outcomes with RAS-I alone, but continued vigilance is necessary to determine long-term prognosis.