Tiger attack at a Japanese safari park: a case report.

BACKGROUND: Big cat bites are highly lethal due to the enormous bite force of these animals. This article reviews the morphology of these types of injuries and key points of management through a survival case at a Japanese safari park. CASE PRESENTATION: We report the case of a 26-year-old female keeper who was attacked by a tiger. She was quickly transported to our university hospital by ambulance helicopter. The keeper was severely bitten on the head and face and had wounds all over her body. Craniofacial repair was performed by emergency surgery. She suffered mild facial nerve paralysis and trismus because of being bitten by the tiger and is currently recovering. CONCLUSIONS: A multidisciplinary approach of the severe tiger bites successfully treated a young woman cosmetically and mentally. Animal farms and zoos that keep tigers should take strict measures to avoid direct confrontation with tigers.

Association between neuromuscular blocking agent use and outcomes among out-of-hospital cardiac arrest patients treated with extracorporeal cardiopulmonary resuscitation and target temperature management: A secondary analysis of the SAVE-J II study.

Background: Neuromuscular blocking agents are used to control shivering in cardiac arrest patients treated with target temperature management. However, their effect on outcomes in patients treated with extracorporeal cardiopulmonary resuscitation is unclear. Methods: This study was a secondary analysis of the SAVE-J II study, a retrospective multicenter study of 2175 out-of-hospital cardiac arrest patients treated with extracorporeal cardiopulmonary resuscitation in Japan. We classified patients into those who received neuromuscular blocking agents and those who did not and compared in-hospital mortality and incidence rates of favorable neurological outcome and in-hospital pneumonia between the groups using multivariable regression models and stabilized inverse probability weighting with propensity scores. Results: Six hundred sixty patients from the SAVE-J II registry were analyzed. Neuromuscular blocking agents were used in 451 patients (68.3%). After adjusting for potential confounders, neuromuscular blocking agents use was not significantly associated with in-hospital mortality (aHR 0.88; 95% CI, 0.67-1.14), favorable neurological outcome (aOR 0.85; 95% CI, 0.60-1.11), or pneumonia (aOR 1.52; 95% CI, 0.85-2.71). The results for in-hospital mortality (aHR 0.89; 95% CI, 0.64-1.25), favorable neurological outcome (aOR 0.94; 95% CI, 0.59-1.48) and pneumonia (aOR 1.59; 95% CI, 0.74-3.41) were similar after weighting was performed. Conclusions: Although data on the rationale for using neuromuscular blocking agents were unavailable, their use was not significantly associated with outcomes in out-of-hospital cardiac arrest patients treated with extracorporeal cardiopulmonary resuscitation and targeted temperature management. Neuromuscular blocking agents should be used based on individual clinical indications.

Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for adult convulsive status epilepticus: a multicentre non-inferiority randomised control trial.

OBJECTIVE: Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy, but higher safety. Therefore, we herein compared LEV with FPHT in adult SE. METHODS: We initiated a multicentre randomised control trial in emergency departments with adult patients with convulsive SE. Diazepam was initially administered, followed intravenously by FPHT at 22.5 mg/kg or LEV at 1000-3000 mg. The primary outcome was assigned as the seizure cessation rate within 30 min of the administration of the study drug. RESULTS: A total of 176 adult patients with SE were enrolled (82 FPHT and 94 LEV), and 3 were excluded from the full analysis set. Seizure cessation rates within 30 min were 83.8% (67/80) in the FPHT group and 89.2% (83/93) in the LEV group. The difference in these rates was 5.5% (95% CI -4.7 to 15.7, p=0.29). The non-inferiority of LEV to FPHT was confirmed with p<0.001 by the Farrington-Manning test. No significant differences were observed in the seizure recurrence rate or intubation rate within 24 hours. Serious adverse events developed in three patients in the FPHT group and none in the LEV group (p=0.061). CONCLUSION: The efficacy of LEV was similar to that of FPHT for adult SE following the administration of diazepam. LEV may be recommended as a second-line treatment for SE along with phenytoin/FPHT. TRIAL REGISTRATION NUMBER: jRCTs031190160.

Characteristics of patients who received helicopter emergency medical services in Japan from 2012 to 2019: a retrospective analysis of data from Tochigi Prefecture.

BACKGROUND: Helicopter Emergency Medical Services (HEMS) has been in operation in Japan since 2001, allowing patients almost anywhere in the nation to receive on-scene emergency treatment from physicians. However, there is insufficient literature on the characteristics of the patients who use Japanese HEMS. Thus, this study aimed to investigate the overall characteristics of patients receiving HEMS care within a single prefecture in Japan. METHODS: We retrospectively analyzed the data of 5163 patients-in Tochigi Prefecture-who received HEMS care from 2012 to 2019. Descriptive statistics were used to analyze the following aspects of care: diagnosis, severity, background characteristics, geographical and environmental variables, immediate pre-hospital intervention, transportation type, and short-term clinical outcomes. RESULTS: Among 7370 HEMS requests received during the study period, treatment was provided to 5163 patients (1.8 cases per day; 3489 men [67.6%]). Nearly 55% (n = 2856) of patients were aged above 60 years. Age peaks were observed at 0-9 years and 60-69 years. The median distance from the base hospital to the site was 26.7 km. The age-standardized rate of HEMS treatment was 30.3 patients per 100,000 people. Cases of trauma and cardiovascular diseases were the most common (65.3%). Most individuals aged 0-9 years and 60-69 years had neurological disease (seizures accounted for 80.5% of this group) and cardiovascular disease, respectively. The number of patients was similar across all four seasons. After immediate pre-hospital intervention, 81.6% of patients receiving HEMS care were transferred by the helicopter ambulance (53.4% and 28.2% to the base hospital and to other hospitals, respectively). Overall, 56.6% of patients receiving HEMS care were transferred to the base hospital, and the short-term recovery rate was above 75%. Intravenous drip and oxygen administration were the most common pre-hospital interventions (93.1% and 72.7%, respectively). CONCLUSIONS: This study is the first to describe the overall characteristics of HEMS patients using comprehensive data of all HEMS patients in one prefecture in Japan. Further research using both local- and national-level data is needed to accelerate the understanding of the benefits of HEMS.

Phenytoin versus other antiepileptic drugs as treatments for status epilepticus in adults: a systematic review and meta-analysis.

AIM: Status epilepticus (SE) is a life-threatening neurological emergency. There is insufficient evidence regarding which antiepileptic therapy is most effective in patients with benzodiazepine-refractory convulsive SE. Therefore, this study aimed to evaluate intravenous phenytoin (PHT) and other intravenous antiepileptic medications for SE. METHODS: We searched PubMed, the Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi for published randomized controlled trials (RCTs) in humans up to August 2019. We compared outcomes between intravenous PHT and other intravenous medications. The important primary composite outcomes were the successful clinical cessation of seizures, mortality, and neurological outcomes at discharge. The reliability of the level of evidence for each outcome was compared using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: A total of 1,103 studies were identified from the databases, and 10 RCTs were included in the analysis. The ratio of successful clinical seizure cessation was significantly lower (risk ratio [RR] 0.89; 95% confidence interval [CI], 0.82-0.97) for patients treated with intravenous PHT than with other medications. When we compared mortality and neurological outcomes at discharge, we observed no significant differences between patients treated with PHT and those treated with other medications. The RRs were 1.07 (95% CI, 0.55-2.08) and 0.91 (95% CI, 0.72-1.15) for mortality and neurological outcomes at discharge, respectively. CONCLUSIONS: Our findings showed that intravenous PHT was significantly inferior to other medications in terms of the cessation of seizures. No significant differences were observed in mortality or neurological outcomes between PHT and other medications.

Transmission of toxigenic Corynebacterium ulcerans infection with airway obstruction from cats to a human.

BACKGROUND: Infections caused by Corynebacterium ulcerans, a zoonotic pathogen, have been reported worldwide. This microorganism is known to produce the diphtheria toxin and cause diphtheria-like illness. CASE PRESENTATION: A 63-year-old woman with a history of diabetes and hypertension developed cold and flu-like symptoms, which gradually progressed into respiratory distress. Therefore, the patient was intubated for dyspnea with pseudomembrane formation. A toxin-producing strain of C. ulcerans was identified, also detected in the patient's domestic cats. Multilocus sequence typing confirmed all strains, including the patient's isolate, as ST337. CONCLUSION: Multilocus sequence typing revealed zoonotic transmission of C. ulcerans from domestic cats to a human.

Conventional risk prediction models fail to accurately predict mortality risk among patients with coronavirus disease 2019 in intensive care units: a difficult time to assess clinical severity and quality of care.

Since the start of the coronavirus disease 2019 (COVID-19) pandemic, it has remained unknown whether conventional risk prediction tools used in intensive care units are applicable to patients with COVID-19. Therefore, we assessed the performance of established risk prediction models using the Japanese Intensive Care database. Discrimination and calibration of the models were poor. Revised risk prediction models are needed to assess the clinical severity of COVID-19 patients and monitor healthcare quality in ICUs overwhelmed by patients with COVID-19.

Development and validation of the predictive risk of death model for adult patients admitted to intensive care units in Japan: an approach to improve the accuracy of healthcare quality measures.

BACKGROUND: The Acute Physiology and Chronic Health Evaluation (APACHE) III-j model is widely used to predict mortality in Japanese intensive care units (ICUs). Although the model's discrimination is excellent, its calibration is poor. APACHE III-j overestimates the risk of death, making its evaluation of healthcare quality inaccurate. This study aimed to improve the calibration of the model and develop a Japan Risk of Death (JROD) model for benchmarking purposes. METHODS: A retrospective analysis was conducted using a national clinical registry of ICU patients in Japan. Adult patients admitted to an ICU between April 1, 2018, and March 31, 2019, were included. The APACHE III-j model was recalibrated with the following models: Model 1, predicting mortality with an offset variable for the linear predictor of the APACHE III-j model using a generalized linear model; model 2, predicting mortality with the linear predictor of the APACHE III-j model using a generalized linear model; and model 3, predicting mortality with the linear predictor of the APACHE III-j model using a hierarchical generalized additive model. Model performance was assessed with the area under the receiver operating characteristic curve (AUROC), the Brier score, and the modified Hosmer-Lemeshow test. To confirm model applicability to evaluating quality of care, funnel plots of the standardized mortality ratio and exponentially weighted moving average (EWMA) charts for mortality were drawn. RESULTS: In total, 33,557 patients from 44 ICUs were included in the study population. ICU mortality was 3.8%, and hospital mortality was 8.1%. The AUROC, Brier score, and modified Hosmer-Lemeshow p value of the original model and models 1, 2, and 3 were 0.915, 0.062, and < .001; 0.915, 0.047, and < .001; 0.915, 0.047, and .002; and 0.917, 0.047, and .84, respectively. Except for model 3, the funnel plots showed overdispersion. The validity of the EWMA charts for the recalibrated models was determined by visual inspection. CONCLUSIONS: Model 3 showed good performance and can be adopted as the JROD model for monitoring quality of care in an ICU, although further investigation of the clinical validity of outlier detection is required. This update method may also be useful in other settings.

The Japanese Intensive care PAtient Database (JIPAD): A national intensive care unit registry in Japan.

PURPOSE: The Japanese Intensive care PAtient Database (JIPAD) was established to construct a high-quality Japanese intensive care unit (ICU) database. MATERIALS AND METHODS: A data collection structure for consecutive ICU admissions in adults (≥16 years) and children (≤15 years) has been established in Japan since 2014. We herein report a current summary of the data in JIPAD for admissions between April 2015 and March 2017. RESULTS: There were 21,617 ICU admissions from 21 ICUs (217 beds) including 8416 (38.9%) for postoperative or procedural monitoring, defined as adult admissions following elective surgery or for procedures and discharged alive within 24 h, 11,755 (54.4%) critically ill adults other than monitoring, and 1446 (6.7%) children. The standardized mortality ratios (SMRs) based on the Acute Physiology and Chronic Health Evaluation (APACHE) III-j, APACHE II, and Simplified Acute Physiology Score II scores in adults ranged from 0.387 to 0.534, whereas the SMR based on the Paediatric Index of Mortality 2 in children was 0.867. CONCLUSION: The data revealed that the SMRs based on general severity scores in adults were low because of high proportions of elective and monitoring admission. The development of a new mortality prediction model for Japanese ICU patients is needed.

Variations in infection sites and mortality rates among patients in intensive care units with severe sepsis and septic shock in Japan.

BACKGROUND: Accurate and early identification of infection sites might help to drive crucial decisions regarding the treatment of sepsis. We aimed to determine the clinical and etiological features of infection according to sites among patients with severe sepsis in Japan. METHODS: This secondary analysis of a multicenter, prospective cohort study included 59 intensive care units (ICU) and proceeded between January 2016 and March 2017. The study cohort comprised 1184 adults (≥ 16 years) who were admitted to an ICU with severe sepsis and septic shock diagnosed according to the sepsis-2 criteria. Sites of infection diagnosed by physicians in charge at the time of arrival comprised the lung, abdomen, urinary tract, soft tissue, bloodstream, central nervous system (CNS), and undifferentiated infections. The primary outcome was in-hospital mortality. RESULTS: The most common sites of infection were the lungs (31.0%), followed by intra-abdominal sites (26.3%), the urinary tract (18.4%), and soft tissue (10.9%). The characteristics of the patients with severe sepsis across seven major suspected infection sites were heterogeneous. Septic shock was more frequent among patients with intra-abdominal (72.2%) and urinary tract (70.2%) infections than other sites. The in-hospital mortality rate due to severe sepsis and septic shock of a pooled sample was 23.4% (range, 11.9% [urinary tract infection] to 47.6% [CNS infection]). After adjusting for clinical background, sepsis severity, and stratification according to the presence or absence of shock, variations in hospital mortality across seven major sites of infection remained essentially unchanged from those for crude in-hospital mortality; adjusted in-hospital mortality rates ranged from 7.7% (95%CI, - 0.3 to 15.8) for urinary tract infection without shock to 58.3% (95%CI, 21.0-95.7) for CNS infection with shock in a generalized estimating equation model. Intra-abdominal and urinary tract infections were statistically associated with less in-hospital mortality than pneumonia. Infections of the CNS were statistically associated with higher in-hospital mortality rates than pneumonia in a logistic regression model, but not in the generalized estimating equation model. CONCLUSIONS: In-hospital mortality and clinical features of patients with severe sepsis and septic shock were heterogeneous according to sites of infection.

Is Whole-Body CT Associated With Reduced In-Hospital Mortality in Children With Trauma? A Nationwide Study.

OBJECTIVES: We aimed to investigate whether whole-body CT for children with trauma is associated with a different mortality than only selective CT. DESIGN: A multicenter, retrospective cohort study. SETTING: Nationwide trauma registry from 183 tertiary emergency medical centers in Japan. PATIENTS: We enrolled pediatric trauma patients less than 16 years old who underwent whole-body CT or selective CT from 2004 to 2014. INTERVENTIONS: We classified the patients into a whole-body CT group if they underwent head, chest, abdomen, and pelvis CT and a selective CT group if they underwent at least one, but not all, of the above scans. MEASUREMENTS AND MAIN RESULTS: We analyzed data from 9,170 eligible patients (males, 6,362 [69%]; median age, 9 yr [6-12 yr]). Of these, 3,501 (38%) underwent whole-body CT. The overall in-hospital mortality was 180 of 9,170 (2.0%), that of patients who underwent whole-body CT was 102 of 3,501 (2.9%), and that of patients who underwent selective CT was 78 of 5,669 (1.4%). After adjusted multilevel logistic regressions and propensity score matching, the whole-body CT group demonstrated no significant difference in terms of in-hospital mortality compared with the selective CT group. The adjusted odds ratios (whole-body CT vs selective CT) for in-hospital mortality were as follows: multilevel logistic regression model 1 (1.05 [95% CI, 0.70-1.56]); multilevel logistic regression model 2 (0.72 [95% CI, 0.44-1.17]); propensity score-matched model 1 (0.98 [95% CI, 0.65-1.47]); and propensity score-matched model 2 (0.71 [95% CI, 0.46-1.08]). Subgroup analyses also revealed similarities between CT selection and in-hospital mortality. CONCLUSIONS: In this nationwide study, whole-body CT was frequently used among Japanese children with trauma. However, compared with the use of selective CT, our results did not support the use of whole-body CT to reduce in-hospital mortality. Selective use of imaging may result in less radiation exposure and provide more benefits than whole-body CT to pediatric trauma patients.

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries.

BACKGROUND: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. METHODS: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. RESULTS: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. CONCLUSIONS: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02010073 . Registered on 12 December 2013.

Ten-year inhospital mortality trends for patients with trauma in Japan: a multicentre observational study.

OBJECTIVES: Trauma is one of the main causes of death in Japan, and treatments and prognoses of these injuries are constantly changing. We therefore aimed to investigate a 10-year trend (2004-2013) in inhospital mortality among patients with trauma in Japan. DESIGN: Multicentre observational study. SETTING: Japanese nationwide trauma registry (the Japan Trauma Data Bank) data. PARTICIPANTS: All patients with trauma whose Injury Severity Score (ISS) were 3 and above, who were aged 15 years or older, and whose mechanisms of injury (MOI) were blunt and penetrating between 2004 and 2013 (n=90 833). OUTCOME MEASURES: A 10-year trend in inhospital mortality. RESULTS: Inhospital mortality for all patients with trauma significantly decreased over the study decade in our Cochran-Armitage test (P<0.001). Similarly, inhospital mortality for patients with ISS 16 or more and patients who scored 50% or better on the Trauma and Injury Severity Score (TRISS) probability of survival scale significantly decreased (P<0.001). In addition, the OR for inhospital mortality of these three patient groups decreased yearly after adjusting for age, gender, MOI, ISS, Glasgow Coma Scale, systolic blood pressure and respiratory rate on hospital arrival in multivariable logistic regression analyses. Furthermore, inhospital mortality for patient with blunt trauma significantly decreased in injury mechanism-stratified Mantel-extension testing (P<0.001). Finally, multivariable logistic regression analyses showed that the OR for inhospital mortality of patients with ISS 16 and over decreased each year after adding and adjusting for means of transportation and usage of whole-body CT. CONCLUSION: Inhospital mortality for patients with trauma in Japan significantly decreased during the study decade after adjusting for patient characteristics, injury severity and the response environment after injury.

Ulinastatin did not reduce mortality in elderly multiple organ failure patients: a retrospective observational study in a single center ICU.

Aim: Our aim was to evaluate the effect of ulinastatin on 28-day mortality in patients who developed multiple organ failure (MOF) related to their acute illness and were admitted to the intensive care unit (ICU). Methods: We carried out a retrospective observational study of MOF patients in a general ICU of a tertiary care hospital in Japan from January 2009 to December 2012. The primary outcome was 28-day all-cause mortality. Secondary outcomes were ventilator-free days, ICU-free days, and vasopressor-free days at day 28. We investigated the association between ulinastatin treatment and outcomes using multivariable regression analysis. Results: A total of 212 MOF patients were included, 79 (37%) of whom received ulinastatin. The median age was 70 years (interquartile range, 60-77) and median APACHE II score was 25 (interquartile range, 19-29). Overall 28-day mortality was 20%. There were no significant differences between the ulinastatin group and the control group in age, gender, or APACHE II score. The ulinastatin group had higher prevalence of sepsis (44% versus 22%, P = 0.001). Multivariable logistic regression analysis showed that ulinastatin was not associated with 28-day mortality (odds ratio = 1.22; 95% confidence interval, 0.54-2.79). Moreover, ulinastatin did not reduce the mortality in patients with sepsis (odds ratio = 1.92; 95% confidence interval, 0.52-7.13). However, ICU-free days and ventilator-free days was significantly fewer in the ulinastatin group than control group. Conclusions: In this retrospective observational study, ulinastatin was not associated with mortality in elderly patients with established MOF, although it might be related to patient's utility.

Resuscitative endovascular balloon occlusion of the aorta versus aortic cross clamping among patients with critical trauma: a nationwide cohort study in Japan.

BACKGROUND: Measures of aortic occlusion (AO) for resuscitation in patients with severe torso trauma remain controversial. Our aim was to characterize the current use of resuscitative endovascular balloon occlusion of the aorta (REBOA) and resuscitative open aortic cross-clamping (ACC), and to evaluate whether REBOA should be an alternative method to resuscitative open ACC. METHODS: This study was a retrospective cohort study between 2004 and 2013 from a nationwide trauma registry in Japan. Participants were selected who underwent either REBOA or ACC. Their characteristics, interventions, and outcomes were analyzed to compare REBOA and ACC directly. The primary outcome was in-hospital mortality and the secondary outcome was mortality in the emergency department. Logistic regression analysis was performed to compare the outcomes between REBOA and ACC with adjustment for severity; 1:1 propensity score matching was also performed. RESULTS: Of the 159,157 trauma patients, 903 were eligible based on the selection criteria. Overall, 405/607 patients (67%) who had REBOA died compared to 210/233 patients (90%) who had ACC. Patients with REBOA had higher revised trauma score (RTS) (mean ± SD, 5.2 ± 2.0 vs. 4.2 ± 2.2; P < 0.001) but higher Injury Severity Score (ISS) (median (interquartile); 34 (25) vs. 34 (20); P < 0.001), and higher probability of survival (0.43 ± 0.36 vs. 0.27 ± 0.30; P < 0.001) compared to those with ACC. REBOA had an odds ratio (OR) for in-hospital mortality of 0.309 (95% confidence interval (CI) = 0.190-0.502) adjusting for trauma and injury severity score using a logistic regression model (n = 903). Similar associations were observed adjusting for RTS (OR = 0.224; 95% CI = 0.129-0.700) or adjusting for ISS (OR, 0.188; 95% CI, 0.116 to 0.303). In the propensity score-matched cohort (n = 304), REBOA was associated with lower mortality compared to ACC (OR, 0.261; 95% CI, 0.130 to 0.523). Patients with REBOA had less severe chest complications than those with ACC (Abbreviated Injury Scale thorax, 3.8 ± 0.8 vs. 4.2 ± 0.8; P < 0.001), although physiological severity and backgrounds were similar in this population. CONCLUSIONS: Patients who underwent AO had a high mortality. REBOA might be a favorable alternative method to resuscitative ACC for severe torso trauma although some indication bias could still remain. Further studies are needed to elucidate optimal indications.

Total syntheses of (+)- and (-)-pestalotiopsin A.

An enantioselective total synthesis of both enantiomers of caryophyllene-type sesquiterpenoid pestalotiopsin A has been achieved, thereby establishing the absolute stereochemistry of natural (+)-pestalotiopsin A. Highlights of the synthesis include a [2 + 2] cycloaddition of N-propioloyl Oppolzer's camphorsultam and ketene dialkyl acetal and subsequent highly stereoselective 1,4-hydride addition/protonation, an aldol reaction of functionalized bicyclic lactone with aldehyde, an efficient intramolecular Nozaki-Hiyama-Kishi (NHK) reaction for the construction of the highly strained (E)-cyclononene ring, and a palladium-catalyzed reduction of allylic mesylate with retention of the E configuration.