Zinc Deficiency and Heart Failure: A Systematic Review of the Current Literature.

Zinc is an essential micronutrient that impacts the cardiovascular system through modulation of oxidative stress. It is unknown whether zinc levels are affected in heart failure (HF), and whether the association, if present, is causal. A systematic search for publications that report coexisting zinc deficiency in patients with HF was performed to provide an overview of the pathophysiological and epidemiological aspects of this association (last search April 2019). Review of the literature suggests multiple potential pathophysiologic causes for zinc deficiency in HF as a result of impaired micronutrient consumption, hyper-inflammatory state, upregulation of the renin-angiotensin-aldosterone axis, diminished absorption, and hyperzincuria from HF medications. In a longitudinal study of patients with HF in the setting of intestinal malabsorption, there was partial cardiomyocyte and left ventricular ejection fraction recovery with intravenous selenium and zinc supplementation. Two randomized double-blind control trials evaluating micronutrient and macronutrient supplementation including zinc in patients with HF found improvement in echocardiographic findings compared with placebo. Two recently completed studies evaluated the role for zinc supplementation in 2 different HF populations: a trial of zinc supplementation in patients with non-ischemic HF, and a trial of micronutrient supplementation (including B vitamins, vitamin D, and zinc) in veterans with systolic dysfunction; the results of which are still pending. Several pathobiological pathways to link zinc deficiency with the development and deterioration of HF are presented. Preliminary clinical data are supportive of such an association and future studies should further investigate the effects of zinc supplementation on outcomes in patients with HF.

Salt Taste Recognition in a Heart Failure Cohort.

BACKGROUND: Heart failure (HF) disproportionately affects older adults. Dietary sodium indiscretion is frequently implicated in HF decompensation. The affinity for and ability to taste salt in this process is unexplored. We sought to evaluate differences in salt taste by age and HF diagnosis and to map changes after hospitalization for acute decompensated heart failure (ADHF). METHODS: Seventy-two subjects underwent initial salt-taste testing during hospitalization for ADHF. Follow-up taste testing occurred at discharge and 1, 4, and 12 weeks after hospitalization. Three different groups were included as control subjects and underwent 1-time salt-taste testing: 10 patients with stable HF, 10 healthy older adults, and 10 healthy younger adults. Salt-taste testing was completed with the use of commercially available and validated Salsave test strips with increasing concentrations of NaCl (0.6-1.6 mg/cm2) to identify salt taste recognition threshold. Respectively, 2-sample t tests, multiple regression, and linear mixed-effects modeling were used for intergroup comparisons, to adjust for confounders, and to assess the effect of time after discharge from ADHF hospitalization. RESULTS: The baseline salt taste recognition threshold was lowest in the young healthy control group (0.62 [SD 0.05] mg/cm2 NaCl) compared with the healthy older control subjects (0.92 [SD 0.29] mg/cm2 NaCl), stable HF outpatients, (1.06 [SD 0.22] mg/cm2 NaCl), and ADHF subjects on admission (1.06 [SD 0.48] mg/cm2 NaCl). There was a strong trend toward higher recognition threshold in HF patients (P = .051) that was independent from age and other potential confounders. Serial salt-taste testing in the ADHF group demonstrated a decrease in recognition threshold that persisted over the 12 weeks after discharge (1.04 [SD 0.44] to 0.76 [SD 0.22] mg/cm2 NaCl; P = .003). DISCUSSION: When compared with young healthy control subjects, HF patients have impaired recognition of salt taste. The salt taste recognition threshold decreases after hospitalization for ADHF. This change demonstrates the first evidence of the phenomenon known as the "hedonic shift" in HF, in which the threshold to recognize salt taste decreases after prescribed sodium restriction.

Evaluating the safety and efficacy of sodium-restricted/Dietary Approaches to Stop Hypertension diet after acute decompensated heart failure hospitalization: design and rationale for the Geriatric OUt of hospital Randomized MEal Trial in Heart Failure (GOURMET-HF).

BACKGROUND: Heart failure (HF) is a major public health problem affecting predominantly older adults. Nonadherence to diet remains a significant contributor to acute decompensated HF (ADHF). The sodium-restricted Dietary Approaches to Stop Hypertension (DASH/SRD) eating plan reduces cardiovascular dysfunction that can lead to ADHF and is consistent with current HF guidelines. We propose that an intervention that promotes adherence to the DASH/SRD by home-delivering meals will be safe and improve health-related quality of life (QOL) in older adults after hospitalization for ADHF. METHODS/DESIGN: This is a 3-center, randomized, single-blind, controlled trial of 12-week duration designed to determine the safety and efficacy of home-delivered DASH/SRD-compliant meals in older adults after discharge from ADHF hospitalization. Sixty-six subjects will be randomized in a 1:1 stratified fashion by gender and left ventricular ejection fraction (<50% vs ≥50%). Study subjects will receive either preprepared, home-delivered DASH/SRD-compliant meals or usual dietary advice for 4weeks after hospital discharge. Investigators will be blinded to group assignment, food diaries, and urinary electrolyte measurements until study completion. The primary efficacy end point is the change in the Kansas City Cardiomyopathy Questionnaire summary scores for health-related QOL from study enrollment to 4weeks postdischarge. Safety evaluation will focus on hypotension, renal insufficiency, and hyperkalemia. Exploratory end points include echocardiography, noninvasive vascular testing, markers of oxidative stress, and salt taste sensitivity. CONCLUSION: This randomized controlled trial will test the efficacy, feasibility, and safety of 4weeks of DASH/SRD after ADHF hospitalization. By testing a novel dietary intervention supported by multiple levels of evidence including preliminary data in outpatients with stable HF, we will address a critical evidence gap in the care of older patients with ADHF. If effective and safe, this intervention could be scaled to assess effects on readmission and healthcare costs in older adults after ADHF.

Patients who require non-cardiac surgery in acute coronary syndrome.

The coexistence of an acute coronary syndrome (ACS) and non-cardiac surgery (NCS) in an individual patient can be summarized in two challenging clinical scenarios for the treating physician: 1) Post-operative patients who develop ACS and 2) Patients with ACS who subsequently require NCS. Both settings are characterized by a struggle on the part of treating physicians attempting to optimize antithrombotic therapies for ACS while minimizing post-surgical bleeding risk. In this review we address specific clinical issues related to patients with coexistent NCS and ACS, discussing possible management strategies balancing ischemic and bleeding risk in these complex patient scenarios.

Retrospective outcome data for hematopoietic stem cell transplantation in patients with concurrent coronary artery disease.

Hematopoietic stem cell transplantation (HSCT) represents an extended period of physiologic stress. It is unknown whether patients with pre-existing coronary artery disease (CAD) may be poor transplant candidates. There are no data analyzing the risk of transplantation in this population. Sixty-nine patients with CAD who underwent 72 transplantations, autologous and allogeneic, were identified retrospectively. Fifty-five percent of these patients had prior percutaneous coronary intervention, 42% had verifiable history of myocardial infarction, and 23% had prior coronary artery bypass grafting. Outcomes were compared to 1109 patients without established CAD who underwent 1183 transplants during the same time period. Cancer diagnoses in the 2 groups were similar, predominantly lymphoma, multiple myeloma, and leukemia. There was no significant difference between the CAD group and the control group with respect to type of transplant (autologous 68% versus 64%, P = .612, myeloablative 86% versus 85%, P = .867). Treatment-related mortality was no different in the CAD group versus the control group (5.6% versus 4.9%, P = .777), nor were there differences in mortality at 1 year (15.3% versus 16.6%, P = .871), urgent intensive care unit admission (11.1% versus 9.9%, P = .686), or length of stay (25.5 days versus 28.4 days, P = .195). These findings suggest many patients with underlying coronary artery disease may be safely managed through hematopoietic stem cell transplantation.

A Virtual Cardiovascular Care Program for Prevention of Heart Failure Readmissions in a Skilled Nursing Facility Population: Retrospective Analysis.

BACKGROUND: Patients with heart failure (HF) in skilled nursing facilities (SNFs) have 30-day hospital readmission rates as high as 43%. A virtual cardiovascular care program, consisting of patient selection, initial televisit, postconsultation care planning, and follow-up televisits, was developed and delivered by Heartbeat Health, Inc., a cardiovascular digital health company, to 11 SNFs (3510 beds) in New York. The impact of this program on the expected SNF 30-day HF readmission rate is unknown, particularly in the COVID-19 era. OBJECTIVE: The aim of the study was to assess whether a virtual cardiovascular care program could reduce the 30-day hospital readmission rate for patients with HF discharged to SNF relative to the expected rate for this population. METHODS: We performed a retrospective case review of SNF patients who received a virtual cardiology consultation between August 2020 and February 2021. Virtual cardiologists conducted 1 or more telemedicine visit via smartphone, tablet, or laptop for cardiac patients identified by a SNF care team. Postconsult care plans were communicated to SNF clinical staff. Patients included in this analysis had a preceding index admission for HF. RESULTS: We observed lower hospital readmission among patients who received 1 or more virtual consultations compared with the expected readmission rate for both cardiac (3% vs 10%, respectively) and all-cause etiologies (18% vs 27%, respectively) in a population of 3510 patients admitted to SNF. A total of 185/3510 patients (5.27%) received virtual cardiovascular care via the Heartbeat Health program, and 40 patients met study inclusion criteria and were analyzed, with 26 (65%) requiring 1 televisit and 14 (35%) requiring more than 1. Cost savings associated with this reduction in readmissions are estimated to be as high as US $860 per patient. CONCLUSIONS: The investigation provides initial evidence for the potential effectiveness and efficiency of virtual and digitally enabled virtual cardiovascular care on 30-day hospital readmissions. Further research is warranted to optimize the use of novel virtual care programs to transform delivery of cardiovascular care to high-risk populations.

Salt Taste Sensitivity and Heart Failure Outcomes Following Heart Failure Hospitalization.

Salt taste sensitivity can change after heart failure (HF) hospitalization, however the relation between changes in salt taste sensitivity with HF symptoms, biomarkers, and outcomes is unknown. We assessed salt taste sensitivity over 12 weeks following HF hospitalization using a validated, point-of-care salt taste test. Subjects were divided into 2 groups: increase or no increase in salt taste sensitivity. HF biomarkers and outcomes were compared using 2-sample t tests and log-transformed t tests for non-normally distributed parameters. Baseline characteristics generally did not differ for subjects with an increase in salt taste sensitivity over 12 weeks compared with those without an increase in salt taste sensitivity. The total number of 12-week hospital days was 60 versus 121 days, with an average number of hospital days of 5.45 [3.88] versus 11.00 [6.74] (p = 0.03) among those hospitalized in the groups with an increase versus no increase in salt taste sensitivity, respectively. In conclusion, changes in salt taste sensitivity occurred in some but not all subjects in a 12-week period following HF hospitalization. Subjects with increased salt taste sensitivity over this time period were rehospitalized for fewer days. Improved salt taste sensitivity may represent a novel prognostic factor in postdischarge patients with HF.

Home-Delivered Meals Postdischarge From Heart Failure Hospitalization.

Background In patients with heart failure (HF), malnutrition and dietary sodium excess are common and may worsen outcomes. No prior studies have provided low-sodium, nutritionally complete meals following HF hospitalization. Methods and Results The GOURMET-HF study (Geriatric Out-of-Hospital Randomized Meal Trial in Heart Failure) randomized patients discharged from HF hospitalization to 4 weeks of home-delivered sodium-restricted Dietary Approaches to Stop Hypertension meals (DASH/SRD; 1500 mg sodium/d) versus usual care. The primary outcome was the between-group change in the Kansas City Cardiomyopathy Questionnaire summary score from discharge to 4 weeks postdischarge. Additional outcomes included changes in the Kansas City Cardiomyopathy Questionnaire clinical summary score and cardiac biomarkers. All patients were followed 12 weeks for death/all-cause readmission and potential diet-related adverse events (symptomatic hypotension, hyperkalemia, acute kidney injury). Sixty-six patients were randomized 1:1 at discharge to DASH/SRD versus usual care (age, 71±8 years; 30% female; ejection fraction, 39±18%). The Kansas City Cardiomyopathy Questionnaire summary score increased similarly between groups (DASH/SRD 46±23-59±20 versus usual care 43±19-53±24; P=0.38), but the Kansas City Cardiomyopathy Questionnaire clinical summary score increase tended to be greater in DASH/SRD participants (47±22-65±19 versus 45±20-55±26; P=0.053). Potentially diet-related adverse events were uncommon; 30-day HF readmissions (11% versus 27%; P=0.06) and days rehospitalized within that timeframe (17 versus 55; P=0.055) trended lower in DASH/SRD participants. Conclusions Home-delivered DASH/SRD after HF hospitalization appeared safe in selected patients and had directionally favorable effects on HF clinical status and 30-day readmissions. Larger studies are warranted to clarify the effects of postdischarge nutritional support in patients with HF. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02148679.

Which Intraprocedural Thrombotic Events Impact Clinical Outcomes After Percutaneous Coronary Intervention in Acute Coronary Syndromes?: A Pooled Analysis of the HORIZONS-AMI and ACUITY Trials.

OBJECTIVES: This study sought to determine the extent to which individual components of intraprocedural thrombotic events (IPTEs) are associated with adverse events. BACKGROUND: IPTEs occurring during percutaneous coronary intervention (PCI) are associated with adverse in-hospital and late outcomes in patients with acute coronary syndromes. METHODS: A total of 6,591 patients who underwent PCI for non-ST-segment elevation acute coronary syndromes/ST-segment elevation myocardial infarction in the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) and HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) trials underwent detailed frame-by-frame core laboratory angiographic analysis to assess for IPTEs. The associations of IPTE components with death, major bleeding, and major adverse cardiac events at 30 days were assessed using univariable analyses and multivariable models. RESULTS: The overall incidence of IPTEs was 7.7%, with a greater incidence in ST-segment elevation myocardial infarction patients (12.2%) compared with non-ST-segment elevation acute coronary syndromes patients (3.5%). Specific components of IPTEs included no-reflow/slow reflow in 58.0%, new/worsened thrombus in 35.3%, distal embolization in 34.9%, abrupt closure in 19.8%, and intraprocedural stent thrombosis (IPST) in 9.5% of patients. Each IPTE component was independently associated with 30-day death, major bleeding, and MACE in multivariable models, with the strongest association observed for IPST (MACE hazard ratio: 7.51 [95% confidence interval: 4.36 to 12.94]). CONCLUSIONS: The occurrence of IPTEs is not infrequent among high-risk acute coronary syndromes patients undergoing PCI, and each IPTE component was associated with subsequent adverse events. Although IPST represented <10% of IPTE events overall, it was the component with the strongest association with adverse events.

Risk of thrombocytopenia with glycoprotein IIb/IIIa inhibitors across drugs and patient populations: a meta-analysis of 29 large placebo-controlled randomized trials.

AIMS: Glycoprotein IIb/IIIa inhibitors (GPIs) reduce myocardial infarction and peri-procedural thrombotic complications in patients undergoing percutaneous coronary intervention (PCI); however, they may cause bleeding and thrombocytopenia, which are associated with poor clinical outcomes. Although the risk of bleeding has been well characterized, the extent of the risk of thrombocytopenia remains uncertain. In this meta-analysis, we aim to evaluate the risk of thrombocytopenia associated with GPI compared with placebo across drugs and patient populations. METHODS AND RESULTS: Risk ratios were calculated for thrombocytopenia (<100 000 platelets/mm(3)) and severe thrombocytopenia (<50 000 platelets/mm(3)) in 29 randomized large trials (>1000 patients) of GPI vs. placebo involving a total of 123 419 patients. We used meta-analysis techniques to estimate the summary effect across all trials, in pre-specified sub-groups, and in sensitivity analyses to assess the robustness of the data. Glycoprotein IIb/IIIa inhibitor use increases the rate of thrombocytopenia [risk ratio (RR) = 1.62, 95% confidence interval (CI) 1.48-1.78] and severe thrombocytopenia (RR = 3.52, 95% CI 2.87-4.30) compared with placebo. These findings are consistent by route of administration (oral vs. intravenous). Patients with ST-segment elevation myocardial infarction (RR 2.66, 95% CI 2.12-3.34) and elective PCI (RR 2.78, 95% CI 1.76-4.40) treated with a GPI had higher risks of thrombocytopenia than patients with non-ST-segment elevation acute coronary syndrome (RR 1.41, 95% CI 1.25-1.58; P < 0.001 for heterogeneity by sub-group). CONCLUSIONS: The administration of GPI compared with placebo was associated with a 63% increased risk of thrombocytopenia (<100 000 platelets/mm(3)), and >3-fold increased risk of severe thrombocytopenia (<50 000 platelets/mm(3)). This corresponds to an average of 10-20 additional cases of thrombocytopenia per 1000 patients given GPIs, of which 6-7 cases are severe.

Impact of Paclitaxel Dose on Tissue Pharmacokinetics and Vascular Healing: A Comparative Drug-Coated Balloon Study in the Familial Hypercholesterolemic Swine Model of Superficial Femoral In-Stent Restenosis.

OBJECTIVES: This study sought to compare the effect of paclitaxel-coated balloon (PCB) concentration on tissue levels and vascular healing using 3 different PCB technologies (In.Pact Pacific = 3 µg/mm(2), Lutonix = 2 µg/mm(2) and Ranger = 2 µg/mm(2)) in the experimental setting. BACKGROUND: The optimal therapeutic dose for PCB use has not been determined yet. METHODS: Paclitaxel tissue levels were measured up to 60 days following PCB inflation (Ranger and In.Pact Pacific) in the superficial femoral artery of healthy swine (18 swine, 36 vessels). The familial hypercholesterolemic swine model of superficial femoral artery in-stent restenosis (6 swine, 24 vessels) was used in the efficacy study. Two weeks following bare-metal stent implantation, each in-stent restenosis site was randomly treated with a PCB or an uncoated control balloon (Sterling). Quantitative vascular analysis and histology evaluation was performed 28 days following PCB treatment. RESULTS: All PCB technologies displayed comparable paclitaxel tissue levels 4 h following balloon inflation. At 28 days, all PCB had achieved therapeutic tissue levels; however, the In.Pact PCB resulted in higher tissue concentrations than did the other PCB groups at all time points. Neointimal inhibition by histology was decreased in all PCB groups compared with the control group, with a greater decrease in the In.Pact group. However, the neointima was more mature and contained less peri-strut fibrin deposits in both 2-µg/mm(2) PCB groups. CONCLUSIONS: Compared with the clinically established PCB dose, lower-dose PCB technologies achieve lower long-term tissue levels but comparable degrees of neointimal inhibition and fewer fibrin deposits. The impact of these findings in restenosis reduction and clinical outcomes needs to be further investigated.

Dietary interventions for heart failure in older adults: re-emergence of the hedonic shift.

Dietary non-adherence to sodium restriction is an important contribution to heart failure (HF) symptom burden, particularly in older adults. While knowledge, skills, and attitudes toward sodium restriction are important, sodium intake is closely linked to the ability to taste salt. The 'hedonic shift' occurs when sodium restriction induces changes in an individual's salt taste that lower subsequent salt affinity. Older adults often have compromised salt taste and higher dietary salt affinity due to age-related changes. Older HF patients may have additional loss of salt taste and elevated salt appetite due to comorbid conditions, medication use, and micronutrient or electrolyte abnormalities, creating a significant barrier to dietary adherence. Induction of the hedonic shift has the potential to improve long-term dietary sodium restriction and significantly impact HF outcomes in older adults.

Association between intraprocedural thrombotic events and adverse outcomes after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (a Harmonizing Outcomes With RevasculariZatiON and Stents in Acute Myocardial Infarction [HORIZONS-AMI] Substudy).

The present study sought to determine the extent to which adverse angiographic events encountered during percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI) are associated with adverse clinical outcomes. Patients with STEMI represent a cohort at particularly high risk of intraprocedural thrombotic events (IPTEs). The overall frequency and implications of IPTEs occurring in patients with STEMI have not been systematically quantified in previous studies. A total of 3,163 patients undergoing primary percutaneous coronary intervention with stent implantation for STEMI in the Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial underwent detailed frame-by-frame core laboratory angiographic analysis to assess IPTEs. The clinical outcomes at 30 days were compared between the patients with and without IPTEs. IPTEs, defined as the development of new or increasing thrombus, abrupt vessel closure, no reflow, slow reflow, and distal embolization at any point during the procedure, occurred in 386 patients (12.2%). The independent predictors of IPTE were thrombus at baseline, lesion length, and randomization to bivalirudin; the patients with IPTEs were also more likely to receive bailout glycoprotein IIb/IIIa inhibitors and unplanned thrombectomy. Compared with patients without IPTEs, the patients with IPTEs had higher 30-day rates of composite major adverse cardiovascular events (death, myocardial infarction, ischemic target vessel revascularization, and stroke; 7.8% vs 4.2%, p = 0.002), major bleeding not related to coronary artery bypass grafting (11.8% vs 6.5%, p <0.001), and all-cause death (4.2% vs 1.8%, p = 0.002). On multivariate analysis, IPTEs were independently associated with 30-day major adverse cardiovascular events, major bleeding, and death. In conclusion, the development of IPTEs in patients undergoing primary percutaneous coronary intervention for STEMI was associated with subsequent adverse outcomes, including major adverse cardiovascular events, major bleeding, and death. Additional studies of strategies to decrease the occurrence of IPTEs are warranted.

The P-glycoprotein transport system and cardiovascular drugs.

Permeability glycoprotein (P-gp) mediates the export of drugs from cells located in the small intestine, blood-brain barrier, hepatocytes, and kidney proximal tubule, serving a protective function for the body against foreign substances. Intestinal absorption, biliary excretion, and urinary excretion of P-gp substrates can therefore be altered by either the inhibition or induction of P-gp. A wide spectrum of drugs, such as anticancer agents and steroids, are known P-gp substrates and/or inhibitors, and many cardiovascular drugs have recently been observed to have clinically relevant interactions as well. We review the interactions among commonly prescribed cardiovascular drugs that are P-gp substrates and observe interactions involving P-gp that may be relevant to clinical practice. Cardiovascular drugs with narrow therapeutic indexes (e.g., antiarrhythmic agents, anticoagulant agents) have demonstrated large increases in concentrations when coadministered with potent P-gp inhibitors, thus increasing the risk for drug toxicity. Therefore, dose adjustment or use of alternative agents should be considered when strong P-gp-mediated drug-drug interactions are present. Finally, interactions between novel drugs and known P-gp inhibitors are now being systematically evaluated during drug development, and recommended guidelines for the administration of P-gp substrate drugs will be expanded.

Bridging therapy after recent stent implantation: case report and review of data.

For patients requiring surgery within their first year following coronary stent placement, maximizing the prevention of stent thrombosis with antiplatelet therapy while minimizing the risk of intraoperative bleeding has become a management challenge for cardiologists, surgeons and anesthesiologists. In this manuscript, we describe a case of a patient who received three stents (two of which were drug-eluting) and 7 months later was bridged with intravenous eptifibatide, a short-acting glycoprotein (GP) IIb/IIIa inhibitor, for 3 days prior to bronchoscopy and cervical mediastinoscopy for a suspected lung cancer. We then review the current literature for data and guidelines describing the use of short-acting GP IIb/IIIa as bridge therapy. Finally, we provide recommendations, based on our experience combined with this review, for bridge therapy in the perioperative period for patients with recent coronary stents.

Age-period-cohort analysis of colorectal cancer in East Anglia, 1971-2005.

BACKGROUND: This study aimed to investigate the incidence trends of colorectal cancer by sex and subsite, in East Anglia from 1971 to 2005. METHODS: Using data from the Eastern Cancer Registration and Information Centre, we examined the time trends and the effect of age, period of diagnosis and birth cohort on the incidence of colorectal cancer by sex and subsite. RESULTS: Between 1971 and 2005, 23875 males and 22651 females were registered with colorectal cancer in East Anglia. During this period, the increase in the incidence trends was higher among males, more recent periods of diagnosis, and proximal colon. Cohort effects were statistically significant in distal and rectal cancers in males (p<0.001 and p=0.05, respectively), and in proximal colon in females (p<0.001). Period effects were statistically significant across all subsites and both sexes (p<0.001 for all). CONCLUSIONS: Period effects were significant across all subsites for both sexes, whereas cohort effects varied in their significance levels depending on subsite and sex. We suggest that the period effect may be due to an increase in the use of colonoscopy for diagnostic or opportunistic screening, and the cohort effect may be due to aetiological differences in CRC between sexes and subsites.

Dramatic improvement in pulmonary hypertension with rapamycin.

This is a report of a 61-year-old woman with improved pulmonary arterial hypertension following treatment with rapamycin for an islet cell tumor of the pancreas with liver metastases.

Total synthesis of (-)-hennoxazole A.

An enantioselective, convergent total synthesis of the antiviral marine natural product (-)-hennoxazole A is completed in 14 steps (longest linear sequence) from commercially available 4-methyloxazole-2-carboxylic acid. Synthesis of the C(1)-C(15) pyran/bisoxazole fragment takes advantage of an aldol-like coupling between a dimethyl acetal and an N-acetylthiazolidinethione for the direct, stereoselective installation of the C(8)-methoxy-bearing stereocenter. A one-pot acetoacetate acylation/decarboxylation/cyclodehydration of another elaborate thiazolidinethione allows for rapid assembly of the pyran-based ring system. Synthesis of the C(15)-C(25) skipped triene side chain fragment makes use of a [2,3]-Wittig-Still rearrangement for efficient installation of the trisubstituted Z-double bond. Key late-stage coupling of the two fragments is effected by deprotonation of the methyl group on the bisoxazole system using lithium diethylamide, followed by alkylation with an allylic bromide side chain segment to form the C(15)-C(16) bond.