A randomized, double-blind, placebo-controlled, dose-escalating phase IIa trial to evaluate the safety, tolerability, efficacy, and pharmacokinetics of multiple oral doses of Pynegabine tablets as add-on therapy in patients with focal epilepsy.

AIMS: This study aims to investigate the safety, tolerability, efficacy, and pharmacokinetics of Pynegabine as an add-on therapy in the treatment of focal epilepsy. METHODOLOGY: This is a protocol phase-IIa, randomized, double-blinded, placebo-controlled, multicenter study in patients with focal epilepsy from multiple centers in China who have been treated with at least 2 ASMs without effective control. The study involves an 8-week run-in period with stable use of previous medications. Patients are then randomized to receive either Pynegabine or a placebo. Sentinel administration is performed initially, and subsequent patients are randomized based on safety assessments. Three dose cohorts (15, 20, and 25 mg/d) are established. Efficacy is assessed through various measures, including seizure frequency, CGI score, PGI score, HAMA score, HAMD score, MoCA scale score, QOLIE-31 scale score, and 12 h-EEG score. Safety evaluations, PK blood samples, concomitant medications, and adverse events are also recorded. CONCLUSION: Data from the study will be used to evaluate the safety, tolerability, efficacy, and pharmacokinetics of Pynegabine tablets as add-on therapy for focal epilepsy.

A Comparison of Optical Coherence Tomography Angiography Metrics and Artifacts on Scans of Different Sizes in Diabetic Macular Ischemia: The effect of different size scans on DMI evaluation.

PURPOSE: Changes in the foveal avascular zone (FAZ) metrics over time are key outcome measures for clinical trials in diabetic macular ischemia (DMI). However, artifacts and automatically delineated FAZ measurements may influence the results. We aimed to compare the artifact frequency and FAZ metrics on 3 × 3 versus 6 × 6 mm optical coherence tomography angiography (OCTA) macular scans in patients with DMI. DESIGN: Prospective, comparative image quality analysis with one-year follow-up. METHODS: Patients with diabetic retinopathy (DR) were recruited if they presented with OCTA evidence of DMI, defined as an automated FAZ (aFAZ) ≥0.5 mm2 or parafoveal capillary nonperfusion (CNP) ≥1 quadrant if the aFAZ <0.5 mm2. Only those who had both size scans were included in the analysis. The types of artifacts and FAZ delineation errors were graded before manual correction. After excluding scans with poor quality, the aFAZ, corrected FAZ (cFAZ), whole image superficial vessel density (wiSVD), and whole image deep vessel density (wiDVD) were compared on both size scans. RESULTS: Fifty-seven patients (81 eyes) with paired OCTA 3 × 3 and 6 × 6 mm scans at baseline were included in the image quality analysis. The 6 × 6 mm scan presented with more severe motion artifact (P = .02). Conversely, the 3 × 3 mm scans were more susceptible to mild decentration (P = .009). After removing all the poor-quality images, 55 eyes with both size scans entered the longitudinal analysis. The 3 × 3 mm FAZ was significantly larger than the 6 × 6 mm FAZ using either aFAZ or cFAZ (both P < .05). In contrast, the 6 × 6 mm wiSVD and wiDVD were remarkably higher than those on the 3 × 3 mm scans (both P < .001). There was a steady increase in cFAZ over one year on both size scans (both P < .01). However, the 3 × 3 mm aFAZ decreased numerically at 52 weeks (P = .02). After reviewing all the scans, poor identification of parafoveal CNP was the most common reason for erroneous aFAZ delineation. CONCLUSIONS: In DMI, the FAZ metrics are best evaluated on the 3 × 3 scan due to better resolution. However, manual correction of the FAZ margin is needed. The frequency of artifacts and aFAZ delineation errors suggest that further technical refinement is required.

Long-term exposure to NO2 and PM2.5 and the occurrence of chronic kidney disease among patients with type 2 diabetes in Taiwan.

BACKGROUND: Individuals diagnosed with type 2 diabetes (T2D) frequently exhibit chronic kidney disease (CKD) which may be caused by environmental hazards such as exposure to air pollutants. However, limited research has explored the effects of prolonged exposure to air pollutants on CKD development in this population. This study examines the relationship between long-term exposure to air pollutants and CKD incidence in a longitudinal cohort of individuals with type 2 diabetes in Taiwan METHODS: Between 2003 and 2005, we recruited 1316 T2D patients (693 females [52.66 %]; mean age 56.16 ± 8.97 years). Patients were followed until December 31, 2012, with at least two clinical visits. Baseline demographics, medical history, and biomarker levels were collected. The development of CKD was determined by eGFR level < 60 mL/min/1.73 m2. Monthly averages of nitrogen dioxide (NO2) and fine particulate matter [PM ≤ 2.5 µm in aerodynamic diameter (PM2.5)] were acquired from 72 ambient air monitoring stations. The kriging method was employed to estimate the exposure levels to PM2.5, NO2, temperature, and relative humidity in the participants' residential areas. Cox regression with time-dependent covariates regression was applied to assess the impact of long-term exposure to air pollutants and CKD risk. RESULTS: Of 992 patients with normal renal function at baseline, 411 (41.43 %) experienced CKD occurrence over a median follow-up period of 5.45 years. The incidence of CKD was 93.96 cases per 1000 person-years. In multivariable adjusted models, patients exposed to PM2.5 levels above the third quartile of (>33.44 µg/m3) and NO2 levels above the fourth quartile (>22.55 ppb) were found to have an increased risk of CKD occurrence compared to lower exposure levels. CONCLUSIONS: This longitudinal study highlights the increased risk of CKD in individuals with type 2 diabetes due to prolonged exposure to NO2 and PM2.5, emphasizing the need for tailored air quality management strategies for this high-risk population.

Trends on Prevalence, All-Cause Mortality, and Survival Status of Dementia Patients in Rural China Based on Pooling Analysis.

Objectives: No study has reported secular trends in dementia prevalence, all-cause mortality, and survival status in rural China. Methods: We established two cohorts (XRRCC1 and XRRCC2) in the same region of China, 17 years apart, to compare dementia prevalence, all-cause mortality, and survival status, and performed regression analysis to identify associated factors. Results: Dementia prevalence was 3.49% in XRRCC1 and 4.25% in XRRCC2, with XRRCC2 showing a significantly higher prevalence (OR = 1.79, 95%CI: 1.2-2.65). All-cause mortality rates for dementia patients were 62.0% in XRRCC1 and 35.7% in XRRCC2. Mortality in the normal population of XRRCC2 decreased by 66% compared to XRRCC1, mainly due to improved survival rates in women with dementia. Dementia prevalence was positively associated with age >65, spouse-absent status, and stroke, and negatively associated with ≥6 years of education. Conclusion: Dementia prevalence in rural China increased over 17 years, while mortality decreased. Major risk factors include aging, no spouse, and stroke, with higher education offering some protection.

Natural history and complications of normocalcemic hyperparathyroidism: a retrospective cohort study.

Normocalcemic hyperparathyroidism (NHPT) is variably defined, and information regarding complications and natural history are scarce. We aimed to describe the phenotype of NHPT in relation to hypercalcemic hyperparathyroidism (PHPT) and controls, to determine risk of progression, and to develop a predictive model for progression to PHPT. This is a retrospective chart review of 232 patients at a tertiary medical center, comparing 75 controls, 73 patients with NHPT, and 84 with PHPT. NHPT was intermediate in biochemical profile between controls and PHPT with respect to cCa, iPTH, intraindividual coefficient of variant of cCa, phosphorus, and 25(OH)D. NHPT patients had an increased adjusted risk of urolithiasis (OR 5.34, 95%CI, 2.41-12.71, P < .001) and fragility fractures (OR 4.53, 95%CI, 1.63-14.84, P = .006) versus controls, after adjustment for age, sex, and BMI. Fewer NHPT compared with PHPTH patients achieved cure with parathyroidectomy (P = .001). NHPT more often had nonlocalizing imaging or polyglandular disease (P = .005). Parathyroidectomy improved biochemical but not BMD parameters in NHPT. Over a median follow-up of 4.23 (IQR 1.76-5.31) years, NHPT patients managed expectantly experienced no change in iPTH, and progression to PHPT occurred in 9%. An XGBoost model combining 6 factors for progression (mean index 2 iPTH, mean index 2 cCa, 24-h urinary calcium, age, 25(OH)D, and presence of urolithiasis) had an area under the curve 1.00 (95%CI, 1.00-1.00, P < .001) for predicting combined progression. NHPT is a mild variant of PHPT at intermediate risk of urolithiasis and fragility fractures. Cure was less often achieved with parathyroidectomy, which did not improve BMD parameters. Progression was infrequent with conservative management. Because only a minority progressed to PHPT, in addition to lower surgical success rates, we suggest conservative management for the majority of NHPT unless risk factors for progression are identified.

Association between sidedness and survival among chemotherapy refractory metastatic colorectal cancer patients treated with trifluridine/tipiracil or regorafenib.

BACKGROUND: The impact of sidedness on survival of later-line treatment in patients with metastatic colorectal cancer (mCRC) is undetermined. This study aimed to investigate the association between sidedness and survival among chemotherapy refractory patients with mCRC treated with trifluridine/tipiracil (TAS-102) or regorafenib or both. PATIENTS AND METHODS: Patients with mCRC treated with TAS-102 or regorafenib between 2015 and 2020 was retrospectively collected. Patients were stratified into TAS-102 first and regorafenib first, then subdivided into TAS-102 followed by regorafenib (T-R) and regorafenib followed by TAS-102 (R-T) groups. The oncologic outcomes were presented with time-to-treatment failure (TTF) and overall survival (OS). RESULTS: After matching, 376 TAS-102 patients and 376 regorafenib patients were included for outcomes comparison. TTF had insignificant differences while OS was significantly different between TAS-102 and regorafenib groups. Median TTF and OS were 1.9 months versus 2.0 months (P = .701) and 9.1 months versus 7.0 months (P = .008) in TAS-102 and regorafenib, respectively. The OS benefits were consistent regardless primary tumor location. Subgroup analysis with 174 T-R patients and 174 R-T patients was investigated for treatment sequences. TTF and OS had significant differences in both groups. Median TTF and OS were 8.5 months versus 6.3 months (P = .001) and 14.4 months versus 12.6 months (P = .035) in T-R and R-T groups, respectively. The TTF and OS benefits were persisted regardless primary tumor location. CONCLUSION: TAS-102 first provided a better survival benefit in chemotherapy refractory patients with mCRC across all sidedness. Further prospective studies are warranted to validate our conclusions.

The Role of Sole Lift in Treating Pediatric Idiopathic Scoliosis with Mild Thoracolumbar/Lumbar Curve.

OBJECTIVE: Lower limb discrepancy (LLD) was frequently observed in patients with idiopathic scoliosis (IS), potentially associated with etiopathogenesis. Although sole lifts had been proposed as a conservative treatment for IS, evidence supporting their efficacy was limited. This study aimed to assess the effects of sole lift intervention on pediatric patients with mild IS, specifically focusing on thoracolumbar/lumbar (TL/L) curvature. METHODS: Twenty patients, with an average age of 12.3 ± 3.1 years and presenting mild TL/L curve (15.6° ± 6.2°), were selected from a pool of 267 pediatric IS patients in the outpatient of our spine center from February 2023 to August 2023. Inclusion criteria comprised a main TL/L curve ranging between 10° and 40°, the lower limb positioned at the convexity of the main curve, and LLD of less than 2 cm; individuals requiring bracing or surgical intervention were excluded. Custom sole lifts were used to address the shorter lower limb with the objective of leveling the pelvis. Radiographic evaluations were conducted both before and after intervention using standing full spine posteroanterior radiographs and full leg length radiographs. Statistical analysis was undertaken to evaluate curve correction and its associations with other influencing factors. RESULTS: The mean structural and functional LLD were 7.1 ± 4.5 mm and 7.1 ± 4.1 mm, respectively. Among the 20 patients, four exhibited structural LLD greater than 10 mm. The average follow-up duration was 6.4 ± 1.9 months (range: 3-8 months). Following sole lift intervention (7.0 ± 3.0 mm), a significant reduction was observed in the TL/L curve compared to the pre-sole lifting measurements (15.6° ± 6.2° vs. 12.1° ± 7.2°, p < 0.001), as well as a notable decrease in the thoracic curve (12.2° ± 4.0° vs. 8.6° ± 6.3°, p = 0.064). Nine patients experienced a significant curve reduction of ≥5°, while eight showed a reduction between 0° and 5°; however, two patients exhibited no change in curve magnitude. Furthermore, the correction rate of the TL/L curve correlated significantly with functional LLD (r = -0.484, p = 0.030) and pelvic obliquity (r = -0.556, p = 0.011), highlighting the active pelvic compensation in maintaining balance between the spine and lower limbs. Conversely, no significant correlation was observed between curve correction and structural LLD (p > 0.05). Additionally, even after adjusting for other influencing factors, the TL/L Cobb angle remained significantly different between pre- and post-sole lifting (p = 0.037). CONCLUSION: This study confirmed the effectiveness of sole lift intervention in correcting TL/L and thoracic curves among the mild IS children with a main TL/L curve, providing a supplementary conservative treatment option for patients with the lower limb at the convexity of the main curve. Moreover, our findings underscored the active compensation of the lower limbs and the pelvis in the etiopathogenesis of IS, highlighting the importance of considering their influence in treatment strategies.

Association of thrombotic microangiopathy with interferon therapy for hepatitis B: a case report.

BACKGROUND: Thrombotic microangiopathy is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. The pathological features include vascular damage that is manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall. Thrombocytopenia is one of the common adverse effects of interferon therapy. However, a more serious but rare side effect is thrombotic microangiopathy. CASE PRESENTATION: We report the case of a 36-year-old Asian male patient with clinical manifestations of hypertension, blurred vision, acute renal failure, thrombocytopenia, and thrombotic microangiopathy. Renal biopsy showed interstitial edema with fibrosis, arteriolar thickening with vitreous changes, and epithelial podocytes segmental fusion. Immunofluorescence microscopy showed C3(+), Ig A(+) deposition in the mesangial region, which was pathologically consistent with thrombotic microangiopathy renal injury and Ig A deposition. The patient had a history of hepatitis B virus infection for more than 5 years. Lamivudine was used in the past, but the injection of long-acting interferon combined with tenofovir alafenamide fumarate was used since 2018. The comprehensive clinical investigation and laboratory examination diagnosed the condition as thrombotic microangiopathy kidney injury caused by interferon. After stopping interferon in his treatment, the patient's renal function partially recovered after three consecutive therapeutic plasma exchange treatments and follow-up treatment without immunosuppressant. The renal function of the patient remained stable. CONCLUSIONS: This report indicates that interferon can induce thrombotic microangiopathy with acute renal injury, which can progress to chronic renal insufficiency.

Rhein Inhibits Cell Development and Aflatoxin Biosynthesis via Energy Supply Disruption and ROS Accumulation in Aspergillus flavus.

Aspergillus flavus and its carcinogenic secondary metabolites, aflatoxins, not only cause serious losses in the agricultural economy, but also endanger human health. Rhein, a compound extracted from the Chinese herbal medicine Rheum palmatum L. (Dahuang), exhibits good anti-inflammatory, anti-tumor, and anti-oxidative effects. However, its effect and underlying mechanisms against Aspergillus flavus have not yet been fully illustrated. In this study, we characterized the inhibition effect of rhein on A. flavus mycelial growth, sporulation, and aflatoxin B1 (AFB1) biosynthesis and the potential mechanism using RNA-seq analysis. The results indicate that A. flavus mycelial growth and AFB1 biosynthesis were significantly inhibited by 50 µM rhein, with a 43.83% reduction in colony diameter and 87.2% reduction in AFB1 production. The RNA-seq findings demonstrated that the differentially expressed genes primarily participated in processes such as spore formation and development, the maintenance of cell wall and membrane integrity, management of oxidative stress, the regulation of the citric acid cycle, and the biosynthesis of aflatoxin. Biochemical verification experiments further confirmed that 50 µM rhein effectively disrupted cell wall and membrane integrity and caused mitochondrial dysfunction through disrupting energy metabolism pathways, leading to decreased ATP synthesis and ROS accumulation, resulting in impaired aflatoxin biosynthesis. In addition, a pathogenicity test showed that 50 µM rhein inhibited A. flavus spore growth in peanut and maize seeds by 34.1% and 90.4%, while AFB1 biosynthesis was inhibited by 60.52% and 99.43%, respectively. In conclusion, this research expands the knowledge regarding the antifungal activity of rhein and provides a new strategy to mitigate A. flavus contamination.

Unraveling the antifungal and anti-aflatoxin B1 mechanisms of piperitone on Aspergillus flavus.

Aspergillus flavus infects important crops and produces carcinogenic aflatoxins, posing a serious threat to food safety and human health. Biochemical analysis and RNA-seq were performed to investigate the effects and mechanisms of piperitone on A. flavus growth and aflatoxin B1 biosynthesis. Piperitone significantly inhibited the growth of A. flavus, AFB1 production, and its pathogenicity on peanuts and corn flour. Differentially expressed genes (DEGs) associated with the synthesis of chitin, glucan, and ergosterol were markedly down-regulated, and the ergosterol content was reduced, resulting in a disruption in the integrity of the cell wall and cell membrane. Moreover, antioxidant genes were down-regulated, the correspondingly activities of antioxidant enzymes such as catalase, peroxidase, and superoxide dismutase were reduced, and levels of superoxide anion and hydrogen peroxide were increased, leading to a burst of reactive oxygen species (ROS). Accompanied by ROS accumulation, DNA fragmentation and cell autophagy were observed, and 16 aflatoxin cluster genes were down-regulated. Overall, piperitone disrupts the integrity of the cell wall and cell membrane, triggers the accumulation of ROS, causes DNA fragmentation and cell autophagy, ultimately leading to defective growth and impaired AFB1 biosynthesis.

3D hierarchical Ti3C2/TiO2 composite via in situ oxidation for improved lithium-ion storage.

To address the intrinsic limitations of both TiO2 and MXenes, we propose an effective strategy for the engineering of a 3D Ti3C2/TiO2 nanorod hybrid, where the in situ synthesized TiO2 nanorods are homogeneously decorated onto the surface of 3D Ti3C2 MXene via simple oxidation. As the LIB anode, it demonstrates exceptional long-term cycling stability with a specific capacity of 384.1 mA h g-1 after 600 cycles at 1.0 A g-1.

The New South Wales Mouse Plague 2020-2021: A One Health description.

A mouse plague occurred in Eastern Australia from spring 2020 to winter 2021, impacting an area of around 180,000 km2. It harmed human physical and psychological health, damaged the natural and built environment, and endangered farmed, domestic and native animals. However, the mouse plague was overshadowed by the COVID-19 pandemic, especially as the end of the plague coincided with the arrival and surge of the COVID-19 delta strain in rural New South Wales (NSW). In this article, we systematically overview the multiple impacts of the plague and highlight their complex interactions. Using a One Health framework, we comprehensively review the i) human, ii) animal and iii) environmental impacts including economic dimensions. Given the damage that the mouse plague caused to infrastructure, we consider the environment from two perspectives: the natural and the built environment. This One Health description of the 2020-2021 mouse plague identifies priorities for preparedness, response and recovery at local, regional land levels to inform response and management of future mouse plague events in Australia. It also highlights the need for ongoing collaboration between researchers and practitioners in the human, animal and environmental health sectors.

Terpinen-4-ol from tea tree oil prevents Aspergillus flavus growth in postharvest wheat grain.

Plant volatile organic compounds (PVOCs) have gained increasing attention for their role in preventing fungal spoilage and insect contamination in postharvest agro-products owing to their effectiveness and sustainability. In this study, the essential oil was extracted from fresh M. alternifolia (tea tree) leaves, and the fumigation vapor of tea tree oil (TTO) completely inhibited the growth of Aspergillus flavus on agar plates at a concentration of 1.714 µL/mL. Terpinen-4-ol was identified as the major component (40.76 %) of TTO volatiles analyzed using headspace gas chromatography-mass spectrometry. Terpinen-4-ol vapor completely inhibited the A. flavus growth on agar plates and 20 % moisture wheat grain at 0.556 and 1.579 µL/mL, respectively, indicating that terpinen-4-ol serves as the main antifungal constituent in TTO volatiles. The minimum inhibitory concentration of terpinen-4-ol in liquid-contact culture was 1.6 µL/mL. Terpinen-4-ol treatment caused depressed, wrinkled, and punctured mycelial morphology and destroyed the plasma membrane integrity of A. flavus. Metabolomics analysis identified significant alterations in 93 metabolites, with 79 upregulated and 14 downregulated in A. flavus mycelia exposed to 1.6 µL/mL terpinen-4-ol for 6 h, involved in multiple cellular processes including cell membrane permeability and integrity, the ABC transport system, pentose phosphate pathway, and the tricarboxylic acid cycle. Biochemical analysis and 2,7-dichlorofluorescein diacetate staining showed that terpinen-4-ol induced oxidative stress and mitochondrial dysfunction in A. flavus mycelia. This study provides new insights into the antifungal effects of the main TTO volatile compounds terpinen-4-ol on the growth of A. flavus.

Synergistic antifungal mechanism of cinnamaldehyde and nonanal against Aspergillus flavus and its application in food preservation.

Aspergillus flavus colonization on agricultural products during preharvest and postharvest results in tremendous economic losses. Inspired by the synergistic antifungal effects of essential oils, the aims of this study were to explore the mechanism of combined cinnamaldehyde and nonanal (SCAN) against A. flavus and to evaluate the antifungal activity of SCAN loading into diatomite (DM). Shriveled mycelia were observed by scanning electron microscopy, especially in the SCAN treatment group. Calcofluor white staining, transmission electron microscopy, dichloro-dihydro-fluorescein diacetate staining and the inhibition of key enzymes in tricarboxylic acid cycle indicated that the antifungal mechanism of SCAN against A. flavus was related to the cell wall damage, reactive oxygen species accumulation and energy metabolism interruption. RNA sequencing revealed that some genes involved in antioxidation were upregulated, whereas genes responsible for cell wall biosynthesis, oxidative stress, cell cycle and spore development were significantly downregulated, supporting the occurrence of cellular apoptosis. In addition, compared with the control group, conidia production in 1.5 mg/mL DM/cinnamaldehyde, DM/nonanal and DM/SCAN groups were decreased by 27.16%, 48.22% and 76.66%, respectively, and the aflatoxin B1 (AFB1) contents decreased by 2.00%, 73.02% and 84.15%, respectively. These finding suggest that DM/SCAN complex has potential uses in food preservation.

m6A methyltransferase AflIme4 orchestrates mycelial growth, development and aflatoxin B1 biosynthesis in Aspergillus flavus.

Aflatoxin B1 (AFB1), a highly toxic secondary metabolite produced by Aspergillus flavus, poses a severe threat to agricultural production, food safety and human health. The methylation of mRNA m6A has been identified as a regulator of both the growth and AFB1 production of A. flavus. However, its intracellular occurrence and function needs to be elucidated. Here, we identified and characterized a m6A methyltransferase, AflIme4, in A. flavus. The enzyme was localized in the cytoplasm, and knockout of AflIme4 significantly reduced the methylation modification level of mRNA. Compared with the control strains, ΔAflIme4 exhibited diminished growth, conidial formation, mycelial hydrophobicity, sclerotium yield, pathogenicity and increased sensitivity to CR, SDS, NaCl and H2O2. Notably, AFB1 production was markedly inhibited in the A. flavus ΔAflIme4 strain. RNA-Seq coupled with RT-qPCR validation showed that the transcriptional levels of genes involved in the AFB1 biosynthesis pathway including aflA, aflG, aflH, aflK, aflL, aflO, aflS, aflV and aflY were significantly upregulated. Methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) analysis demonstrated a significant increase in m6A methylation modification levels of these pathway-specific genes, concomitant with a decrease in mRNA stability. These results suggest that AflIme4 attenuates the mRNA stability of genes in AFB1 biosynthesis by enhancing their mRNA m6A methylation modification, leading to impaired AFB1 biosynthesis. Our study identifies a novel m6A methyltransferase AflIme4 and highlights it as a potential target to control A. flavus growth, development and aflatoxin pollution.

Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing.

Background: Mechanical forces are indispensable for bone healing, disruption of which is recognized as a contributing cause to nonunion or delayed union. However, the underlying mechanism of mechanical regulation of fracture healing is elusive. Methods: We used the lineage-tracing mouse model, conditional knockout depletion mouse model, hindlimb unloading model and single-cell RNA sequencing to analyze the crucial roles of mechanosensitive protein polycystin-1 (PC1, Pkd1) promotes periosteal stem/progenitor cells (PSPCs) osteochondral differentiation in fracture healing. Results: Our results showed that cathepsin (Ctsk)-positive PSPCs are fracture-responsive and mechanosensitive and can differentiate into osteoblasts and chondrocytes during fracture repair. We found that polycystin-1 declines markedly in PSPCs with mechanical unloading while increasing in response to mechanical stimulus. Mice with conditional depletion of Pkd1 in Ctsk+ PSPCs show impaired osteochondrogenesis, reduced cortical bone formation, delayed fracture healing, and diminished responsiveness to mechanical unloading. Mechanistically, PC1 facilitates nuclear translocation of transcriptional coactivator TAZ via PC1 C-terminal tail cleavage, enhancing osteochondral differentiation potential of PSPCs. Pharmacological intervention of the PC1-TAZ axis and promotion of TAZ nuclear translocation using Zinc01442821 enhances fracture healing and alleviates delayed union or nonunion induced by mechanical unloading. Conclusion: Our study reveals that Ctsk+ PSPCs within the callus can sense mechanical forces through the PC1-TAZ axis, targeting which represents great therapeutic potential for delayed fracture union or nonunion.

The complexities of decision-making in food waste valorization: A critical review.

The efficient utilization of food waste (FW) resources through Food Waste Valorization (FWV) has received increasing attention in recent years. Various decision-making studies have been undertaken to facilitate FWV implementation, such as the studies on decision-making framework and FWV technology assessment. Food waste hierarchy is a widely discussed framework in FW management, but it was found too simplified and does not always contribute positively to environmental sustainability. Moreover, decision-making studies in FWV often focus on specific aspects of the food system and employ distinctive decision-making approaches, making it difficult to compare the results from different studies. Therefore, our literature review is conducted to provide a comprehensive understanding of FWV decision-making. This study identifies what decisions are needed, and three levels of decisions are revealed: system-level, FW stream-level, and FWV option-level. The assessment approaches and criteria used to support decision-making in FWV are also collected and analyzed. Building upon these findings, an hourglass model is synthesized to provide a holistic illustration of decision-making in FWV. This study untangles the complexities of FWV decision-making and sheds light on the limitations of current studies. We anticipate this study will make more people realize that FWV is a multidisciplinary issue and requires the collective participation of researchers, practitioners, policymakers, and consumers. Such collective engagement is essential to effectively address practical challenges and propel the transition of the current food system toward a more resource-efficient paradigm.

The Natural History of Retinal Sensitivity Loss in Diabetic Macular Ischemia over One Year Evaluated by Microperimetry.

Background/Objectives: This one-year prospective observational study, conducted at two centers, aimed to report the natural history of retinal sensitivity (RS) loss in diabetic macular ischemia (DMI). Methods: Patients with stable-treated proliferative diabetic retinopathy (PDR) were recruited if there was evidence of DMI on optical coherence tomography angiography, defined as a foveal avascular zone ≥ 0.5 mm2 or parafoveal capillary dropout ≥ 1 quadrant. The minimal visual acuity required for performing microperimetry (MP) was ≥54 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent 20/80). The overall RS (oRS) and pointwise sensitivity (PWS) within the 3 × 3 mm macula were assessed at baseline and twelve months. A value <25 decibels (dB) was defined as impaired RS, and a decrease of 2 and 7 dB was regarded as mild and severe loss, respectively. Results: A total of 88 patients (97 eyes) were included. No statistically significant MP changes were detected at one year. However, 10% of the cohort lost oRS ≥ 2 dB, and 73% lost ≥2 dB PWS in ≥5 loci, whereas 1% lost oRS ≥ 7 dB, and 4% lost ≥7 dB PWS in ≥5 loci. The foveola and temporal parafovea were the most vulnerable to severe RS loss. Compared to their counterpart, eyes with baseline oRS ≥ 25 dB had significantly more RS loss in the macula and superior parafovea (55% versus 32% and 53% versus 28%, both p = 0.01). Conclusions: Rather than oRS loss, ≥2 dB loss in PWS in ≥5 loci is a more feasible outcome measure for clinical trials in DMI.

A retrospective cohort of tumor-induced osteomalacia and case series of malignant disease.

OBJECTIVE: We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with tumor-induced osteomalacia (TIO), with a focus on patients with non-localizing and malignant TIO. METHODS: This is a retrospective cohort of TIO patients in an academic medical center, diagnosed between January 1998 to May 2023. We described their demographics, biochemistries, tumor features, localization, treatment and complications. RESULTS: Of 68 patients diagnosed with TIO, 49 (72%) were localizing and 5 (7.4%) were malignant. Of 50 patients who attempted localizing procedures, 29 (58%) achieved cure. 20 (40%) had persistent disease due to wrong tumor targeted, or refractory or recurrent tumors, despite up to 6 procedural attempts. There was no difference in demographics, phosphorus or baseline fibroblast growth factor-23 (FGF23) levels between localizing versus non-localizing groups, and malignant versus non-malignant groups. Lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. 60% of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R=0.566, p<0.001) but was not associated with malignancy risk (p=0.479). A cut-off FGF23 of >20 times upper limit of normal in the presence of normal renal function (p=0.025), and recurrence after initial cure (p=0.013) were factors significantly associated with malignancy. The non-localizing group had lower survival than localizing group (p=0.0097). CONCLUSIONS: TIO is a condition with significant morbidity. Very high FGF23 level and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in non-localizing TIO should be further explored.

Evaluation of Malignancy Risk of Ampullary Tumors Detected by Endoscopy Using 2-[18F]FDG PET/CT.

OBJECTIVE: We aimed to investigate whether 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) can aid in evaluating the risk of malignancy in ampullary tumors detected by endoscopy. MATERIALS AND METHODS: This single-center retrospective cohort study analyzed 155 patients (79 male, 76 female; mean age, 65.7 ± 12.7 years) receiving 2-[18F]FDG PET/CT for endoscopy-detected ampullary tumors 5-87 days (median, 7 days) after the diagnostic endoscopy between June 2007 and December 2020. The final diagnosis was made based on histopathological findings. The PET imaging parameters were compared with clinical data and endoscopic features. A model to predict the risk of malignancy, based on PET, endoscopy, and clinical findings, was generated and validated using multivariable logistic regression analysis and an additional bootstrapping method. The final model was compared with standard endoscopy for the diagnosis of ampullary cancer using the DeLong test. RESULTS: The mean tumor size was 17.1 ± 7.7 mm. Sixty-four (41.3%) tumors were benign, and 91 (58.7%) were malignant. Univariable analysis found that ampullary neoplasms with a blood-pool corrected peak standardized uptake value in early-phase scan (SUVe) ≥ 1.7 were more likely to be malignant (odds ratio [OR], 16.06; 95% confidence interval [CI], 7.13-36.18; P < 0.001). Multivariable analysis identified the presence of jaundice (adjusted OR [aOR], 4.89; 95% CI, 1.80-13.33; P = 0.002), malignant traits in endoscopy (aOR, 6.80; 95% CI, 2.41-19.20; P < 0.001), SUVe ≥ 1.7 in PET (aOR, 5.43; 95% CI, 2.00-14.72; P < 0.001), and PET-detected nodal disease (aOR, 5.03; 95% CI, 1.16-21.86; P = 0.041) as independent predictors of malignancy. The model combining these four factors predicted ampullary cancers better than endoscopic diagnosis alone (area under the curve [AUC] and 95% CI: 0.925 [0.874-0.956] vs. 0.815 [0.732-0.873], P < 0.001). The model demonstrated an AUC of 0.921 (95% CI, 0.816-0.967) in candidates for endoscopic papillectomy. CONCLUSION: Adding 2-[18F]FDG PET/CT to endoscopy can improve the diagnosis of ampullary cancer and may help refine therapeutic decision-making, particularly when contemplating endoscopic papillectomy.