Practical problems with missing data are common, and many methods have been developed concerning the validity and/or efficiency of statistical procedures. On a central focus, there have been ...longstanding interests on the mechanism governing data missingness, and correctly deciding the appropriate mechanism is crucially relevant for conducting proper practical investigations. In this paper, we present a new hypothesis testing approach for deciding between the conventional notions of missing at random and missing not at random in generalized linear models in the presence of instrumental variables. The foundational idea is to develop appropriate discrepancy measures between estimators whose properties significantly differ only when missing at random does not hold. We show that our testing approach achieves an objective data‐oriented choice between missing at random or not. We demonstrate the feasibility, validity, and efficacy of the new test by theoretical analysis, simulation studies, and a real data analysis.
We assessed the survival outcomes associated with real‐world bisphosphonate use, stratified by fracture site, type, administration, and duration of treatment, among patients with osteoporosis. A ...systematic review that incorporates our findings was conducted to provide up‐to‐date evidence on survival outcomes with bisphosphonate treatment in real‐world settings. Patients diagnosed with osteoporosis who had been hospitalized for major fractures were identified from Taiwan’s National Health Insurance Research Database 2008–2017 and followed until 2018. There were 24,390 new bisphosphonate users who were classified and compared with 76,725 nonusers of anti‐osteoporosis medications in terms of survival outcomes using Cox model analysis. An inverse probability of treatment weighted Cox model and landmark analyses for minimizing immortal time bias were also performed. Bisphosphonate users vs. nonusers had a significantly lower mortality risk, regardless of fracture site (hazard ratios (95% confidence intervals) for patients with any major fracture, hip fracture, and vertebral fracture: 0.90 (0.88, 0.93), 0.83 (0.80, 0.86), and 0.86 (0.82, 0.89), respectively). Compared with nonuse, zoledronic acid (0.77 (0.73, 0.82)) was associated with the lowest mortality, followed by ibandronate (0.85 (0.78, 0.93)) and alendronate/risedronate (0.93 (0.91, 0.96)). Using bisphosphonates for ≥ 3 years had lower mortality (0.60 (0.53, 0.67)) than using bisphosphonates for < 3 years (0.98 (0.95, 1.01)). Intravenous bisphosphonates had a lower mortality than that of oral bisphosphonates. Our results are consistent with the systematic review findings among real‐world populations. In conclusion, bisphosphonate use, especially persistence to intravenous bisphosphonates (e.g., zoledronic acid), may reduce post‐fracture mortality among patients with osteoporosis, particularly those with hip/vertebral fractures. This supports the rational use of bisphosphonates in post‐fracture care.
With the widespread use of nanoenabled agrochemicals, it is essential to evaluate the food safety of nanomaterials (NMs)-treated vegetable crops in full life cycle studies as well as their potential ...impacts on human health. Tomato seedlings were foliarly sprayed with 50 mg/L ZnO NMs, including ZnO quantum dots (QDs) and ZnO nanoparticles once per week over 11 weeks. The foliar sprayed ZnO QDs increased fruit dry weight and yield per plant by 39.1% and 24.9, respectively. It also significantly increased the lycopene, amino acids, Zn, B, and Fe in tomato fruits by 40.5%, 15.1%, 44.5%, 76.2%, and 12.8%, respectively. The tomato fruit metabolome of tomatoes showed that ZnO NMs upregulated the biosynthesis of unsaturated fatty acids and sphingolipid metabolism and elevated the levels of linoleic and arachidonic acids. The ZnO NMs-treated tomato fruits were then digested in a human gastrointestinal tract model. The results of essential mineral release suggested that the ZnO QDs treatment increased the bioaccessibility of K, Zn, and Cu by 14.8–35.1% relative to the control. Additionally, both types of ZnO NMs had no negative impact on the α-amylase, pepsin, and trypsin activities. The digested fruit metabolome in the intestinal fluid demonstrated that ZnO NMs did not interfere with the normal process of human digestion. Importantly, ZnO NMs treatments increased the glycerophospholipids, carbohydrates, amino acids, and peptides in the intestinal fluids of tomato fruits. This study suggests that nanoscale Zn can be potentially used to increase the nutritional value of vegetable crops and can be an important tool to sustainably increase food quality and security.
Systematic understanding of the impact of nanomaterials (NMs) on the health and activity of plant-associated microorganisms is required for sustainable development of efficient nano-enabled ...agrochemicals. Zinc (Zn) is an essential micronutrient for plant growth and development. It plays a vital role in various physiological processes, including enzyme activation, protein synthesis, cell division, etc. The present study investigated the effects of foliar exposure to different sizes of ZnO particles, including ZnO quantum dots (ZnO QDs, 4.06 nm), ZnO nanoparticles (ZnO NPs, 60.0 nm), bulk-scale ZnO particles (ZnO BPs, 464.5 nm), and Zn ions at an equivalent Zn molar concentration (0.61 mM) on the endophytic and rhizosphere microbial communities of pumpkin seedlings. ZnO QDs increased the total plant biomass by 24.6% as compared to the control. ZnO QDs also increased the contents of total chlorophyll and carotenoids, elevated micronutrient (Zn, Fe, and B) uptake, and triggered the activities of antioxidant enzymes, such as peroxidase (POD), polyphenol oxidase (PPO), and catalase (CAT), as compared to controls. The composition and diversity of the endophytic and rhizosphere bacterial or fungal communities were significantly altered as a function of ZnO NM size, and a significant difference between the control and ZnO treatments was also evident. Linear discriminant effect size analysis (LEfSe) shows that the putative beneficial host microbes Steroidobacter (relative abundance, RA: 1.05%) and Paenibacillus (RA: 0.59%) were enriched in pumpkin seedlings treated with ZnO QDs, which may lead to greater plant growth, nutrient acquisition, and stress resistance. Cooccurrence networks indicate that ZnO QDs increased both node and link numbers of the bacterial networks by 46.94 and 123.38% in the roots, which could further stabilize the microbial community and confer resistance to environmental disturbance. Our overall findings demonstrate that ZnO QDs could enhance plant growth both directly by improving physiological performances and indirectly by modulating beneficial endophytic and rhizosphere microorganisms. Thus, nano-enabled strategies can be a promising and sustainable approach to increase crop growth and resistance to stress.
Prognostic survival models are commonly evaluated in terms of both their calibration and their discrimination. Comparing observed and predicted survival curves can assess calibration, while ...discrimination is typically summarized through comparison of the properties of cases or subjects who experience an event, and the properties of controls represented by eventfree individuals. For binary data, discrimination is characterized either by using the relative ranks of cases and controls and a receiver operating characteristic (ROC) curve, or by summarizing the magnitude of risk placed on cases and controls through calculation of the discrimination slope (DS). In this article, we propose a risk-based measure of time-varying discrimination that generalizes the discrimination slope to allow use with incident events and hazard models. We refer to the new measure as the hazard discrimination summary (HDS) since it compares the relative risk among incident cases to their associated dynamic risk set controls. We introduce both a model-based estimation procedure that adopts the Cox model, and an alternative approach that locally relaxes the proportional hazards assumption. We illustrate the proposed methods using both a benchmark survival data set, and an oncology study where primary interest is in the time-varying performance of candidate biomarkers.
Mutations in sorting nexin 10 (Snx10) have recently been found to account for roughly 4% of all human malignant osteopetrosis, some of them fatal. To study the disease pathogenesis, we investigated ...the expression of Snx10 and created mouse models in which Snx10 was knocked down globally or knocked out in osteoclasts. Endocytosis is severely defective in Snx10-deficient osteoclasts, as is extracellular acidification, ruffled border formation, and bone resorption. We also discovered that Snx10 is highly expressed in stomach epithelium, with mutations leading to high stomach pH and low calcium solubilization. Global Snx10-deficiency in mice results in a combined phenotype: osteopetrosis (due to osteoclast defect) and rickets (due to high stomach pH and low calcium availability, resulting in impaired bone mineralization). Osteopetrorickets, the paradoxical association of insufficient mineralization in the context of a positive total body calcium balance, is thought to occur due to the inability of the osteoclasts to maintain normal calcium-phosphorus homeostasis. However, osteoclast-specific Snx10 knockout had no effect on calcium balance, and therefore led to severe osteopetrosis without rickets. Moreover, supplementation with calcium gluconate rescued mice from the rachitic phenotype and dramatically extended life span in global Snx10-deficient mice, suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human osteopetrosis that has previously gone unrecognized. We conclude that tissue-specific effects of Snx10 mutation need to be considered in clinical approaches to this disease entity. Reliance solely on hematopoietic stem cell transplantation can leave hypocalcemia uncorrected with sometimes fatal consequences. These studies established an essential role for Snx10 in bone homeostasis and underscore the importance of gastric acidification in calcium uptake.
Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here ...we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood-brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.
Reports of human rickettsial infection in Indonesia are limited. This study sought to characterize the epidemiology of human rickettsioses amongst patients hospitalized with fever at 8 tertiary ...hospitals in Indonesia.
Acute and convalescent blood from 975 hospitalized non-dengue patients was tested for Rickettsia IgM and IgG by ELISA. Specimens from cases with seroconversion or increasing IgM and/or IgG titers were tested for Rickettsia IgM and IgG by IFA and Rickettsia genomes using primers for Rickettsia (R.) sp, R. typhi, and Orientia tsutsugamushi. Testing was performed retrospectively on stored specimens; results did not inform patient management.
R. typhi, R. rickettsii, and O. tsutsugamushi IgG antibodies were identified in 269/872 (30.8%), 36/634 (5.7%), and 19/504 (3.8%) of samples, respectively. For the 103/975 (10.6%) non-dengue patients diagnosed with acute rickettsial infection, presenting symptoms included nausea (72%), headache (69%), vomiting (43%), lethargy (33%), anorexia (32%), arthralgia (30%), myalgia (28%), chills (28%), epigastric pain (28%), and rash (17%). No acute rickettsioses cases were suspected during hospitalization. Discharge diagnoses included typhoid fever (44), dengue fever (20), respiratory infections (7), leptospirosis (6), unknown fever (6), sepsis (5), hepatobiliary infections (3), UTI (3), and others (9). Fatalities occurred in 7 (6.8%) patients, mostly with co-morbidities.
Rickettsial infections are consistently misdiagnosed, often as leptospirosis, dengue, or Salmonella typhi infection. Clinicians should include rickettsioses in their differential diagnosis of fever to guide empiric management; laboratories should support evaluation for rickettsial etiologies; and public policy should be implemented to reduce burden of disease.
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