Nucleotide excision repair gene polymorphisms and hepatoblastoma susceptibility in Eastern Chinese children:A five-center case-control study

Objective:Nucleotide excision repair(NER)plays a vital role in maintaining genome stability,and the effect of NER gene polymorphisms on hepatoblastoma susceptibility is still under investigation.This study aimed to evaluate the relationship between NER gene polymorphisms and the risk of hepatoblastoma in Eastern Chinese Han children.Methods:In this five-center case-control study,we enrolled 966 subjects from East China(193 hepatoblastoma patients and 773 healthy controls).The TaqMan method was used to genotype 19 single nucleotide polymorphisms(SNPs)in NER pathway genes,including ERCC1,XPA,XPC,XPD,XPF,and XPG.Then,multivariate logistic regression analysis was performed,and odds ratios(ORs)and 95%confidence intervals(95%CIs)were utilized to assess the strength of associations.Results:Three SNPs were related to hepatoblastoma risk.XPC rs2229090 and XPD rs3810366 significantly contributed to hepatoblastoma risk according to the dominant model(adjusted OR=1.49,95%CI=1.07−2.08,P=0.019;adjusted OR=1.66,95%CI=1.12−2.45,P=0.012,respectively).However,XPD rs238406 conferred a significantly decreased risk of hepatoblastoma under the dominant model(adjusted OR=0.68,95%CI=0.49−0.95;P=0.024).Stratified analysis demonstrated that these significant associations were more prominent in certain subgroups.Moreover,there was evidence of functional implications of these significant SNPs suggested by online expression quantitative trait loci(eQTLs)and splicing quantitative trait loci(sQTLs)analysis.Conclusions:In summary,NER pathway gene polymorphisms(XPC rs2229090,XPD rs3810366,and XPD rs238406)are significantly associated with hepatoblastoma risk,and further research is required to verify these findings.

An exploration of the breastfeeding behaviors of women aftercesarean section: A qualitative study

Objectives:To explore the factors affecting breastfeeding behaviors in women after cesarean section.Methods:This is a qualitative study that used a phenomenological approach.This study used individual face-to-face interviews with 19 women who underwent a cesarean section in a Women and Children’s Hospital in China between July to September 2019.Information saturationwas used to determine sample size.Data were analyzed using a thematic content analysis method.Themes were developed based on the theory of planned behavior.Results:Thirteen(68.42%)had a planned cesarean section,and six(31.58%)cesarean sections were unplanned or emergent.Three major themes emerged:ambivalent attitude about breastfeeding,motivation to comply with the traditional cultural norms,and barriers and challenges.The motivating factors for breastfeeding after cesarean sections included perceived benefits of human milk,support from healthcare professionals,and responsibility for breastfeeding.The challenges for breastfeeding after cesarean sections included physical discomfort,knowledge and skills deficit of breastfeeding,lactation deficiency,and lack of knowledge and coping skills in managing their depressive mood after cesarean sections.There were a couple of neutral factors,such as the influences of family and peers.These factors could influence women either positively as facilitators or negatively as barriers.Conclusions:The findings can offer valuable information for healthcare professionals to help women breastfeed after cesarean sections.To promote women’s breastfeeding behaviors after cesarean sections,it is necessary to change women’s attitudes,belief systems,and the external environments and help them become more confident.

Expert Consensus on Nutritional Support for Children with Congenital Heart Disease(2023 Edition)

The second edition of the expert consensus on pediatric nutrition was formed based on a global update of pedia-tric nutrition guidelines or consensus worldwide,the management of congenital heart disease,and the results of multi-center clinical nutrition research for congenital heart disease following thefirst Chinese consensus edition of 2016.The consensus was also shaped by the results of three discussion sessions and two questionnaires con-ducted by the 13-member collaboration group.This process was informed by both clinical guidelines and expert consensus.The quality of literature,both in English and Chinese,and the level of recommendations were evaluated using the Grading of Recommendations Assessment,Development,and Evaluations(GRADE)system.

Effects of Different Culture Conditions and Growth States on the Structure and Hemostatic Properties of Coscinodiscus sp.

As a renewable marine inorganic material,Coscinodiscus sp.has significant potential in the field of rapid hemostasis.However,the low yield of Coscinodiscus sp.seriously limits the application.In this study,two new culture modes were adopted to increase the production of Coscinodiscus sp.,the effect of changes in culture conditions and growth status on the hemostatic activity of diatoms was detected.To prevent Coscinodiscus sp.from sinking in culture,the suspension culture mode was realized by adding0.5%agar.The semi-continuous high nutrient concentration culture mode increased the cell density of Coscinodiscus sp.to 11000cells mL^(-1)and shorten the culture cycle to 5 d.In terms of coagulation activity,the addition of frustules reduced the in vitro coagulation time by half and the activation time of coagulation by 70%.The hemolysis rate and cytotoxicity of frustules harvested in the two culture modes did not change significantly.The results showed that suspension culture mode and high nutrient concentration culture mode only changed the growth state of Coscinodiscus sp.,while the hemostatic performance remained stable.

Systemic immune-inflammation index combined with pediatric appendicitis score in assessing the severity and prognosis for paediatric appendicitis

BACKGROUND Pediatric appendicitis is a common cause of abdominal pain in children and is recognized as a significant surgical emergency.A prompt and accurate diagnosis is essential to prevent complications such as perforation and peritonitis.AIM To investigate the predictive value of the systemic immune-inflammation index(SII)combined with the pediatric appendicitis score(PAS)for the assessment of disease severity and surgical outcomes in children aged 5 years and older with appendicitis.METHODS Clinical data of 104 children diagnosed with acute appendicitis were analyzed.The participants were categorized into the acute appendicitis group and chronic appendicitis group based on disease presentation and further stratified into the good prognosis group and poor prognosis group based on prognosis.The SII and PAS were measured,and a joint model using the combined SII and PAS was constructed to predict disease severity and surgical outcomes.RESULTS Significant differences were observed in the SII and PAS parameters between the acute appendicitis group and chronic appendicitis group.Correlation analysis showed associations among the SII,PAS,and disease severity,with the combined SII and PAS model demonstrating significant predictive value for assessing disease severity[aera under the curve(AUC)=0.914]and predicting surgical outcomes(AUC=0.857)in children aged 5 years and older with appendicitis.CONCLUSION The study findings support the potential of integrating the SII with the PAS for assessing disease severity and predicting surgical outcomes in pediatric appendicitis,indicating the clinical utility of the combined SII and PAS model in guiding clinical decision-making and optimizing surgical management strategies for pediatric patients with appendicitis.

Diagnostic significance of serum levels of serum amyloid A,procalcitonin,and high-mobility group box 1 in identifying necrotising enterocolitis in newborns

BACKGROUND Necrotising enterocolitis(NEC)is a critical gastrointestinal emergency affecting premature and low-birth-weight neonates.Serum amyloid A(SAA),procalcitonin(PCT),and high-mobility group box 1(HMGB1)have emerged as potential biomarkers for NEC due to their roles in inflammatory response,tissue damage,and immune regulation.AIM To evaluate the diagnostic value of SAA,PCT,and HMGB1 in the context of NEC in newborns.METHODS The study retrospectively analysed the clinical data of 48 newborns diagnosed with NEC and 50 healthy newborns admitted to the hospital.Clinical,radiological,and laboratory findings,including serum SAA,PCT,and HMGB1 Levels,were collected,and specific detection methods were used.The diagnostic value of the biomarkers was evaluated through statistical analysis,which was performed using chi-square test,t-test,correlation analysis,and receiver operating characteristic(ROC)analysis.RESULTS The study demonstrated significantly elevated levels of serum SAA,PCT,and HMGB1 Levels in newborns diagnosed with NEC compared with healthy controls.The correlation analysis indicated strong positive correlations among serum SAA,PCT,and HMGB1 Levels and the presence of NEC.ROC analysis revealed promising sensitivity and specificity for serum SAA,PCT,and HMGB1 Levels as potential diagnostic markers.The combined model of the three biomarkers demonstrating an extremely high area under the curve(0.908).CONCLUSION The diagnostic value of serum SAA,PCT,and HMGB1 Levels in NEC was highlighted.These biomarkers potentially improve the early detection,risk stratification,and clinical management of critical conditions.The findings suggest that these biomarkers may aid in timely intervention and the enhancement of outcomes for neonates affected by NEC.

Development and validation of tongue imaging-based radiomics tool for the diagnosis of insomnia degree:a two-center study

Background:Traditional Chinese medicine(TCM)is commonly used for the diagnosis and treatment of insomnia,with tongue diagnosis being particularly important.The aim of our study was to develop and validate a novel tongue imaging-based radiomics(TIR)method for accurately diagnosing insomnia severity.Methods:This two-center analysis prospectively enrolled 399 patients who underwent tongue imaging between July and October 2021 and divided them into primary and validation cohorts by study center.Here,we referred to the Insomnia Severity Index(ISI)standard and the degree of insomnia was evaluated as absent,subthreshold,moderate,or severe.For developed the TIR diagnostic tool,a U-Net algorithm was used to segment tongue images.Subsequently,seven imaging features were selected from the extracted high-throughout radiomics features using the least absolute shrinkage and selection operator algorithm.Then,the final radiomics model was developed in the primary cohort and tested in the independent validation cohort.Finally,we assessed and compared the diagnostic performance differences between TCM tongue diagnosis and our TIR diagnostic tool with the ISI gold standard.The confusion matrix was calculated to evaluate the diagnostic performance.Results:Seven tongue imaging features were selected to build the TIR tool,with showing good correlations with the insomnia degree.The TIR method had an accuracy of 0.798,a macro-average sensitivity of 0.78,a macro-average specificity of 0.906,a weighted-average sensitivity of 0.798,and a weighted specificity of 0.916,showing a significantly better performance compared to the average performance of three experienced TCM physicians(mean accuracy of 0.458,P<0.01).Conclusions:The preliminary study demonstrates the potential application of TIR in the diagnosis of insomnia degree and measurement of sleep health.The integration of quantitative imaging analysis and machine learning algorithms holds promise for advancing both of TCM and precision sleep medicine.

Brain magnetic resonance imaging findings and radiologic review of maple syrup urine disease:Report of three cases

BACKGROUND Maple syrup urine disease(MSUD)is a rare autosomal-recessive disorder that affects branched-chain amino acid(BCAA)metabolism and is named after the distinctive sweet odor of affected infants’urine.This disease is characterized by the accumulation of BCAAs and corresponding branched-chain ketoacids of leucine,isoleucine,and valine in the plasma,urine,and cerebrospinal fluid.However,the mechanisms of MSUD-induced brain damage remain poorly defined.The accumulation of BCAAs in the brain inhibits the activity of pyruvate dehydrogenase andα-ketoglutarate,disrupting the citric acid cycle and consequently impacting the synthesis of amino acids,causing cerebral edema and abnormal myelination.CASE SUMMARY We report three neonates admitted to our hospital with the classic subtype of MSUD.All three patients,with a transient normal period,presented with poor feeding,vomiting,poor weight gain,and increasing lethargy after birth.Laboratory testing revealed metabolic acidosis.The serum tandem mass spectrometry amino acid profile showed elevated plasma levels of BCAAs(leucine,isoleucine,and valine).Brain magnetic resonance imaging(MRI)presented abnormal signals mainly involving the globus pallidus,thalamus,internal capsule,brainstem,and cerebellar white matter,which represent the typical myelinated areas in normal full-term neonates.CONCLUSION In our patients,MRI showed typical features,in concordance with the available literature.Early detection and timely treatment are very helpful for the prognosis of MSUD patients.Therefore,we discuss the neuroimaging features of MSUD to enhance the knowledge of pediatricians about this disease.

Management of granulomatous lobular mastitis: an international multidisciplinary consensus(2021 edition)

Granulomatous lobular mastitis(GLM) is a rare and chronic benign inflammatory disease of the breast. Difficulties exist in the management of GLM for many front-line surgeons and medical specialists who care for patients with inflammatory disorders of the breast. This consensus is summarized to establish evidence-based recommendations for the management of GLM. Literature was reviewed using PubMed from January 1, 1971 to July 31, 2020. Sixty-six international experienced multidisciplinary experts from 11 countries or regions were invited to review the evidence.Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Experts discussed and concluded 30 recommendations on historical definitions,etiology and predisposing factors, diagnosis criteria, treatment, clinical stages, relapse and recurrence of GLM. GLM was recommended as a widely accepted definition. In addition, this consensus introduced a new clinical stages and management algorithm for GLM to provide individual treatment strategies. In conclusion, diagnosis of GLM depends on a combination of history, clinical manifestations, imaging examinations, laboratory examinations and pathology.The approach to treatment of GLM should be applied according to the different clinical stage of GLM. This evidencebased consensus would be valuable to assist front-line surgeons and medical specialists in the optimal management of GLM.

Ductus Arteriosus Stent Compared with Surgical Shunt for Infants with Ductal-Dependent Pulmonary Blood Flow: A Systematic Review and Meta-Analysis

The aim of this study was to perform a systematic review and meta-analysis to evaluate the safety and efficacy of ductus arteriosus stent(DAS)compared with surgical systemic-pulmonary artery shunt(SPS)in patients with ductal-dependent pulmonary blood flow.A literature search was conducted in PubMed,Embase,and the Cochrane Library databases from their inception to December 2020.Two reviewers independently screened the articles,evaluated the quality of the articles,and collected the data.Meta-analyses were conducted using fixed and random effects models.We used the I-square(I2)test to examine heterogeneity and the funnel plot Egger’s test was used to test for publication bias.We analyzed nine studies including 842 patients were included in the present study(DAS:n=295;SPS:n=547).There was a benefit in favor of DAS group for medium-term mortality(RR,0.63;95%CI,[0.40,0.99];P=0.91,I^(2)=0%).DAS group demonstrated a reduced risk for complications compared with SPS(RR,0.46;95%CI,[0.29,0.72];P=0.78,I^(2)=0%).There was an increased risk for unplanned reintervention for DAS(RR,1.77;95%CI,[1.42,2.20];P=0.61,I2=0%).DAS demonstrated shorter mean intensive care unit length of stay(MD,–5.12;95%CI,[–7.33,–2.91];P=0.005,I^(2)=76%).There was also demonstrated higher postprocedure oxygen saturation for SPS over DAS(MD,1.78;95% CI,[0.92,2.64];P=0.46,I2=0%).There was no difference between the two groups in terms of mortality within 30 days,Nakata Index,and hospital length of stay.Conclusions:In terms of initial palliative surgical in the ductal-dependent pulmonary blood flow,DAS demonstrated a lower risk of medium-term mortality,lower risk of complications,higher risk of unplanned reintervention,shorter ICU length of stay,and higher postprocedure oxygen saturation compared with SPS.

Transcatheter Closure of Perimembranous Ventricular Septal Defect Using the Amplatzer Duct Occluder II

Objective:To evaluate the efficacy of Amplatzer duct occluder II(ADO II)in the treatment of perimembranous ventricular septal defect(pmVSD)in children.Methods:Between June 2017 and June 2020,13 patients with pmVSD had attempted transcatheter closure using ADO II,seven of patients were used antegrade approach and six of them were used retrograde approach.Results:There were 8 males and 5 females,age from 1 to 7 years,weight from 10.5 to 31.0 kg,and VSD size from 2.0 to 4.0 mm.Procedure was successful in all cases with the outer diameter of the occluders ranging from 4 to 6 mm.No aortic,tricuspid regurgitation or residual shunt was found in the immediate ultrasound assessment.No arrhythmia was observed in the Holter monitoring 3 days after the intervention.Discharge echocardiography indicated complete shunt closure.No evidence of occluder prolapse,malignant arrhythmia,or intensed valve regurgitation was seen on a median follow-up of 18 months(range,6 to 36 months).Conclusions:Based on our experience,ADO II showed good efficacy in the early and middle stages of pediatric pmVSD closures.

Resolvin D1 Induces mTOR-independent and ATG5-dependent Autophagy in BV-2 Microglial Cells

Objective The activation state of microglia is known to occupy a central position in the pathophysiological process of cerebral inflammation.Autophagy is a catabolic process responsible for maintaining cellular homeostasis.In recent years,autophagy has been demonstrated to play an important role in neuroinflammation.Resolvin D1(RvD1)is a promising therapeutic mediator that has been shown to exert substantial anti-inflammatory and proresolving activities.However,whether RvD1-mediated resolution of inflammation in microglia is related to autophagy regulation needs further investigation.The present study aimed to explore the effect of RvD1 on microglial autophagy and its corresponding pathways.Methods Mouse microglial cells(BV-2)were cultured,treated with RvD1,and examined by Western blotting,confocal immunofluorescence microscopy,transmission electron microscopy,and flow cytometry.Results RvD1 promoted autophagy in both BV-2 cells and mouse primary microglia by favoring the maturation of autophagosomes and their fusion with lysosomes.Importantly,RvD1 had no significant effect on the activation of mammalian target of rapamycin(mTOR)signaling.Furthermore,RvD1-induced mTOR-independent autophagy was confirmed by observing reduced cytoplasmic calcium levels and suppressed calcium/calmodulin-dependent protein kinase II(CaMK II)activation.Moreover,by downregulating ATG5,the increased phagocytic activity induced by RvD1 was demonstrated to be tightly controlled by ATG5-dependent autophagy.Conclusion The present work identified a previously unreported mechanism responsible for the role of RvD1 in microglial autophagy,highlighting its therapeutic potential against neuroinflammation.

Creation of high position fetal balloon atrial septoplasty for hypoplastic left heart syndrome and highly restrictive atrial septum: A case report and literature review

Background:Fetal balloon atrial septoplasty(BAS)is performed through the restrictive foramen ovale in fetal cases with established hypoplastic left heart syndrome(HLHS)and an intact or highly restrictive atrial septum(RAS).Methods:In the current report,we present a case of high position BAS in a fetus with HLHS/RAS.Results:Echocardiography confirmed an adequate atrial opening above the foramen ovale and fetal pleural effusion resolved spontaneously 1 day after the procedure.Conclusion:To the best of our knowledge,the creation of a high position hole in the thinner part of the atrial septum,instead of the restrictive tiny hole,has not been reported in fetal cases with HLHS/RAS.

Observation of the clinical effects of catgut implantation at acupoints on postpartum obesity with insulin resistance

To observe the effect of catgut implantation at acupoints on the treatment of patients with postpartum obesity and insulin resistance.Methods:A total of 120 patients with postpartum obesity and insulin resistance were randomly divided into treatment and control groups(60 patients per group).The treatment group was administered catgut implantation at acupoints while the control group received acupuncture alone for 12 weeks.The patients’body parameters,including body mass index(BMI),waist-to-hip ratio(WHR),fat percentage(FP),fasting blood glucose(FPG),fasting insulin(FINS),insulin resistance index(HOMA-IR),total cholesterol(TC),triglycerides(T),high-density lipoprotein(HDL-C),low-density lipoprotein(LDL-C),and other biochemical indexes of blood lipids,were compared before and after treatment to investigate the efficacy of catgut implantation and acupuncture on postpartum obesity with insulin resistance.Results:The overall response rates were 93.33%and 85%in the treatment and control groups,respectively.After treatment,BMI,WHR,FP,FINS,HOMA-IR,TC,TG,and LDL-C decreased,HDL-C increased(P<0.05),and FPG did not change significantly(P>0.05)in both groups;however,the changes in the treatment group were superior to those in the control group(P<0.05).Conclusion:Both catgut implantation and acupuncture therapy showed good effects on improving postpartum obesity with insulin resistance.The therapeutic effect of catgut implantation on postpartum obesity was better than that of acupuncture therapy,and was therefore worthy of clinical application.

Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5

Programmed cell death-1(PD-1)/programmed cell death ligand-1(PD-L1)blocking therapy has become a major pillar of cancer immunotherapy.Compared with antibodies targeting,small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed.Here we identified berberine(BBR),a proven anti-inflammation drug,as a negative regulator of PDL1 from a set of traditional Chinese medicine(TCM)chemical monomers.BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells.In addition,BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumorinfiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells(MDSCs)and regulatory T-cells(Tregs).BBR triggered PD-L1 degradation through ubiquitin(Ub)/proteasome-dependent pathway.Remarkably,BBR selectively bound to the glutamic acid76 of constitutive photomorphogenic-9 signalosome 5(CSN5)and inhibited PD-1/PD-L1 axis through its deubiquitination activity,resulting in ubiquitination and degradation of PD-L1.Our data reveals a previously unrecognized antitumor mechanism of BBR,suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.

Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR

Programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)cascade is an effective therapeutic target for immune checkpoint blockade(ICB)therapy.Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity.Using flow cytometry-based assay,we identify tubeimoside-1(TBM-1)as a promising antitumor immune modulator that negatively regulates PD-L1 level.TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1.Furthermore,TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma(LLC)and B16 melanoma tumor xenograft via activating tumor-infiltrating T-cell immunity.Mechanistically,TBM-1 triggers PD-L1 lysosomal degradation in a TFEB-dependent,autophagy-independent pathway.TBM-1 selectively binds to the mammalian target of rapamycin(m TOR)kinase and suppresses the activation of m TORC1,leading to the nuclear translocation of TFEB and lysosome biogenesis.Moreover,the combination of TBM-1 and anti-CTLA-4 effectively enhances antitumor T-cell immunity and reduces immunosuppressive infiltration of myeloid-derived suppressor cells(MDSCs)and regulatory T(Treg)cells.Our findings reveal a previously unrecognized antitumor mechanism of TBM-1 and represent an alternative ICB therapeutic strategy to enhance the efficacy of cancer immunotherapy.

Newborn screening with targeted sequencing:a multicenter investigation and a pilot clinical study in China

Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 465 causative genes for 596 early-onset, relatively high incidence, and potentially actionable severe inherited diseases in our Newborn Screening with Targeted Sequencing(NESTS) program to screen 11,484 babies in 8 Women and Children’s hospitals nationwide in China retrospectively. The positive rate from preliminary screening of NESTS was 7.85%(902/11,484). With 45.89%(414/902) follow-up of preliminary positive cases, the overall clinically confirmative diagnosis rate of monogenic disorders was 12.07%(50/414), estimating an average of 0.95%(7.85% × 12.07%) clinical diagnosis rate, suggesting that monogenic disorders account for a considerable proportion of birth defects. The disease/gene spectrum varied in different regions of China. NESTS was implemented in a hospital by screening 3923 newborns to evaluate its clinical application. The turn-around time of a primary report, including the sequencing period of < 7 days, was within 11 days by our automatic interpretation pipeline. Our results suggest that NESTS is feasible and cost-effective as a first-tier NBS program, which will change the status of current clinical practice of NBS in China.

Study on the challenge and influence of the built thermal environment on elderly health in rural areas:Evidence from Shandong,China

Elderly health is increasingly recognized as a worldwide challenge with the continuous social aging trend.This study aimed to investigate the thermal conditions of the elderly in rural areas of Shandong,China.The thermal sensation and physiological response performances of elderly participants were examined in their own houses.Results show a clear seasonal pattern in cardiovascular disease mortality,cold stress increases the cardiovascular disease risk.The coal-based stoves serve as the main source of home heating and their limited coverage of the room area gave rise to poor quality of thermal comfort.The analysis of skin temperature for those under 65 and above did not reveal any significant difference in response to different indoor temperatures.The regression results confirm that a colder home leads to a rising value of the elderly’s systolic blood pressure,rising by more than 1 mmHg for every 1℃decrease in indoor temperature and thus posing a greater risk of cardiovascular diseases.The systolic blood pressure value of older subjects rise more when they are exposed to decreasing indoor temperatures,possibly due to an age-related decline in their ability to maintain stability of blood pressure.It is noteworthy that the average blood velocity of older subjects reduces less in response to decreasing indoor temperatures,indicating a weakened capacity to resist cold stress and its associated high risk of hypertension.This investigation provides evidence in favor of improving the thermal environment of the elderly and reducing their risk of cardiovascular diseases.

Genetic Architecture of Childhood Kidney and Urological Diseases in China

Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration system is being imple-mented based on the Chinese Children Genetic Kidney Disease Database(CCGKDD).In this study,all the patients with kidney and urological diseases were recruited from 2014 to 2020.Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features.The genetic diagnosis was confirmed in 883 of 2256(39.1%)patients from 23 provinces in China.Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome(SRNS,23.5%),glomerulonephritis(GN,32.2%),congenital anomalies of the kidney and urinary tract(CAKUT,21.2%),cystic renal disease(3.9%),renal calcinosis/stone(3.6%),tubulopathy(9.7%),and chronic kidney disease of unknown etiology(CKDu,5.8%).The pathogenic variants of 105 monogenetic disorders were identified.Ten distinct genomic disorders were identified as pathogenic copy number variants(CNVs)in 11 patients.The diagnostic yield differed by subgroups,and was highest in those with cystic renal disease(66.3%),followed by tubulopathy(58.4%),GN(57.7%),CKDu(43.5%),SRNS(29.2%),renal calcinosis/stone(29.3%)and CAKUT(8.6%).Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions.We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed.Our data demonstrate the utility of family-based exome sequencing,and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.