In situ chemoimmunotherapy hydrogel elicits immunogenic cell death and evokes efficient antitumor immune response.

BACKGROUND: Chemoimmunotherapy has shown promising advantages of eliciting immunogenic cell death and activating anti-tumor immune responses. However, the systemic toxicity of chemotherapy and tumor immunosuppressive microenvironment limit the clinical application. METHODS: Here, an injectable sodium alginate hydrogel (ALG) loaded with nanoparticle albumin-bound-paclitaxel (Nab-PTX) and an immunostimulating agent R837 was developed for local administration. Two murine hepatocellular carcinoma and breast cancer models were established. The tumor-bearing mice received the peritumoral injection of R837/Nab-PTX/ALG once a week for two weeks. The antitumor efficacy, the immune response, and the tumor microenvironment were investigated. RESULTS: This chemoimmunotherapy hydrogel with sustained-release character was proven to have significant effects on killing tumor cells and inhibiting tumor growth. Peritumoral injection of our hydrogel caused little harm to normal organs and triggered a potent antitumor immune response against both hepatocellular carcinoma and breast cancer. In the tumor microenvironment, enhanced immunogenic cell death induced by the combination of Nab-PTX and R837 resulted in 3.30-fold infiltration of effector memory T cells and upregulation of 20 biological processes related to immune responses. CONCLUSIONS: Our strategy provides a novel insight into the combination of chemotherapy and immunotherapy and has the potential for clinical translation.

A Thermosensitive Bi-Adjuvant Hydrogel Triggers Epitope Spreading to Promote the Anti-Tumor Efficacy of Frameshift Neoantigens.

Tumor-specific frameshift mutations encoding peptides (FSPs) are highly immunogenic neoantigens for personalized cancer immunotherapy, while their clinical efficacy is limited by immunosuppressive tumor microenvironment (TME) and self-tolerance. Here, a thermosensitive hydrogel (FSP-RZ-BPH) delivering dual adjuvants R848 (TLR7/8 agonist) + Zn2+ (cGAS-STING agonist) is designed to promote the efficacy of FSPs on murine forestomach cancer (MFC). After peritumoral injection, FSP-RZ-BPH behaves as pH-responsive sustained drug release at sites near the tumor to effectively transform the immunosuppressive TME into an inflammatory type. FSP-RZ-BPH orchestrates innate and adaptive immunity to activate dendritic cells in tumor-draining lymph nodes and increase the number of FSPs-reactive effector memory T cells (TEM) in tumor by 2.9 folds. More importantly, these TEM also exhibit memory responses to nonvaccinated neoantigens on MFC. This epitope spreading effect contributes to reduce self-tolerance to maintain long-lasting anti-tumor immunity. In MFC suppressive model, FSP-RZ-BPH achieves 84.8% tumor inhibition rate and prolongs the survival of tumor-bearing mice with 57.1% complete response rate. As a preventive tumor vaccine, FSP-RZ-BPH can also significantly delay tumor growth. Overall, the work identifies frameshift MFC neoantigens for the first time and demonstrates the thermosensitive bi-adjuvant hydrogel as an effective strategy to boost bystander anti-tumor responses of frameshift neoantigens.

Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer.

Background: Colorectal cancer (CRC) is a prevalent malignancy with diverse molecular characteristics. The NGS-based approach enhances our comprehension of genomic landscape of CRC and may guide future advancements in precision oncology for CRC patients. Method: In this research, we conducted an analysis using Next-Generation Sequencing (NGS) on samples collected from 111 individuals who had been diagnosed with CRC. We identified somatic and germline mutations and structural variants across the tumor genomes through comprehensive genomic profiling. Furthermore, we investigated the landscape of driver mutations and their potential clinical implications. Results: Our findings underscore the intricate heterogeneity of genetic alterations within CRC. Notably, BRAF, ARID2, KMT2C, and GNAQ were associated with CRC prognosis. Patients harboring BRAF, ARID2, or KMT2C mutations exhibited shorter progression-free survival (PFS), whereas those with BRAF, ARID2, or GNAQ mutations experienced worse overall survival (OS). We unveiled 80 co-occurring and three mutually exclusive significant gene pairs, enriched primarily in pathways such as TP53, HIPPO, RTK/RAS, NOTCH, WNT, TGF-Beta, MYC, and PI3K. Notably, co-mutations of BRAF/ALK, BRAF/NOTCH2, BRAF/CREBBP, and BRAF/FAT1 correlated with worse PFS. Furthermore, germline AR mutations were identified in 37 (33.33%) CRC patients, and carriers of these variants displayed diminished PFS and OS. Decreased AR protein expression was observed in cases with AR germline mutations. A four-gene mutation signature was established, incorporating the aforementioned prognostic genes, which emerged as an independent prognostic determinant in CRC via univariate and multivariate Cox regression analyses. Noteworthy BRAF and ARID2 protein expression decreases detected in patients with their respective mutations. Conclusion: The integration of our analyses furnishes crucial insights into CRC's molecular characteristics, drug responsiveness, and the construction of a four-gene mutation signature for predicting CRC prognosis.

The Comparison of Two Whole-Genome Amplification Approaches for Noninvasive Preimplantation Genetic Testing (ni-PGT) and the Application Scenario of ni-PGT during the Fresh Cycle.

Recently, noninvasive preimplantation genetic testing (ni-PGT) using degenerate oligonucleotide primer PCR (DOP-PCR) and multiple annealing and looping-based amplification cycle (MALBAC)-based whole-genome amplification (WGA) methods has demonstrated predictable results in embryo testing. However, a considerable heterogeneity of results has been reported in numerous studies on these two WGA methods. Our aim was to evaluate the current WGA method for ni-PGT while further clarifying the applicable scenarios of ni-PGT in the fresh cycle. A total of 173 embryos were tested with trophectoderm biopsy and ni-PGT. In the whole preimplantation genetic testing, the clinical concordance rates of the detection results of DOP-PCR and MALBAC with the corresponding trophectoderm biopsy results were 64.12% (84/131) and 68.99% (89/129), respectively (P = 0.405). However, in the detection of abnormal embryos, the detection efficiency of ni-PGT is significantly improved [MALBAC: 96.55% versus 68.99% (P < 0.001); and DOP-PCR: 89.09% versus 64.12% (P < 0.001)]. In addition, the diagnostic efficiency of ni-PGT in low-quality blastocysts was significantly higher than that in high-quality blastocysts [MALBAC: 95.24% versus 51.85% (P = 0.001); and DOP-PCR: 91.30% versus 48.15% (P = 0.001)]. These results contribute to further understanding ni-PGT and to clarifying its application scenario in the fresh cycle.

From micro to macro: The role of seawater in maintaining structural integrity and bioactivity of granules in treating antibiotic-laden mariculture wastewater.

Granular sludge (GS) has superior antibiotic removal ability to flocs, due to GS's layered structure and rich extracellular polymeric substances. However, prolonged exposure to antibiotics degrades the performance and stability of GS. This study investigated how a seawater matrix might help maintain the structural integrity and bioactivity of granules. The results demonstrated that GS had better sulfadiazine (SDZ) removal efficiency in a seawater matrix (85.6 %) than in a freshwater matrix (57.6 %); the multiple ions in seawater enhanced boundary layer diffusion (kiR1 = 0.0805 mg·g-1·min-1/2 and kiR2 = 0.1112 mg·g-1·min-1/2) and improved adsorption performance by 15 % (0.123 mg/g-SS freshwater vs. 0.141 mg/g-SS seawater). Moreover, multiple hydrogen bonds (1-3) formed between each SDZ and lipid bilayer fortified the adsorption. Beyond S-N and S-C bond hydrolyses that took place in freshwater systems, there was an additional biodegradation pathway for GS to be cultivated in a saltwater system that involved sulfur dioxide extrusion. This additional pathway was attributable to the greater microbial diversity and larger presence of sulfadiazine-degrading bacteria containing SadAC genes, such as Leucobacter and Arthrobacter, in saltwater wastewater. The findings of this study elucidate how seawater influences GS properties and antibiotic removal ability.

Urogenital tract and rectal microbiota composition and its influence on reproductive outcomes in infertile patients.

Introduction: Microbiota in the human body are closely related to human diseases. Female urogenital tract and rectal microbes have been considered as important factors affecting female pregnancy, but the mechanism is unknown. Methods: Cervical, vaginal, urethral, and rectal swabs were collected from 22 infertile patients and 10 controls, and follicular fluid was extracted from 22 infertile patients. The microbial composition of different sampling sites of infertile patients was examined. By comparing the microbial composition difference between infertile patients and controls and combining bioinformatics methods to analyze the potential impact of the female urogenital tract (cervical, vaginal and urethral) and rectal microbial diversity on female infertility and pregnancy outcomes. Results: Lactobacillus predominated in the female urogenital tract, but its abundance decreased in infertile patients, whereas the abundance of Gardnerella and Atopobium increased. The microbial changes in the urethra had the same trend as that in the vagina. Compared with healthy controls, the cervical and rectal microbial diversity of infertile patients were significantly increased and decreased, respectively. There might be interactions between microbes in different parts of female. Geobacillus thermogeniticans was enriched in the urogenital tract and rectum of infertile patients, and has a good predictive effect on infertility. Compared with infertile patients, L. johnsonii was enriched in the vagina, urethra, and intestine of the control group. L. acidophilus in follicular fluid might be associated with Non-pregnancy. Conclusion: This study found that the microbial composition of infertile patients was changed compared with that of healthy people. The translocation of Lactobacillus between the rectum and urogenital tract might play a protective barrier role. The changes of Lactobacillus and Geobacillus might be related to female infertility or pregnancy outcome. The study provided a theoretical basis for the future treatment of female infertility from the perspective of microorganisms by detecting the microbial changes associated with female infertility.

Achieving tetracycline removal enhancement with granules in marine matrices: Performance, adaptation, and mechanism studies.

Using the aerobic granular sludge (AGS) to improve tetracycline (TET) removal in the treatment of mariculture wastewater was investigated in the present study. The AGS rapidly adapted to and was sustained in seawater matrices with a robust granule strength (k = 0.0014) and a more stable sludge yield than the activated sludge (AS) (0.14 vs 0.11 g-VSS/g-CODrem). The compact structure provided the AGS with an anoxic environment, which favored the growth of N (37.3 %) and P removal bacteria (30.4 %) and the expression of functional genes (nos, nor, and nar), resulting in more than 62 % TN and TP removals, respectively. Similar abundances of aromatic compound-degrading bacteria (∼34 %) in both reactors (AGS and AS) led to comparable TET biodegradation efficiencies (∼0.045 mg/g-VSS). The greater size and surface area of the AGS expanded the boundary layer diffusion region, leading to 16 % increases in the granule's TET adsorption capacity.

Incorporation of liver chemistry score in predicting survival of liver-involved advanced gastric cancer patients who received palliative chemotherapy.

BACKGROUND: Gastric cancer liver metastasis (GCLM) patients usually accompany by abnormal serum liver function tests (LFTs) more or less; however, the prognostic value of LFTs is not fully understood. This study aimed to develop a liver chemistry score (LCS) based on LFTs and incorporate it into prognosis determination for GCLM patients who received palliative chemotherapy. METHODS: Data were derived from hospitalized GCLM patients in two general hospitals in China. LCS was generated based on the results of LFTs by LASSO regression. Cutoff value of the score was determined by restricted cubic spline. The score was then incorporated into Cox regression analysis to construct a predictive nomogram; the model was then evaluated internally and externally by AUC of time-dependent receiver operating characteristic curves (ROC) and calibration curves. RESULTS: Three hundred and thirty-six and 72 patients were included in development and validation cohort, respectively. LASSO regression analysis in development cohort finally reached a two-parametric LCS calculated on AST and ALP levels as 0.03343515 × ln (AST, U/L) + 0.02687997 × ln (ALP, U/L), and 0.232 was set as optimal cutoff value. Patients in low (LCS < 0.232) or high (LCS ≥ 0.232) score group experienced different survival times; median OS was 13.54 (95% CI: 11.1-15.6) months in the low LCS group and 7.3 (6.6-9.3) months in the high LCS group (p < 0.001). A nomogram including LCS and other clinical parameters was constructed and showed superior performance than model not including LCS. AUC of 6-month ROC improved from 0.647 (95% CI: 0.584-0.711) to 0.699 (0.638-0.759) in internal validation, and 0.837 (0.734-0.940) to 0.875 (0.784-0.966) in external validation. CONCLUSIONS: Liver chemistry score is useful in determining the prognosis of gastric cancer patients with liver metastasis and may be helpful to clinicians in decision-making.

Microbiological composition of follicular fluid in patients undergoing IVF and its association with infertility.

PROBLEM: In recent years, the incidence of female infertility has risen sharply, which is affected by many factors. It was recognized that female reproductive tract microbes play a role in the process of female conception. If the reproductive tract microbes could solve a certain proportion of infertility, it would certainly reduce the pain and economic burden of many patients. The objective of this study was to investigate the microbial community composition of follicular fluid in infertile patients and its potential impact on infertility. METHOD OF STUDY: Follicular fluid from 49 primary infertility and 52 secondary infertility patients was collected by a negative pressure needle, and the microbiota was analyzed by 16S rDNA sequencing. RESULTS: It was found that Lactobacillus, especially L. crispatus, might have a positive effect on female pregnancy. Considering the presence or absence of male factors and different body mass indices, L. iners might inhibit female pregnancy. However, L. iners seemed to play a positive role in egg maturation, while Gardnerella and Cutibacterium acnes might have a negative effect on female pregnancy. CONCLUSIONS: This study suggested the potential role of Lactobacillus in follicular fluid in improving female infertility and provided a theoretical basis for the future microbiological treatment of female infertility.

Effectiveness of gastrodin for migraine: A meta-analysis.

Background: Gastrodia elata Blume (GEB), a traditional Chinese medicine, has been widely used to treat dizziness, numbness of limbs, and infantile convulsion, among other issues. Gastrodin is the main component of GEB. This meta-analysis aimed to evaluate the efficacy and safety of gastrodin in the treatment of migraine. Methods: Ten electronic databases, namely the Cochrane Library, Embase, EBSCO, PubMed, Web of Science, CENTRAL, CNKI (China National Knowledge Infrastructure), CBM (Chinese Biomedicine Database), WanFang, and VIP (Chinese Scientific Journals Database), were searched for randomized controlled trials (RCTs) of gastrodin for migraine published before September 2021. The data were analyzed by RevMan 5.3 software and evaluated by GRADEpro. Results: A total of 1,332 subjects were included in 16 RCTs. The meta-analysis showed that gastrodin was significantly effective in treating migraine (RR = 1.21, 95%CI = [1.17, 1.27]), reducing the pain degree (MD = -1.65, 95% CI = [-2.28, -1.02]), reducing the frequency of migraine attack (SMD = -2.77, 95% CI = [-3.92, -1.62]), shortening the duration of migraine attack (SMD = -1.64, 95% CI = [-2.35, -0.93]), and slowing average arterial cerebral blood flow velocity (SMD = -3.19, 95% CI = [-5.21, -1.17]), as well as being safe. Conclusions: This systematic review revealed gastrodin is effective and safe in the treatment of migraine. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=197094, identifier: CRD42020197094.

Removal of tetracycline by aerobic granular sludge from marine aquaculture wastewater: A molecular dynamics investigation.

Although biological treatment of marine aquaculture wastewater is promising, the fundamental principles driving the adsorption of tetracycline to microbial cell membrane are not well understood. Using a combination of experiments and molecular dynamics (MD) simulations, the mechanism underlying the biological removal of tetracycline from seawater was investigated. More than 90% tetracycline removal was achieved in an aerobic granular sludge system, with degradation accounting for 30% of total removal. A model of the tetracycline-dipalmitoylphosphatidylcholine lipid bilayers was established to elucidate the transport mechanism of tetracycline from bulk solution to microorganisms' cell membrane. 62% of the driving force for tetracycline adsorption on the cell membrane originated from electrostatic attraction. The electrophilic groups on tetracycline (amino and aromatic groups) were attracted to the phosphate groups in the cell membrane. Sodium ions, which are abundant in seawater, decreased the interaction energy between tetracycline and the cell membrane.

Prognosis prediction of stage IV colorectal cancer patients by mRNA transcriptional profile.

BACKGROUND: Stage IV colorectal cancer patients with liver metastasis represent a special group of CRC patients with poor prognosis. The prognostic factors have not been investigated for stage IV CRC patients undergoing primary cancer resection but not candidates for metastasis resection. METHODS: Ninety-nine stage IV CRC patients who underwent primary cancer resection without metastasis resection were retrospectively recruited. Both whole-exome sequencing (WES) and RNA-seq were performed with frozen primary cancer tissues, using para-cancerous normal tissues as the control. Valid data were obtained from 78 patients for WES and 84 patients for RNA-seq. Univariate, multivariate Cox analyses were performed and Nomogram model was established to predict patient prognosis. RESULTS: The correlation between patient prognosis and clinicopathological factors, mutational status, or mRNA level changes was examined. Univariate (p = 0.0007) and subsequent multivariate analyses on clinicopathological factors showed that location (left or right) was the only independent risk factor for patient prognosis (HR = 3.63; 95% CI: 1.56-8.40, p = 0.003), while T, N, M staging, gender, race, location (rectum or colon), and pathological types were not stratifying factors. The mutational status of APC, TP53, KRAS, TTN, SYNE1, SMAD4, PIK3CA, RYR2, and BRAF did not show significant stratification in patient prognosis. RNA-seq showed that genes related to membrane function, ion channels, transporters, or receptors were among those with significant mRNA level alterations. Univariate analysis identified 97 genes with significantly altered mRNA levels, while NEUROD1, FGF18, SFTA2, PLAC1, SAA2, DSCAML1, and OTOP3 were significant in multivariate analysis. A risk model was established to stratify the prognosis of stage IV CRC patients. A Nomogram model was established with these genes to predict individual patient prognosis. CONCLUSIONS: A panel of eight genes with significant mRNA level alterations was capable of predicting the prognosis and risk of the specific patient group. Future prospective study is needed to validate the model.

Effect of Vitamin D Supplementation on In Vitro Fertilization Outcomes: A Trial Sequential Meta-Analysis of 5 Randomized Controlled Trials.

Despite numerous studies indicating an imperative role of vitamin D for reproduction, the importance of vitamin D supplementation on in vitro fertilization (IVF) outcomes remains controversial. We therefore performed this meta-analysis to investigate the IVF outcomes of vitamin D supplementation in infertile women with vitamin D deficiency. We systematically searched PubMed, Embase and the Cochrane library for identifying all relevant studies published before August 2021. Pregnancy rate was defined as the primary outcome while good quality embryo, fertilization rate, ongoing pregnancy, and miscarriage were secondary outcomes. We used Review Manager 5.3 (RevMan) to conduct meta-analysis and examined the robustness of the primary outcome by trial sequential analysis. Five studies were included in the final analysis and it suggested that vitamin D supplementation was associated with improved chemical pregnancy rate (risk ratio [RR] = 1.53, 95% confidence interval [CI] = 1.06 to 2.20, p = 0.02) but not benefited in improving clinical pregnancy rate (RR = 1.34, 95% CI = 0.81 to 2.24, p = 0.25) and all secondary outcomes. Trial sequential analysis suggested further studies are needed to confirm this conclusion. We concluded that vitamin D supplementation should be prescribed to improve chemical pregnancy in infertile women with vitamin D deficiency and more studies are required to further confirm this finding.

Detection of magneto-optical Kerr signals via weak measurement with frequency pointer.

Detection of the magneto-optical Kerr effect with high precision is of great significance but has challenges in the field of magnetic physics and spintronic devices. Kerr rotation angle and Kerr ellipticity always coexist and are difficult to distinguish, which jointly determines the light intensity received by the detector and limits the improvement of measurement precision. In this Letter, a nonlinear weak measurement scheme for magneto-optical Kerr signals with a frequency pointer is proposed. The Kerr rotation and Kerr ellipticity can be separately detected by constructing different pre-selections and choosing the appropriate coupling strength. Moreover, two signals obtained through the weak measurement scheme have higher precision and signal-to-noise ratio compared with the standard polarimetry scheme. Our method may have important applications in the field of magneto-optic parameters measurement or magnetic sensors.

Associations between respiratory and vascular function in early childhood.

BACKGROUND AND OBJECTIVE: The link between respiratory and vascular health is well documented in adult populations. Impaired lung function is consistently associated with thicker arteries and higher incidence of cardiovascular disease. However, there are limited data on this relationship in young children and the studies that exist have focussed on populations at high risk of cardiorespiratory morbidity. We determined if an association exists between respiratory and cardiovascular function in young children and, if so, whether it is confounded by known cardiorespiratory risk factors. METHODS: Respiratory and vascular data from a prospective cohort study established to evaluate the health implications 3 years after coal mine fire smoke exposure in children aged 3-5 years were used. Respiratory function was measured using the forced oscillation technique and included resistance at 5 Hz (R5 ), reactance at 5 Hz (X5 ) and area under the reactance curve (AX). Vascular health was measured by carotid intima-media thickness (ultrasound) and pulse wave velocity (arterial tonometry). Regression analyses were used to examine the relationship between the respiratory Z-scores and cardiovascular measures. Subsequent analyses were adjusted for potential confounding by maternal smoking during pregnancy, maternal education and exposure to fine particulate matter <2.5 µm in aerodynamic diameter (PM2.5 ). RESULTS: Peripheral lung function (X5 and AX), but not respiratory system resistance (R5 ), was associated with vascular function. Adjustment for maternal smoking, maternal education and early life exposure to PM2.5 had minimal effect on these associations. CONCLUSION: These observations suggest that peripheral lung stiffness is associated with vascular stiffness and that this relationship is established early in life.

Early life exposure to coal mine fire smoke emissions and altered lung function in young children.

BACKGROUND AND OBJECTIVE: Long-term respiratory risks following exposure to relatively short periods of poor air quality early in life are unknown. We aimed to evaluate the association between exposure to a 6-week episode of air pollution from a coal mine fire in children aged <2 years, and their lung function 3 years after the fire. METHODS: We conducted a prospective cohort study. Individual exposure to 24-h average and peak concentrations of particulate matter with an aerodynamic diameter <2.5 µm in diameter (PM2.5 ) during the fire were estimated using dispersion and chemical transport modelling. Lung function was measured using the forced oscillation technique (FOT), generating standardized Z-scores for resistance and reactance at a frequency of 5 Hz (Rrs5 and Xrs5 ), and area under the reactance curve (AX). We used linear regression models to assess the associations between PM2.5 exposure and lung function, adjusted for potential confounders. RESULTS: Of the 203 infants originally recruited, 84 aged 4.3 ± 0.5 years completed FOT testing. Median (interquartile range, IQR) for average and peak PM2.5 were 7.9 (6.8-16.8) and 103.4 (60.6-150.7) µg/m3 , respectively. The mean ± SD Z-scores for Rrs5 , Xrs5 and AX were 0.56 ± 0.80, -0.76 ± 0.88 and 0.72 ± 0.92, respectively. After adjustment for potential confounders including maternal smoking during pregnancy, a 10 µg/m3 increase in average PM2.5 was significantly associated with worsening AX (ß-coefficient: 0.260; 95% CI: 0.019, 0.502), while the association between a 100-µg/m3 increase in peak PM2.5 and AX was borderline (0.166; 95% CI: -0.002, 0.334). CONCLUSION: Infant exposure to coal mine fire emissions could be associated with long-term impairment of lung reactance.

Exposure to air pollution during the first 1000 days of life and subsequent health service and medication usage in children.

BACKGROUND: Evidence of health effects following early life exposure to short-to-medium duration of high pollution levels is extremely limited. OBJECTIVES: We aimed to evaluate the associations between: 1. intrauterine exposure to fine particulate matter (PM2.5) from coal mine fire emissions and the frequencies of general practitioner attendances and dispensations of prescribed asthma inhalers, steroid skin creams, and antibiotics during the first year of life; 2. infant exposure and those outcomes during the year following the fire. METHODS: All participants were recruited from the Latrobe Valley of Victoria, Australia. Participants' 24-h average and hourly peak mine fire-specific PM2.5 exposures from 09/02/2014 to 31/03/2014 were estimated using chemical transport modelling. Outcome data were obtained from the Australian Medicare Benefits Schedule and Pharmaceutical Benefits Scheme from each child's birth to 31/12/2016. We used negative binomial and logistic regression models to independently assess risks of the outcomes associated with every 10 and 100 µg m-3 increase in average or peak PM2.5 exposure, respectively, while adjusting for potential confounders. RESULTS: We included 286 of 311 children whose parents consented to be linked, comprising 77 with no exposure, 88 with intrauterine exposure and 121 with exposure in infancy. 10- and 100- µg m-3 increases in average and peak PM2.5 exposure during infancy were associated with greater incidence of antibiotics being dispensed during the year following the fire: the adjusted incidence rate ratios were 1.24 (95% CI 1.02, 1.50, p = 0.036) and 1.14 (1.00, 1.31, p = 0.048) respectively. No other significant associations were observed. CONCLUSION: Exposure to coal mine fire emissions during infancy was associated with increased dispensing of antibiotics. This could reflect increased childhood infections or increased prescriptions of antibiotics in the year following the fire.

Gene-based association analysis of survival traits via functional regression-based mixed effect cox models for related samples.

The importance to integrate survival analysis into genetics and genomics is widely recognized, but only a small number of statisticians have produced relevant work toward this study direction. For unrelated population data, functional regression (FR) models have been developed to test for association between a quantitative/dichotomous/survival trait and genetic variants in a gene region. In major gene association analysis, these models have higher power than sequence kernel association tests. In this paper, we extend this approach to analyze censored traits for family data or related samples using FR based mixed effect Cox models (FamCoxME). The FamCoxME model effect of major gene as fixed mean via functional data analysis techniques, the local gene or polygene variations or both as random, and the correlation of pedigree members by kinship coefficients or genetic relationship matrix or both. The association between the censored trait and the major gene is tested by likelihood ratio tests (FamCoxME FR LRT). Simulation results indicate that the LRT control the type I error rates accurately/conservatively and have good power levels when both local gene or polygene variations are modeled. The proposed methods were applied to analyze a breast cancer data set from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). The FamCoxME provides a new tool for gene-based analysis of family-based studies or related samples.

Long-term impacts of prenatal and infant exposure to fine particulate matter on wheezing and asthma: A systematic review and meta-analysis.

This systematic review aimed to summarize epidemiologic evidence regarding long-term effects of prenatal and infant particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5) exposure on wheezing and asthma. METHODS: Epidemiologic data investigating the associations between ambient PM2.5 exposures during prenatal or the first 2 years of life and wheezing or asthma throughout life were extracted from five databases. All included studies were assessed according to the Critical Appraisal Skills Programme checklists. We performed meta-analyses if ≥2 studies estimated the effects of continuous PM2.5. RESULTS: Nine of 18 eligible studies were suitable for meta-analyses. For prenatal PM2.5 exposure and asthma by 10 years of age (n = 4), the overall risk estimate per 10-unit increase (95% confidence interval) was 1.12 (1.00, 1.26). Although meta-analysis of prenatal exposure and wheezing by 4 years of age (n = 5) was not possible due to inconsistent exposure and outcome assessments, four studies found strong positive associations with wheeze by 2 years of age. The overall risk of developing asthma (n = 5) and wheezing (n = 3) by 8 years of age for infant PM2.5 exposure was 1.14 (0.96, 1.35) and 1.49 (0.99, 2.26), respectively. One large high-quality study reporting risk differences not suitable for meta-analysis demonstrated significant associations between prenatal or infant PM2.5 exposure and childhood asthma. High heterogeneity was present among studies of prenatal exposures and asthma, whereas studies of other associations showed low heterogeneity. There was insufficient evidence about susceptible subgroups. CONCLUSIONS: The limited and inconsistent evidence is suggestive of an association between early life PM2.5 exposure and wheezing/asthma. Large standardized studies are needed to explore the associations and identify vulnerable populations.