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BackgroundNovel β-lactam antibiotics as well as other kinds of antibiotics have been used to treat complicated urinary tract infections (cUTIs); however, their efficacy and safety remain controversial.ObjectiveWe conducted a systematic review with meta-analysis to explore the efficacy and safety of novel β-lactam antibiotics versus other antibiotics against cUTIs.MethodsPubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched systematically from inception through 15 March 2024 for clinical trials comparing novel β-lactam antibiotics with other antibiotics for treatment of cUTIs. Random-effects models were used to evaluate the impact of treatment on the risk ratio (RR) of clinical response, microbiologic response, adverse effects (AEs), serious adverse effects (SAEs). The quality of evidence was evaluated with the Cochrane Risk of Bias assessment tool. The review was registered in INPLASY (INPLASY202440054).ResultsTen randomized controlled trials involving 5, 925 patients met our inclusion criteria. Our meta-analysis revealed that there was no significant difference in overall clinical response (RR = 1.02), AEs (RR = 1.07), SAEs (RR = 1.20) between novel β-lactam antibiotics groups and other antibiotics groups. However, a significant difference was found in a subgroup of clinical cure rates at the end of treatment between novel β-lactam antibiotics groups and carbapenems groups, with low heterogeneity (RR = 1.02). A significant difference was observed in microbiologic response (RR = 1.11). Subgroup analysis revealed a significant difference in microbiologic response between novel BBL/BLS groups and carbapenems groups (RR = 1.13, I2 = 21%, P = 0.005). Differences was observed between novel BBL/BLS groups and piperacillin/tazobactam sodium groups (RR = 1.21, I2 = 70%, P = 0.02). Similar results were obtained from subgroup analysis of the difference in microbiologic response between novel β-lactam antibiotics groups and ertapenem groups (RR = 0.92, I2 = 0, P = 0.01).ConclusionNovel β-lactam antibiotics had similar overall clinical cure, AEs, SAE, to other antibiotics in the treatment of cUTIs. However, novel β-lactam antibiotics demonstrated superior clinical cure rates compared to carbapenems in a subgroup analysis, and exhibited better microbiologic response than other antibiotics.

Using object-based deep learning for the urban land cover classification has become a mainstream method. This study proposed an urban land cover classification method based on segments’ object features, deep features, and spatial association features. The proposed method used the synthetic semivariance function to determine the hyperparameters of the superpixel segmentation and subsequently optimized the image superpixel segmentation result. A convolutional neural network and a graph convolutional neural network were used to obtain segments’ deep features and spatial association features, respectively. The random forest algorithm was used to classify segments based on the multidimension features. The results showed that the image superpixel segmentation results had the significant impact on the classification results. Compared with the pixel-based method, the segment-based methods generally yielded the higher classification accuracy. The strategy of multidimension feature fusion can combine the advantages of each single-dimension feature to improve the classification accuracy. The proposed method utilizing multidimension features was more efficient than traditional methods used for the urban land cover classification. The fusion of segments’ object features, deep features, and spatial association features was the best solution for achieving the urban land cover classification.

Abstract Background Presently, global aging has become increasingly serious, whereas the health concerns brought by aging have become a public issue that warrants an urgent solution from all countries across the world. Therefore, this research paper discusses the influence of neighborhood health on elderly individuals’ health, and extending a realistic basis for the other economies to improve the neighborhood environment and promote the health of the elderly. Methods Based on the data of CHARLS2018, this research paper adopts the samples that fulfill the study requirements (N = 7326). we constructed a comprehensive research framework integrating oprobit regression model, heterogeneity analysis, conditional mixed process(CMP)robustness testing, Furthermore, the KHB decomposition method is implemented to ascertain the influential mechanism of NMH and NPH on the mental- and physical health of elderly persons. Results The oprobit regression model analysis indicates that NMH 0.434 and NPH 0.550 exert positive influences on the elderly’s mental- and physical health. Meanwhile, the effects of conditional mixed process on NMH and NPH stand at 0.381 and4.372, which are different from the oprobit regression results; thereby, indicating the existence of endogeneity. Afterward, KHB mediating effect confirms that Internet use, gift reciprocity, and charity activity contribute 30.21% and 16.83% to mental- and physical health, respectively. Conclusions Firstly, the NMH and NPH demonstrate a positive influence on the mental- and physical health of the elder population. However, there exist heterogeneous differences. Secondly, the conditional mixed process deals with the endogeneity of NMH and NPH. Thirdly, social integration, social interaction, and social engagement serve as significant transmission mechanisms for the influences of NMH and NPH on the health of elderly persons.

Background: Carbapenems and β-lactam and β‐lactamase inhibitors (BLBLIs) have been used empirically in nosocomial pneumonia, but their efficacy and safety are controversial. Objective: We carried out a systematic review with meta-analysis to evaluate the efficacy and safety of carbapenems versus BLBLIs against nosocomial pneumonia. Methods: PubMed, Embase, Cochrane Central Register of Controlled Trials, CNKI, Wangfang, VIP and Sinomed were searched systematically through April 29, 2023 for clinical trials comparing carbapenems with BLBLIs for treatment of nosocomial pneumonia. Random-effects models were used to evaluate the impact of treatment on the risk ratio (RR) of all-cause mortality, clinical response, microbiologic response, resistance by Pseudomonas aeruginosa, adverse effects (AEs), and serious adverse effects. The quality of the evidence was assessed with the Cochrane risk of bias tool. The review was registerted in the INPLASY (INPLASY202340113). Results: Seven randomized controlled trials containing 3306 patients met our inclusion criteria Our meta-analysis showed no significant difference in all-cause mortality (RR = 0.88, 95% confidence interval [CI] = 0.75–1.03, I2 = 0%) or clinical cure (1.02, 0.96–1.09, 30%) or clinical failure (1.19, 0.97–1.47, 0%) or microbiologic clinical cure (0.98, 0.89–1.06, 40%) or Pseudomonas aeruginosa resistance (RR 2.43, CI 0.86–6.81, 49%, P = 0.09) or adverse events (0.98, 0.93–1.02, 0%) between carbapenems groups versus BLBLIs groups, but a significant difference was found for severe adverse events (RR 0.83, CI 0.73−0.94, 0%). Conclusion: Differences in the prevalence of mortality, clinical cure, or clinical failure were not observed between carbapenems groups versus BLBLIs groups in terms of nosocomial pneumonia. The use of carbapenems was linked to a tendency towards the emergence of P. aeruginosa resistance, however, no statistically significant difference was observed.

Abstract Background Immune responses, especially type 2 immunity, might be related to the prevalence of thyroid nodules, while the key regulators and potential pathways are remaining largely unknown. In addition, the immune status of individuals could be affected by mixed metabolic background. Herein our aim was to investigate the adjusted association between ultrasound-diagnosed low risk thyroid nodules and immune responses, excluding the interference of metabolic effects on immunity. Methods We retrospectively enrolled 1764 subjects who underwent a thorough thyroid ultrasound examination. To eliminate the interference of confounders, we used propensity score matching (PSM) to match age, gender, cigarette smoking and alcohol drinking, parameters that are related with metabolic syndrome (MetS). Then the potential effectors of immune responses involved in the laboratorial assays were evaluated. Binary logistic regression analysis was used to assess the independent predictors of thyroid nodules in a multivariate manner. Results The 1172 subjects were remained after PSM, and differences of demographic background between subjects with and without thyroid nodules were eliminated. Metabolic parameters comprising blood pressure, fasting blood glucose, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein and serum uric acid were shown no significant difference between post-PSM subjects with and without thyroid nodules. Among the biochemistry and hematological parameters, white blood cell count and the positive rate of eosinophil percentage were increased in subjects with thyroid nodules than in those without thyroid nodules. In contrast, the positive rate of basophil percentage was lower in subjects with thyroid nodules than in those without thyroid nodules. In addition, the thyroid function test results showed that subjects with thyroid nodules had higher positive rates of antithyroglobulin antibody (TgAb) and antithyroid peroxidase antibody (TPOAb) than subjects without thyroid nodules. The logistic regression analysis indicated that the positive value of TgAb as well as high level of white blood cell count and BMI could serve as independent risk factors of thyroid nodules. Conclusions The type 2 immune responses mediated by increased level of eosinophils, along with positive value of TgAb and TPOAb were associated with the presence of thyroid nodules. In addition, the potential role of basophils in protecting against thyroid nodules and the pathogenesis of immune-metabolic status remains to be elucidated.

Basu Jayati et al. examine how T-cell receptor (TCR) engagement with MHC ligands can contribute toward adoption of CD4 and CD8 cell fates during development. By using an in vivo mutagenesis approach in mice, their results suggest potential mechanisms linking TCR signaling to ThPOK expression and differential immune lineage choice.

PurposeThis study aimed to evaluate the effectiveness of smartphone otoscope telemedicine in the rural medical consortium in East China in the COVID-19 era.MethodsThis prospective study was conducted within a rural medical consortium that provides health care services by integrating medical resources in the same area. When a patient visited primary health care (PHC) for ear diseases, the PHC provider used a smartphone otoscope to examine the patient's external ear canal and eardrum, and then sent photos or videos of the patient's ear to the otolaryngologist at the lead hospital via WeChat group. The otolaryngologist provided remote diagnosis and management recommendations to the PHC provider. The following data were recorded: age and gender, outpatient diagnosis, disease duration, sides, duration of treatment, telemedicine visits, treatment outcomes, patient satisfaction, and PHC providers' self-evaluation score.ResultsA total of 83 patients were included in the study, including 43 males and 40 females, with a mean age of 44.6 ± 19.7 years (range 3–83 years). The duration of treatment for these patients was 14.0 (7,14) days. PHC visits were 2.2 ± 1.1 times (range: 1–7 times). Telemedicine visits ranged from 1 to 5, with a mean of 1.8 ± 0.9. Among of patients, 62 (74.7%) were cured, 21 (25.3%) improved, and 0 (0%) were ineffective. Sixty-five patients (78.3%) were very satisfied, 16 (19.3%) patients were somewhat satisfied, and two patients (2.4%) were dissatisfied. Based on the self-reported helpfulness, the primary health care providers assessed telemedicine as very helpful (n = 63, 75.9%), helpful (n = 20, 24.1%), and unhelpful (n = 0, 0%).ConclusionsSmartphone otoscope telemedicine in the medical consortium can effectively improve the ability of rural PHC providers to diagnose and treat ear diseases, save time and costs for patients, and improve patient satisfaction.

In China, Budd-Chiari syndrome has been transliterated into six names according to the pronunciation of the letters. To standardize and unify the Chinese names of the disease, multi-disciplinary experts suggest translating Budd-Chiari syndrome into hepatic vein inferior venal cava obstruction syndrome as its Chinese name after reaching a consensus through discussion.

ObjectivesTo assess the potential of a radiomics approach of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) in the diagnosis of cardiac amyloidosis (CA).Materials and MethodsThis retrospective study included 200 patients with biopsy-proven light-chain (AL) amyloidosis. CA was diagnosed on the basis of systemic amyloidosis confirmed with evidence of cardiac involvement by imaging and clinical biomarkers. A total of 139 patients [54 ± 8 years, 75 (54%) men] in our institution were divided into training cohort [n = 97, mean age of 53 ± 8 years, 54 (56%) men] and internal validation cohort [n = 42, mean age: 56 ± 8 years, 21 (50%) men] with a ratio of 7:3, while 61 patients [mean age: 60 ± 9 years, 42 (69%) men] from the other two institutions were enrolled for external validation. Radiomics features were extracted from global (all short-axis images from base-to-apex) left ventricular (LV) myocardium and three different segments (basal, midventricular, and apex) on short-axis LGE images using the phase-sensitive reconstruction (PSIR) sequence. The Boruta algorithm was used to select the radiomics features. This model was built using the XGBoost algorithm. The two readers performed qualitative and semiquantitative assessment of the LGE images based on the visual LGE patterns, while the quantitative assessment was measured using a dedicated semi-automatic CMR software. The diagnostic performance of the radiomics and other qualitative and quantitative parameters were compared by a receiver operating characteristic (ROC) curve analysis. A correlation between radiomics and the degree of myocardial involvement by amyloidosis was tested.ResultsA total of 1,906 radiomics features were extracted for each LV section. No statistical significance was indicated between any two slices for diagnosing CA, and the highest area under the curve (AUC) was found in basal section {0.92 [95% confidence interval (CI), 0.86–0.97] in the LGE images in the training set, 0.89 (95% CI, 0.79–1.00) in the internal validation set, and 0.92 (95% CI, 0.85–0.99) in the external validation set}, which was superior to the visual assessment and quantitative LGE parameters. Moderate correlations between global or basal radiomics scores (Rad-scores) and Mayo stage in all patients were reported (Spearman’s Rho = 0.61, 0.62; all p < 0.01).ConclusionA radiomics analysis of the LGE images provides incremental information compared with the visual assessment and quantitative parameters on CMR to diagnose CA. Radiomics was moderately correlated with the severity of CA. Further studies are needed to assess the prognostic significance of radiomics in patients with CA.

Abstract: The aim is to study the immune function effect of two polysaccharides extracted from traditional Chinese herbs on rats. Ultrasonic-assisted extraction was used to extract the polysaccharide from traditional Chinese medicines. MTT assay was used to determine the effects of two polysaccharides on the conversion of pig peripheral T lymphocytes. For this, 24 Sprague–Dawley rats were selected for the clinical trial and divided into groups B (blank), CK (cyclophosphamide inhibitory control), AP (angelica polysaccharide), and RIP (radix isatidis polysaccharide). Except for group B, other groups can induce the immunodeficiency by using cyclophosphamide. Rats of the AP and RIP groups were given gavage of 1 mL of AP and RIP. The blood was sampled from the eyeball on days 0, 7, 14, 21, 28, and 35, respectively, to determine immune cells, IgG and IgM of immunoglobulin, body weight, and spleen index.Results: The average content of AP and RIP was 51.27 and 14.8%, and the extraction rate was 75.23 and 60.94%. The maximum stimulation index was 1.407 when the concentration of AP was 8,000 μg mL−1 and 1.5 when the concentration of RIP was 125 μg mL−1. Both kinds of polysaccharides can alleviate the decline of white blood cells, lymphocytes, monocytes, neutrophils, and serum IgG and IgM caused by cyclophosphamide. The two polysaccharides can regulate the rapid recovery of weight in immunosuppressed rats and increase the spleen index of immunosuppressed SD rats. The polysaccharides from the two traditional Chinese medicines can alleviate the immunosuppression caused by cyclophosphamide and promote the immune function of the body, which can be used as raw material resources of new veterinary medicine.

Background: Phthalates, which are used as excipients of drugs, have been related to adverse reproductive outcomes. However, the relationships between medication use and phthalate exposure among women undergoing in vitro fertilization (IVF) have not been studied. Objective: To investigate the associations between the medication intake and phthalate metabolites in urine and follicular fluid (FF). Method: Eight phthalate metabolites were measured in urine and FF samples from 274 women undergoing IVF using liquid chromatography-tandem mass spectrometry. Information on recent medication intake was obtained via interview by trained staff. We constructed generalized linear regression models to examine the associations of medication intake with phthalate metabolite concentrations and dose-response relationships between the number of medicines used and metabolite concentrations in two matrices. Results: Four of 10 drugs were used by more than 10% of the participants, including vitamins (23.0%), traditional Chinese medicine (TCM, 22.3%), antioxidants (12.4%) and amoxicillin (10.2%). Participants who had used TCM had 26.0% (95% CI: 0.0, 58.8%), 32.6% (95% CI: 4.2, 68.8%) and 32.3% (95% CI: 2.6, 70.6%) higher urinary mono-n-butyl phthalate (MBP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) concentrations, respectively, than those who had not. Antioxidant intake was associated with a 30.6% (95% CI: −48.5, −6.6%) decrease in the urinary MBP concentration. Compared with non-users, women who reported the use of medicines had 53.2% (95% CI: 2.7, 128.5%) higher concentrations of MMP and a 37.7% (95% CI: −60.7, −1.5%) lower level of MBP in FF, respectively. Conclusion: Our data suggest that the intake of some medications may increase phthalate exposure among women undergoing IVF.

In order to solve the back corona phenomenon caused by high specific resistance dust in electrostatic precipitation process, the circuit topology of DC base voltage superimposed pulse voltage is adopted. Firstly, for the DC base voltage part, a three-phase AC voltage regulator circuit and a subsequent filter circuit are established, and the average values generated by the circuit at different firing angles are analyzed. Secondly, in the pulse generation part, the LCC resonance is discussed according to the mathematical model. Finally, according to the design requirements, the whole circuit is simulated with Simulink module in MATLAB, and compared with the calculated data, it has a high consistency, which verifies the correctness of the design idea.

The R-spondin (RSPO) family of proteins potentiate canonical WNT/β-catenin signaling and may provide a mechanism to fine-tune the strength of canonical WNT signaling. Although several in vitro studies have clearly demonstrated the potentiation of canonical WNT signaling by RSPOs, whether this potentiation actually occurs in normal development and tissue function in vivo still remains poorly understood. Here, we provide clear evidence of the potentiation of canonical WNT signaling by RSPO during mouse facial development by analyzing compound Wnt9b and Rspo2 gene knockout mice and utilizing ex vivo facial explants. Wnt9b;Rspo2 double mutant mice display facial defects and dysregulated gene expression pattern that are significantly more severe than and different from those of Wnt9b or Rspo2 null mutant mice. Furthermore, we found suggestive evidence that the LGR4/5/6 family of the RSPO receptors may play less critical roles in WNT9b:RSPO2 cooperation. Our results suggest that RSPO-induced cooperation is a key mechanism for fine-tuning canonical WNT/β-catenin signaling in mouse facial development.

Abstract Background Phthalates, a class of endocrine disruptors, have been demonstrated to accelerate loss of ovarian follicle pool via disrupting folliculogenesis, and lead to diminished ovarian reserve. However, human data are limited. Here, we aimed to examine whether urinary phthalate metabolites are correlated with markers of ovarian reserve among women attending a fertility clinic. Methods We measured eight phthalate metabolites in urine samples collected from 415 women seeking infertility treatment at the Reproductive Medicine Center of Tongji Hospital, Wuhan, China. Data on measures of ovarian reserve, as indicated by serum anti-Müllerian hormone (AMH) and inhibin B (INHB) levels, were retrieved retrospectively through electronic medical charts. Multivariate linear models were performed to estimate the associations of urinary phthalate metabolites and serum AMH and INHB. We further explored the potential nonlinearity of the relationships with restricted cubic spline analysis. Results Overall, we found largely null associations between urinary phthalate metabolites and serum AMH. The multivariable adjusted differences in serum INHB levels comparing the highest quartile of urinary MEHP to the lowest were − 18.29% (95% CI: − 31.89%, − 1.98%; P-trend = 0.04). Women in the second to fourth quartiles of MEOHP had a significant decrease of − 23.74% (95% CI: −35.85%, − 9.24%), − 19.91% (95% CI: −33.30%, − 3.82%) and − 20.23% (95% CI: −34.43%, − 2.96%), respectively, in INHB levels compared to the first quartile. In the spline analysis, we identified a nonlinear relationship between MEOHP exposure and serum INHB. Conclusions We provided evidence for a negative association between urinary concentrations of certain phthalate metabolites and serum INHB levels, suggesting an adverse effect of phthalates exposure on growing antral follicles. Whether phthalates exposure at environmentally level will pose a risk for ovarian reserve needs further investigation.

Cassia mimosoides Linn has been used from ancient times and used for treating hepatitis for its supposedly medically beneficial properties. In this study, different constituents of the Cassia mimosoides Linn (β-Sitosterol, Oleanolic Acid, Emodin, Carotene, Resorcinol, Luteolin, and α-L-Rhamnose) were evaluated for potential anti-HMG-CoA reductase effect. The inhibitory effects of HMG-CoA reductase of Cassia mimosoides Linn extracts and Pravastatin inhibitor at different concentrations (at doses of 1, 5, 25 or 125 μg/mL, respectively) in reaction system (70 mmol/L phosphate buffer, 200mmol/L NADPH, 5 μg HMG-CoA reductase, 2 mmol/L EDTA, 2 mmol/L cysteamine, 0.06% BSA) into 37°C preheat HMG-CoA for initiating this reaction, and then determined the change of HMG-CoA reductase activity (ΔAΔt) at 340 nm, the inhibition ratio of HMG-CoA reductase activity and its dynamic change of inhibitory effect within 15 min and the descent rate of NADPH. Emodin, Luteolin, β-Sitosterol, Oleanolic Acid, α-L-Rhamnose and Carotene showed good inhibition of HMG-CoA reductase activity. Among them, only the Emodin (1 and 5 μg/mL) groups showed a significant decrease of HMG-CoA reductase activity compared to the Pravastatin (1 and 5 μg/mL) groups respectively. In addition, the HMG-CoA reductase activity in the Emodin and Luteolin (25 and 125 μg/mL) groups was clearly lower than the Pravastatin (25 and 125 μg/mL) groups respectively. And the Emodin and Luteolin (1, 5, 25 or 125 μg/mL) groups exhibited a stable effect on inhibiting the HMG-CoA reductase within 15 min. These findings further support the exploration of Cassia mimosoides Linn as a potential agent for the treatment of hepatitis in future studies.

A pterygium is generally believed to be a chronic inflammatory lesion caused by external stimuli that develops from the conjunctiva and grows onto the cornea. Simple bare sclera excision is the most commonly used method to treat pterygium. However, the high postoperative recurrence rate of pterygium remains a persistent challenge. Mitomycin C (MMC) is an antineoplastic antibiotic that inhibits DNA, RNA, and protein synthesis. In recent years, although MMC has proven useful for the treatment of pterygium, its application has been controversial because of its clear toxicity and the possibility of ocular complications. In the current study, we prospectively recruited patients to receive or not receive a local injection of MMC (0.4 mg/ml). Follow-up was conducted with the patients to determine the postoperative recurrence rate of pterygium and/or to observe any ocular complications. The remarkable results demonstrated that MMC can decrease the postoperative recurrence rate of pterygium without leading to serious eye complications. Further results indicated that MMC can inhibit the activation of the NLRP3 inflammatory signalling pathway and thus downregulate the expression of downstream molecules, including IL-18 and IL-1β. MMC also reduced the expression of inflammatory factors TGF-β1, VEGF, and IL-6. In addition to influencing these factors, MMC suppressed neovascularization and the proliferation of corneal fibroblasts to effectively reduce the recurrence rate of pterygium. Taken together, our results provide a theoretical basis for the development of prevention and treatment strategies for pterygium and suggest that MMC is highly effective as an adjunctive treatment after excision of primary pterygia.

Purpose: To enhance the awareness of rare complications of pelvic fracture and describe the correct diagnosis and effective treatment. Methods: A total of 188 cases of pelvic fractures were retrospectively reviewed, and four patients who suffered from four types of rare pelvic fracture complications were described, namely ureteral obstruction caused by retroperitoneal hematoma-induced abdominal compartment syndrome (ACS), bowel entrapment, external iliac artery injury, and open scrotal sac injury. Results: We demonstrated that combined measures should be employed to prevent the occurrence of ACS following major pelvic fractures. Ureteral catheter support may be a good option at an early stage when ACS occurred. Contrasted computed tomography examination and sufficient awareness are keys to a correct diagnosis of bowel entrapment following pelvic fractures. Recognition of risk factors, early diagnosis, and prompt treatment of suspected injury of the external iliac artery are keys to patient survival and to avoid limb loss. Scrotal and/or testicular injury complicated by pelvic fractures should be carefully treated to maintain normal gonad function. Additionally, establishment of a sophisticated trauma care system and multi-disciplinary coordination are important for correct diagnosis and treatment of rare complications in pelvic fractures. Conclusions: Rare complications of pelvic fractures are difficult to diagnose and negatively impact outcome. Recognition of risk factors and sufficient awareness are essential for correct diagnosis and prompt treatment.

Summary: BRCA1 functions in homologous recombination (HR) both up- and downstream of DNA end resection. However, in cells with 53BP1 gene knockout (KO), BRCA1 is dispensable for the initiation of resection, but whether BRCA1 activity is entirely redundant after end resection is unclear. Here, we found that 53bp1 KO rescued the embryonic viability of a Brca1ΔC/ΔC mouse model that harbors a stop codon in the coiled-coil domain. However, Brca1ΔC/ΔC;53bp1−/− mice were susceptible to tumor formation, lacked Rad51 foci, and were sensitive to PARP inhibitor (PARPi) treatment, indicative of suboptimal HR. Furthermore, BRCA1 mutant cancer cell lines were dependent on truncated BRCA1 proteins that retained the ability to interact with PALB2 for 53BP1 KO induced RAD51 foci and PARPi resistance. Our data suggest that the overall efficiency of 53BP1 loss of function induced HR may be BRCA1 mutation dependent. In the setting of 53BP1 KO, hypomorphic BRCA1 proteins are active downstream of end resection, promoting RAD51 loading and PARPi resistance. : Using a Brca1ΔC mouse model and a panel of BRCA1 mutant cancer cell lines, Nacson et al. show that 53BP1 loss of function induced homologous recombination and PARP inhibitor resistance is suboptimal in the absence of hypomorphic BRCA1 proteins that retain the coiled-coil domain and ability to interact with PALB2. Keywords: BRCA1, 53BP1, homologous recombination, PARP inhibitors, resistance

OBJECTIVE:Phosphatidylserine is exposed on apoptotic cells and is prone to oxidation (OxPS). Here we analyze the association of IgM antibodies against OxPS (anti-OxPS) with the risk of cardiovascular disease (CVD). METHODS:Among sixty-year olds from Stockholm County in Sweden, previously screened for cardiovascular risk factors (2039 men, 2193 women), there were 210 incident CVD-cases identified during a 5-year follow-up. Using a nested case-control design, 622 age- and sex-matched controls were selected. Odds ratios (OR) with 95% intervals (CI) were calculated by conditional logistic regression. IgM anti-OxPS was measured by ELISA. Phagocytosis of apoptotic Jurkat-cells by macrophages was studied by flow cytometry. RESULTS:Anti-OxPS levels were lower among cases (median (interquartile range): 80.7 (60.9-101.0 vs. 84.6 (65.8-109.6); p = 0.047); among men (76.6 (55.8-99.2) vs. 82.0 (63.1-105.1); p = 0.022) and among women 89.6 (72.3-110.1) vs. 89.8 (69.9-114.4); p = 0.79). After adjustment for smoking, BMI, diabetes mellitus type II, hypercholesterolaemia and hypertension, and dividing into quartiles, using the highest quartile (quartile 4) as reference, quartile 3 was associated with a OR of 1.74 (CI 1.08-2.81). Quartiles 2 and 1 had similar associations, the later reaching statistical significance. Among men associations were stronger whereas no significant associations were observed in women. The OR of MI/angina comparing quartile 3 with quartile 4 was 2.31 (CI 1.30-4.11). The OR for quartile 2 and 1, respectively, were similar as for quartile 3. Total IgM increased uptake of apoptotic cells, which was reversed if incubated with OxPS. CONCLUSIONS:IgM anti-OxPS is a novel potential protection marker for CVD, in particular in men. Increased phagocytosis of dying/dead cells could be one potential underlying mechanism.

Multiphase, compositional porous media flow models lead to the solution of highly heterogeneous systems of Partial Differential Equations (PDE). We focus on overlapping Schwarz type methods on parallel computers and on multiscale methods. We present a coarse space [Nataf F., Xiang H., Dolean V., Spillane N. (2011) SIAM J. Sci. Comput. 33, 4, 1623-1642] that is robust even when there are such heterogeneities. The two-level domain decomposition approach is compared to multiscale methods.

C9H12BrN3O3, monoclinic, P21/c, a = 12.0359(15) Å, b = 5.4815(6) Å, c = 20.1931(18) Å, β = 120.780(5)°, V = 1144.6(2) Å3, Z = 4, Rgt(F) = 0.0234, wRref(F2) = 0.0984, T = 298(2) K.