A modular computational framework for medical digital twins.

This paper presents a modular software design for the construction of computational modeling technology that will help implement precision medicine. In analogy to a common industrial strategy used for preventive maintenance of engineered products, medical digital twins are computational models of disease processes calibrated to individual patients using multiple heterogeneous data streams. They have the potential to help improve diagnosis, prognosis, and personalized treatment for a wide range of medical conditions. Their large-scale development relies on both mechanistic and data-driven techniques and requires the integration and ongoing update of multiple component models developed across many different laboratories. Distributed model building and integration requires an open-source modular software platform for the integration and simulation of models that is scalable and supports a decentralized, community-based model building process. This paper presents such a platform, including a case study in an animal model of a respiratory fungal infection.

[Analysis of symptoms and influencing factors of low back work-related musculoskeletal disorders among workers in a container manufacturing factory].

Objective: To investigate the occurrence of low back work-related musculoskeletal disorders (WMSDs) among workers in a container manufacturing factory, and to explore the influencing factors. Methods: In June 2022, 952 workers from a container factory were selected as the research objects by cluster random sampling. Through questionnaire survey, the incidence of low back WMSDs symptoms among workers in the past one year was collected, and the influencing factors of low back WMSDs were analyzed by logistic regression. Results: The incidence rate of low back WMSDs was 46.7% (445/952). The factors with higher exposure at work were frequent slight bending (77.0%, 733/952), frequent overtime (74.1%, 705/952), and the need to turn around while working (62.3%, 593/952). Multivariate logistic regression analysis showed that age over 40 years old, smoking, drinking, often bending over slightly, sitting for a long time, maintaining a large bending posture for a long time, often working overtime, limited operating space, and there was always a need to complete conflicting things in the container manufacturing factory workers were the risks of increasing the low back WMSDs (OR=1.68, 1.96, 2.47, 1.49, 1.84, 2.11, 1.90, 1.82, 2.00, P<0.05). Standing at work, always friendly colleagues, and always supportive and helpful leaders were protective factors for low back WMSDs (OR=0.60, 0.32, 0.40, P<0.05) . Conclusion: The incidence of low back WMSDs symptoms in container manufacturing workers is high, and work-related factors such as frequent slight bending, long time holding large bending posture and limited operating space are the focus of ergonomic intervention in container manufacturing enterprises.

Epistatic interactions between PHOTOPERIOD1, CONSTANS1 and CONSTANS2 modulate the photoperiodic response in wheat.

In Arabidopsis, CONSTANS (CO) integrates light and circadian clock signals to promote flowering under long days (LD). In the grasses, a duplication generated two paralogs designated as CONSTANS1 (CO1) and CONSTANS2 (CO2). Here we show that in tetraploid wheat plants grown under LD, combined loss-of-function mutations in the A and B-genome homeologs of CO1 and CO2 (co1 co2) result in a small (3 d) but significant (P<0.0001) acceleration of heading time both in PHOTOPERIOD1 (PPD1) sensitive (Ppd-A1b, functional ancestral allele) and insensitive (Ppd-A1a, functional dominant allele) backgrounds. Under short days (SD), co1 co2 mutants headed 13 d earlier than the wild type (P<0.0001) in the presence of Ppd-A1a. However, in the presence of Ppd-A1b, spikes from both genotypes failed to emerge by 180 d. These results indicate that CO1 and CO2 operate mainly as weak heading time repressors in both LD and SD. By contrast, in ppd1 mutants with loss-of-function mutations in both PPD1 homeologs, the wild type Co1 allele accelerated heading time >60 d relative to the co1 mutant allele under LD. We detected significant genetic interactions among CO1, CO2 and PPD1 genes on heading time, which were reflected in complex interactions at the transcriptional and protein levels. Loss-of-function mutations in PPD1 delayed heading more than combined co1 co2 mutations and, more importantly, PPD1 was able to perceive and respond to differences in photoperiod in the absence of functional CO1 and CO2 genes. Similarly, CO1 was able to accelerate heading time in response to LD in the absence of a functional PPD1. Taken together, these results indicate that PPD1 and CO1 are able to respond to photoperiod in the absence of each other, and that interactions between these two photoperiod pathways at the transcriptional and protein levels are important to fine-tune the flowering response in wheat.

Trapped Alkali-Metal Rydberg Qubit.

Rydberg interactions of trapped alkali-metal atoms are used widely to facilitate quantum gate operations in quantum processors and repeaters. In most laboratory realizations using this protocol, the Rydberg states are repelled by the trapping laser fields, requiring that the fields be turned off during gate operations. Here we create a quasi-two-level system in a regime of Rydberg excitation blockade for a mesoscopic Rb ensemble of several hundred atoms confined in a magic-wavelength optical lattice. We observe many-body Rabi oscillations between the ground and collective Rydberg state. In addition we use Ramsey interference techniques to obtain the light shifts of both the lower and upper states of the collective qubit. Whereas the coupling producing the Rabi oscillations is enhanced by a factor of sqrt[N], there is no corresponding enhancement for the light shifts. We derive an effective two-level model which is in good agreement with our observations. Trapped Rydberg qubits and an effective two-level description are expected to have broad applicability for studies of quantum simulation and networking using collective encoding in ensembles of neutral atoms.

[Application of three risk assessment methods to noise risk assessment in an automobile foundry enterprise].

Objective: To explore the applicability of three different kinds of noise occupational health risk assessment methods to the occupational health risk assessment of noise exposed positions in an automobile foundry enterprise. Methods: In July 2020, the occupational-health risk assessment of noise-exposed positions was conducted by using the Guidelines for risk management of occupational noise hazard (guideline method) , the International Commission on Mining and Metals Guidelines for Occupational Health Risk Assessment (ICMM) method and the Occupational-health risk index method (index method) respectively, and the results were analyzed and compared. Results: Through the occupational health field investigation, the noise exposure level of the enterprise's main workstations was between 80.3 and 94.8 dB (A) , among which the noise of the posts of shaking-sand, cleaning and modeling was greater than 85 dB (A) ; The noise risk of each position was evaluated by the three methods, and the adjustment risk level was between 2 and 5 assessed using the guideline method, between 2 and 3 assessed using the index method, and 5 evaluated using the ICMM model. Conclusion: Each of the three risk assessment methods has its own advantages and disadvantages. The ICMM model has a large difference in value assignment, and values in the results are larger than expected. The evaluation results of the guideline method and the index method are consistent in some positions, there is certain subjectivity in the evaluation using the index method, and the guideline method is more objective.

[Neck musculoskeletal disorders and their influence factors among welders in an automobile factory].

Objective: To explore the prevalence and risk factors of neck musculoskeletal diseases (MSDs) of welders among an automobile factory. Methods: In June 2019, a cluster random sampling method was used to select 677 electric welders from an automobile manufacturing plant in Shiyan City as the survey objects, and a questionnaire survey was conducted using the "Musculoskeletal Disorders Questionnaire" to analyze the prevalence and influencing factors of neck MSDs, and used logistic regression to analyze the relationship between the influencing factors and the prevalence of cervical MSDs. Results: The prevalence rate of MSDs in neck of welders was 54.8% (371/677) . The exposure rate of occupational factors, from high to low, were neckin a bent formord porsure was 71.6% (486/677) , repetitive head movements was 55.1% (373/677) , working in uncomfortable postures was 48.7% (330/677) and neck twisted was 46.8% (317/677) respectively. Sex, age, educational level, length of service, smoking, neck tilt, neck twist, working in uncomfortable posture and head repetitive movements were the risk factors of neck MSDs (P<0.05) . Multiple logistic regression analysis showed that, the main influencing factors of neck MSDs were sex, education level, age, length of service, smoking, neck tilt, working in uncomfortable posture (OR = 2.11, 2.03, 1.83, 1.21, 1.78, 1.90, 1.58, 95%CI: 1.28~3.48、1.47~2.81、1.33~2.52、1.03~1.41、1.22~2.60、1.28~2.83、1.11~2.27, P<0.05) , rest had protective effect on neck MSDs (OR= 0.38, 95%CI: 0.17~0.88, P<0.05) . Conclusion: Welders in automobile factory was highly exposed to occupational risk factors for neck MSDs. Occupational risk factors such as neck in a bent forward posture, working in an uncomfortable posture, prolonged siting, repetitive head movement should be the focus of intervention.

Short Message Service reminders reduce outpatient colonoscopy nonattendance rate: A randomized controlled study.

BACKGROUND AND AIM: Nonattendance of outpatient colonoscopy leads to inefficient use of health-care resources. We aimed to study the effectiveness of using Short Message Service (SMS) reminder prior in patients scheduled for outpatient colonoscopy on their nonattendance rate. METHODS: Patients who scheduled for an outpatient colonoscopy and had access of SMS were recruited from three clinics in Hong Kong. Patients were randomized to SMS group and standard care (SC) group. All patients were given a written appointment slip on the booking date. In addition, patients in the SMS group received an SMS reminder 7-10 days before their colonoscopy appointment. Patients' demographics, attendance, colonoscopy completion, and bowel preparation quality were recorded. Logistic regression was performed to identify predictors of nonattendance. RESULTS: From November 2013 to October 2019, a total of 2225 eligible patients were recruited. A total of 1079 patients were allocated to the SMS group and 1146 to the SC group. The nonattendance rate of patients in the SMS group was significantly lower than that in the SC group (8.9% vs 11.9%, P = 0.022). There were no significant differences in their baseline characteristics and colonoscopy completion rate and bowel preparation quality. A trend towards a higher rate of adequate bowel preparation was observed in the SMS group when compared with the SC group (69.9% vs 65.8%, P = 0.053). Independent predictors for nonattendance included younger age, underprivilege, and existing diabetes. CONCLUSIONS: An SMS reminder for outpatient colonoscopy is effective in reducing the nonattendance rate and may potentially improve the bowel preparation quality.

[Lengths of the fixed loop and the adjustable loop in the coarse bone tunnel were compared to influence the widening of the femoral bone tunnel and the function of the knee joint].

OBJECTIVE: To evaluate the effects of two different femoral cortical suspension devices (fixation loop and adjustable loop) on tunnel widening and knee function in patients following anterior cruciate ligament reconstruction for 12 months. METHODS: A total of 60 patients who had undergone anterior cruciate ligament reconstruction were included in this study. According to the length of the loop(n)[n= total length of loop-(total length of femoral tunnel-total length of coarse tunnel)] in the rough bone tunnel, the patients were divided into A (adjustable loop was 0 mm in the coarse bone tunnel), B (fixation loop was greater than 0 mm and less than or equal to 10 mm in the coarse bone tunnel) and C (fixation loop was greater than 10 mm in the coarse bone tunnel) groups, of which 11 cases were in group A, 27 cases in group B and 22 cases in group C. In the three-dimensional reconstruction of the knee joint with multi-slice spiral CT, the widening of the bone tunnel in the three groups was compared. At the same time, IKDC, Lysholm and Tegner scores of the patients in the three groups were compared. RESULTS: There were differences in the widening degree of the femoral canal among groups A, B and C, and the median difference of the widening degree of the femoral tunnel 12 months and immediately after the surgery was A < B < C. The difference of femoral canal widening in group A was significantly different from that in groups B and C (P < 0.05).According to the linear regression the relationship between the difference of the width of the femoral canal and the change of the length (n) of the loop in the coarse canal, it was found that there was a linear relationship between the value of n and the difference of the width of the bone canal. With the increase of the value of n, the difference of the width of the bone canal gradually became larger. The median difference of the width of the middle and superior tunnel was negative, while the median difference of the width of the middle and inferior tunnel was positive. During the follow-up, we found that there were no statistical differences in IKDC, Lysholm and Tegner scores among the three groups one year after surgery (P > 0.05). CONCLUSION: Twelve months after surgery, compared with group B (fixed loop group) and group C (fixed loop group), group A (adjustable loop group) had less bone tunnel widening.In groups A, B and C, as the length of the loop in coarse bone tunnel gradually increased, the width of bone tunnel became more significant. At the end of 12 months follow-up after anterior cruciate ligament reconstruction, the medial and inferior femoral tunnel was significantly wider than immediately after surgery, and the medial and superior femoral tunnel had gradually begun to undergo tendon-bone healing. There was no significant difference in knee function scores among groups A, B, and C in the follow-up 12 months after surgery.

[Determination of bisphenol S in urine by vortex-assisted liquid-liquid microextraction with high performance liquid chromatography].

Objective: To establish a method for the determination of bisphenol S in urine using dispersive liquid-liquid microextraction (DLLME) coupled with high performance liquid chromatography (HPLC) . Methods: The acetonitrile, octanol were used as extraction solvent, dispersive solvent respectively, for the preconcentration of bisphenol S. The optimal extraction conditions were optimized by single factor rotations, and methodological performance index were tested. Results: The linear correlation coefficient of bisphenol S in the range of 0.0-160 µg/L is greater than 0.999. The detection limit of this method was 0.76 µg/L, and the recovery rates were 88.06%-103.81%. The intra-and inter-day precisions were 1.78%-2.85% and 2.65%-4.25%, respectively. Conclusion: The method is reliable and sensitive. It is suitable for the determination of bisphenol S in urine samples for occupational exposure populations and non-professional.

[Determination of Methoxyacetic acid in urine by pre-column derivatization-liquid-liquid microextraction coupled with gas chromatography].

Objective: To establish a method for determining methoxyacetic acid in urine by pre-column derivatization-liquid-liquid microextraction coupled with gas chromatography (GC) . Methods: Phosphate buffer solution, tert-butoxyacetic acid (internal standard) and pentafluorobenzyl bromide (derivative) were added to the urine sample. After derived in a water bath at 90 ℃ for 40 min, the mixture was cooled and filtered, then the dichloromethane was used as an extractant. After being shaken and centrifuged, the lower organic phase was sucked and injected into a gas chromatograph, separated by a DB-5 capillary column, and detected by an ECD detector. Results: The linear range of the method was 0.6~60.0 mg/L with the correlation coefficients (r) above 0.999. The average recovery was76.6%~110.7%, the inter-day precision was 8.00%~8.82%, and the detection limit was 0.13 mg/L. Conclusion: The method was founded to be high sensitivity, low organic reagent usage and green. So it is suitable for the detection of methoxyacetic acid in urine of occupational exposure to ethylene glycol monomethyl ether.

[Cumulative noise exposure and the risk of high-frequency hearing loss relationships].

Objective: To explore the dose-response relationship between cumulative noise exposure and high-frequency hearing loss, and further to provide a basis for the control of occupational hazards of noise. Methods: A Meta-analysis of dose-response relationships was performed on the data of eligible literatures published in China from January 2000.1 to December 2019.12. Results: The initial combined Odds Ratio (OR) and its 95%CI in the Meta-analysis were 1.10 (1.08-1.12) . As the Begg's funnel plot and Egger's test indicated publication bias (t=5.97, P<0.01) , the Trim-and-Fill Method was used for OR value adjustment. The adjusted-OR was 1.09 (1.07-1.12) ; sensitivity analysis showed that the results of this Meta-analysis have high stability; subgroup analysis indicated that the ORs of the steady-state noise group and the non-steady-state noise group were 1.10 (1.08-1.12) and 1.14 (1.07-1.21) , the ORs of the old standard group and the new standard group were 1.10 (1.08-1.12) and 1.11 (1.00-1.24) , respectively. The nonlinear dose-response relationship curve demonstrated that the risk of high-frequency hearing loss increases rapidly after CNE reaches 95 dB (A) ·years. Conclusion: There is a definite dose-response relationship between CNE and high-frequency hearing loss, which can be used to predict the risk of high-frequency hearing loss in noisy workers.

[Determination of nickel in urine by ultrasonic-assisted ionic liquid microextraction-graphite furnace atomic absorption spectrometry].

Objective: To set up a new method to determine the nickel of urine in urine using dispersive liquid-liquid microextraction (DLLME) coupled with graphite furnace atomic absorption spectrometry (GFAAS) . Methods: From September 2018 to September 2019, the methanol, pyrrolidine dithiocarbamate and ionic liquid 1-hexyl-3-methyl-imidazolium hexafluorophosphate were used as dispersive solvent, the chelating agent and extraction solvent for the preconcentration of nickel, respectively. After adding into buffer solution of pH 9, ultrasonic dissolving for 10 minutes, centrifugal separation and then discarding the supernatant, the precipitate was saved. Dissolving the precipitate by methanol, mixing thoroughly on a vortex mixer, the 15 µl of the mixed solution was used for determination by graphite furnace atomic absorption spectrometry. Results: The linear correlation coefficient of urine nickel concentration in the range of 2.0-10.0 µg/L, r=0.999, with the detection limitation of 0.43 µg/L. The recovery rate and the relative standard deviations were 95.6%-103.7% and 2.53%-4.82%, respectively. Conclusion: The method, which has low detection limit, high recovery rate and good precision, is suitable for the determination of nickel in urine for the occupational populations exposure to nickel and non-occupational exposure.

[Determination of manganese in human urine by dispersive ionic liquid-liquid microextraction-graphite furnace atomic absorption spectrometry].

Objective: To establish a method for the determination of manganese in urine with graphite furnace atomic absorption spectrometry (GFAAS) by using ionic liquid microextraction. Methods: The ethanol, 8-hydroxyquinoline and ionic liquid 1-octyl-3-methyl-imidazolium hexafluorophosphate were used as dispersive solvent, chelating agent and extraction solvent respectively, for the preconcentration of manganese. After the optimal extraction conditions were optimized by single factor rotations, evaluate the performance indicators such as methodological precision, accuracy, and detection limit. Results: The linear range of urine manganese was 0.0-1.6 µg/L, and the correlation coefficient of standard curve line was 0.992, the detection limit was 0.03 µg/L, the recovery of sample spiked was 84.90%-96.50%, and the relative standard deviation was 0.36%-1.84%. Conclusion: The method has the advantages of low detection limit, high recovery rate and high sensitivity. It is suitable for the determination of manganese in urine samples from occupational exposure populations and the general population.

[Determination of n-butyl alcohol in urine by headspace solid-phase microextraction coupled with gas chromatography].

Objective: To establish a headspace solid phase microextraction-gas chromatography method for determination of n-Butyl alcohol in urine. Methods: In October 2019, the n-butyl alcohol in urine was extracted with a polydimethylsiloxane/divinylbenzene (PDMS/DVB) solid-phase microextraction head. The conditions of salt amount, extraction temperature, extraction time and desorption time were optimized. The separation was performed on HP-5 (30 m×0.32 mm×0.25 µm) capillary column and detected with flame ionization detector. The quantification was based on the external standard curve. Results: The linear relationship of n-butyl alcohol in urine was good in the range of 0.04-3.00 mg/L, the correlation coefficient was 0.999, the detection limit of the method was 0.04 mg/L, the recovery was 77.4%-102.8%, the intra-run precision was 3.67%-8.11%, and the inter-assay precision was 4.94%-6.90%. Conclusion: The method has simple operation, high concentration efficiency and high sensitivity, and it is suitable for the determination of n-butyl alcohol in urine of occupational exposure to n-butyl alcohol.

[Determination of 1-methoxy-2-propanol in urine by headspace solid-phase microextraction coupled with gas chromatography].

Objective: To establish a method for the determination of 1-methoxy-2-propanol in urine using headspace solid phase micro-extraction coupled with gas chromatography. Methods: The 1-methoxy-2-propanol was enriched by headspace solid phase micro-extraction fiber coated with carbene/polydimethylsiloxane (CAR/PDMS) . Single factor rotation method was used to optimize the conditions of extraction temperature, salt amount, and extraction time. The separation was performed on DB-5 (30 m×0.32 mm×0.25 µm) capillary column and detected with flame ionization detector. The quantification was based on the standard curve. Results: The concentration of 1-methoxy-2-propanol in urine was linear in the range of 0.50-10.0 mg/L, and the linear correlation coefficient was 0.9993. The detection limit of the method was 0.14 mg/L, and the limit of quantification was 0.45 mg/L. The recovery was 85.8% to 104.7%, and the RSD of intra- and inter-batch precision were 3.25%-6.65% and 0.81%-3.96%, respectively. Conclusion: The method is high sensitivity and simple operation, and is suitable for the determination of 1-methoxy-2-propanol in urine of occupational exposure population.

[Determination of metabolites of styrene in urine by dispersive liquid-liquid microextraction coupled with high performance liquid chromatography].

Objective: To establish a method for the determination of mandelic acid and phenylglyoxylic acid in the urine of styrene by dispersive liquid-liquid microextraction-high coupled with high performance liquid chromatography. Methods: N-octanol was used as an extractant and ethanol was used as a dispersing agent. The phenylglycolic acid and phenylglyoxylic acid in the urine were extracted, and the upper liquid was taken after vortexing and centrifuged, and then was injected into HPLC for analysis. Results: The linear correlation coefficient of the concentration of phenylglycolic acid in the range of 0~10.0 mg/L was greater than 0.999. The detection limit of the method was 9.9 µg/L, the recovery rates were 86.1%~101.6%. The intraday RSDs of the method were 1.07%~3.76%, and the interday RSDs were 1.24%~3.33%. The linear correlation coefficient of phenylglyoxylic acid in the range of 0.0~2.0 mg/L is greater than 0.999. The detection limit of the method was 2.6 µg/L, the recovery rates were 88.8%~100.3%. The intraday RSDs of the method were 1.02%~ 3.17%, and the interday RSDs were 1.59%~2.41%. Conclusion: The method has low detection limit, high enrichment ratio and good sensitivity, and is suitable for determination of phenylglycolic acid and phenylglyoxylic acid in urine of occupational exposure to styrene.

Effect of air pollution on hospital admissions for systemic lupus erythematosus in Bengbu, China: a time series study.

Recently, exposure to air pollutants has been associated with the development and progression of systemic lupus erythematosus (SLE). The current study aims to evaluate the effects of air pollutants on SLE hospital admissions in Bengbu, China. We performed distributed lag non-linear model combined with quasi-Poisson generalized linear regression to assess the impacts of air pollutants on SLE admissions from 2015 to 2017. Subgroup analyses by admission status (first admission or readmission) were also evaluated. A total of 546 hospital admissions during 2015-2017 were included. For single-day lag structures, the risk effects occurred from lag 2 to lag 9 for the 75th percentile particulate matter (PM)2.5, lag 3 to lag 9 for the 80th percentile PM2.5. For cumulative lag structures, the risk effects occurred from lag 0-5 to lag 0-14 for both 75th PM2.5 and 80th PM2.5, and no significant effect was observed for 90th PM2.5. In addition, the adverse effects on SLE first admissions occurred from lag 0 to lag 1 for NO2, lag 1 to lag 2 for SO2. The maximum effect of PM2.5 on SLE was 4.27 (95% confidence interval: 1.34-13.59) at lag 0-13 day, the minimum effect value was 1.12 (95% confidence interval: 1.03-1.23) at lag 9 day. These findings demonstrate that high PM2.5, NO2 and SO2 are associated with SLE hospital admissions. In addition, this study further revealed that exposure to high concentration of PM2.5 increased the risk of SLE relapse, while high levels of NO2 and SO2 increased the risk of SLE first admissions.

Prevalence and Risk Factors for Cardiac and Liver Iron Overload in Adults with Thalassemia in Malaysia.

We explored the severity and risk factors for cardiac and liver iron overload (IOL) in 69 thalassemia patients who underwent T2* magnetic resonance imaging (T2* MRI) in a Malaysian tertiary hospital from 2011 to 2015. Fifty-three patients (76.8%) had transfusion-dependent thalassemia (TDT) and 16 (23.2%) had non transfusion-dependent thalassemia (NTDT). Median serum ferritin prior to T2* MRI was 3848.0 µg/L (TDT) and 3971.0 µg/L (NTDT). Cardiac IOL was present in 16 (30.2%) TDT patients and two (12.5%) NTDT patients, in whom severe cardiac IOL defined as T2* <10 ms affected six (11.3%) TDT patients. Liver IOL was present in 51 (96.2%) TDT and 16 (100%) NTDT patients, 37 (69.8%) TDT and 13 (81.3%) NTDT patients were in the most severe category (>15 mgFe/gm dry weight). Serum ferritin showed a significantly strong negative correlation with liver T2* in both TDT (rs = -0.507, p = 0.001) and NTDT (r = -0.762, p = 0.002) but no correlation to cardiac T2* in TDT (r = -0.252, p = 0.099) as well as NTDT (r = -0.457, p = 0.100). For the TDT group, regression analysis showed that cardiac IOL was more severe in males (p = 0.022) and liver IOL was more severe in the Malay ethnic group (p = 0.028) and those with higher serum ferritin levels (p = 0.030). The high prevalence of IOL in our study and the poor correlation between serum ferritin and cardiac T2* underline the need to routinely screen thalassemia patients using T2* MRI to enable the early detection of cardiac IOL.

PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet.

PiT-2, a type III sodium-dependent phosphate transporter, is a causative gene for the brain arteriolar calcification in people with familial basal ganglion calcification. Here we examined the effect of PiT-2 haploinsufficiency on vascular calcification in uremic mice using wild-type and global PiT-2 heterozygous knockout mice. PiT-2 haploinsufficiency enhanced the development of vascular calcification in mice with chronic kidney disease fed a high-phosphate diet. No differences were observed in the serum mineral biomarkers and kidney function between the wild-type and PiT-2 heterozygous knockout groups. Micro computed tomography analyses of femurs showed that haploinsufficiency of PiT-2 decreased trabecular bone mineral density in uremia. In vitro, sodium-dependent phosphate uptake was decreased in cultured vascular smooth muscle cells isolated from PiT-2 heterozygous knockout mice compared with those from wild-type mice. PiT-2 haploinsufficiency increased phosphate-induced calcification of cultured vascular smooth muscle cells compared to the wild-type. Furthermore, compared to wild-type vascular smooth muscle cells, PiT-2 deficient vascular smooth muscle cells had lower osteoprotegerin levels and increased matrix calcification, which was attenuated by osteoprotegerin supplementation. Thus, PiT-2 in vascular smooth muscle cells protects against phosphate-induced vascular calcification and may be a therapeutic target in the chronic kidney disease population.

Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: Results of the TPOG-ALL-2002 study.

BACKGROUND: To eliminate cranial irradiation (CrRT)-related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)-directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL). METHODS: This study compared the treatment outcomes of patients overall and patients with a non-CNS-1 status (CNS-2, CNS-3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG-ALL-2002 protocol by the introduction of the modification (era 1 [2002-2008] with CrRT and era 2 [2009-2012] with delayed first TIT and no CrRT). RESULTS: There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2: the 5-year event-free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P = .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P = .960). There were also no differences between non-CNS-1 patients treated in era 1 (n = 76) and era 2 (n =28): the 5-year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P = .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P = .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2. CONCLUSIONS: The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non-CNS-1 status.