Comparison of the diagnostic performance of tryptase and histamine for perioperative anaphylaxis: A multicenter prospective study.

BACKGROUND: Diagnosing perioperative anaphylaxis (POA) is often challenging. Although a guideline recommends measuring tryptase rather than histamine, there is little evidence for this. We aimed to examine the diagnostic performance and appropriate timing of tryptase and histamine measurements for diagnosing anaphylaxis, and the association between Hypersensitivity Clinical Scoring Scheme (HCSS) scores and elevated biomarkers. METHODS: We measured tryptase and histamine levels thrice: 30 min, 2 h, and at least 24 h after an anaphylactic event for patients with suspected anaphylaxis, and at the induction of general anesthesia and 30 min and 2 h after the start of surgery for control patients without a reaction. Absolute values and the magnitude and rate of change from baseline were evaluated. We determined the thresholds of tryptase and histamine levels with the best diagnostic performance and compared their performance. RESULTS: Forty-five patients with perioperative anaphylaxis were included in this study. The control group included 30 patients with uneventful general anesthesia and 12 patients with a suspected but unconfirmed diagnosis of perioperative anaphylaxis. Comparison at the same measurement timings showed that tryptase generally had better diagnostic performance than histamine. Both showed better diagnostic performance when assessed using multiple measurements rather than a single measurement. The best diagnostic performance was seen with the percentage change in the higher tryptase value, whether measured at 30 min or 2 h after anaphylaxis onset, as compared to baseline. However, neither tryptase nor histamine levels correlated with HCSS scores. CONCLUSIONS: Overall, tryptase showed better diagnostic performance than histamine. When multiple tryptase measurements are possible, parameters calculated using two acute phase measurements and the baseline level have better diagnostic performance.

One- versus three-month dual antiplatelet therapy in high bleeding risk patients undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes.

BACKGROUND: A short dual antiplatelet therapy (DAPT) duration has been proposed for patients at high bleeding risk (HBR) undergoing drug-eluting coronary stent (DES) implantation. Whether this strategy is safe and effective after a non-ST-segment elevation acute coronary syndrome (NSTE-ACS) remains uncertain. AIMS: We aimed to compare the impact of 1-month versus 3-month DAPT on clinical outcomes after DES implantation among HBR patients with or without NSTE-ACS. METHODS: This is a prespecified analysis from the XIENCE Short DAPT programme involving three prospective, international, single-arm studies evaluating the safety and efficacy of 1-month (XIENCE 28 USA and Global) or 3-month (XIENCE 90) DAPT among HBR patients after implantation of a cobalt-chromium everolimus-eluting stent. Ischaemic and bleeding outcomes associated with 1- versus 3-month DAPT were assessed according to clinical presentation using propensity score stratification. RESULTS: Of 3,364 HBR patients (1,392 on 1-month DAPT and 1,972 on 3-month DAPT), 1,164 (34.6%) underwent DES implantation for NSTE-ACS. At 12 months, the risk of the primary endpoint of death or myocardial infarction was similar between 1- and 3-month DAPT in patients with (hazard ratio [HR] 1.09, 95% confidence interval [CI]: 0.71-1.65) and without NSTE-ACS (HR 0.88, 95% CI: 0.63-1.23; p-interaction=0.34). The key secondary endpoint of Bleeding Academic Research Consortium (BARC) Type 2-5 bleeding was consistently reduced in both NSTE-ACS (HR 0.57, 95% CI: 0.37-0.88) and stable patients (HR 0.84, 95% CI: 0.61-1.15; p-interaction=0.15) with 1-month DAPT. CONCLUSIONS: Among HBR patients undergoing implantation of an everolimus-eluting stent, 1-month, compared to 3-month DAPT, was associated with similar ischaemic risk and reduced bleeding at 1 year, irrespective of clinical presentation.

CD4+ T cell heterogeneity in gestational age and preeclampsia using single-cell RNA sequencing.

A balance between pro-inflammatory decidual CD4+ T cells and FOXP3+ regulatory T cells (FOXP3+ Tregs) is important for maintaining fetomaternal tolerance. Using single-cell RNA-sequencing and T cell receptor repertoire analysis, we determined that diversity and clonality of decidual CD4+ T cell subsets depend on gestational age. Th1/Th2 intermediate and Th1 subsets of CD4+ T cells were clonally expanded in both early and late gestation, whereas FOXP3+ Tregs were clonally expanded in late gestation. Th1/Th2 intermediate and FOXP3+ Treg subsets showed altered gene expression in preeclampsia (PE) compared to healthy late gestation. The Th1/Th2 intermediate subset exhibited elevated levels of cytotoxicity-related gene expression in PE. Moreover, increased Treg exhaustion was observed in the PE group, and FOXP3+ Treg subcluster analysis revealed that the effector Treg like subset drove the Treg exhaustion signatures in PE. The Th1/Th2 intermediate and effector Treg like subsets are possible inflammation-driving subsets in PE.

Exploiting sweet relief for preeclampsia by targeting autophagy-lysosomal machinery and proteinopathy.

The etiology of preeclampsia (PE), a severe complication of pregnancy with several clinical manifestations and a high incidence of maternal and fetal morbidity and mortality, remains unclear. This issue is a major hurdle for effective treatment strategies. We recently demonstrated that PE exhibits an Alzheimer-like etiology of impaired autophagy and proteinopathy in the placenta. Targeting of these pathological pathways may be a novel therapeutic strategy for PE. Stimulation of autophagy with the natural disaccharide trehalose and its lacto analog lactotrehalose in hypoxia-exposed primary human trophoblasts restored autophagy, inhibited the accumulation of toxic protein aggregates, and restored the ultrastructural features of autophagosomes and autolysosomes. Importantly, trehalose and lactotrehalose inhibited the onset of PE-like features in a humanized mouse model by normalizing autophagy and inhibiting protein aggregation in the placenta. These disaccharides restored the autophagy-lysosomal biogenesis machinery by increasing nuclear translocation of the master transcriptional regulator TFEB. RNA-seq analysis of the placentas of mice with PE indicated the normalization of the PE-associated transcriptome profile in response to trehalose and lactotrehalose. In summary, our results provide a novel molecular rationale for impaired autophagy and proteinopathy in patients with PE and identify treatment with trehalose and its lacto analog as promising therapeutic options for this severe pregnancy complication.

Treatment-resistant hiccups during general anesthesia possibly caused by remimazolam: a case report.

BACKGROUND: Previous reports have described hiccups during general anesthesia that were possibly induced by drugs, including benzodiazepines. However, there are few reports of hiccups caused by remimazolam. Case presentation A 75-year-old woman underwent corneal transplantation under general anesthesia with remimazolam. She presented with hiccups once the effects of muscle relaxants used during induction wore off, which persisted even after various treatments, such as the administration of antipsychotic drugs. However, when remimazolam administration was terminated after surgery to awaken the patient, the hiccups stopped and did not recur after extubation. Evaluation of predicted blood levels of remimazolam suggests that higher levels of remimazolam might cause hiccups. CONCLUSION: Remimazolam might induce hiccups during general anesthesia. Anesthesiologists should consider administering muscle relaxants or changing the anesthetic in cases of refractory hiccups under general anesthesia.

A case of pediatric Perthes' disease with unexplained hyperlactatemia at the time of initial surgery and anesthetic management with remimazolam for the subsequent surgery.

BACKGROUND: The causes of perioperative hyperlactatemia vary, but they are generally associated with hypoperfusion. Here, we report the case of a pediatric patient who developed unexplained hyperlactatemia during anesthesia with propofol and sevoflurane, which recurred during a second surgery under anesthesia with remimazolam. CASE PRESENTATION: An 8-year-old boy with Perthes disease and no remarkable past or family history was scheduled for an osteotomy. Anesthesia was induced with propofol and rocuronium and then maintained with sevoflurane and remifentanil. The patient developed lactic acidosis without hemodynamic instability during anesthesia, with a normal lactate/pyruvate ratio after surgery, suggesting a lack of hypoperfusion. We used remimazolam instead of propofol during the second surgery 6 months later, considering the possibility of drug-induced lactic acidosis, including malignant hyperthermia and propofol infusion syndrome, where the unexplained hyperlactatemia recurred. CONCLUSIONS: Distinguishing the causes of hyperlactatemia, particularly in the absence of other symptoms, is challenging. The lactate/pyruvate ratio during episodes of hyperlactatemia can provide insights into the underlying pathology.

Impact of preprocedural left ventricular systolic function on the safety and durability of percutaneous coronary intervention.

BACKGROUND: Percutaneous coronary intervention (PCI) is considered less safe in patients with reduced ejection fraction (EF), an impression based on older data. Whether the safety and durability of contemporary PCI are different in patients with reduced EF compared with normal EF patients is unknown. METHODS: Patients from the BIOFLOW II, IV and V clinical trials were grouped as normal EF (≥50%) and reduced EF (30%-50%). Using multivariable logistic regression and cox proportional hazards regression, we determined relations of EF category with procedural safety (a composite of cardiac death, myocardial infarction, stroke and urgent coronary artery bypass grafting within 30 days of PCI) and target lesion failure (TLF; comprising cardiac death, target vessel myocardial infarction, target vessel revascularization within 1 year of PCI) respectively. In sensitivity analyses, we regrouped patients into EF < 45% and ≥55% and repeated the aforementioned analyses. RESULTS: In 1685 patients with normal EF (mean age 65 years; 27% women; mean EF 61%) and 259 with low EF (mean age 64 years; 17% women; mean EF 41%), 101 safety and 148 TLF events occurred. Compared with patients in the normal EF group, those with reduced EF had neither a statistically significant higher proportion of safety events, nor a higher multivariable-adjusted risk for such events. Similarly, patients with reduced EF and normal EF did not differ in terms of TLF event proportions or multivariable-adjusted risk for TLF. The results were similar in sensitivity analyses with EF groups redefined to create a 10% between-group EF separation. CONCLUSION: PCI safety and durability outcomes are similar in patients with mild-moderately reduced EF and normal EF.

The relationship between preoperative blood pressure during anesthetic examinations and pre-intubation blood pressure.

BACKGROUND: There have been few reports showing the relationship between blood pressure (BP) measured at clinics preoperatively and BP measured before anesthetic intubation/induction. The purpose of this study was to examine the relationship between BP measured at different times and settings preoperatively and BP measured before intubation/induction. METHODS: A total of 182 patients who underwent general anesthesia between March 2021 and April 2022 in a university hospital were examined. In addition to self-reported BP asked on an anesthetic examination sheet completed by each patient, BPs were measured three times, before, during, and after preoperative examination by the anesthesiologist. The derived parameter was compared with BP measured before intubation at the time of general anesthesia induction. RESULTS: The systolic BP in the intra-examination period had the most significant correlation with pre-intubation systolic BP (r = 0.5230, p < 0.0001, 95% CI = 0.4050 to 0.6238). On Bland-Altman analysis, the intra-examination systolic BP seemed to be similar and showed better agreement with pre-intubation systolic BP than other measured BPs, with a mean bias of 2.2 mmHg and the narrowest 95% limits of agreement (-33.7 to + 38.1 mmHg). CONCLUSIONS: The preoperative systolic BP value measured during the examination by the anesthesiologist was found to be closely related to pre-intubation systolic BP measured in the operating room. Higher BP during the preoperative examination may be a result of anxiety-induced stress or white-coat hypertension. Measuring BP during the anesthesiologist's examination may be useful for predicting hypertension in the pre-intubation period.

Establishing Monoclonal Gammopathy of Undetermined Significance as an Independent Pre-Disease State of Multiple Myeloma Using Raman Spectroscopy, Dynamical Network Biomarker Theory, and Energy Landscape Analysis.

Multiple myeloma (MM) is a cancer of plasma cells. Normal (NL) cells are considered to pass through a precancerous state, such as monoclonal gammopathy of undetermined significance (MGUS), before transitioning to MM. In the present study, we acquired Raman spectra at three stages-834 NL, 711 MGUS, and 970 MM spectra-and applied the dynamical network biomarker (DNB) theory to these spectra. The DNB analysis identified MGUS as the unstable pre-disease state of MM and extracted Raman shifts at 1149 and 1527-1530 cm-1 as DNB variables. The distribution of DNB scores for each patient showed a significant difference between the mean values for MGUS and MM patients. Furthermore, an energy landscape (EL) analysis showed that the NL and MM stages were likely to become stable states. Raman spectroscopy, the DNB theory, and, complementarily, the EL analysis will be applicable to the identification of the pre-disease state in clinical samples.

Sodium-Glucose Cotransporter-2 Inhibitors Stabilize Coronary Plaques in Acute Coronary Syndrome With Diabetes Mellitus.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used in cardiology and are effective in treating acute coronary syndrome (ACS). Their effects on unstable plaque in patients with ACS remains unclear. This study aimed to examine the effectiveness of SGLT2is in coronary plaque based on optical coherence tomography (OCT) images and the prognosis of ACS with type 2 diabetes mellitus. This retrospective study included 109 patients in the total cohort and 29 patients in the OCT cohort. Based on SGLT2i administration after ACS, the total cohort was categorized into non-SGLT2i (n = 69) and SGLT2i (n = 40) groups. The OCT cohort had 15 and 14 patients in the non-SGLT2i and SGLT2i groups, respectively. The OCT images of unstable plaque were analyzed in nonstented lesions during ACS catheterization and at the 6-month follow-up. The total cohort was assessed after 1 year for major adverse cardiovascular events, including all-cause mortality, revascularization, cerebrovascular disease, and heart failure hospitalization. SGLT2is improved unstable lesions with a significantly thicker fibrous cap (48 ± 15 µm vs 26 ± 24 µm, p = 0.005), reduced lipid arc (-29 ± 12° vs -18 ± 14°, p = 0.028), higher % decrease in total lipid arc (-35 ± 13% vs -19 ± 18%, p = 0.01), and lower major adverse cardiovascular event incidence (log-rank p = 0.023, hazard ratio 4.72 [1.08 to 20.63]) and revascularization rate (adjusted hazard ratio 6.77 [1.08 to 42.52]) than the non-SGLT2i group. In conclusion, SGLT2is can improve the markers of plaque stability and may improve the prognosis in patients with type 2 diabetes mellitus.

1- Versus 3-Month DAPT in Older Patients at a High Bleeding Risk Undergoing PCI: Insights from the XIENCE Short DAPT Global Program.

This analysis aimed to evaluate the effect of 1- versus 3-month dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in older patients. Data from 3 prospective, single-arm studies (XIENCE Short DAPT Program), including patients with high bleeding risk successfully treated with an everolimus-eluting stent (XIENCE, Abbott) were analyzed. DAPT was discontinued at 1 or at 3 months in patients free from ischemic events and adherent to DAPT. Patients were stratified according to age (≥75 and <75 years). The primary end point was all-cause death or myocardial infarction (MI). The key secondary end point was Bleeding Academic Research Consortium type 2 to 5 bleeding. The outcomes were assessed from 1 to 12 months after index PCI. Of 3,364 patients, 2,241 (66.6%) were aged ≥75 years. The risk of death or MI was similar with 1- versus 3-month DAPT in patients aged ≥75 (8.5% vs 8.0%, adjusted hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.69 to 1.30) and <75 years (6.9% vs 7.8%, adjusted HR 0.97, 95% CI 0.60 to 1.57, interaction p = 0.478). Bleeding Academic Research Consortium type 2 to 5 bleeding was consistently lower with 1- than with 3-month DAPT in patients aged ≥75 years (7.2% vs 9.4%, adjusted HR 0.66, 95% CI 0.48 to 0.91) and <75 years (9.7% vs 11.9%, adjusted HR 0.86, 95% CI 0.57 to 1.29, interaction p = 0.737). In conclusion, in patients at high bleeding risk who underwent PCI, patients older and younger than 75 years derived a consistent benefit from 1- compared with 3-month DAPT in terms of bleeding reduction, with no increase in all-cause death or MI at 1 year.

Medical issues for female athletes returning to competition after childbirth.

BACKGROUND: In recent years, the number of athletes who aim to return to competition after childbirth has increased. However, few international reports have investigated complications during pregnancy, and changes in physical function after childbirth in many athletes. OBJECTIVE: To conduct a retrospective investigation of medical problems during pregnancy, and postpartum, in female athletes who aim to return to competition after childbirth, and to identify the barriers and facilitators for their return. METHODS: A voluntary web-based survey was aimed at former female athletes who became pregnant with their first child and gave birth during their active sports career. The survey items included respondent background, their exercise activities during and after childbirth, perinatal complications, mode of delivery, symptoms and physical function after childbirth. The participants were divided into a vaginal delivery group and a cesarean section group. RESULTS: Three hundred and twenty-eight (29.1 ± 5.1 years old) former athletes were included in the analysis, and about half reported undertaking exercise during pregnancy. The most common perinatal complication was anemia (27.4%). The appearance of any symptoms after childbirth, including low back pain (44.2%) and urinary incontinence (39.9%), was reported by 80.5%. The rate of urinary incontinence may be higher in the vaginal delivery than in the cesarean section group (p = 0.05). The most common physical decline after childbirth was in muscular strength, followed by speed and endurance. CONCLUSION: Addressing pregnancy-associated anemia and managing low back pain is critical for athletes aiming to return to competition after childbirth. Additionally, interventions to reduce the risk for and treat urinary incontinence are important. In addition, in order to return to competition after childbirth, it is important to strengthen muscles, especially the lower limbs and trunk, as well as to create a training program that takes into account the sport/events.

Age and menstrual cycle may be important in establishing pregnancy in female athletes after retirement from competition.

BACKGROUND: Although it has been shown that amenorrhea associated with low energy availability or relative energy deficiency in sport affects body physiology in female athletes, the association between menstrual dysfunction during active sports careers and reproductive function after retirement is not clear. OBJECTIVE: To investigate the association between menstrual dysfunction during their active sports career and post-retirement infertility in female athletes. METHODS: A voluntary web-based survey was aimed at former female athletes who had become pregnant and gave birth to their first child after retirement. Nine multiple-choice questions were included, on maternal age, competition levels and menstrual cycles during active sports careers, time from retirement to pregnancy, the time of resumption of spontaneous menstruation after retirement, conception method, and mode of delivery, etc. Regarding cases of primary and secondary amenorrhea among the abnormal menstrual cycle group, only those whose spontaneous menstruation had not recovered from retirement to the time of pregnancy were included in the study. The association between the presence of abnormal menstrual cycles from active sports careers to post-retirement pregnancy and the implementation of infertility treatment was evaluated. RESULTS: The study population included 613 female athletes who became pregnant and gave birth to their first child after retiring from competitive sports. Of the 613 former athletes, the infertility treatment rate was 11.9%. The rate of infertility treatment was significantly higher in athletes with abnormal than normal menstrual cycles (17.1% vs. 10.2%, p = 0.0225). Multivariable logistic regression analysis showed that maternal age (adjusted odds ratio [OR] 1.194; 95% confidence interval [CI] 1.129, 1.262) and abnormal menstrual cycles (OR and 1.903; adjusted OR 1.105, 3.278) were the relevant factors for infertility treatment. CONCLUSION: It was suggested that menstrual dysfunction that persist from active sports careers to post-retirement may be a factor in infertility when trying to conceive after retirement.

One-year safety and effectiveness of the Agent paclitaxel-coated balloon for the treatment of small vessel disease and in-stent restenosis.

The Agent device consists of a semi-compliant balloon catheter, which is coated with a therapeutic low-dose formulation of paclitaxel (2 µg/mm2) blended with an inactive excipient acetyl-tri-n-butyl citrate (ATBC). AGENT Japan SV is a randomized controlled study that enrolled 150 patients from 14 Japanese sites treated with Agent or SeQuent Please paclitaxel-coated balloon. This study also includes a single-arm substudy evaluating the safety and effectiveness of Agent in patients with in-stent restenosis (ISR). Patients with a single de novo native lesion (lesion length ≤ 28 mm and reference diameter ≥ 2.00 to < 3.00 mm) were randomized 2:1 to receive either Agent (n = 101) or SeQuent Please (n = 49). The ISR substudy enrolled 30 patients with lesion length ≤ 28 mm and reference diameter ≥ 2.00 to ≤ 4.00 mm. In the SV RCT, target lesion failure (TLF) at 1 year occurred in four patients treated with Agent (4.0%) versus one patient with SeQuent Please (2.0%; P = 1.00). None of the patients in either treatment arm died. There were no significant differences in the rates of myocardial infarction, target lesion revascularization and target lesion thrombosis through 1 year. In the ISR substudy, the 1-year rates of TLF and target lesion thrombosis were 6.7% and 0.0%, respectively. These data support the safety and effectiveness of the Agent paclitaxel-coated balloon in patients with small vessels and ISR.

Long-Term Assessment of Survival After Transcatheter Aortic Valve Implantation　- Insights From the International Transcatheter Aortic Valve Implantation Registry.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an established treatment for severe aortic stenosis (AS), but despite estimates of life expectancy after TAVI being essential in heart team discussion, these data are scarce. Therefore, the current study sought to assess long-term survival and its trends in relation to chronological age, surgical risk, and treatment period.Methods and Results: We included 2,414 consecutive patients who underwent TAVI for severe symptomatic AS between 2008 and 2021 at 2 international centers. For the analysis, long-term survival was evaluated according to age, surgical risk, and treatment period categorized into 3 groups, respectively. The longest follow-up was 13.5 years. Overall survival was 67.6% at 5 years and 26.9% at 10 years. Younger patients, lower surgical risk, and later treatment period showed better survival (log-rank P<0.001, respectively). In the multivariate analysis, age <75years, lower surgical risk, and later time period were significantly associated with better survival. The incidence of paravalvular leakage ≥moderate, red blood cell transfusion, and acute kidney injury were independently associated with increasing risk of 5-year death. CONCLUSIONS: In a real-world registry, survival was substantial following TAVI, especially in younger and lower surgical-risk patients, with improving outcomes over time. This should be considered in heart team discussions of life-long management for AS patients after TAVI.

Initial results of transcatheter modification of left atrial appendage by obliteration with device in patients with nonvalvular atrial fibrillation: Real-world data from the TERMINATOR registry.

BACKGROUND: Percutaneous left atrial appendage closure (LAAC) has increased for those who need alternative to long-term anticoagulation with non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: From September 2019, after initiating WATCHMAN (Boston Scientific, Maple Grove, MN, USA) device implantation, we established Transcatheter Modification of Left Atrial Appendage by Obliteration with Device in Patients from the NVAF (TERMINATOR) registry. Utilizing 729 patients' data until January 2022, we analyzed percutaneous LAAC data regarding this real-world multicenter prospective registry. A total of 729 patients were enrolled. Average age was 74.9 years and 28.5 % were female. Paroxysmal AF was 37.9 % with average CHADS2 3.2, CHA2DS2-VASc 4.7, and HAS-BLED score of 3.4. WATCHMAN implantation was successful in 99.0 %. All-cause deaths were 3.2 %, and 1.2 % cardiovascular or unexplained deaths occurred during follow-up [median 222, interquartile range (IQR: 93-464) days]. Stroke occurred in 2.2 %, and the composite endpoint which included cardiovascular or unexplained death, stroke, and systemic embolism were counted as 3.4 % [median 221, (IQR: 93-464) days]. Major bleeding defined as BARC type 3 or 5 was seen in 3.7 %, and there was 8.6 % of all bleeding events in total [median 219, (IQR: 93-464) days]. CONCLUSIONS: These preliminary data demonstrated percutaneous LAAC with WATCHMAN device might have a potential to reduce stroke and bleeding events for patients with NVAF. Further investigation is mandatory to confirm the long-term results of this strategy using this transcatheter local therapy instead of life-long systemic anticoagulation.