Spinal Anesthesia or General Anesthesia for Hip Surgery in Older Adults.

BACKGROUND: The effects of spinal anesthesia as compared with general anesthesia on the ability to walk in older adults undergoing surgery for hip fracture have not been well studied. METHODS: We conducted a pragmatic, randomized superiority trial to evaluate spinal anesthesia as compared with general anesthesia in previously ambulatory patients 50 years of age or older who were undergoing surgery for hip fracture at 46 U.S. and Canadian hospitals. Patients were randomly assigned in a 1:1 ratio to receive spinal or general anesthesia. The primary outcome was a composite of death or an inability to walk approximately 10 ft (3 m) independently or with a walker or cane at 60 days after randomization. Secondary outcomes included death within 60 days, delirium, time to discharge, and ambulation at 60 days. RESULTS: A total of 1600 patients were enrolled; 795 were assigned to receive spinal anesthesia and 805 to receive general anesthesia. The mean age was 78 years, and 67.0% of the patients were women. A total of 666 patients (83.8%) assigned to spinal anesthesia and 769 patients (95.5%) assigned to general anesthesia received their assigned anesthesia. Among patients in the modified intention-to-treat population for whom data were available, the composite primary outcome occurred in 132 of 712 patients (18.5%) in the spinal anesthesia group and 132 of 733 (18.0%) in the general anesthesia group (relative risk, 1.03; 95% confidence interval [CI], 0.84 to 1.27; P = 0.83). An inability to walk independently at 60 days was reported in 104 of 684 patients (15.2%) and 101 of 702 patients (14.4%), respectively (relative risk, 1.06; 95% CI, 0.82 to 1.36), and death within 60 days occurred in 30 of 768 (3.9%) and 32 of 784 (4.1%), respectively (relative risk, 0.97; 95% CI, 0.59 to 1.57). Delirium occurred in 130 of 633 patients (20.5%) in the spinal anesthesia group and in 124 of 629 (19.7%) in the general anesthesia group (relative risk, 1.04; 95% CI, 0.84 to 1.30). CONCLUSIONS: Spinal anesthesia for hip-fracture surgery in older adults was not superior to general anesthesia with respect to survival and recovery of ambulation at 60 days. The incidence of postoperative delirium was similar with the two types of anesthesia. (Funded by the Patient-Centered Outcomes Research Institute; REGAIN ClinicalTrials.gov number, NCT02507505.).

Long-term Outcomes with Spinal versus General Anesthesia for Hip Fracture Surgery: A Randomized Trial.

BACKGROUND: The effects of spinal versus general anesthesia on long-term outcomes have not been well studied. This study tested the hypothesis that spinal anesthesia is associated with better long-term survival and functional recovery than general anesthesia. METHODS: A prespecified analysis was conducted of long-term outcomes of a completed randomized superiority trial that compared spinal anesthesia versus general anesthesia for hip fracture repair. Participants included previously ambulatory patients 50 yr of age or older at 46 U.S. and Canadian hospitals. Patients were randomized 1:1 to spinal or general anesthesia, stratified by sex, fracture type, and study site. Outcome assessors and investigators involved in the data analysis were masked to the treatment arm. Outcomes included survival at up to 365 days after randomization (primary); recovery of ambulation among 365-day survivors; and composite endpoints for death or new inability to ambulate and death or new nursing home residence at 365 days. Patients were included in the analysis as randomized. RESULTS: A total of 1,600 patients were enrolled between February 12, 2016, and February 18, 2021; 795 were assigned to spinal anesthesia, and 805 were assigned to general anesthesia. Among 1,599 patients who underwent surgery, vital status information at or beyond the final study interview (conducted at approximately 365 days after randomization) was available for 1,427 (89.2%). Survival did not differ by treatment arm; at 365 days after randomization, there were 98 deaths in patients assigned to spinal anesthesia versus 92 deaths in patients assigned to general anesthesia (hazard ratio, 1.08; 95% CI, 0.81 to 1.44, P = 0.59). Recovery of ambulation among patients who survived a year did not differ by type of anesthesia (adjusted odds ratio for spinal vs. general, 0.87; 95% CI, 0.67 to 1.14; P = 0.31). Other outcomes did not differ by treatment arm. CONCLUSIONS: Long-term outcomes were similar with spinal versus general anesthesia.

Pain, Analgesic Use, and Patient Satisfaction With Spinal Versus General Anesthesia for Hip Fracture Surgery : A Randomized Clinical Trial.

BACKGROUND: The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported. OBJECTIVE: To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia. DESIGN: Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505). SETTING: 46 U.S. and Canadian hospitals. PARTICIPANTS: Patients aged 50 years or older undergoing hip fracture surgery. INTERVENTION: Spinal or general anesthesia. MEASUREMENTS: Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care. RESULTS: A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups. LIMITATION: Missing outcome data and multiple outcomes assessed. CONCLUSION: Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institute.

Outcomes with spinal versus general anesthesia for patients with and without preoperative cognitive impairment: Secondary analysis of a randomized clinical trial.

INTRODUCTION: The effect of spinal versus general anesthesia on the risk of postoperative delirium or other outcomes for patients with or without cognitive impairment (including dementia) is unknown. METHODS: Post hoc secondary analysis of a multicenter pragmatic trial comparing spinal versus general anesthesia for adults aged 50 years or older undergoing hip fracture surgery. RESULTS: Among patients randomized to spinal versus general anesthesia, new or worsened delirium occurred in 100/295 (33.9%) versus 107/283 (37.8%; odds ratio [OR] 0.85; 95% confidence interval [CI] 0.60 to 1.19) among persons with cognitive impairment and 70/432 (16.2%) versus 71/445 (16.0%) among persons without cognitive impairment (OR 1.02; 95% CI 0.71 to 1.47, p = 0.46 for interaction). Delirium severity, in-hospital complications, and 60-day functional recovery did not differ by anesthesia type in patients with or without cognitive impairment. DISCUSSION: Anesthesia type is not associated with differences in delirium and functional outcomes among persons with or without cognitive impairment.

Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in TTN (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM. METHODS: Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including TTN, and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated. RESULTS: Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected P [P*]=1.2×10-46). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, P*=7.0×10-8), DSP (odds ratio=14.9, P*=1.0×10-8), and BAG3 (odds ratio=53.1, P*=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, P=2.5×10-4), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery. CONCLUSIONS: This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.

The Evolution of Plasmid Transfer Rate in Bacteria and Its Effect on Plasmid Persistence.

AbstractPlasmids are extrachromosomal segments of DNA that can transfer genes between bacterial cells. Many plasmid genes benefit bacteria but cause harm to human health by granting antibiotic resistance to pathogens. Transfer rate is a key parameter for predicting plasmid dynamics, but observed rates are highly variable, and the effects of selective forces on their evolution are unclear. We apply evolutionary analysis to plasmid conjugation models to investigate selective pressures affecting plasmid transfer rate, emphasizing host versus plasmid control, the costs of plasmid transfer, and the role of recipient cells. Our analyses show that plasmid-determined transfer rates can be predicted with three parameters (host growth rate, plasmid loss rate, and the cost of plasmid transfer on growth) under some conditions. We also show that low-frequency genetic variation in transfer rate can accumulate, facilitating rapid adaptation to changing conditions. Furthermore, reduced transfer rates due to host control have limited effects on plasmid prevalence until low enough to prevent plasmid persistence. These results provide a framework to predict plasmid transfer rate evolution in different environments and demonstrate the limited impact of host mechanisms to control the costs incurred when plasmids are present.

The role of hosts, plasmids and environment in determining plasmid transfer rates: A meta-analysis.

Plasmids transfer at highly variable rates that spread over 10 orders of magnitude. While rates have been measured for decades and it is known that the rates are affected bysome biotic and abiotic factors, it is unclear how and to what extent these factors determine the rates of transfer. We performed a meta-analysis of 1224 published transfer rates from 33 papers (filtered to 612 transfer rates) to assess this variation. Over three quarters of the variation can be predicted, with plasmid repression and media type (solid versus liquid) identified as general variables explaining the most variation. Of the host and plasmid identities, identity of the recipient bacterium explained the most variation, up to 34% in some models, and more than any other explanatory variable. These results emphasize the role of the recipient in determining the rate of transfer, and show an improved range of transfer values and their correlates that can be used in future when modeling plasmid persistence.

Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.

Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.

Early improvement in serial echocardiographic studies in heart failure patients predicts long term survival-a pilot study.

BACKGROUND: Several echocardiographic measures have prognostic value in heart failure (HF). However, no definitive data exist on how changes in these parameters with treatment affect survival in this patient population. We hypothesized that early improvement on echocardiography could predict long-term survival. METHODS AND RESULTS: We conducted a retrospective review of 404 patients seen in the HF clinic from 2002 to 2008 (6.5 years). Patients had one echocardiogram ≤1 year before and another ≥1 month (10 ± 7 months) after treatment onset. We studied changes in standard echocardiographic parameters, including left (LV) and right (RV) ventricular size and/or function (systolic and/or diastolic), valvular (mitral and tricuspid) function, and pulmonary artery pressure. Survival curves and hazard ratios were generated for patients showing improvement on the 2nd echocardiogram versus those who did not. Multivariable analyses were performed adjusting for age, sex, ischemic etiology, and significant baseline echocardiographic parameters. Average follow-up was 2.9 ± 1.5 years. Improvement in LV end-systolic dimension, RV function, and mitral regurgitation were independent predictors of 5-year survival (P < .05) and, importantly, more predictive than baseline values of these parameters alone (higher hazard ratios). CONCLUSIONS: Early echocardiographic improvement is strongly associated with 5-year survival in patients with HF. Serial echocardiography may aid in stratifying patient care.

Prognostic and Therapeutic Implications of Frailty in Older Adults with Heart Failure.

Frailty is increasingly recognized in older adults with cardiovascular disease, particularly in those with heart failure (HF). A growing body of evidence has shown that frailty has a negative effect on survival, hospitalizations, disability, and quality of life. Beyond frailty, additional domains captured by a comprehensive geriatric assessment contribute incremental value in predicting outcomes and identifying treatment targets. Exercise training is ideally suited to this setting as it can concomitantly improve physical frailty and HF symptoms. Multidisciplinary disease management programs offer a number of benefits for frail HF patients; invasive procedures carry a higher risk of morbidity than in non-frail counterparts, and evidence-based drugs and devices have an uncertain value and warrant further research. While more data accrues, difficult therapeutic decisions should be individualized using a shared patient-centered decision making approach.

Optimizing care in early phase cancer trials: The role of palliative care.

Advancements in cancer treatment have led to improved survival rates, with early phase clinical trials (EPCTs) serving as important initial steps in evaluating novel therapies. Recent studies have shown that response rates in these trials have doubled in the last twenty years. Patients who enroll on EPCTs have advanced cancer and heightened symptomatology yet maintain a robust performance status that qualifies them for clinical trial participation. It is well established that many of these patients have needs that can be addressed by palliative care, including symptom management, value assessments, advance care planning, and psychosocial and spiritual support. Several small studies have aimed to identify the most beneficial palliative care intervention for this cohort of patients, ranging from formal clinic-based multidisciplinary palliative care interventions to home-based interventions. While outcomes have trended towards benefit for patients, especially pertaining to psychological well-being, most studies were not powered to detect additional benefits for improved physical symptom management, reduction in care utilization or increased length of time on trial. In this review, we discuss the unique palliative care needs of this population and what we can learn from results of past interventional studies. We advocate for a tailored palliative care approach that acknowledges the time toxicity experienced by patients enrolled in EPCTs and address challenges posed by shortages within the palliative care workforce.

Access to heart failure care post emergency department visit: do we meet established benchmarks and does it matter?

BACKGROUND: The Canadian Cardiology Society recommends that patients should be seen within 2 weeks after an emergency department (ED) visit for heart failure (HF). We sought to investigate whether patients who had an ED visit for HF subsequently consult a physician within the current established benchmark, to explore factors related to physician consultation, and to examine whether delay in consultation is associated with adverse events (AEs) (death, hospitalization, or repeat ED visit). METHODS: Patients were recruited by nurses at 8 hospital EDs in Québec, Canada, and interviewed by telephone within 6 weeks of discharge and subsequently at 3 and 6 months. Clinical variables were extracted from medical charts by nurses. We used Cox regression in the analysis. RESULTS: We enrolled 410 patients (mean age 74.9 ± 11.1 years, 53% males) with a confirmed primary diagnosis of HF. Only 30% consulted with a physician within 2 weeks post-ED visit. By 4 weeks, 51% consulted a physician. Over the 6-month follow-up, 26% returned to the ED, 25% were hospitalized, and 9% died. Patients who were followed up within 4 weeks were more likely to be older and have higher education and a worse quality of life. Patients who consulted a physician within 4 weeks of ED discharge had a lower risk of AEs (hazard ratio 0.59, 95% CI 0.35-0.99). CONCLUSION: Prompt follow-up post-ED visit for HF is associated with lower risk for major AEs. Therefore, adherence to current HF guideline benchmarks for timely follow-up post-ED visit is crucial.

Comparison of Questionnaire and Performance-Based Physical Frailty Scales to Predict Survival and Health-Related Quality of Life in Patients With Heart Failure.

Background Frailty is prevalent in older adults with heart failure and is associated with poor outcomes; however, there remains uncertainty on how to measure frailty in clinical practice. Methods and Results A multicentric prospective cohort study was assembled at 4 heart failure clinics to compare the prognostic value of 3 physical frailty scales in ambulatory patients with heart failure. Outcomes were all-cause death or hospitalization and health-related quality of life using the 36-Item Short Form survey questionnaire (SF-36) at 3 months. Multivariable regression was adjusted for age, sex, Meta-Analysis Global Group in Chronic Heart Failure score, and baseline SF-36 score. The cohort included 215 patients (mean age 77.6 years). All 3 frailty scales were independently associated with death or hospitalization at 3 months; the adjusted odds ratios standardized per 1 SD worsening of the Short Physical Performance Battery; Fried, and strength, assistance with walking, rising from a chair, climbing stairs, and falls scales were 1.67 (95% CI, 1.09-2.55), 1.60 (95% CI, 1.04-2.46), and 1.55 (95% CI, 1.03-2.35), respectively, with C statistics of 0.77 to 0.78. All 3 frailty scales were independently associated with worsening SF-36 scores, especially the Short Physical Performance Battery, for which 1 SD worsening of frailty translated to a decrement of -5.86 (-8.55 to -3.17) and -5.51 (-7.82 to -3.21) points in the Physical Component Score and Mental Component Score. Conclusions All 3 physical frailty scales were associated with death, hospitalization, and reduced health-related quality of life in ambulatory patients with heart failure. Questionnaire or performance-based physical frailty scales can be used to offer prognostic value and a therapeutic target in this vulnerable population. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03887351.

Using mortuary and burial data to place COVID-19 in Lusaka, Zambia within a global context.

Reported COVID-19 cases and associated mortality remain low in many sub-Saharan countries relative to global averages, but true impact is difficult to estimate given limitations around surveillance and mortality registration. In Lusaka, Zambia, burial registration and SARS-CoV-2 prevalence data during 2020 allow estimation of excess mortality and transmission. Relative to pre-pandemic patterns, we estimate age-dependent mortality increases, totalling 3212 excess deaths (95% CrI: 2104-4591), representing an 18.5% (95% CrI: 13.0-25.2%) increase relative to pre-pandemic levels. Using a dynamical model-based inferential framework, we find that these mortality patterns and SARS-CoV-2 prevalence data are in agreement with established COVID-19 severity estimates. Our results support hypotheses that COVID-19 impact in Lusaka during 2020 was consistent with COVID-19 epidemics elsewhere, without requiring exceptional explanations for low reported figures. For more equitable decision-making during future pandemics, barriers to ascertaining attributable mortality in low-income settings must be addressed and factored into discourse around reported impact differences.

Alternative epidemic indicators for COVID-19 in three settings with incomplete death registration systems.

Not all COVID-19 deaths are officially reported, and particularly in low-income and humanitarian settings, the magnitude of reporting gaps remains sparsely characterized. Alternative data sources, including burial site worker reports, satellite imagery of cemeteries, and social media-conducted surveys of infection may offer solutions. By merging these data with independently conducted, representative serological studies within a mathematical modeling framework, we aim to better understand the range of underreporting using examples from three major cities: Addis Ababa (Ethiopia), Aden (Yemen), and Khartoum (Sudan) during 2020. We estimate that 69 to 100%, 0.8 to 8.0%, and 3.0 to 6.0% of COVID-19 deaths were reported in each setting, respectively. In future epidemics, and in settings where vital registration systems are limited, using multiple alternative data sources could provide critically needed, improved estimates of epidemic impact. However, ultimately, these systems are needed to ensure that, in contrast to COVID-19, the impact of future pandemics or other drivers of mortality is reported and understood worldwide.

Implantable cardiac defibrillators and sudden death in recent onset nonischemic cardiomyopathy: results from IMAC2.

BACKGROUND: Given the potential for recovery in recent onset nonischemic cardiomyopathy (ROCM), the timing and need for implantable cardioverter-defibrillator (ICDs) remains controversial. We examined the utilization of ICDs and the impact on survival for subjects with ROCM. METHODS AND RESULTS: An National Heart, Lung, and Blood Institute sponsored registry enrolled 373 subjects with ROCM, all with a left ventricular ejection fraction (LVEF) ≤0.40 and ≤6 months of symptoms. The mean age was 45 ± 14 years, 38% were female, 21% black, 75% New York Heart Association II/III, and the mean LVEF was 0.24 ± 0.08. Survival was comparable for subjects with an ICD within 1 month of entry (n = 43, 1/2/3 year % survival = 97/97/92) and those with no ICD at 1 month (n = 330, % survival = 98/97/95, P = .30) and between those with and without an ICD at 6 months (ICD, n = 73, 1/2/3 year % survival = 98/98/95; no ICD, n = 300, % survival = 98/96/95, P = .95). There were only 6 sudden cardiac deaths (SCD) noted (% survival free from SCD = 99/98/97) and these occurred in 1.9% of subjects without ICD and 0.9% of those with a device (P = .50). CONCLUSIONS: In a multicenter cohort of ROCM the risk of SCD was low at 1% per year. Early ICD placement did not impact survival and can be deferred while assessing potential for myocardial recovery.

Outcomes for women and men who attend a heart failure clinic: results of a 12-month longitudinal study.

BACKGROUND: Although prevalence of heart failure (HF) is similar in women and men, more men are admitted to specialized HF clinics, possibly owing to a perception that men benefit more. Our aim was to describe 1-year outcomes in men and women attending specialized HF clinics. METHODS AND RESULTS: We enrolled 531 newly referred patients (mean age 66 years, 26% women) to 1 of 6 HF multidisciplinary clinics in Quebec. Data were collected at time of entry to the clinic and 6 and 12 months later. The 3 main outcomes, mortality, disease evolution (New York Heart Association functional class, quality of life, 6-minute walk), and number of hospital admissions/emergency department visits were analyzed separately. Survival was higher in women than in men (adjusted hazard ratio 2.53, 95% confidence interval 1.10-5.80). Both women and men improved over the 12-month period in terms of quality of life, 6-minute walk, and lower use of hospital and emergency department. Persons who at entry to the clinic had more severe disease showed more improvement. Deterioration over the year was associated with higher number of comorbidities, but not with age or gender. CONCLUSIONS: Both men and women with HF who attend specialized HF clinics improved, including those with more severe disease.

Vascular tone and the genomics of hypertension.

Hypertension is a common condition that is a well-described risk factor for the development of cerebrovascular disease, myocardial infarction and heart failure. Medical therapy for hypertension may not only prevent development of these potentially devastating illnesses but may be used to treat high blood pressure, which coexists with these conditions. Therapeutic response to medical therapy for hypertension is variable and may be related to the individual genetic profile of patients. We have described here only several of the HTN-related polymorphisms that may impact clinical response in patients who have high blood pressure and coexisting conditions. Future studies are needed to identify other potential genotypes that may influence therapeutic response in addition to clinical trials of specific medical therapy in individual patients based on specific genotypes.

Bromonium ion induced transannular oxonium ion formation-fragmentation in model obtusallene systems and structural reassignment of obtusallenes V-VII.

Ring-closing metathesis was used to construct the strained 11-membered ring of obtusallenes II (and IV). Bromonium ion induced transannular oxonium ion formation-fragmentation gave the macrocyclic carbon skeleton of obtusallene VII with a bromine atom at C-13, in line with a previously published hypothesis. An additional brominated [5.5.1]bicyclotridecane adduct that must arise from a bromonium ion induced transannular oxonium ion formation-fragmentation could also be isolated, suggesting that this adduct represents the core of an as yet undiscovered natural product. An authentic sample of obtusallene V was studied by NMR spectroscopy, and the position of the halogens at C-7 and C-13 was reassigned on the basis of a (13)C NMR chlorine induced isotopic shift. This revised structure was subsequently confirmed by X-ray crystallography. These findings allow us to confidently conclude that the structures of obtusallenes VII and VI should also be reassigned.