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Abstract Background Health technology assessment (HTA) has become essential in many countries over the past few years, and the demand for HTA professionals has increased in academia, governments, and industries. This study aimed to examine which courses are most important and which training activities are most helpful for the development of HTA proficiency as perceived by HTA experts. Methods The survey questionnaire was developed by literature review and expert opinion. Convenience sampling was used to survey HTA experts from the industrial sector, academic/research units, and government/independent assessment organizations using an online survey tool, SurveyCake. We collected respondents’ demographic information and asked them to assess the importance of each course included in an HTA program on a 5-point Likert Scale (1 = least important; 5 = highly important). In addition, respondents were asked to assess the extent to which various activities are helpful for HTA proficiency development. Results A total of 158 domestic and overseas experts in HTA-related fields were invited to participate in the survey and 68 completed the questionnaire. Among the respondents, the majority were female (57.4%) and working in academia (44.1%). The mean ± standard deviation of respondents’ age and number of years spent in HTA-related fields were 43.2 ± 11.0 years and 11.3 ± 9.9 years, respectively. The course that was rated the most important was “Pharmacoeconomics/Cost-effectiveness analysis” with a score of 4.8 ± 0.4 points, followed by “Health economics” at 4.7 ± 0.7 points. Moreover, internships at HTA-related institutions were perceived to be the most helpful training activity for HTA proficiency development. Conclusions Our study findings provide a better understanding of the requirements for developing HTA proficiency and can serve as a reference for the modification of current HTA education and training programs.

Objective: To compare the real-world effectiveness and costs of eribulin to those of capecitabine in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. Methods: This study extracted data from the Health and Welfare Database in Taiwan to identify MBC patients, and then eribulin and capecitabine users were matched at a 1:1 ratio by age, residential region, Charlson Comorbidity Index score, and molecular subtype of BC cell. The overall survival (OS) and time-to-treatment discontinuation (TTD) curves were plotted using the Kaplan–Meier method. Healthcare utilization and costs between the two groups were compared. Results: A total of 24,550 MBC patients were identified, and 298 patients were enrolled in each group after matching. The median OS was 11.8 months for eribulin (95%CI: 11.5–13.5 months) and 15.2 months for capecitabine (95%CI: 15.3–17.9 months; HR = 1.7, p 4 prior chemotherapy agents (OS: HR 1.1, 95%CI 0.8–1.5; TTD: HR 1.2, 95%CI 0.9–1.7). The total healthcare costs per patient during the treatment period were NT$580,523.8 for eribulin versus NT$497,223.8 for capecitabine (p

Abstract We aimed to compare the (1) clinical outcomes including composite cardiovascular outcomes, cardiovascular death, and all-cause death, and (2) healthcare costs of using liraglutide and basal insulin as an initial treatment for patients with type 2 diabetes mellitus (T2DM) and high cardiovascular diseases (CVD) risk. This is a retrospective cohort study using Taiwan’s Health and Welfare Database. A total of 1057 patients treated with liraglutide were identified and matched with 4600 patients treated with basal insulin. The liraglutide group had a lower risk of a composite CVD outcome (hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.50–0.85; p

Background: New developments in medications for metastatic breast cancer (MBC) can be of great benefit to patients, but unfortunately these medicines also increase expenditures. Cost-utility analyses (CUAs) are needed to allocate health resources properly, and health utility values are required to calculate quality-adjusted life years in those CUAs. Objective: The aims of this study were to measure health utility values for several MBC-related health states and certain breast cancer treatment-related grade 3/4 adverse drug reactions (ADRs). In addition, we examined whether different methods and respondents’ characteristics would influence the utility values elicited. Methods: A cross-sectional survey was conducted. The visual analogue scale (VAS) and time trade-off (TTO) methods were used to measure health utilities. Four MBC and nine ADR health states were selected for evaluation based on literature review and expert opinion. Information about respondents’ demographic and clinical characteristics were collected to examine the relationship between utilities and participant characteristics. Results: A total of 102 patients participated in this study. The TTO-elicited values were higher than the VAS-derived scores except for two MBC-related health states. Among the MBC health states assessed, the TTO preference score ranged from 0.04 (palliative MBC) to 0.62 (responding MBC). For grade 3/4 ADRs, the mean TTO-derived utility values ranged from 0.35 (nausea/vomiting) to 0.79 (fatigue). The ranking of the preference scores derived from the VAS was similar to that of the TTO-elicited scores. Conclusion: This study obtained health state utility values for MBC and grade 3/4 ADRs using both the TTO and the VAS, which provides useful data for future CUAs.

Objective: Treatment options for HER-2-positive metastatic breast cancer (mBC) patients have expanded markedly since trastuzumab approval in 1998. Several other regimens are now available, including pertuzumab plus trastuzumab plus docetaxel, T-DM1, capecitabine plus lapatinib, and trastuzumab plus lapatinib. This study assesses the cost-effectiveness of four treatment sequences for HER-2-positive mBC according to the Taiwanese National Health Insurance Administration (TNHIA). Methods: Costs (U.S. Dollars) and effectiveness (quality-adjusted life years) of four treatment sequences for HER-2-positive mBC patients were examined using a Markov model over a lifetime horizon. Transition probabilities, disease progression, and probability of adverse events and survival were derived from clinical trial data. Costs and health utilities were estimated from TNHIA, Taipei Medical University Hospital, and the literature. Deterministic, probabilistic sensitivity analyses and a scenario analysis examined parameter uncertainty and accounted for drug wastage in dosage and cost calculations. Results: Sequence 3 (1st line: trastuzumab plus docetaxel; 2nd line: T-DM1; 3rd line: trastuzumab plus lapatinib) was the most cost-effective sequence followed by sequence 1 (1st line: pertuzumab plus trastuzumab plus docetaxel; 2nd line: T-DM1; 3rd line: capecitabine plus lapatinib), and sequence 4 (1st line: trastuzumab plus docetaxel; 2nd line: trastuzumab plus lapatinib; 3rd line: trastuzumab plus capecitabine), respectively. The model was sensitive to costs and transition probabilities, but not particularly sensitive to the wastage assumption. Conclusions: From the perspective of the TNHIA, trastuzumab plus docetaxel as 1st line followed by T-DM1 and trastuzumab plus lapatinib as 2nd and 3rd line represents the most cost-effective strategy among the four sequences considered for treating HER-2-positive mBC patients.

The present data article aims to describe the input parameters for a Markov model assessing the cost-effectiveness of four treatment sequences for patients with HER-2 positive metastatic breast cancer. The model input parameters include costs for physician visits, drugs, adverse event management, computed tomography (CT) scan, laboratory tests, echocardiogram, utilities, disutilities as well as the shape and scale parameters of a log-logistic distribution used for the transition probabilities. Keywords: Markov model, Metastatic breast cancer, Cost-effectiveness analysis, Treatment sequence

Aim. This study aimed at (1) examining the misconceptions of patients with diabetes in Taiwan and (2) examining the association between patients’ diabetes knowledge and their demographic characteristics. Methods. A cross-sectional survey was conducted at a metropolitan hospital in northern Taiwan. A total of 501 outpatients with diabetes were recruited, mostly from the hospital’s endocrinology and metabolism clinic, nephrology clinic, and dialysis center. A self-developed questionnaire that consisted of demographic information and a diabetes knowledge test was administered. The knowledge test included 10 True/False questions and 6 multiple-choice questions that aimed at identifying patients’ common misconceptions about diabetes. Results. A perfect score on the diabetes knowledge test was 16 points, and the mean±SD score of the respondents was 11.5±2.8. The most common misconception was “People can always feel when their blood sugar level is high.” (64%), followed by “Taking insulin hurts the kidneys and may result in a need for dialysis.” (52%) and “Being a vegetarian helps control blood sugar levels.” (48%). The total knowledge scores were significantly associated with education levels (rs=0.39, p

Background. Diabetes mellitus (DM) has become a significant worldwide public health problem and economic burden because a great proportion of healthcare costs has been spent on the treatment of DM and its related complications. The aim of this study was to examine the costs and length of stay (LoS) of hospitalizations due to diabetes-related complications in Taiwan. Methods. This study is a retrospective claim database analysis using the Longitudinal Cohort of Diabetes Patients, with 2012 used as the base year. The hospitalization costs and LoS per admission were estimated for each complication of interest using data from the LHDB 2004 to 2012 cohorts. The presence of eight DM-related complications were identified using the ICD-9-CM codes and procedure codes. ANOVA was used to examine the relationships of diabetes duration with the LoS and costs of the complications. Results. A total of 27,473 DM patients who were hospitalized in 2012 due to one of the examined DM-related complications were identified. The most common complications that caused the hospitalizations were nonfatal stroke (34.7%) and nonfatal ischemic heart disease (IHD) (28.7%). Amputation was the complication with the longest hospital stay, with a mean±SD of 21.6±14.1 days, followed by nonfatal stroke (13.6±11.3), ulcer (12.7±11.8), and fatal IHD (12.2±13.6). The complications with the greatest hospitalization cost were fatal IHD (mean=TWD 306,209.8; median=TWD 221,417.0; 1TWD=0.034USD) and fatal myocardial infarction (mean=TWD 272,840.1; median=TWD 174,008). Conclusions. This study indicates that DM-related complications are associated with significant hospital LoS and costs. The study results could be useful for economic evaluations of diabetes treatments and the estimation of the overall economic impact of diabetes.

Due to the chronic nature of diabetes along with their complications, they have been recognised as a major health issue, which results in significant economic burden. This study aims to estimate the direct medical cost associated with type 2 diabetes mellitus (T2DM) in Singapore in 2010 and to examine both the relationship between demographic and clinical state variables with the total estimated expenditure. The National Healthcare Group (NHG) Chronic Disease Management System (CDMS) database was used to identify patients with T2DM in the year 2010. DM-attributable costs estimated included hospitalisations, accident and emergency (A&E) room visits, outpatient physician visits, medications, laboratory tests and allied health services. All charges and unit costs were provided by the NHG. A total of 500 patients with DM were identified for the analyses. The mean annual direct medical cost was found to be $2,034, of which 61% was accounted for by inpatient services, 35% by outpatient services, and 4% by A&E services. Independent determinants of total costs were DM treatments such as the use of insulin only (p

Antiferromagnetic (AF) and ferrimagnetic (FiM) thin films have burgeoning significance in memory and computing applications due to their robustness and ultrafast and energy-efficient switching dynamics. Mn3Ga features a multitude of spin orders that can be meticulously controlled with stoichiometry, temperature, and strain modulations. In this work, we have carefully designed three suitable stacks of Mn3Ga thin films on MgO (111), STO (111) and STO (111)/Ta substrates deposited across varying substrate temperatures up to 500°C. The delicate interplay of strain and temperature tuning is examined by characterizing their magnetic, crystallographic, and morphological properties. The FiM tetragonal τ-Mn3Ga and AF hexagonal ε-Mn3Ga phases display relatively low saturation magnetizations of 10–60 and ≤ 20 kA/m, respectively. No preferential in-plane or out-of-plane magnetic anisotropy is observed for both τ- and ε-Mn3Ga phases. Critically, we observed that the STO strain-regulated τ-phase is stabilized over a wider temperature window and provides more compact, uniformly dispersed grains with average grain size of ~ 100 nm. This work establishes a sturdy methodology in understanding Mn3Ga thin film growth for eventual AF- and FiM-based memory and computing applications. [ABSTRACT FROM AUTHOR]

The Mn3Ga material is a promising candidate for memory and computing devices owing to its rich crystalline structures of tunable ferrimagnetic and collinear and non-collinear antiferromagnetic phases. In particular, Mn3Ga with non-collinear antiferromagnetic order exhibits giant anomalous and topological Hall conductivities and is a potential material platform for hosting spin-related quantum phenomena. In this study, we demonstrate Mn3Ga films grown on thermally oxidized Si substrates, with and without the Ta buffer, under different deposition temperatures (Ts). With increasing Ts, the dominant crystalline structure across all Mn3Ga films evolves from a cubic to hybrid tetragonal and hexagonal texture, wherein the crystalline orientation of spins endows the films with in-plane magnetic anisotropy. For Ta/Mn3Ga and Mn3Ga films grown under high Ts, the inhomogeneity in surface energy of the buffer layer results in a non-uniform granular film in the former. Notably, the Mn3Ga films of hexagonal texture exhibit topological Hall signatures. The density functional theory calculations on the hexagonal Mn3Ga phase corroborated with the experimental magnetic, structural, and transport properties. These findings establish an important platform for tailoring Mn3Ga films toward multifunctional applications. [ABSTRACT FROM AUTHOR]

Abstract Temperature variability has substantial socioeconomic impacts through its association with the frequency and severity of heat extremes. Under anthropogenic influence, climate models project seasonally-dependent amplifications of near-surface temperature variability over some sectors of the Southern Hemisphere, and robust positive trends have already been observed in recent decades. Here we show that the amplification of subweekly temperature variability simulated by the multi-model ensemble mean of the sixth phase of the Coupled Model Intercomparison Project (CMIP6) over South Africa, Australia, and South America is often substantially smaller than in reanalyses in recent decades, reaching a similar amplification only at the end of the 21st century due to a weaker amplification of subweekly variance generation efficiency. Analysis of a large model ensemble indicates that this discrepancy may be due to internal climatic variability suggesting that the recent rapid amplification seen in reanalyses may slow down or even temporarily reverse in the near future.

Abstract Catalytic asymmetric hydroboration of unsaturated bonds has been recognized as the most straightforward method for the construction of chiral organoboron compounds. Although catalytic asymmetric hydroboration of alkenes has been well-developed, enantioselective hydroboration of allenes still remains rare probably due to the challenges in controlling the enantio-, stereo-, and regioselectivity. Additionally, the hydroboration products might go through over-borohydride, making the catalytic asymmetric dihydroboration of allenes challenging. Here, we report a cobalt-catalyzed asymmetric dihydroboration of allenes using a ligand relay strategy with two simple ligands. This protocol shows excellent enantio-, stereo-, and regioselectivity with positive functional group compatibilities in the construction of chiral 1,4-diboronate products. The applications of this reaction are demonstrated by various product derivatizations, gram-scale reactions, and the preparation of artigenin analogues. Mechanistic studies indicate that the achiral ligand controls the first hydroboration of allenes, and the chiral oxazoline iminopyridine ligand is responsible for the subsequent isomerization and asymmetric hydroboration.

Abstract The East Asian summer monsoon (EASM) supplies vital rainfall for over one billion people. El Niño-Southern Oscillation (ENSO) markedly affects the EASM, but its impacts are more robust following El Niño than La Niña. Here, we show that this asymmetry arises from the asymmetry in ENSO evolution: though most El Niño events last for one year, La Niña events often persist for 2-3 years. In the summers between consecutive La Niña events, the concurrent La Niña opposes the delayed effect of the preceding winter La Niña on the EASM, causing a reduction in the magnitude and coherence of climate anomalies. Results from a large ensemble climate model experiment corroborate and strengthen the observational analysis with an order of magnitude increase in sample size. The apparent asymmetry in the impacts of the ENSO on the EASM can be reduced by considering the concurrent ENSO, in addition to the ENSO state in the preceding winter. This has important implications for seasonal climate forecasts.

Abstract Nipah virus infection, one of the top priority diseases recognized by the World Health Organization, underscores the urgent need to develop effective countermeasures against potential epidemics and pandemics. Here, we identify a fully human single-domain antibody that targets a highly conserved cryptic epitope situated at the dimeric interface of the Nipah virus G protein (receptor binding protein, RBP), as elucidated through structures by high-resolution cryo-electron microscopy (cryo-EM). This unique binding mode disrupts the tetramerization of the G protein, consequently obstructing the activation of the F protein and inhibiting viral membrane fusion. Furthermore, our investigations reveal that this compact antibody displays enhanced permeability across the blood-brain barrier (BBB) and demonstrates superior efficacy in eliminating pseudovirus within the brain in a murine model of Nipah virus infection, particularly compared to the well-characterized antibody m102.4 in an IgG1 format. Consequently, this single-domain antibody holds promise as a therapeutic candidate to prevent Nipah virus infections and has potential implications for vaccine development.

Abstract Arctic (E22G) mutation in amyloid-β (Aβ enhances Aβ40 fibril accumulation in Alzheimer’s disease (AD). Unlike sporadic AD, familial AD (FAD) patients with the mutation exhibit more Aβ40 in the plaque core. However, structural details of E22G Aβ40 fibrils remain elusive, hindering therapeutic progress. Here, we determine a distinctive W-shaped parallel β-sheet structure through co-analysis by cryo-electron microscopy (cryoEM) and solid-state nuclear magnetic resonance (SSNMR) of in-vitro-prepared E22G Aβ40 fibrils. The E22G Aβ40 fibrils displays typical amyloid features in cotton-wool plaques in the FAD, such as low thioflavin-T fluorescence and a less compact unbundled morphology. Furthermore, kinetic and MD studies reveal previously unidentified in-vitro evidence that E22G Aβ40, rather than Aβ42, may trigger Aβ misfolding in the FAD, and prompt subsequent misfolding of wild-type (WT) Aβ40/Aβ42 via cross-seeding. The results provide insight into how the Arctic mutation promotes AD via Aβ40 accumulation and cross-propagation.

Abstract Background Tumor tissues comprise cancer cells and stromal cells, and their interactions form the cancer microenvironment. Therefore, treatments targeting cells other than cancer cells are also actively being developed, and among them, treatment targeting PD-1, an immune checkpoint molecule that is important in tumor immune evasion, has also been indicated for head and neck cancer. PD-L1, a ligand of PD-1, is expressed in both tumor cells and stromal cells, and the scoring system based on the combined positivity rates of both types of cells, the combined positive score (CPS), is used for predicting treatment effect. However, much is unknown regarding the expression of PD-L1. In this study, we histopathologically examined factors controlling the expression of PD-1/PD-L1. This study included 37 patients who underwent resection surgery for tongue squamous cell carcinoma in the Department of Oral and Maxillofacial Surgery at Tokyo Dental College Suidobashi Hospital. The expression levels of PD-L1, α-SMA, and p53 were assessed by immunohistochemical staining. Results Seven participants had CPS ≥ 20, twenty-four participants had 1 ≤ CPS

Abstract The relationship of weight change has extended to accelerated ageing, yet little is known about the association between weight change and anti-aging protein α-Klotho. This study included 10,972 subjects from the National Health and Nutrition Examination Survey 2007–2016. Participants were measured body weight and height at baseline and recalled weight at young adulthood and middle adulthood. α-Klotho concentrations were quantified. Generalized linear regression models were used to assess the association between weight change and α-Klotho. Across adulthood, maximal overweight, non-obese to obese, and stable obesity were consistently associated with lower serum Klotho levels. Compared with participants who remained at normal weight, from middle to late adulthood, participants experiencing maximal overweight, moving from the non-obese to obese, and maintaining obesity had 27.97 (95% CI: − 46.57 to − 9.36), 39.16 (95% CI: − 61.15 to − 17.18), and 34.55 (95% CI: − 55.73 to − 13.37) pg/ml lower α-Klotho, respectively; similarly, from young to late adulthood, those had 29.21 (95% CI: − 47.00 to − 11.42) , 34.14 (95% CI: − 52.88 to − 15.40), and 36.61 (95% CI: − 65.01 to − 8.21) lower, respectively. Interestingly, from middle to late adulthood, the absolute weight change values of 590 participants who changed from obese to non-obese were negatively associated with serum α-Klotho. Each 1 kg of weight loss during the process of changing from obese to non-obese brought about a relative increase in α-Klotho levels of 3.03 pg/ml. The findings suggest the potential role of weight management across adulthood for aging.

Abstract Background Peritoneal dialysis (PD)-associated peritonitis is a serious complication that can lead to PD discontinuation and mortality. Tsukamurella species are uncommon opportunistic pathogens that can cause peritonitis, often necessitating catheter removal. Case presentation A 46-year-old woman with a 1.5-year history of PD presented with fever and lower abdominal pain, along with cloudy peritoneal effluent showing an elevated cell count. Empiric antibiotic therapy with ciprofloxacin, cefazolin, and ceftazidime was started for PD-associated peritonitis. The peritoneal effluent culture yielded a gram-positive rod with weak acid-fast staining. A rebound in the cell count necessitated a switch of antibiotics to meropenem and vancomycin. This led to improvement, and the treatment was switched to oral levofloxacin on day 30 and the patient was discharged on day 35. Subsequently, 16S rRNA gene sequencing confirmed the isolate as Tsukamurella inchonensis. Conclusion This case highlights the challenges in identifying and treating Tsukamurella peritonitis. Successful treatment without catheter removal in this case suggests that early detection and appropriate antibiotics may enable catheter salvage in this rare infection. However, further research is needed to establish optimal treatment strategies.

Uterine adenomyomas of endocervical type are rare benign tumors of the uterine cervix commonly presented as cyst-like, dilated glandular structures within polypoid masses. A premenopausal woman in her 50s was referred to our hospital because of an increasing watery vaginal discharge. A multifocal cyst measuring 5 × 4.5 cm in size projecting into the endocervical canal was revealed on a contrast-enhanced MRI. The fluid within the tumor showed a hypointense signal on T1-weighted imaging (T1WI) and a hyperintense signal on T2-weighted imaging (T2WI). On T2WI, most of the septa within the tumor showed a slightly hyperintense to hypointense signal, whereas some areas revealed a strong hypointense signal; the contrast effect on the septum was satisfactory. On the T2WI taken 2 years previously, the tumor was a 4.5 × 3.5 cm polypoid mass protruding from the posterior endocervical wall. Contrastingly, the current T2WI showed that the stem was no longer identifiable because of tumor growth. Because previous imaging showed that the tumor was a stalked tumor protruding from the posterior endocervical wall, the imaging diagnosis was uterine adenomyoma of the endocervical type. A biopsy suggested the possibility of a minimal deviation adenocarcinoma (MDA). Hence, a total hysterectomy was performed. The final diagnosis confirmed the uterine adenomyoma of endocervical type. Uterine adenomyoma of the endocervical type might be difficult to differentiate from MDA in small biopsy specimens; therefore, evaluation of morphology by MRI is considered important in preoperative diagnosis.

Mango has frequently encountered severe climate and environmental challenges such as low temperatures, seriously affecting the sustainable development of the industry. In the study, physiological measurements showed that the activities of superoxide dismutase (SOD) and peroxidase (POD) were found to be higher in Jinhuang (JH) mango plants than those of Tainong (TN) mango plants under cold stress, indicating cold tolerant (JH) and non-cold tolerant (TN) mango varieties were firstly determined. Subsequently, transcriptomics showed 8,337 and 7,996 differentially expressed genes (DEGs) were respectively identified in JH and TN mango varieties treated at 4 °C for 36 h, while more DEGs (10,683 and 10,723) were screened when treated at 4 °C for 72 h. Quantitative real-time PCR (qRT-PCR) of the selected DEGs confirmed their transcriptional levels displayed agreement to the transcriptome data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed two primary cold resistant regulation pathways, photosynthesis-antenna proteins pathway and photosynthesis pathway, were both significant annotated in the two mango varieties, indicating share the common regulation mechanism response to cold stress. However, five specific cold resistant pathways, such as amino acid and carbohydrate metabolisms, were identified in JH mango variety with cold stress for longer duration, indicating the specific regulation pathways in the cold tolerant mango varieties. Furthermore, 43 ethylene-responsive transcription factors (ERFs) were significantly annotated in JH mango after cold-treated for 72 h comparing with the control group, and three of them ERF109-1, ERF017-1 and ERF017-2 were highly expressed, which may play important regulatory roles in plant cold resistance. These results provided insights into the primary and specific molecular mechanisms of different mango varieties resistance to chill.

Abstract Background Mango (Mangifera indica L.) is grown in Hainan, Guangdong, Yunnan, Sichuan, and Fujian provinces and Guanxi autonomous region of China. However, trees growing in these areas suffer severe cold stress during winter, which affects the yield. To this regard, data on global metabolome and transcriptome profiles of leaves are limited. Here, we used combined metabolome and transcriptome analyses of leaves of three mango cultivars with different cold stress tolerance, i.e. Jinhuang (J)—tolerant, Tainung (T) and Guiremang No. 82 (G)—susceptible, after 24 (LF), 48 (MF) and 72 (HF) hours of cold. Results A total of 1,323 metabolites belonging to 12 compound classes were detected. Of these, amino acids and derivatives, nucleotides and derivatives, and lipids accumulated in higher quantities after cold stress exposure in the three cultivars. Notably, Jinhuang leaves showed increasing accumulation trends of flavonoids, terpenoids, lignans and coumarins, and alkaloids with exposure time. Among the phytohormones, jasmonic acid and abscisic acid levels decreased, while N6-isopentenyladenine increased with cold stress time. Transcriptome analysis led to the identification of 22,526 differentially expressed genes. Many genes enriched in photosynthesis, antenna proteins, flavonoid, terpenoid (di- and sesquiterpenoids) and alkaloid biosynthesis pathways were upregulated in Jihuang leaves. Moreover, expression changes related to phytohormones, MAPK (including calcium and H2O2), and the ICE-CBF-COR signalling cascade indicate involvement of these pathways in cold stress responses. Conclusion Cold stress tolerance in mango leaves is associated with regulation of primary and secondary metabolite biosynthesis pathways. Jasmonic acid, abscisic acid, and cytokinins are potential regulators of cold stress responses in mango leaves.

Abstract The Pacific/North American (PNA) pattern is a major low‐frequency variability in boreal winter. A recent modeling study suggested that PNA variability increases through extratropical atmosphere‐ocean coupling, but the effect was not fully extracted due to a particular experimental design. By comparing coupled and two sets of uncoupled large‐ensemble global model simulations, here we show that the PNA‐induced horseshoe‐shaped sea‐surface temperature (SST) anomaly in the North Pacific returns a non‐negligible influence on the PNA itself. Its magnitude depends on the presence or absence of atmosphere‐ocean coupling. The coupling accounts for ∼16% of the PNA variance, while the horseshoe‐shaped SST anomaly explains only 5% under the uncoupled condition. The coupling reduces the damping of available potential energy by modulating turbulent heat fluxes and precipitation, magnifying the PNA variance. Precipitation processes in the extratropics as well as tropics are therefore important for realistically representing PNA variability and thereby regional weather and climate.