First patient diagnosed with lipoprotein glomerulopathy and Alport syndrome.

Alport syndrome (AS) is one of the most common inherited kidney disorders, involving pathogenic variants of COL4A3, COL4A4 and COL4A5 genes that lead to disruption of the normal structure of collagen IV protein through improper chain or heterotrimer folding or degradation of heterotrimer components. Lipoprotein glomerulopathy (LPG) is an autosomal dominant disease involving APOE gene mutations disturbing lipoprotein metabolism. We report the first case with both AS and LPG in an 11-year-old girl. The patient presented with blepharedema, and decreased vision. Laboratory examinations showed hematemesis, proteinuria, hypoproteinemia, hyperlipidemia and progressive renal failure. Renal biopsy showed the changes of LPG and AS. Whole-exome sequencing (WES) identified two pathogenic variants, c.127C > T in exon 3 of APOE gene, and c.930 + 1G > A in exon 15 of COL4A4 gene. We emphasize the importance of early completion of renal biopsy and WES for early diagnosis of LPG and AS.

BMI trajectories in late middle age, genetic risk, and the incident diabetes in older adults: evidence from a 26-year longitudinal study.

This study investigated the association between BMI trajectories in late middle age and incident diabetes in later years. A total of 11,441 participants aged 50-60 years from the Health and Retirement Study with at least two self-reported BMI records were included. Individual BMI trajectories representing average BMI changes per year were generated using multilevel modeling. Adjusted risk ratios (ARRs) and 95% confidence intervals (95% CIs) were calculated. Associations between BMI trajectories and diabetes risk in participants with different genetic risks were estimated for 5720 participants of European ancestry. BMI trajectories were significantly associated with diabetes risk in older age (slowly increasing vs. stable: ARR 1.31, 95% CI 1.12-1.54; rapidly increasing vs. stable: ARR 1.5, 95% CI 1.25-1.79). This association was strongest for normal-initial-BMI participants (slowly increasing: ARR 1.34, 95% CI 0.96-1.88; rapidly increasing: ARR 2.06, 95% CI 1.37-3.11). Participants with a higher genetic liability to diabetes and a rapidly increasing BMI trajectory had the highest risk for diabetes (ARR 2.15, 95% CI 1.67-2.76). These findings confirmed that BMI is the leading risk factor for diabetes and that although the normal BMI group has the lowest incidence rate for diabetes, people with normal BMI are most sensitive to changes in BMI.

Genome-wide identification and expression analysis of wall-associated kinase (WAK) and WAK-like kinase gene family in response to tomato yellow leaf curl virus infection in Nicotiana benthamiana.

BACKGROUND: Tomato yellow leaf curl virus (TYLCV) is a major monopartite virus in the family Geminiviridae and has caused severe yield losses in tomato and tobacco planting areas worldwide. Wall-associated kinases (WAKs) and WAK-like kinases (WAKLs) are a subfamily of the receptor-like kinase family implicated in cell wall signaling and transmitting extracellular signals to the cytoplasm, thereby regulating plant growth and development and resistance to abiotic and biotic stresses. Recently, many studies on WAK/WAKL family genes have been performed in various plants under different stresses; however, identification and functional survey of the WAK/WAKL gene family of Nicotiana benthamiana have not yet been performed, even though its genome has been sequenced for several years. Therefore, in this study, we aimed to identify the WAK/WAKL gene family in N. benthamiana and explore their possible functions in response to TYLCV infection. RESULTS: Thirty-eight putative WAK/WAKL genes were identified and named according to their locations in N. benthamiana. Phylogenetic analysis showed that NbWAK/WAKLs are clustered into five groups. The protein motifs and gene structure compositions of NbWAK/WAKLs appear to be highly conserved among the phylogenetic groups. Numerous cis-acting elements involved in phytohormone and/or stress responses were detected in the promoter regions of NbWAK/WAKLs. Moreover, gene expression analysis revealed that most of the NbWAK/WAKLs are expressed in at least one of the examined tissues, suggesting their possible roles in regulating the growth and development of plants. Virus-induced gene silencing and quantitative PCR analyses demonstrated that NbWAK/WAKLs are implicated in regulating the response of N. benthamiana to TYLCV, ten of which were dramatically upregulated in locally or systemically infected leaves of N. benthamiana following TYLCV infection. CONCLUSIONS: Our study lays an essential base for the further exploration of the potential functions of NbWAK/WAKLs in plant growth and development and response to viral infections in N. benthamiana.

Association between fish oil supplementation and cancer risk according to fatty fish consumption: A large prospective population-based cohort study using UK Biobank.

Whether regular fish oil supplementation is associated with cancer risk is controversial. We aimed to evaluate the association of fish oil supplementation on cancer risk according to fatty fish consumption patterns. From the UK Biobank cohort, 470 804 participants with fish oil supplementation data were included. A total of 147 316 individuals with fish oil supplementation were in the exposed group; the other 323 488 were in the unexposed group. No association was found between self-report regular fish oil supplementation and overall cancer risk (hazard ratio [HR] = 0.97, 95% confidence intervals [CIs] = 0.95-1). Stratified by fatty fish consumption level, we found the association between fish oil supplementation and lower cancer risk in participants who consumed fatty fish less than two times per week, with association noted for both overall cancer (HR = 0.96, 95% CI = 0.94-0.99) and some specific cancers (colon cancer: HR = 0.84, 95% CI = 0.75-0.94; hepatobiliary cancer: HR = 0.74, 95% CI = 0.58-0.96; lung cancer: HR = 0.87, 95% CI = 0.78-0.98). On the contrary, a higher risk of breast cancer was observed (HR = 1.16, 95% CI = 1.01-1.32) in participants who consumed fatty fish at least two times per week. In conclusion, our findings underscore the need to refine recommendations for nutritional supplements according to inherent diet habits.

Integrated next-generation sequencing and comparative transcriptomic analysis of leaves provides novel insights into the ethylene pathway of Chrysanthemum morifolium in response to a Chinese isolate of chrysanthemum virus B.

BACKGROUND: Chrysanthemum virus B (CVB), a key member of the genus Carlavirus, family Betaflexiviridae, causes severe viral diseases in chrysanthemum (Chrysanthemum morifolium) plants worldwide. However, information on the mechanisms underlying the response of chrysanthemum plants to CVB is scant. METHODS: Here, an integrated next-generation sequencing and comparative transcriptomic analysis of chrysanthemum leaves was conducted to explore the molecular response mechanisms of plants to a Chinese isolate of CVB (CVB-CN) at the molecular level. RESULTS: In total, 4934 significant differentially expressed genes (SDEGs) were identified to respond to CVB-CN, of which 4097 were upregulated and 837 were downregulated. Gene ontology and functional classification showed that the majority of upregulated SDEGs were categorized into gene cohorts involved in plant hormone signal transduction, phenylpropanoid and flavonoid biosynthesis, and ribosome metabolism. Enrichment analysis demonstrated that ethylene pathway-related genes were significantly upregulated following CVB-CN infection, indicating a strong promotion of ethylene biosynthesis and signaling. Furthermore, disruption of the ethylene pathway in Nicotiana benthamiana, a model plant, using virus-induced gene silencing technology rendered them more susceptible to cysteine-rich protein of CVB-CN induced hypersensitive response, suggesting a crucial role of this pathway in response to CVB-CN infection. CONCLUSION: This study provides evidence that ethylene pathway has an essential role of plant in response to CVB and offers valuable insights into the defense mechanisms of chrysanthemum against Carlavirus.

Copper-induced oxidative stress, transcriptome changes, intestinal microbiota, and histopathology of common carp (Cyprinus carpio).

Copper (Cu) is a common contaminant in aquatic environments, which could cause physiological dysfunction in aquatic organisms. However, few studies have comprehensively examined the impact of copper toxicity in freshwater fish over the past decade. In this research, the oxidative stress, liver transcriptome, intestinal microbiota, and histopathology of common carp (C. carpio) in response to Cu exposure were studied, by exposing juvenile carp to 0.2 mg/ml Cu2+ for 30 days. The results revealed that Cu2+ could induce significant changes in malondialdehyde (MDA) content and antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)) activity. The changes in antioxidant enzyme activities indicate that Cu can induce oxidative stress by generating reactive oxygen species (ROS) content. RNA-seq analysis of the liver identified 1069 differentially expressed genes (DEGs) after treatment with 2.0 mg/L Cu2+. Among the DEGs, 490 genes were upregulated and 579 genes were downregulated. GO functional enrichment analysis revealed that Cu could affect the fatty acid biosynthetic process, carnitine biosynthetic process, and activity of carboxylic acid transmembrane transporter. Meanwhile, the most significantly enriched KEGG pathway also included the lipid metabolism pathway. In addition, Cu2+ exposure increased bacterial richness and changed bacterial composition. At the phylum level, we found that the ratio of Bacteroidetes to Firmicutes was increased in the treatment carps, which can regulate intestinal epithelium function and reduce inflammation and immune responses. At the genus level, the abundances of 11 genera were significantly altered after exposure to Cu2+. The altered composition of the microbial community caused by Cu exposure may play a useful role in compensation of the intestinal lesions by Cu exposure. Furthermore, we found that Cu2+ exposure could cause histological alterations such as structural damage to the liver and intestines. The results of this research contribute to a better understanding of mechanisms related to Cu toxicity in fish.

A case report of precocious puberty related to Rett syndrome and a literature review.

Rett syndrome is an X-linked dominant disorder, and the typical phenotype includes intractable epileptic seizures and severe mental retardation, in particular, a rapid regression in language and limited progress in psychomotor development. Premature breast and pubic hair development and advanced bone age are signs of precocious puberty (PP), defined as puberty occurring before 8 years of age in girls. There are rare reports about precious puberty associated with Rett syndrome. Herein, we report the case of a patient with Rett syndrome with precocious puberty. Her first signs of PP occurred 6 months prior to presentation (at 7.5 years old), and the laboratory measurements, including tests of bone age and gonadotropin-releasing hormone stimulation, were positive for PP. PP was controlled after treatment with leuprorelin 3.75 mg for one year. In addition, the genetic and phenotypic spectrum of previously reported cases of Rett syndrome with precocious puberty are reviewed and summarized.

Disulfiram-loaded CuO2 nanocarriers for enhanced synergistic chemodynamic chemotherapy.

Disulfiram (DSF) metabolites exhibit antitumor properties when bound to Cu2+. This combination also promotes the generation of reactive oxygen species (ROS), ultimately leading to tumor cell death. In this study, CuO2 served as a carrier for DSF, forming a dual-drug delivery system with Cu2+ and DSF encapsulated in polydopamine (PDA). In the final delivery system, CuO2 (DSF-CuO2@PDA) was hydrolyzed at the tumor site, releasing both Cu2+ and H2O2. Cu2+ reacts with DSF metabolites to form Bis(diethyldithiocarbamate)-Cu (CuET), which triggers a Fenton-like reaction that generates ROS. Chemotherapy and chemodynamic therapy exhibited significant tumor-suppressive capabilities, with an inhibition rate of 61 %. In addition, the DSF-CuO2@PDA complex demonstrated superlative tumor-targeting ability and biocompatibility.

In situ generation of copper(â ¡)/diethyldithiocarbamate complex through tannic acid/copper(â ¡) network coated hollow mesoporous silica for enhanced cancer chemodynamic therapy.

The Cu2+ complex formed by the coordination of disulfiram (DSF) metabolite diethyldithiocarbamate (DTC), Cu(DTC)2, can effectively inhibit tumor growth. However, insufficient Cu2+ levels in the tumor microenvironment can impact tumor-suppressive effects of DTC. In this study, we proposed a Cu2+ and DSF tumor microenvironment-targeted delivery system. This system utilizes hollow mesoporous silica (HMSN) as a carrier, after loading with DSF, encases it using a complex of tannic acid (TA) and Cu2+ on the outer layer. In the slightly acidic tumor microenvironment, TA/Cu undergoes hydrolysis, releasing Cu2+ and DSF, which further form Cu(DTC)2 to inhibit tumor growth. Additionally, Cu2+ can engage in a Fenton-like reaction with H2O2 in the tumor microenvironment to form OH, therefore, chemodynamic therapy (CDT) and Cu(DTC)2 are used in combination for tumor therapy. In vivo tumor treatment results demonstrated that AHD@TA/Cu could accumulate at the tumor site, achieving a tumor inhibition rate of up to 77.6 %. This study offers a novel approach, circumventing the use of traditional chemotherapy drugs, and provides valuable insights into the development of in situ tumor drug therapies.

Integrated microbiome and metabolome analyses reveal the effects of low pH on intestinal health and homeostasis of crayfish (Procambarus clarkii).

Low pH (LpH) poses a significant challenge to the health, immune response, and growth of aquatic animals worldwide. Crayfish (Procambarus clarkii) is a globally farmed freshwater species with a remarkable adaptability to various environmental stressors. However, the effects of LpH stress on the microbiota and host metabolism in crayfish intestines remain poorly understood. In this study, integrated analyses of antioxidant enzyme activity, histopathological damage, 16S rRNA gene sequencing, and liquid chromatography-mass spectrometry (LC-MS) were performed to investigate the physiology, histopathology, microbiota, and metabolite changes in crayfish intestines exposed to LpH treatment. The results showed that LpH stress induced obvious changes in superoxide dismutase and catalase activities and histopathological alterations in crayfish intestines. Furthermore, 16S rRNA gene sequencing analysis revealed that exposure to LpH caused significant alterations in the diversity and composition of the crayfish intestinal microbiota at the phylum and genus levels. At the genus level, 14 genera including Bacilloplasma, Citrobacter, Shewanella, Vibrio, RsaHf231, Erysipelatoclostridium, Anaerorhabdus, Dysgonomonas, Flavobacterium, Tyzzerella, Brachymonas, Muribaculaceae, Propionivibrio, and Comamonas, exhibited significant differences in their relative abundances. The LC-MS analysis revealed 859 differentially expressed metabolites in crayfish intestines in response to LpH, including 363 and 496 upregulated and downregulated metabolites, respectively. These identified metabolites exhibited significant enrichment in 24 Kyoto Encyclopedia of Genes and Genomes pathways (p < 0.05), including seven and 17 upregulated and downregulated pathways, respectively. These pathways are mainly associated with energy and amino acid metabolism. Correlation analysis revealed a strong correlation between the metabolites and intestinal microbiota of crayfish during LpH treatment. These findings suggest that LpH may induce significant oxidative stress, intestinal tissue damage, disruption of intestinal microbiota homeostasis, and alterations in the metabolism in crayfish. These findings provide valuable insights into how the microbial and metabolic processes of crayfish intestines respond to LpH stress.

Function of stem cells in radiation-induced damage.

PURPOSE: The aim of this review is to discuss previous studies on the function of stem cells in radiation-induced damage, and the factors affecting these processes, in the hope of improving our understanding of the different stem cells and the communication networks surrounding them. This is essential for the development of effective stem cell-based therapies to regenerate or replace normal tissues damaged by radiation. CONCLUSION: In salivary glands, senescence-associated cytokines and inflammation-associated cells have a greater effect on stem cells. In the intestinal glands, Paneth cells strongly affect stem cell-mediated tissue regeneration after radiation treatment. In the pancreas, ß-cells as well as protein C receptor positive (Procr) cells are expected to be key cells in the treatment of diabetes. In the bone marrow, a variety of cytokines such as CXC-chemokine ligand 12 (CXCL12) and stem cell factor (SCF), contribute to the functional recovery of hematopoietic stem cells after irradiation.

Integrated comparative transcriptome and weighted gene co-expression network analysis provide valuable insights into the response mechanisms of crayfish (Procambarus clarkii) to copper stress.

One of the significant limitations of aquaculture worldwide is the prevalence of divalent copper (Cu). Crayfish (Procambarus clarkii) are economically important freshwater species adapted to a variety of environmental stimuli, including heavy metal stresses; however, large-scale transcriptomic data of the hepatopancreas of crayfish in response to Cu stress are still scarce. Here, integrated comparative transcriptome and weighted gene co-expression network analyses were initially applied to investigate gene expression profiles of the hepatopancreas of crayfish subjected to Cu stress for different periods. As a result, 4662 significant differentially expressed genes (DEGs) were identified following Cu stress. Bioinformatics analyses revealed that the "focal adhesion" pathway was one of the most significantly upregulated response pathways following Cu stress, and seven DEGs mapped to this pathway were identified as hub genes. Furthermore, the seven hub genes were examined by quantitative PCR, and each was found to have a substantial increase in transcript abundance, suggesting a critical role of the "focal adhesion" pathway in the response of crayfish to Cu stress. Our transcriptomic data can be a good resource for the functional transcriptomics of crayfish, and these results may provide valuable insights into the molecular response mechanisms underlying crayfish to Cu stress.

Case report: Early-onset renal failure as presenting sign of Lesch-Nyhan disease in infancy.

Lesch-Nyhan disease (LND) is a rare X-linked recessive disease caused by pathogenic mutations of the HPRT1 gene. The typical clinical manifestations include cerebral palsy, intellectual disability, dysarthria, self-injurious behavior, and gouty arthritis in children. This report describes a Chinese boy aged 2 months and 7 days with a significantly elevated uric acid concentration accompanied by renal dysfunction and, notably, brain imaging changes. Whole-exome sequencing revealed a hemizygous mutation of HPRT1 in nucleotide 508 from cytosine to thymine (c.508C > T), resulting in a nonsense mutation (p.R170X). The incidence of LND is extremely low in China, and hyperuricemia is a common clinical manifestation. Therefore, the possibility of LND should be considered in children with increased uric acid in infancy accompanied by brain imaging changes or neurological dysfunction. Moreover, genetic testing is needed to provide adequate genetic counseling to the family, and should be conducted as early as possible in such children to avoid misdiagnosis or delayed diagnosis.

Comparison of Second-Line Treatments for Patients with Platinum-Resistant Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Systematic Review and Bayesian Network Meta-Analysis.

Several new drugs and combination strategies can be used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma in the second-line treatment. Questions regarding the relative efficacy and safety of any two of the multiple second-line treatment strategies have emerged. This study aims to compare second-line treatments for patients with platinum-resistant recurrent or metastatic head and neck squamous cell carcinoma. Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify relevant articles. Direct and indirect evidence in terms of the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events grade ≥ 3 (grade ≥ 3 trAE) were analyzed in this Bayesian network meta-analysis. A total of twenty-three trials involving 5039 patients were included. These studies compared 20 different treatments, including the standard of care (SOC: docetaxel, methotrexate, or cetuximab), PD-1 inhibitors (nivolumab or pembrolizumab), durvalumab, tremelimumab, durvalumab + tremelimumab, palbociclib + SOC, tivantinib + SOC, sorafenib + SOC, EMD1201081 + SOC, vandetanib + SOC, PX-866 + SOC, 5-fluorouracil + SOC, cixutumumab + SOC, gefitinib + SOC, cabazitaxel, nolatrexed, duligotuzumab, zalutumumab, gefitinib, and afatinib. Among the currently available treatment options, compared to the standard of care (SOC: docetaxel, methotrexate, or cetuximab), the PD inhibitor significantly improved OS, ORR, and grade ≥ 3 trAE. Afatinib presented a better PFS and ORR than the SOC. Compared with afatinib, the PD-1 inhibitor had a better OS but a worse PFS. In conclusion, compared to the SOC, the PD-1 inhibitor significantly improved the OS, ORR, and grade ≥ 3 trAE. Afatinib presented a better PFS and ORR than the SOC. Compared with afatinib, the PD-1 inhibitor had a better OS but a worse PFS.

Associations of sleep and circadian phenotypes with COVID-19 susceptibility and hospitalization: an observational cohort study based on the UK Biobank and a two-sample Mendelian randomization study.

STUDY OBJECTIVES: Sleep and circadian phenotypes are associated with several diseases. The present study aimed to investigate whether sleep and circadian phenotypes were causally linked with coronavirus disease 2019 (COVID-19)-related outcomes. METHODS: Habitual sleep duration, insomnia, excessive daytime sleepiness, daytime napping, and chronotype were selected as exposures. Key outcomes included positivity and hospitalization for COVID-19. In the observation cohort study, multivariable risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated. Two-sample Mendelian randomization (MR) analyses were conducted to estimate the causal effects of the significant findings in the observation analyses. Odds ratios (ORs) and the corresponding 95% CIs were calculated and compared using the inverse variance weighting, weighted median, and MR-Egger methods. RESULTS: In the UK Biobank cohort study, both often excessive daytime sleepiness and sometimes daytime napping were associated with hospitalized COVID-19 (excessive daytime sleepiness [often vs. never]: RR = 1.24, 95% CI = 1.02-1.5; daytime napping [sometimes vs. never]: RR = 1.12, 95% CI = 1.02-1.22). In addition, sometimes daytime napping was also associated with an increased risk of COVID-19 susceptibility (sometimes vs. never: RR = 1.04, 95% CI = 1.01-1.28). In the MR analyses, excessive daytime sleepiness was found to increase the risk of hospitalized COVID-19 (MR IVW method: OR = 4.53, 95% CI = 1.04-19.82), whereas little evidence supported a causal link between daytime napping and COVID-19 outcomes. CONCLUSIONS: Observational and genetic evidence supports a potential causal link between excessive daytime sleepiness and an increased risk of COVID-19 hospitalization, suggesting that interventions targeting excessive daytime sleepiness symptoms might decrease severe COVID-19 rate.

Local radiotherapy versus nonradiotherapy to distant lesions for metastatic nasopharyngeal carcinoma: Retrospective cohort study.

BACKGROUND: To evaluate the efficiency of local radiotherapy to metastatic lesions in patients with metastatic nasopharyngeal carcinoma (mNPC). METHODS: The overall survival was observed and compared for mNPC patients who received local radiotherapy versus nonradiotherapy to metastatic lesions by using the Kaplan-Meier method and Cox analysis. RESULTS: One hundred and nine patients with NPC were involved in this study, with 61 (56.0%) received radiotherapy to metastatic sites and 48 (44.0%) did not receive radiotherapy to metastatic sites. The 2- and 5-year OS for patients who received local radiotherapy to metastatic lesions were 65.8% and 35.7%, and for patients who did not receive radiotherapy to metastatic lesions were 45.3% and 26.2%. The multivariable adjusted hazard radios for local radiotherapy versus nonradiotherapy to metastatic lesions were 0.482 (95% confidence interval is 0.278-0.834, p = 0.009). CONCLUSIONS: Local radiotherapy to metastatic lesions might be a protective factor for patients with mNPC.

The prognostic role of radiotherapy and radiotherapy target in cervical lymph node metastatic squamous cell carcinoma with unknown primary: a retrospective study.

OBJECTIVES: Aim to analyze the effect of radiotherapy for cervical lymph node metastatic carcinoma with unknown primary (CCUP) and compare the survival benefits between Comprehensive radiotherapy and Involved Field radiotherapy. MATERIALS AND METHODS: The patients diagnosed with CCUP between 2009 and 2019 in our institution were analyzed retrospectively. The categorical variables were tested by χ2 test. Kaplan-Meier method was used for survival analysis. Log-rank test and Cox proportional hazards regression were performed with overall survival (OS) and disease-free survival (DFS) as the primary outcome variables. RESULTS: Of 139 patients, 64.7% (90/139) of them received radiotherapy. Of the 90 patients who underwent radiotherapy, 45.6% (41/90) received Involved Field radiotherapy and the rest 49 patients received Comprehensive radiotherapy. The median follow-up of 139 patients is 69 months. The 1-year, 3-year, and 5-year OS rates are 87%, 62%, and 39%, respectively, and the DFS rates are 73%, 45%, and 29%, respectively. Multivariate analysis of 139 patients with CCUP shows that differentiation grade, N stage, radiotherapy, and the length of the largest lymph node (DmaxLN) are the independent prognostic factors for both OS and DFS. Subgroup analysis of 90 patients who received radiotherapy shows that the Comprehensive radiotherapy group has a better OS (P < 0.001) and DFS (P < 0.001) compared with Involved Field radiotherapy. CONCLUSION: Radiotherapy is the independent prognostic factor for CCUP. Comprehensive radiotherapy may be superior to Involved Field radiotherapy in survival benefits.

A de novo heterozygous variant in KAT6A is associated with a newly named neurodevelopmental disorder Arboleda-Tham syndrome-a case report.

Arboleda-Tham syndrome (OMIM#616268) is a newly named neurodevelopmental disorder, which is an autosomal dominant hereditary disease characterized by genetic variants. The clinical manifestations include global developmental delay, primary microcephaly, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. Currently, due to restricted knowledge of Arboleda-Tham syndrome and less specific pathological manifestations, it is difficult to diagnose at the early stages of the disease. Here, we present a case with obvious growth retardation and intellectual disability, accompanied by other manifestations including dysmorphic features of the ears, facial dysmorphism, right cryptorchidism, and inguinal hernia. Routine laboratory tests including blood-urine tandem mass spectrometry, urine gas chromatographic mass spectrometry, karyotype, echocardiography, automatic auditory brainstem responses, serum levels of calcium, phosphorus, vitamin D, creatine kinase (CK), and CK isoenzyme (CK-MB), and brain magnetic resonance imaging showed negative results. A de novo heterozygous variant in KAT6A, c.57delA (p.Val20*), was detected by trio-based whole exome sequencing and subsequent validation by Sanger sequencing in the patient, which was absent in both the parents. The patient received rehabilitation and nutritional intervention. The testis reduction and orchiopexy was scheduled when he was 1 year old. Our report extends the phenotype-genotype map of Arboleda-Tham syndrome, and also expands the mutant spectrum of the KAT6A gene. Moreover, this case emphasizes the timely conduction of whole exome sequencing for the early diagnosis of Arboleda-Tham syndrome, and spares patients from meaningless examinations and ineffective treatments.

Association of body pain and chronic disease: evidence from a 7-year population-based study in China.

BACKGROUND: Evidence is limited on the risk impact of body pain on future chronic disease. The present study aimed to investigate the association between body pain and chronic diseases. METHODS: Data were analyzed using four waves of the China Health and Retirement Longitudinal Study with 17 708 individual respondents aged 45 years and older. The association between body pain and chronic disease was estimated in both a cross-sectional cohort (2011) and a longitudinal cohort (2011-2018). The key outcomes include the incidence of overall and any specific chronic diseases. The associations among different body pain sites and 10 independent chronic disease risks were also assessed. FINDINGS: A total of 17 128 participants in 2011 were included in the cross-sectional cohort and 5611 participants were included in the 2011-2018 longitudinal cohort. Body pain showed an association with overall chronic disease in both the cross-sectional models (OR 2.71, 95% CI 2.47 to 2.98) and longitudinal model (risk ratio (RR) 1.21, 95% CI 1.07 to 1.35). Moreover, body pain was found to be associated with an increased risk of chronic respiratory disease (RR 1.43, 95% CI 1.06 to 1.92), heart disease (RR 1.45, 95% CI 1.12 to 1.89), kidney disease (RR 1.83, 95% CI 1.28 to 2.6), and digestive disease (RR 1.48, 95% CI 1.17 to 1.88). CONCLUSION: Body pain is associated with major disease and mortality. Future clinical research should be targeted to whether or not improved pain control can mitigate this population-level disease burden.

Influence of target dose heterogeneity on dose sparing of normal tissue in peripheral lung tumor stereotactic body radiation therapy.

OBJECTIVE: To evaluate the influence of target dose heterogeneity on normal tissue dose sparing for peripheral lung tumor stereotactic body radiation therapy (SBRT). METHODS: Based on the volumetric-modulated arc therapy (VMAT) technique, three SBRT plans with homogeneous, moderate heterogeneous, and heterogeneous (HO, MHE, and HE) target doses were compared in 30 peripheral lung tumor patients. The prescription dose was 48 Gy in 4 fractions. Ten rings outside the PTV were created to limit normal tissue dosage and evaluate dose falloff. RESULTS: When MHE and HE plans were compared to HO plans, the conformity index of the PTV was increased by approximately 0.08. The median mean lung dose (MLD), V5, V10, V20 of whole lung, D2%, D1cc, D2cc of the rib, V30 of the rib, D2% and the maximum dose (Dmax) of the skin, and D2% and Dmax of most mediastinal organs at risk (OARs) and spinal cord were reduced by up to 4.51 Gy or 2.8%. Analogously, the median Dmax, D2% and mean dose of rings were reduced by 0.71 to 8.46 Gy; and the median R50% and D2cm were reduced by 2.1 to 2.3 and 7.4% to 8.0%, respectively. Between MHE and HE plans there was little to no difference in OARs dose and dose falloff beyond the target. Furthermore, the dose sparing of rib V30 and the mean dose of rings were negatively correlated with the rib and rings distance from tumor, respectively. CONCLUSIONS: For peripheral lung tumor SBRT, target conformity, normal tissue dose, and dose falloff around the target could be improved by loosening or abandoning homogeneity. While there was negligible further dose benefit for the maximum target dose above 125% of the prescription, dose sparing of normal tissue derived from a heterogeneous target decreased as the distance from the tumor increased.