Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomised trials

BACKGROUND The safety and efficacy of drug-eluting stents (DES) in the treatment of coronary artery disease have been assessed in several randomised trials. However, none of these trials were powered to assess the safety and efficacy of DES in women because only a small proportion of recruited participants were women. We therefore investigated the safety and efficacy of DES in female patients during long-term follow-up. METHODS We pooled patient-level data for female participants from 26 randomised trials of DES and analysed outcomes according to stent type (bare-metal stents, early-generation DES, and newer-generation DES). The primary safety endpoint was a composite of death or myocardial infarction. The secondary safety endpoint was definite or probable stent thrombosis. The primary efficacy endpoint was target-lesion revascularisation. Analysis was by intention to treat. FINDINGS Of 43,904 patients recruited in 26 trials of DES, 11,557 (26·3%) were women (mean age 67·1 years [SD 10·6]). 1108 (9·6%) women received bare-metal stents, 4171 (36·1%) early-generation DES, and 6278 (54·3%) newer-generation DES. At 3 years, estimated cumulative incidence of the composite of death or myocardial infarction occurred in 132 (12·8%) women in the bare-metal stent group, 421 (10·9%) in the early-generation DES group, and 496 (9·2%) in the newer-generation DES group (p=0·001). Definite or probable stent thrombosis occurred in 13 (1·3%), 79 (2·1%), and 66 (1·1%) women in the bare-metal stent, early-generation DES, and newer-generation DES groups, respectively (p=0·01). The use of DES was associated with a significant reduction in the 3 year rates of target-lesion revascularisation (197 [18·6%] women in the bare-metal stent group, 294 [7·8%] in the early-generation DES group, and 330 [6·3%] in the newer-generation DES group, p<0·0001). Results did not change after adjustment for baseline characteristics in the multivariable analysis. INTERPRETATION The use of DES in women is more effective and safe than is use of bare-metal stents during long-term follow-up. Newer-generation DES are associated with an improved safety profile compared with early-generation DES, and should therefore be thought of as the standard of care for percutaneous coronary revascularisation in women. FUNDING Women in Innovation Initiative of the Society of Cardiovascular Angiography and Interventions.

Active implementation strategy of CONSORT adherence by a dental specialty journal improved randomized clinical trial reporting.

OBJECTIVE To describe a novel CONsolidated Standards of Reporting Trials (CONSORT) adherence strategy implemented by the American Journal of Orthodontics and Dentofacial Orthopedics (AJO-DO) and to report its impact on the completeness of reporting of published trials. STUDY DESIGN AND SETTING The AJO-DO CONSORT adherence strategy, initiated in June 2011, involves active assessment of randomized clinical trial (RCT) reporting during the editorial process. The completeness of reporting CONSORT items was compared between trials submitted and published during the implementation period (July 2011 to September 2013) and trials published between August 2007 and July 2009. RESULTS Of the 42 RCTs submitted (July 2011 to September 2013), 23 were considered for publication and assessed for completeness of reporting, seven of which were eventually published. For all published RCTs between 2007 and 2009 (n = 20), completeness of reporting by CONSORT item ranged from 0% to 100% (Median = 40%, interquartile range = 60%). All published trials in 2011-2013, reported 33 of 37 CONSORT (sub) items. Four CONSORT 2010 checklist items remained problematic even after implementation of the adherence strategy: changes to methods (3b), changes to outcomes (6b) after the trial commenced, interim analysis (7b), and trial stopping (14b), which are typically only reported when applicable. CONCLUSION Trials published following implementation of the AJO-DO CONSORT adherence strategy completely reported more CONSORT items than those published or submitted previously.

Hyperthermia-related clinical trials on cancer treatment within the ClinicalTrials.gov registry

PURPOSE Hyperthermia has been shown to improve the effectiveness of chemotherapy and radiotherapy in the treatment of cancer. This paper summarises all recent clinical trials registered in the ClinicalTrials.gov registry. MATERIALS AND METHODS The records of 175,538 clinical trials registered at ClinicalTrials.gov were downloaded on 29 September 2014 and a database was established. We searched this database for hyperthermia or equivalent words. RESULTS A total of 109 trials were identified in which hyperthermia was part of the treatment regimen. Of these, 49 trials (45%) had hyperthermic intraperitoneal chemotherapy after cytoreductive surgery (HIPEC) as the primary intervention, and 14 other trials (13%) were also testing some form of intraperitoneal hyperthermic chemoperfusion. Seven trials (6%) were testing perfusion attempts to other locations (thoracic/pleural n = 4, limb n = 2, hepatic n = 1). Sixteen trials (15%) were testing regional hyperthermia, 13 trials (12%) whole body hyperthermia, seven trials (6%) superficial hyperthermia and two trials (2%) interstitial hyperthermia. One remaining trial tested laser hyperthermia. CONCLUSIONS In contrast to the general opinion, this analysis shows continuous interest and ongoing clinical research in the field of hyperthermia. Interestingly, the majority of trials focused on some form of intraperitoneal hyperthermic chemoperfusion. Despite the high number of active clinical studies, HIPEC is a topic with limited attention at the annual meetings of the European Society for Hyperthermic Oncology and the Society of Thermal Medicine. The registration of on-going clinical trials is of paramount importance for the achievement of a comprehensive overview of available clinical research activities involving hyperthermia.

Determinants of adherence to highly active antiretroviral therapy for HIV-infected children: A research synthesis

Highly active antiretroviral therapy (HAART) has taken HIV-infection from a rapidly terminal illness to one that is a slowly progressive, chronic illness. HIV-infected children can now live long, normal lives. Today, four classes of antiretroviral medications are widely used and several antiretrovirals are available in each class, but resistance and cross-resistance to these medications can occur very quickly if the patient does not adhere to strict medication dosing guidelines. One method to improve pediatric adherence to antiretrovirals is to focus on identified determinants of adherence at clinical visits, but very few studies have been conducted to identify determinants of adherence to antiretrovirals and the best methods to measure adherence in the pediatric population. This research synthesis found adherence factors related to children can be divided into child-identified factors and caregiver-identified factors. Child identified factors include medication-related, demographic-related, cognitive-related, psychosocial-related, and biological marker-related barriers to adherence. Caregiver identified factors include medication-related, cognitive-related, relationship-related, and psychosocial-related barriers to adherence. More randomized clinical trials are needed to identify determinants to adherence, identify methods to best measure adherence, and to identify the best interventions to improve adherence in HIV-infected children and adolescents. ^

William Osler: Original Papers 1881-1897

Part 1: 1881-1888 On Some Points in the Etiology and Pathology of Ulcerative Endocarditis, 1881 On Certain Parasites in the Blood of the Frog, 1883 The Third Corpuscle of the Blood, 1883 On the Use of Arsenic in Certain Forms of Anaemia, 1886 Antifebrin, 1887 Case of Arterio-Venous Aneurism of the Axillary Artery and Vein of Fourteen Year's Duration, 1887 Typhilitis and Appendicitis, 1888 Part 2: 1889-1892 Annual Address - License to Practice 1889 Case of Syphiloma of the Cord of the Cauda Equina-Death From Diffuse Central Myelitis, 1889 On a Case of Simple Idiopathic Muscular Atrophy, Involving the Face and the Scapulo-Humeral Muscles, 1889 Note on Intra-Thoracic Growths Developing from the Thyroid Gland, 1889 On the Value of Laveran's Organisms in the Diagnosis of Malaria, 1889 On the Form of Convulsive Tic Associated with Corprolalia, Etc., 1890 A Case of Sensory Aphasia Word-blindness with Hemianopsia, 1891 Rudolf Virchow: The Man and the Student, 1891 The Healing of Tuberculosis, 1892 The Cold-Bath Treatment of Typhoid Fever, 1892 Part 3: 1893 Remarks on the Varieties of Chronic Chorea, and a Report Upon Two Families of the Hereditary Form, With One Autopsy, 1893 Note on Arsenical Neuritis Following the use of Fowler's Solution, 1893 Note on a Remarkable House Epidemic of Typhoid Fever, 1893 Cases of Sub-Phrenic Abscess, 1893 On Sporadic Cretinism in America, 1893 Notes on Tuberculosis in Children, 1893 Part 4: 1849-1895 Parotitis in Pneumonia, Case of Pericarditis Treated by Incision and Drainage, 1894 The Army Surgeon, 1894 Introductory Remarks to Course of Clinical Demonstrations on Typhoid Fever, 1894 Cancer of the Stomach with Very Rapid Course, 1895 Case of Sporadic Cretinism (Infantile Myxcedema) Treated Successfully with Thyroid Extract, 1895 Visible Contractile Tumour of the Pylorus Following Ulcer of the Stomach, 1895 On the Association of Enormous Heart Hypertrophy, Chronic Proliferative Peritonitis, and Recurring Ascites, with Adherent Pericardium, 1895 Teaching and Thinking the Two Functions of a Medical School, 1895 The Practical Value of Laveran's Discoveries, 1895 Part 5 1896 Addison's Disease, 1896 On Six Cases of Addison's Disease, 1896 Hemiplegia in Typhoid Fever Thomas Dover (of Dover's Powder) Physician and Buccaneer, 1896 John Keats The Apothecary Poet, 1896 On The Classification of the Tics or Habit Movements, 1896 The Cerebral Complication of Raynaud's Disease, 1896 Part 6: 1897 On Certain Features in the Prognosis of Pneumonia, 1897 Clinical Lecture on Mitral Stenosis - Sudden Death - Ball Thrombus in the Left Auricle, 1897 The Diagnosis of Malarial Fever, 1897 The Functions of a State Faculty (President's Address), 1897 A Clinical Lecture on The Ball-Valve Gall-Stone in the Common Duct, 1897 Pneumonia (Review of Cases studied), 1897 Internal Medicine as a Vocation, 1897 Back Notes

Active Optical Sensors for Tree Stem Detection and Classification in Nurseries.

Active optical sensing (LIDAR and light curtain transmission) devices mounted on a mobile platform can correctly detect, localize, and classify trees. To conduct an evaluation and comparison of the different sensors, an optical encoder wheel was used for vehicle odometry and provided a measurement of the linear displacement of the prototype vehicle along a row of tree seedlings as a reference for each recorded sensor measurement. The field trials were conducted in a juvenile tree nursery with one-year-old grafted almond trees at Sierra Gold Nurseries, Yuba City, CA, United States. Through these tests and subsequent data processing, each sensor was individually evaluated to characterize their reliability, as well as their advantages and disadvantages for the proposed task. Test results indicated that 95.7% and 99.48% of the trees were successfully detected with the LIDAR and light curtain sensors, respectively. LIDAR correctly classified, between alive or dead tree states at a 93.75% success rate compared to 94.16% for the light curtain sensor. These results can help system designers select the most reliable sensor for the accurate detection and localization of each tree in a nursery, which might allow labor-intensive tasks, such as weeding, to be automated without damaging crops.

Attenuation of virulence in Mycobacterium tuberculosis expressing a constitutively active iron repressor

Iron is an essential nutrient for the survival of most organisms and has played a central role in the virulence of many infectious disease pathogens. Mycobacterial IdeR is an iron-dependent repressor that shows 80% identity in the functional domains with its corynebacterial homologue, DtxR (diphtheria toxin repressor). We have transformed Mycobacterium tuberculosis with a vector expressing an iron-independent, positive dominant, corynebacterial dtxR hyperrepressor, DtxR(E175K). Western blots of whole-cell lysates of M. tuberculosis expressing the dtxR(E175K) gene revealed the stable expression of the mutant protein in mycobacteria. BALB/c mice were infected by tail vein injection with 2 × 105 organisms of wild type or M. tuberculosis transformed with the dtxR mutant. At 16 weeks, there was a 1.2 log reduction in bacterial survivors in both spleen (P = 0.0002) and lungs (P = 0.006) with M. tuberculosis DtxR(E175K). A phenotypic difference in colonial morphology between the two strains also was noted. A computerized search of the M. tuberculosis genome for the palindromic consensus sequence to which DtxR and IdeR bind revealed six putative “iron boxes” within 200 bp of an ORF. Using a gel-shift assay we showed that purified DtxR binds to the operator region of five of these boxes. Attenuation of M. tuberculosis can be achieved by the insertion of a plasmid containing a constitutively active, iron-insensitive repressor, DtxR(E175K), which is a homologue of IdeR. Our results strongly suggest that IdeR controls genes essential for virulence in M. tuberculosis.

Yeast chorismate mutase in the R state: Simulations of the active site

The isomerization of chorismate to prephenate by chorismate mutase in the biosynthetic pathway that forms Tyr and Phe involves C5—O (ether) bond cleavage and C1—C9 bond formation in a Claisen rearrangement. Development of negative charge on the ether oxygen, stabilized by Lys-168 and Glu-246, is inferred from the structure of a complex with a transition state analogue (TSA) and from the pH-rate profile of the enzyme and the E246Q mutant. These studies imply a protonated Glu-246 well above pH 7. Here, several 500-ps molecular dynamics simulations test the stability of enzyme–TSA complexes by using a solvated system with stochastic boundary conditions. The simulated systems are (i) protonated Glu-246 (stable), (ii) deprotonated Glu-246 (unstable), (iii) deprotonated Glu-246 plus one H2O between Glu-246 and the ether oxygen (unstable), (iv) the E246Q mutant (stable), and (v) addition of OH− between protonated Glu-246 and the ether oxygen. In (v), a local conformational change of Lys-168 displaced the OH− into the solvent region, suggesting a possible rate-determining step that precedes the catalytic step. In a 500-ps simulation of the enzyme complexed with the reactant chorismate or the product prephenate, no water molecule remained near the oxygen of the ligand. Calculations using the linearized Poisson–Boltzmann equation show that the effective pKa of Glu-246 is shifted from 5.8 to 8.1 as the negative charge on the ether oxygen of the TSA is changed from −0.56 electron to −0.9 electron. Altogether, these results support retention of a proton on Glu-246 to high pH and the absence of a water molecule in the catalytic steps.

Semirational design of active tumor suppressor p53 DNA binding domain with enhanced stability

We have designed a p53 DNA binding domain that has virtually the same binding affinity for the gadd45 promoter as does wild-type protein but is considerably more stable. The design strategy was based on molecular evolution of the protein domain. Naturally occurring amino acid substitutions were identified by comparing the sequences of p53 homologues from 23 species, introducing them into wild-type human p53, and measuring the changes in stability. The most stable substitutions were combined in a multiple mutant. The advantage of this strategy is that, by substituting with naturally occurring residues, the function is likely to be unimpaired. All point mutants bind the consensus DNA sequence. The changes in stability ranged from +1.27 (less stable Q165K) to −1.49 (more stable N239Y) kcal mol−1, respectively. The changes in free energy of unfolding on mutation are additive. Of interest, the two most stable mutants (N239Y and N268D) have been known to act as suppressors and restored the activity of two of the most common tumorigenic mutants. Of the 20 single mutants, 10 are cancer-associated, though their frequency of occurrence is extremely low: A129D, Q165K, Q167E, and D148E are less stable and M133L, V203A and N239Y are more stable whereas the rest are neutral. The quadruple mutant (M133LV203AN239YN268D), which is stabilized by 2.65 kcal mol−1 and Tm raised by 5.6°C is of potential interest for trials in vivo.

Evolution of an enzyme active site: The structure of a new crystal form of muconate lactonizing enzyme compared with mandelate racemase and enolase

Muconate lactonizing enzyme (MLE), a component of the β-ketoadipate pathway of Pseudomonas putida, is a member of a family of related enzymes (the “enolase superfamily”) that catalyze the abstraction of the α-proton of a carboxylic acid in the context of different overall reactions. New untwinned crystal forms of MLE were obtained, one of which diffracts to better than 2.0-Å resolution. The packing of the octameric enzyme in this crystal form is unusual, because the asymmetric unit contains three subunits. The structure of MLE presented here contains no bound metal ion, but is very similar to a recently determined Mn2+-bound structure. Thus, absence of the metal ion does not perturb the structure of the active site. The structures of enolase, mandelate racemase, and MLE were superimposed. A comparison of metal ligands suggests that enolase may retain some characteristics of the ancestor of this enzyme family. Comparison of other residues involved in catalysis indicates two unusual patterns of conservation: (i) that the position of catalytic atoms remains constant, although the residues that contain them are located at different points in the protein fold; and (ii) that the positions of catalytic residues in the protein scaffold are conserved, whereas their identities and roles in catalysis vary.

[Admittatur of Benjamin Dolbeare (Harvard AB 1763)], 1760

Notebook with a handwritten copy of the 1734 College laws and additional laws approved by the Corporation between 1756 and 1760 in English prepared by Harvard undergraduate Benjamin Dolbeare and signed by President Edward Holyoke, Tutors Belcher Hancock and Thomas Marsh, and William Kneeland and Josephus Jackson on January 12, 1760.

Notes of proceedings and cases determined in the high court of errors and appeals, the court of chancery, and the orphans court of the state of Delaware, 1792-1832

Contains summaries of cases heard by the Delaware Supreme Court and the Delaware Appeals Court in the counties of Sussex, Kent, and Newcastle covering a variety of legal topics. Supposedly based on Wilson's Red Book.