Artificial intelligence-based plasma exosome label-free SERS profiling strategy for early lung cancer detection.

As a lung cancer biomarker, exosomes were utilized for in vitro diagnosis to overcome the lack of sensitivity of conventional imaging and the potential harm caused by tissue biopsy. However, given the inherent heterogeneity of exosomes, the challenge of accurately and reliably recognizing subtle differences in the composition of exosomes from clinical samples remains significant. Herein, we report an artificial intelligence-assisted surface-enhanced Raman spectroscopy (SERS) strategy for label-free profiling of plasma exosomes for accurate diagnosis of early-stage lung cancer. Specifically, we build a deep learning model using exosome spectral data from lung cancer cell lines and normal cell lines. Then, we extracted the features of cellular exosomes by training a convolutional neural network (CNN) model on the spectral data of cellular exosomes and used them as inputs to a support vector machine (SVM) model. Eventually, the spectral features of plasma exosomes were combined to effectively distinguish adenocarcinoma in situ (AIS) from healthy controls (HC). Notably, the approach demonstrated significant performance in distinguishing AIS from HC samples, with an area under the curve (AUC) of 0.84, sensitivity of 83.3%, and specificity of 83.3%. Together, the results demonstrate the utility of exosomes as a biomarker for the early diagnosis of lung cancer and provide a new approach to prescreening techniques for lung cancer.

The AestheCode System: A Safe and Efficient Guide for AestheFill Injection.

AestheFill is a biostimulator based on poly-D,L-lactic acid. It is supplied as lyophilized powders and is referred to as a versatile biostimulator. According to the amount of water added, the suspensions can be vary in thickness which can be divided into four groups for different indications: the thickest suspension (D1.5-3) for nose or chin augmentation, thick suspension (D3-6) for deep wrinkle correction, thin suspension (D6-12) for shallow wrinkle correction, and super-thin suspension (D12-24) for skin rejuvenation. However, practitioners may be confused about which filler thickness, injection layer, method, and amount should be chosen for their patients. Biostimulators tend to form non-inflammatory nodules if technical mishaps occur during injection. Based on 10 years of AestheFill injection experience, the authors proposed the AestheCode system for the safe and effective injection of AestheFill.Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Retrograde flow phenomenon of poly-D,L-lactic acid filler injection over lower eyelids.

The occurrence of 'retrograde flow along the cannula/needle tract' during filler injections has not been extensively addressed in the existing literature, possibly because it is often imperceptible unless the injection is conducted at a superficial layer. In our experience with poly-D,L-lactic acid filler for lower eyelid injections, we have observed and documented this phenomenon through the skin. This article aims to elucidate and illustrate the retrograde flow phenomenon and discuss the factors influencing it.

Overexpression of COX7A1 Promotes the Resistance of Gastric Cancer to Oxaliplatin and Weakens the Efficacy of Immunotherapy.

Gastric cancer (GC) is one of the most common clinical malignant tumors worldwide, with high morbidity and mortality. Presently, the overall response rate to immunotherapy is low, and current methods for predicting the prognosis of GC are not optimal. Therefore, novel biomarkers with accuracy, efficiency, stability, performance ratio, and wide clinical application are needed. Based on public data sets, the chemotherapy cohort and immunotherapy cohort from Sun Yat-sen University Cancer Center, a series of bioinformatics analyses, such as differential expression analysis, survival analysis, drug sensitivity prediction, enrichment analysis, tumor immune dysfunction and exclusion analysis, single-sample gene set enrichment analysis, stemness index calculation, and immune cell infiltration analysis, were performed for screening and preliminary exploration. Immunohistochemical staining and in vitro experiments were performed for further verification. Overexpression of COX7A1 promoted the resistance of GC cells to Oxaliplatin. COX7A1 may induce immune escape by regulating the number of fibroblasts and their cellular communication with immune cells. In summary, measuring the expression levels of COX7A1 in the clinic may be useful in predicting the prognosis of GC patients, the degree of chemotherapy resistance, and the efficacy of immunotherapy.

Lower class competence stereotypes of the upper class increase class conflict: mediation by intergroup envy and moderation by upward social mobility belief.

Background: With increasing gaps between the rich and poor, potential risk factors for class conflict have attracted increasing attention from researchers. Although cognitive factors are known to be significant predictors of class-conflict behavior, limited attention has been paid to competence stereotypes of the upper class. When considering economic inequality, people pay more attention to competence stereotypes of the upper class, which may have adverse effects. This study aimed to investigate the relationship between competence stereotypes held by the lower class about the upper class and class conflict, and to test the mediating role of intergroup envy in this relationship and the moderating role of upward social mobility belief. Methods: Data were collected from a convenience sample from a comprehensive university in China. Based on scores on subjective and objective class scales, 284 lower-class college students (103 males and 181 females) aged 18-24 were selected to participate (both their subjective and objective scores were lower than 3 points). Their endorsement of upper-class competence stereotypes, intergroup envy, upward social mobility beliefs, and class conflict were measured using a well-validated self-report questionnaire. Results: The main data were analyzed using correlation analysis, the SPSS macro PROCESS (Model 7), and simple slope analysis. The results show a significant positive correlation between competence stereotypes held by lower-class college students toward the higher class and class conflict, and this connection was mediated by intergroup envy. Moreover, the indirect effect of intergroup envy on this link was moderated by upward social mobility beliefs; this effect was stronger for college students with lower upward social mobility beliefs. Conclusion: This study broadens our understanding of how and when competence stereotypes among the lower class concerning the upper class are related to class conflict. Researchers and policymakers should pay special attention to competence stereotypes of the upper class, especially intergroup envy and class conflict among lower-class individuals with lower levels of upward social mobility beliefs.

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.

Exposure-Response to High PM 2.5 Levels for Cardiovascular Events in High-risk Older Adults in Taiwan.

Background: Multiple studies from countries with relatively lower PM 2.5 level demonstrated that acute and chronic exposure even at lower than recommended level, e.g., 9 µg/m 3 in the US increased the risk of cardiovascular (CV) events. However, limited studies using individual level data exist from countries with a wider range of PM levels to illustrate shape of the exposure-response curve throughout the range including > 20 µg/m 3 PM 2·5 concentrations. Taiwan with its policies reduced PM 2.5 over time provide opportunities to illustrate the dose response curves and how reductions of PM 2.5 over time correlated with CV events incidence in a nationwide sample. Methods: Using data from the 2009-2019 Taiwan National Health Insurance Database linked to nationwide PM2.5 data. We examined the shape and magnitude of the exposure-response curve between seasonal average PM 2·5 level and CV events-related hospitalizations among older adults at high-risk for CV events. We used history-adjusted marginal structural models including potential confounding by individual demographic factors, baseline comorbidities, and health service measures. To quantify the risk below and above 20 µg/m 3 we conducted stratified Cox regression. We also plotted PM 2.5 and CV events from 2009-2019 as well as average temperature as a comparison. Findings: Using the PM 2.5 concentration <15 µg/m 3 (Taiwan regulatory standard) as a reference, the seasonal average PM 2.5 concentration (15-23.5µg/m 3 and > 23.5 µg/m 3 ) were associated with hazard ration of 1.13 (95%CI 1.09-1.18) and 1.19 (95%CI 1.14-1.24), 1.07 (95%CI 1.03-1.11) and 1.14 (95%CI 1.10-1.18), 1.22 (95%CI 1.08-1.38) and 1.31 (95%CI 1.16-1.48), 1.04 (95%CI 0.98-1.10) and 1.10 (95%CI 1.04-1.16) respectively for HF, IS/TIA,PE/DVT and MI/ACS. A nonlinear relationship between PM 2·5 and CV events outcomes was observed at PM 2·5 levels above 20 µg/m 3 . Interpretation: A nonlinear exposure-response relationship between PM2·5 concentration and the incidence of cardiovascular events exists when PM2.5 is higher than the levels recommended by WHO Air Quality Guidelines. Further lowering PM2·5 levels beyond current regulatory standards may effectively reduce the incidence of cardiovascular events, particularly HF and DVT, and can lead to tangible health benefits in high-risk elderly population.

The novel HLA-C*14:155 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-C*14:155 differs from HLA-C*14:02:01:01 by one nucleotide in exon 1.

Sofosbuvir-velpatasvir in children 3-17 years old with hepatitis C virus infection.

BACKGROUND: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated. METHODS: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group. FINDINGS: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range. INTERPRETATION: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection.

Association of reproductive lifespan and age at menopause with depression: Data from NHANES 2005-2018.

BACKGROUND: The association between reproductive lifespan and depression in older women is unclear. We conducted this analysis to explore whether a shorter reproductive lifespan is associated with higher odds of depression, while also considering the age at menarche and age at menopause. METHODS: This observational study used data from the National Health and Nutrition Examination Survey (NHANES), which was conducted between 2005 and 2018. Reproductive lifespan was defined as years from age at menarche to age at menopause. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9). Multivariable logistic regression models were used to explore the relationship between the association of reproductive life span, age at menarche and age at menopause with the incidence of depression. RESULTS: Totally, 2947 patients aged 60 and above were enrolled in the trial, with 241 individuals (8.18 %) diagnosed with depression. Higher odds of depression were found to be significantly correlated with a shorter reproductive lifespan [Odds Ratio (OR) = 0.95, 95 % Confidence interval (CI) = 0.92-0.98] or an earlier ager at menopause (OR = 0.95, 95 % CI = 0.92-0.99), according to the results of multivariable logistic regression analysis after full adjustment. Subgroup analysis and interaction tests indicated a similar association. LIMITATIONS: The cross-sectional study could not yield any conclusions regarding causality. CONCLUSION: In this large cross-sectional study, our result suggested that populations with a shorter reproductive lifespan or an earlier age at menopause were significantly more likely to have depressive symptoms in older U.S. women. Further large-scale prospective studies are warranted for a comprehensive analysis of the role of the reproductive lifespan and age at menopause in depression.

Construction of a gene model related to the prognosis of patients with gastric cancer receiving immunotherapy and exploration of COX7A1 gene function.

BACKGROUND: GC is a highly heterogeneous tumor with different responses to immunotherapy, and the positive response depends on the unique interaction between the tumor and the tumor microenvironment (TME). However, the currently available methods for prognostic prediction are not satisfactory. Therefore, this study aims to construct a novel model that integrates relevant gene sets to predict the clinical efficacy of immunotherapy and the prognosis of GC patients based on machine learning. METHODS: Seven GC datasets were collected from the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) database and literature sources. Based on the immunotherapy cohort, we first obtained a list of immunotherapy related genes through differential expression analysis. Then, Cox regression analysis was applied to divide these genes with prognostic significancy into protective and risky types. Then, the Single Sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to score the two categories of gene sets separately, and the scores differences between the two gene sets were used as the basis for constructing the prognostic model. Subsequently, Weighted Correlation Network Analysis (WGCNA) and Cytoscape were applied to further screen the gene sets of the constructed model, and finally COX7A1 was selected for the exploration and prediction of the relationship between the clinical efficacy of immunotherapy for GC. The correlation between COX7A1 and immune cell infiltration, drug sensitivity scoring, and immunohistochemical staining were performed to initially understand the potential role of COX7A1 in the development and progression of GC. Finally, the differential expression of COX7A1 was verified in those GC patients receiving immunotherapy. RESULTS: First, 47 protective genes and 408 risky genes were obtained, and the ssGSEA algorithm was applied for model construction, showing good prognostic discrimination ability. In addition, the patients with high model scores showed higher TMB and MSI levels, and lower tumor heterogeneity scores. Then, it is found that the COX7A1 expressions in GC tissues were significantly lower than those in their corresponding paracancerous tissues. Meanwhile, the patients with high COX7A1 expression showed higher probability of cancer invasion, worse clinical efficacy of immunotherapy, worse overall survival (OS) and worse disease-free survival (DFS). CONCLUSIONS: The ssGSEA score we constructed can serve as a biomarker for GC patients and provide important guidance for individualized treatment. In addition, the COX7A1 gene can accurately distinguish the prognosis of GC patients and predict the clinical efficacy of immunotherapy for GC patients.

Metabolic syndrome risk in adult coffee drinkers with the rs301 variant of the LPL gene.

BACKGROUND: Metabolic syndrome (MetS), a cluster of metabolic and cardiovascular risk factors is influenced by environmental, lifestyle, and genetic factors. We explored whether coffee consumption and the rs301 variant of the lipoprotein lipase (LPL) gene are related to MetS. METHODS: We conducted multiple logistic regression analyses using data gathered from 9523 subjects in Taiwan Biobank (TWB). RESULTS: Our findings indicated that individuals who consumed coffee had a reduced odds ratio (OR) for MetS (0.750 (95% confidence interval [CI] 0.653-0.861) compared to non-coffee drinkers. Additionally, the risk of MetS was lower for individuals with the 'TC' and 'CC' genotypes of rs301 compared to those with the 'TT' genotype. Specifically, the OR for MetS was 0.827 (95% CI 0.721-0.949) for the 'TC' genotype and 0.848 (95% CI 0.610-1.177) for the 'CC' genotype. We observed an interaction between coffee consumption and the rs301 variant, with a p-value for the interaction of 0.0437. Compared to the reference group ('no coffee drinking/TT'), the ORs for MetS were 0.836 (95% CI 0.706-0.992) for 'coffee drinking/TT', 0.557 (95% CI 0.438-0.707) for 'coffee drinking/TC', and 0.544 (95% CI 0.319-0.927) for 'coffee drinking/CC'. Notably, MetS was not observed in non-coffee drinkers regardless of their rs301 genotype. CONCLUSION: Our findings suggest that rs301 genotypes may protect against MetS in Taiwanese adults who consume coffee compared to non-coffee drinkers.

Bile acids inhibit ferroptosis sensitivity through activating farnesoid X receptor in gastric cancer cells.

BACKGROUND: Gastric cancer (GC) is associated with high mortality rates. Bile acids (BAs) reflux is a well-known risk factor for GC, but the specific mechanism remains unclear. During GC development in both humans and animals, BAs serve as signaling molecules that induce metabolic reprogramming. This confers additional cancer phenotypes, including ferroptosis sensitivity. Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression. However, it is not fully defined if BAs can influence GC progression by modulating ferroptosis. AIM: To reveal the mechanism of BAs regulation in ferroptosis of GC cells. METHODS: In this study, we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis. We used gain and loss of function assays to examine the impacts of farnesoid X receptor (FXR) and BTB and CNC homology 1 (BACH1) overexpression and knockdown to obtain further insights into the molecular mechanism involved. RESULTS: Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells. This effect correlated with increased glutathione (GSH) concentrations, a reduced GSH to oxidized GSH ratio, and higher GSH peroxidase 4 (GPX4) expression levels. Subsequently, we confirmed that BAs exerted these effects by activating FXR, which markedly increased the expression of GSH synthetase and GPX4. Notably, BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR. Finally, our results suggested that FXR could significantly promote GC cell proliferation, which may be closely related to its anti-ferroptosis effect. CONCLUSION: This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSH-GPX4 axis in GC cells. This work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.

Salvage therapy for refractory sudden sensorineural hearing loss (RSSNHL): a systematic review and network meta-analysis.

OBJECTIVE: Approximately 30-50% of sudden sensorineural hearing loss (SSNHL) patients show poor response to systemic steroid therapy. Additionally, the most appropriate treatment for patients with refractory sudden sensorineural hearing loss (RSSNHL) is unknown. This study aimed to explore the best treatment for RSSNHL. DESIGN: Using a frequentist contrast-based model and PRISMA guidelines, this study compared five salvage regimes: intratympanic injection of steroids (ITS), hyperbaric oxygen (HBO) therapy, post auricle steroid injection (PSI), ITS combined with HBO therapy, and continued systemic steroids. STUDY SAMPLE: We searched the PubMed, EMBASE, Web of Science, and Cochrane Library databases for randomised controlled trials and cohort studies comparing treatment regimens for RSSNHL. RESULTS: Compared with the control group (no additional treatment), PSI and ITS demonstrated significant improvements. The mean hearing gain was greater after PSI (11.1 dB [95% CI, 4.4-17.9]) than after ITS (7.7 dB [95% CI, 4.8-10.7]). When a restricted definition of RSSNHL was used, the ITS + HBO therapy showed the largest difference in improvement for pure tone average compared with the control group (14.5 dB [95% CI, 4.2-25.0]). CONCLUSIONS: The administration of either PSI or ITS leads to the greatest therapeutic effect in patients with RSSNHL. However, a consensus on the definition of RSSNHL is needed.

Immune-stealth VP28-conjugated heparin nanoparticles for enhanced and reversible anticoagulation.

Heparins are a family of sulfated linear negatively charged polysaccharides that have been widely used for their anticoagulant, antithrombotic, antitumor, anti-inflammatory, and antiviral properties. Additionally, it has been used for acute cerebral infarction relief as well as other pharmacological actions. However, heparin's self-aggregated macrocomplex may reduce blood circulation time and induce life-threatening thrombocytopenia (HIT) complicating the use of heparins. Nonetheless, the conjugation of heparin to immuno-stealth biomolecules may overcome these obstacles. An immunostealth recombinant viral capsid protein (VP28) was expressed and conjugated with heparin to form a novel nanoparticle (VP28-heparin). VP28-heparin was characterized and tested to determine its immunogenicity, anticoagulation properties, effects on total platelet count, and risk of inducing HIT in animal models. The synthesized VP28-heparin trimeric nanoparticle was non-immunogenic, possessed an average hydrodynamic size (8.81 ± 0.58 nm) optimal for the evasion renal filtration and reticuloendothelial system uptake (hence prolonging circulating half-life). Additionally, VP28-heparin did not induce mouse death or reduce blood platelet count when administered at a high dosein vivo(hence reducing HIT risks). The VP28-heparin nanoparticle also exhibited superior anticoagulation properties (2.2× higher prothrombin time) and comparable activated partial thromboplastin time, but longer anticoagulation period when compared to unfractionated heparin. The anticoagulative effects of the VP28-heparin can also be reversed using protamine sulfate. Thus, VP28-heparin may be an effective and safe heparin derivative for therapeutic use.

Ambient Heat and Risk of Serious Hypoglycemia in Older Adults With Diabetes Using Insulin in the U.S. and Taiwan: A Cross-National Case-Crossover Study.

OBJECTIVE: To measure the association between ambient heat and hypoglycemia-related emergency department visit or hospitalization in insulin users. RESEARCH DESIGN AND METHODS: We identified cases of serious hypoglycemia among adults using insulin aged ≥65 in the U.S. (via Medicare Part A/B/D-eligible beneficiaries) and Taiwan (via National Health Insurance Database) from June to September, 2016-2019. We then estimated odds of hypoglycemia by heat index (HI) percentile categories using conditional logistic regression with a time-stratified case-crossover design. RESULTS: Among ∼2 million insulin users in the U.S. (32,461 hypoglycemia case subjects), odds ratios of hypoglycemia for HI >99th, 95-98th, 85-94th, and 75-84th percentiles compared with the 25-74th percentile were 1.38 (95% CI, 1.28-1.48), 1.14 (1.08-1.20), 1.12 (1.08-1.17), and 1.09 (1.04-1.13) respectively. Overall patterns of associations were similar for insulin users in the Taiwan sample (∼283,000 insulin users, 10,162 hypoglycemia case subjects). CONCLUSIONS: In two national samples of older insulin users, higher ambient temperature was associated with increased hypoglycemia risk.