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Parameters of subpopulations can be more relevant than those of superpopulations. For example, a healthcare provider may be interested in the effect of a treatment plan for a specific subset of their patients; policymakers may be concerned with the impact of a policy in a particular state within a given population. In these cases, the focus is on a specific finite population, as opposed to an infinite superpopulation. Such a population can be characterized by fixing some attributes that are intrinsic to them, leaving unexplained variations like measurement error as random. Inference for a population with fixed attributes can then be modelled as inferring parameters of a conditional distribution. Accordingly, it is desirable that confidence intervals are conditionally valid for the realized population, instead of marginalizing over many possible draws of populations. We provide a statistical inference framework for parameters of finite populations with known attributes. Leveraging the attribute information, our estimators and confidence intervals closely target a specific finite population. When the data are from the population of interest, our confidence intervals attain asymptotic conditional validity, given the attributes, and are shorter than those for superpopulation inference. In addition, we develop procedures to infer parameters of new populations with differing covariate distributions; the confidence intervals are also conditionally valid for the new populations under mild conditions. Our methods extend to situations where the fixed information has a weaker structure or is only partially observed. We demonstrate the validity and applicability of our methods using simulated data and a real-word dataset for predicting car prices. [ABSTRACT FROM AUTHOR]

Background There is little information on the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients undergoing peritoneal dialysis (PD) complicated with hypertension or heart failure (HF). This study was designed to evaluate the pharmacokinetics and pharmacodynamics of SV in PD patients with complications of hypertension or HF. Methods This was an open-label and cross-sectional study investigating PD patients diagnosed with hypertension or New York Heart Association Class II–IV HF. The concentrations of valsartan, sacubitril and sacubitrilat (LBQ657) were measured by ultra-performance liquid chromatography tandem mass spectrometry in plasma, urine and peritoneal dialysate samples. Pharmacodynamics were evaluated by comparing changes in mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP), mean sitting heart rate, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). Results Forty patients with PD were enrolled including 27 (67.5%) patients with hypertension, 4 (10%) patients with HF and 9 (22.5%) patients with both hypertension and HF. This study included three treatment cohorts: 50 mg twice daily (BID), 100 mg once daily and 100 mg BID. The plasma maximum drug concentrations in the 100 mg BID group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for LBQ657. The 24-h recovery rate of LBQ657 was 3.77% in urine and 2.23% in peritoneal dialysate. After taking SV, msSBP and msDBP decreased by 19.25 ± 10.32 mmHg and 10.10 ± 8.00 mmHg from baseline, respectively. NT-proBNP decreased by 1436.50 (0.00–18 198.00) from baseline, while LVEF increased by 5.00 (–0.25 to 9.25) from baseline after SV treatment. Conclusions PD and residual renal function contributed only to a minor degree to the elimination of LBQ657. Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF. [ABSTRACT FROM AUTHOR]

Research has suggested that a rigid dichotomy between small and professional talk is misleading given the porous nature of 'types' of talk. Yet, other research considers this distinction helpful in understanding the functions of talk in situated contexts. This article contributes to this discussion by discussing one type of small talk—co-topical small talk (CST). Drawing from Hudak and Maynard's (2011) understanding of CST as talk that combines instrumental and small talk, we further discuss the bigness of such talk in holistic medical encounters. Specifically, we focus on the ambiguity embedded in participants' turns that allows the navigation of topics between the small/big talk distinctions. We use Conversation Analysis focusing on a routine traditional Chinese medicine doctor–patient encounter. Our data present a case where CST comfortably and appropriately emerges and develops into extensive troubles talk that forms the main activity in caring for older adults. We conclude that the smallness/bigness of talk is determined by the nature of the context and the relevancy of the topic to the encounter. [ABSTRACT FROM AUTHOR]

Objectives To determine whether music engagement influences middle-aged and older adults' performance on episodic memory tasks. Method Secondary data analysis of a sample (N = 4,592) of cognitively healthy adults from the 2016 Health and Retirement Study was used for this study. Multivariable regression models were used to analyze the cross-sectional differences in performance on tasks of episodic memory between participants who listened to music (n = 3,659) or sang or played an instrument (n = 989). Results On average, participants recalled 10.3 words out of a possible 20. Regression analyses showed that both listening to music and singing or playing an instrument were independently associated with significantly better episodic memory. Discussion The findings provide the first population-based evidence that music engagement is associated with better episodic memory among middle-aged and older adults. Future studies should examine whether the relationship between music engagement and episodic memory can be replicated in other populations and that the association persists in longitudinal studies. [ABSTRACT FROM AUTHOR]

Background Motoric Cognitive Risk (MCR) syndrome, a predementia syndrome characterized by cognitive complaints and slow gait, may have an underlying vascular etiology. Elevated blood levels of homocysteine, a known vascular risk factor, have been linked to physical and cognitive decline in older adults, though the relationship with MCR is unknown. We aimed to identify the association between homocysteine and MCR risk. Methods We examined the association between baseline homocysteine levels and incident MCR using Cox proportional hazard models in 1826 community-dwelling older adults (55% women) from 2 cohorts (Einstein Aging Study [EAS] and Quebec Longitudinal Study on Nutrition and Successful Aging [NuAge]). We calculated hazard ratios (HR) with 95% confidence intervals (CI), for each cohort as well as stratified by sex and vascular disease/risk factors. Results Median follow-up time was 2.2 years in EAS and 3.0 years in NuAge. Individuals with elevated baseline homocysteine levels (>14 µmol/L) had a significantly higher risk of incident MCR compared to those with normal levels in NuAge (HR 1.41, 95% CI: 1.01–1.97, p  = .04), after adjusting for covariates. Our exploratory stratified analyses found that these associations were significant only in men with vascular disease/risk factors. Conclusions Higher blood homocysteine levels are associated with an increased risk of developing MCR in older adults, particularly in men with vascular disease or vascular risk factors. [ABSTRACT FROM AUTHOR]

Aims Vascular calcification is highly prevalent in atherosclerosis, diabetes, and chronic kidney disease. It is associated with increased morbidity and mortality in patients with cardiovascular disease. Matrix metalloproteinase 3 (MMP-3), also known as stromelysin-1, is part of the large matrix metalloproteinase family. It can degrade extracellular matrix components of the arterial wall including elastin, which plays a central role in medial calcification. In this study, we sought to determine the role of MMP-3 in medial calcification. Methods and results We found that MMP-3 was increased in rodent models of medial calcification as well as in vascular smooth muscle cells (SMCs) cultured in a phosphate calcification medium. It was also highly expressed in calcified tibial arteries in patients with peripheral arterial disease (PAD). Knockdown and inhibition of MMP-3 suppressed phosphate-induced SMC osteogenic transformation and calcification, whereas the addition of a recombinant MMP-3 protein facilitated SMC calcification. In an ex vivo organ culture model and a rodent model of medial calcification induced by vitamin D3, we found that MMP-3 deficiency significantly suppressed medial calcification in the aorta. We further found that medial calcification and osteogenic transformation were significantly reduced in SMC-specific MMP-3-deficient mice, suggesting that MMP-3 in SMCs is an important factor in this process. Conclusion These findings suggest that MMP-3 expression in vascular SMCs is an important regulator of medial calcification and that targeting MMP-3 could provide a therapeutic strategy to reduce it and address its consequences in patients with PAD. [ABSTRACT FROM AUTHOR]

Vulnerability segmentation (VS), an important mechanism for protecting plants from drought, hypothesizes that the distal organs of a plant should be more susceptible to embolism than the basal organs. However, experimental studies testing the VS hypothesis for trees are limited and have reached inconsistent conclusions. Here, we tested the VS hypothesis with three angiosperms and four conifers co-existing in a temperate forest in northeastern China. The results showed that the difference in vulnerability to cavitation between leaves and branches (P 50leaf–branch) was positive for the conifers but negative for the angiosperms, implying that the conifers rather than the angiosperms exhibited VS. The conifers had lower leaf hydraulic safety margins and more embolism-resistant branches than the angiosperms. Although the angiosperms did not display VS, they took a hydraulic compensatory strategy (e.g. great leaf and branch hydraulic conductivities) to maintain the water supply of their leaves. In addition, we found a significant trade-off between the sapwood-specific hydraulic conductivity (K SS) and xylem pressure inducing 50% loss of hydraulic conductivity (P 50branch) across all species. Both K SS and P 50branch increased with the area-based light-saturated photosynthetic rate (A area), suggesting that increased embolism resistance of branches comes at the cost of reduced hydraulic efficiency, which in turn constrains the photosynthesis. A area was negatively correlated with P 50leaf–branch, further indicating that the conifers had strong VS and were associated with a conservative strategy. Conversely, the angiosperms displayed an acquisitive strategy, tending to have higher A area, leaf and branch hydraulic conductivities, but lower embolism resistance. These differentiations in the functional traits between the angiosperms and conifers provide potential mechanisms for their co-existence in this temperate forest community. [ABSTRACT FROM AUTHOR]

Glycerol, which is an inevitable by-product of biodiesel production, is an ideal carbon source for the production of carotenoids due to its low price, good availability and chemically reduced status, which results in a low requirement for additional reducing equivalents. In this study, an alternative carbon-utilization pathway was constructed in Escherichia coli to enable more efficient β-carotene production from glycerol. An aldehyde reductase gene (alrd) and an aldehyde dehydrogenase gene (aldH) from Ralstonia eutropha H16 were integrated into the E. coli chromosome to form a novel glycerol-utilization pathway. The β-carotene specific production value was increased by 50% after the introduction of alrd and aldH. It was found that the glycerol kinase gene (garK), alrd and aldH were the bottleneck of the alternative glycerol metabolic pathway, and modulation of garK gene with an mRS library further increased the β-carotene specific production value by 13%. Finally, co-modulation of genes in the introduced aldH-alrd operon led to 86% more of β-carotene specific production value than that of the strain without the alternative glycerol-utilization pathway and the glycerol-utilization rate was also increased. In this work, β-carotene production of E. coli was significantly improved by constructing and optimizing an alternative glycerol-utilization pathway. This strategy can potentially be used to improve the production of other isoprenoids using glycerol as a cheap and abundant substrate, and therefore has industrial relevance. [ABSTRACT FROM AUTHOR]

Stripe rust is a devastating fungal disease of wheat caused by Puccinia striiformis f. sp tritici (Pst). The WHEAT KINASE START1 (WKS1) resistance gene has an unusual combination of serine/threonine kinase and START lipid binding domains and confers partial resistance to Pst. Here, we show that wheat (Triticum aestivum) plants transformed with the complete WKS1 (variant WKS1.1) are resistant to Pst , whereas those transformed with an alternative splice variant with a truncated START domain (WKS1.2) are susceptible. WKS1.1 and WKS1.2 preferentially bind to the same lipids (phosphatidic acid and phosphatidylinositol phosphates) but differ in their protein-protein interactions. WKS1.1 is targeted to the chloroplast where it phosphorylates the thylakoid-associated ascorbate peroxidase (tAPX) and reduces its ability to detoxify peroxides. Increased expression of WKS1.1 in transgenic wheat accelerates leaf senescence in the absence of Pst. Based on these results, we propose that the phosphorylation of tAPX by WKS1.1 reduces the ability of the cells to detoxify reactive oxygen species and contributes to cell death. This response takes several days longer than typical hypersensitive cell death responses, thus allowing the limited pathogen growth and restricted sporulation that is characteristic of the WKS1 partial resistance response to Pst. [ABSTRACT FROM AUTHOR]

Background Patients with lupus podocytopathy show a high incidence of acute kidney injury (AKI) and relapse, but the risk factors and mechanisms were unclear. This study analysed the clinicopathological features and risk factors for AKI and relapse in lupus podocytopathy patients. Methods The cohort of lupus podocytopathy was generated by screening the biopsies of patients with lupus nephritis (LN) from 2002 to 2022 and was divided into the mild glomerular lesion (MGL) and focal segmental glomerulosclerosis (FSGS) groups based on glomerular morphological characteristics. The acute (ATI) and chronic (CTI) tubulointerstitial lesions were semi-quantitatively scored. Logistic and Cox regressions were employed to identify the risk factors for AKI and relapse, respectively. Results Among 6052 LN cases, 98 (1.6%) were diagnosed as lupus podocytopathy, with 71 in the MGL group and 27 in the FSGS group. All patients presented with nephrotic syndrome and 33 (34.7%) of them had AKI. Seventy-seven (78.6%) patients achieved complete renal response (CRR) within 12 weeks of induction treatment, in which there was no difference in the CRR rate between glucocorticoid monotherapy and combination therapy with glucocorticoids plus immunosuppressants. Compared with the MGL group, patients in the FSGS group had significantly higher incidences of hypertension and haematuria; in addition, they had higher Systemic Lupus Erythematosus Disease Activity Index 2000, ATI and CTI scores but a significantly lower CRR rate. Urinary protein ≥7.0 g/24 h and serum C3 ≤0.750 g/l were independent risk factors for AKI. During a median follow-up of 78 months, 57 cases (60.0%) had relapse and none reached the kidney endpoint. Failure to achieve CRR within 12 weeks, maintenance with glucocorticoid monotherapy and AKI at onset were independent risk factors for kidney relapse. Conclusions In this study, histological subtypes of lupus podocytopathy were found to be associated with clinical features and treatment response. In addition, several risk factors associated with AKI occurrence and kidney relapse were identified. [ABSTRACT FROM AUTHOR]

Objective: Concurrent autonomous cortisol secretion (ACS) in patients wit h primary aldosteronism (PA) is being reported more frequently. Several somatic mutations including PRKACA, GNAS, and CTNNB1 were identified in cortisolproducing adenomas (CPAs). The presence of these mutations in u nilateral PA (uPA) patients concurrent with ACS (uPA/ACS) is not well known. This study aimed to investigate the prevalence of these mutations and their clinical vs pathological characteristics in uPA/ACS. Design: This is a retrospective cohort study. Methods: Totally 98 uPA patients from the Taiwan Primary Aldosteronism Investigation registry having overnight 1-mg dexamethasone suppression test (DST) and adrenalectomy from 201 6 to 2018 were enrolled. Their adrenal tumors were tested for PRKACA, GNAS, and CTNNB1 mutations. Results: 11 patients had CPA-related mutations (7 PRKACA and 4 GNAS). The patients carrying these mutations had higher post-DST cortisol (5.6 vs 2.6 µg/dL, P = 0.003) and larger adenoma (2.2 ± 0.3 vs 1.9 ± 0.7 cm, P = 0.025). Adenomas with these mutations had a higher prevalence of non-cl assical uPA (72.7% vs 26.3%, P = 0.014). Numerically, slightly more complete clinical success of uPA patients with these mutations was noticed after adrenalectomy, although it was statistically non-significant. Post-DST cortisol levels, adenoma size >1.9 cm, and the interaction of adenoma size >1.9 cm with potassium level were found to be associated with the presence of these mutations. Conclusion: Our study showed that CPA-related mutations were detected in 36.7% of uPA/ACS adenomas. The presence of these mutations was associated with higher post-DST cortisol levels, larger adenoma sizes, and a high percentage of non-classical uPA. However, these mutations did not significa ntly affect the clinical and biochemical outcomes after adrenalectomy of uPA/ACS patients but they showed a better tren d. [ABSTRACT FROM AUTHOR]

Aims Trastuzumab, the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (ERBB2/HER2), is currently used as a first-line treatment for HER2 (+) tumours. However, trastuzumab increases the risk of cardiac complications without affecting myocardial structure, suggesting a distinct mechanism of cardiotoxicity. Methods and results We used medium from trastuzumab-treated human umbilical vein endothelial cells (HUVECs) to treat CCC-HEH-2 cells, the human embryonic cardiac tissue-derived cell lines, and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess the crosstalk between vascular endothelial cells (VECs) and cardiomyocytes. Protein mass spectrometry analysis was used to identify the key factors from VECs that regulate the function of cardiomyocytes. We applied RNA-sequencing to clarify the mechanism, by which PTX3 causes cardiac dysfunction. We used an anti-human/rat HER2 (neu) monoclonal antibody to generate a rat model that was used to evaluate the effects of trastuzumab on cardiac structure and function and the rescue effects of lapatinib on trastuzumab-induced cardiac side effects. Medium from trastuzumab-treated HUVECs apparently impaired the contractility of CCC-HEH-2 cells and iPSC-CMs. PTX3 from VECs caused defective cardiomyocyte contractility and cardiac dysfunction in mice, phenocopying trastuzumab treatment. PTX3 affected calcium homoeostasis in cardiomyocytes, which led to defective contractile properties. EGFR/STAT3 signalling in VECs contributed to the increased expression and release of PTX3. Notably, lapatinib, a dual inhibitor of EGFR/HER2, could rescue the cardiac complications caused by trastuzumab by blocking the release of PTX3. Conclusion We identified a distinct mode of cardiotoxicity, wherein the activation of EGFR/STAT3 signalling by trastuzumab in VECs promotes PTX3 excretion, which contributes to the impaired contractility of cardiomyocytes by inhibiting cellular calcium signalling. We confirmed that lapatinib could be a feasible preventive agent against trastuzumab-induced cardiac complications and provided the rationale for the combined application of lapatinib and trastuzumab in cancer therapy. [ABSTRACT FROM AUTHOR]

Background Heterozygous loss-of-function mutations in the tumour necrosis factor alpha induced protein 3 (TNFAIP3) gene cause an early-onset auto-inflammatory disease named haploinsufficiency of A20 (HA20). Here we describe three unrelated patients with autoimmune lupus nephritis (LN) phenotypes carrying three novel mutations in the TNFAIP3 gene. Methods Whole-exome sequencing (WES) was used to identify the causative mutations in three biopsy-proven LN patients. Sanger sequencing and quantitative polymerase chain reaction (qPCR) were used to validate the mutations identified by WES. RNA sequencing, qPCR and cytometric bead array was used to detect inflammatory signatures in the patients. Results The patients predominantly presented with an autoimmune phenotype, including autoimmune haemolytic anaemia, multipositive autoantibodies and LN. Additionally, novel phenotypes of allergy and pericardial effusion were first reported. WES identified three novel heterozygous mutations in the TNFAIP3 gene, including a novel splicing mutation located in the canonical splicing site (c.634+2T>C) resulting in an intron 4 insertion containing a premature stop codon, a de novo novel copy number variation (exon 7–8 deletion) and a novel nonsense mutation c.1300_1301delinsTA causing a premature stop codon. We further identified hyperactivation signatures of nuclear factor- kappa B and type I IFN signalling and overproduction of pro-inflammatory cytokines in the blood. This report expanded the phenotype to a later age, as two girls were diagnosed at age 3 years and one man at age 29 years. Conclusions Kidney involvement may be the main feature of the clinical spectrum of HA20, even in adults. Genetic screening should be considered for early-onset LN patients. [ABSTRACT FROM AUTHOR]

Background the relationship between low-density lipoprotein cholesterol (LDL-C) and adverse outcomes among the older people remains controversial. Objective to further clarify the association between admission LDL-C levels and cardiovascular mortality (CVM) among oldest old individuals (≥80 years) with acute myocardial infarction (AMI). Design a prospective cohort study. Setting two-centre. Subjects a consecutive sample of 1,224 oldest old individuals with AMI admitted to Beijing FuWai and Shenzhen FuWai hospitals. Methods all individuals were subdivided according to baseline LDL-C levels (<1.8, 1.8–2.6 and ≥ 2.6 mmol/l) and further stratified by high-sensitivity C-reactive protein (hsCRP) concentrations (<10 and ≥10 mg/l). The primary outcome was CVM. The time from admission to the occurrence of CVM or the last follow-up was analysed in Kaplan–Meier and Cox analyses. Results the median age of the overall population was 82 years. During an average of 24.5 months' follow-up, 299 cardiovascular deaths occurred. Kaplan–Meier analysis showed that LDL-C < 1.8 mmol/l group had the highest CVM among oldest old individuals with AMI. Multivariate Cox regression analysis further revealed that compared with those with LDL-C levels <1.8 mmol/l, subjects with LDL-C levels ≥2.6 mmol/l (hazard ratio: 0.67, 95% confidence interval: 0.46–0.98) had significantly lower risk of CVM, especially in those with high hsCRP levels. Moreover, when categorising according to LDL-C and hsCRP together, data showed that individuals with low LDL-C and high hsCRP levels had the highest CVM. Conclusions LDL-C < 1.8 mmol/l was associated with a high CVM after AMI in oldest old individuals, especially when combined with high hsCRP levels, which may need to be confirmed by randomised controlled trials. [ABSTRACT FROM AUTHOR]